Nitrating Agent Research Articles

A simple and efficient nitrating agent to achieve N-n-butyl-N-(2-nitroxyethyl) nitramine (Bu-NENA) and theoretical study of its compatibility with polyglycidyl nitrate (PGN) and glycidyl azide polymer (GAP)

A simple and efficient nitrating agent to achieve N-n-butyl-N-(2-nitroxyethyl) nitramine (Bu-NENA) and theoretical study of its compatibility with polyglycidyl nitrate (PGN) and glycidyl azide polymer (GAP)

A Cytochrome P450 TxtE Model System with Mechanistic and Theoretical Evidence for a Heme Peroxynitrite Active Species

AbstractThe cytochrome P450 homolog, TxtE, efficiently catalyzes the direct and regioselective aromatic nitration of the indolyl moiety of L‐tryptophan to 4‐nitro‐L‐tryptophan, using nitric oxide (NO) and dioxygen (O2) as co‐substrates. Pathways for such direct and selective nitration of heteroaromatic motifs present platforms for engineering new nitration biocatalysts for pharmacologically beneficial targets, among a medley of other pivotal industrial applications. Precise mechanistic details concerning this pathway are only weakly understood, albeit a heme iron(III)‐peroxynitrite active species has been postulated. To shed light on this unique reaction landscape, we investigated the indole nitration pathway of a series of biomimetic ferric heme superoxide mimics, [(Por)FeIII(O2−⋅)], in the presence of NO. Therein, our model systems gave rise to three distinct nitroindole products, including 4‐nitroindole, the product analogous to that obtained with TxtE. Moreover, 15N and 18O isotope labeling studies, along with meticulously designed control experiments lend credence to a heme peroxynitrite active nitrating agent, drawing close similarities to the tryptophan nitration mechanism of TxtE. All organic and inorganic reaction components have been fully characterized using spectroscopic methods. Theoretical investigation into several mechanistic possibilities deem a unique indolyl radical based reaction pathway as the most energetically favorable, products of which, are in excellent agreement with experimental findings.

Superoxide Ion-Assisted Radical Cascade Reaction: Synthesis of 3-nitro-4-aryl-2H-chromen-2-ones from Aryl Alkynoate Esters under Methylene Blue Visible Light Photocatalysis

Background: From an industries and academic perspective, there is a need for a method for producing 3-nitro-4-aryl-2H-chromen-2-ones from aryl alkynoate esters that is both economic and environmental benign. In this context, superoxide ion-assisted radical cascade reaction can be an efficient and greener protocol. Objective: Herein, we have demonstrated an unprecedented methylene blue (MB) visible light photocatalysis for the production of a series of 3-nitro-4-aryl-2H-chromen-2-ones from readily available aryl alkynoate esters and a nitrating agent in solution. Methods: Synthesis of 3-nitro-4-aryl-2H-chromen-2-ones has been performed in the presence of aryl alkynoate ester, TBAN, DIPEA, solvent, catalyst and molecular oxygen under visible light irradiation at room temperature. The products were purified by column chromatography using silica gel, and the mixture of ethyl acetate/petroleum ether as an eluting solvent and characterized by IR, NMR and mass spectroscopic analysis. Results: A series of aryl alkynoate esters were successfully nitrated into corresponding 3-nitro-4- aryl-2H-chromen-2-ones with good isolated yields by this protocol, in which the key NO2-radicals formed by the action of superoxide ion (O2−·). Conclusion: In contrast to the literature-reported methods of synthesis of 3-nitro-4-aryl-2Hchromen- 2-ones, the process described here for making 3-nitro-4-aryl-2H-chromen-2-ones uses methylene blue visible light photocatalysis, is inexpensive, mild, does not require a metal precursor or high temperatures, and is successful when using the direct sunlight.

A Cytochrome P450 TxtE Model System with Mechanistic and Theoretical Evidence for a Heme Peroxynitrite Active Species.

The cytochrome P450 homolog, TxtE, efficiently catalyzes the direct and regioselective aromatic nitration of the indolyl moiety of L-tryptophan to 4-nitro-L-tryptophan, using nitric oxideand dioxygenas co-substrates. Pathways for such direct and selective nitration of heteroaromatic motifs present platforms for engineering new nitration biocatalysts for pharmacologically beneficial targets, among a medley of other pivotal industrial applications. Precise mechanistic details concerning this pathway are only weakly understood, albeit a heme iron(III)-peroxynitrite active species has been postulated. To shed light on this unique reaction landscape, we investigated the indole nitration pathway of a series of biomimetic ferric heme superoxide mimics, [(Por)FeIII(O2-•)], in the presence of NO. Therein, our model systems gave rise to three distinct nitroindole products, including 4-nitroindole, the product analogous to that obtained with TxtE. Moreover, 15N and 18O isotope labeling studies, along with meticulously designed control experiments lend credence to a heme peroxynitrite active nitrating agent, drawing close similarities to the tryptophan nitration mechanism of TxtE. All organic and inorganic reaction components have been fully characterized using spectroscopic methods. Theoretical investigation into several mechanistic possibilities deem a unique indolyl radical based reaction pathway as the most energetically favorable, products of which, are in excellent agreement with experimental findings.

An Alternative Method for the Selective Synthesis of Ortho-nitro Anilines Using Bismuth Nitrate Pentahydrate.

Nitroaromatic compounds are important scaffolds used for the syn-thesis of a variety of compounds, such as explosives, herbicides, dyes, perfumes and phar-maceuticals. Bismuth nitrate pentahydrate is a widely used reagent in organic synthesis; how-ever, its utility as a nitrating agent for anilines is underexplored. The aim of this work is to propose and find the proper reaction conditions of an alternative nitrating agent constituted by a mixture of bismuth nitrate / acetic anhydride in DCM with a series of substituted anilines under mild reflux. Several anilines having both activating and deactivating substituents in the ortho, meta and para positions were the substrate for the nitration reaction. Experimental conditions were performed in "one-pot" conditions before product purification. Bi(NO3)3•5H2O demonstrated to be effective and somehow regioselective when it came to the nitration of anilines in the ortho position. Although other products were also identified under these conditions, in most cases, the ortho derivative was the major or even the only product obtained with moderate to high yields in the range of 50% - 96%. Bi(NO3)3•5H2O is an efficient and safe nitrating agent since the use of concen-trated and corrosive acids like sulfuric and nitric is avoided; furthermore, bismuth nitrate is low-priced and no special care nor equipment is required.

Metal and acid-free synthesis of acenaphthenone-2-ylidene ketones in PEG 400 and their radical nitration by TBN in water.

The synthesis of acenaphthenone-2-ylidene ketones has been developed using PEG 400 as a solvent under metal and acid-free conditions. Using TBN as a nitrating agent under atmospheric oxygen, nitration of acenaphthenone-2-ylidene ketones has been accomplished for the first time. Upon nitration, (E)-2-(2-oxo-2-phenylethylidene)acenaphthylen-1(2H)-one and alkyl (E)-2-(2-oxoacenaphthylen-1(2H)-ylidene)acetate give the diastereomer with the same geometry. The variety of substrates employed and low cost and non-toxicity of the chemicals used in this process demonstrate its important applicability. Another noteworthy aspect of the procedure is that, in contrast to previous procedures, it does not use HNO3 or metal nitrates during the transformation.

Photochemically-induced protein tyrosine nitration in vitro and in cellula by 5-methyl-1,4-dinitro-1H-imidazole (DNI): synthesis and biochemical characterization

The photochemical nitrating agent 5-methyl-1,4-dinitro-1H-imidazole (DNI) has been recently described as an effective tool for nitrating tyrosine residues in proteins under 390 nm irradiation (Long T. et al., 2021). Herein, we describe the one-step synthesis of DNI from the precursor 4-methyl-5-nitro-1H-imidazole with good yield (66%) and high purity (>99%). Spectral analysis of DNI reveals two maximum peaks (228 and 290 nm) with maximum nitration yields and kinetics occurring at 290 nm. Electron paramagnetic resonance (EPR)- and mass spectrometry (MS)- spin trapping analysis evidenced the formation of nitrogen dioxide (•NO2) upon irradiation of DNI, implying the homolysis of the N–N bond in the DNI molecule. Irradiation of DNI at 290, 390 nm, or UVA light (315–400 nm), produced tyrosine nitration, with yields approaching ca. 30% with respect to DNI at 290 nm exposure. Indeed, using alpha-synuclein as a model protein, the main protein post-translational modification triggered by DNI was the generation of 3-nitrotyrosine as shown by MS analysis. Additionally, the formation of di-tyrosine was also observed. Finally, intracellular •NO2 production upon DNI photolysis in bovine aortic endothelial cells was evidenced by the nitration of the tyrosine analog probe p-hydroxyphenylacetic acid (PHPA) and cellular protein tyrosine nitration.

Trimetallic spinel CuMnCoO4 as an efficient catalyst for solvent-free nitration of toluene to dinitrotoluene without sulfuric acid

The development of the direct nitration for toluene toward dinitrotoluene (DNT) under solvent-free and without sulfuric acid conditions over a heterogeneous catalyst is critical challenging undertakings for developing the green and efficient synthesis of DNT. Herein, trimetallic spinel CuMnCoO4 was prepared and investigated its catalytic performance for solvent-free toluene nitration with nitric acid as nitration agent in the absence of sulfuric acid. The selectivity of 2,4-dinitrotoluene (2,4-DNT) of the spinel-catalyzed-toluene-nitration-system was 1.6 times higher than that of the system without spinel. Kinetic studies revealed that the reaction step of MNT to DNT is the rate-limiting step and moderately increasing the nitric acid/toluene ratio and reaction temperature could enhance the toluene dinitration process. Characterization measurements showed that trimetallic spinel CuMnCoO4 led to an appropriate vacancy-lattice oxygen pair. The reaction mechanism to elucidate the synergetic effect of vacancy-lattice oxygen pair on promoting the activity of toluene and nitrating agent was proposed.

Enantiocomplementary synthesis of β-adrenergic blocker precursors via biocatalytic nitration of phenyl glycidyl ethers

Enantiopure β-nitroalcohols, as an important class of nitro-containing compounds, are essential building blocks in pharmaceutical and organic chemistry, particularly for the synthesis of β-adrenergic blockers. In this study, we present the successful protein engineering of halohydrin dehalogenase HHDHamb for the enantioselective bio-nitration of various phenyl glycidyl ethers to the corresponding chiral β-nitroalcohols, using the inexpensive, commercially available, and safer nitrite as a nitrating agent. The chiral (R)- and (S)-1-nitro-3-phenoxypropan-2-ols were synthesized by the several enantiocomplementary HHDHamb variants through the whole-cell biotransformation, which showed good catalytic efficiency (up to 43% isolated yields) and high optical purity (up to >99% ee). In addition, we also demonstrated that the bio-nitration method was able to tolerate the substrate at a high concentration of 1000 mM (150 g/L). Furthermore, representative synthesis of two optically active enantiomers of the β-adrenergic blocker metoprolol was successfully achieved by utilizing the corresponding chiral β-nitroalcohols as precursors.

Metal nitrate promoted highly regiospecific ortho–nitration of phenols: Application to the synthesis of nitroxynil

Highly regiospecific ortho–nitration of electronically diverse phenols is accomplished using Fe(NO3)3.9H2O for electron–rich and Cu(NO3)2.6H2O for electron–deficient phenols as the cheap nitrating agents. The reaction is carried out in CH3CN at 90 °C under mild and neutral conditions where structurally diverse phenols afford exclusively ortho–nitration products in moderate to good yields with outstanding tolerance of functional groups. The synthetic application of this strategy was established by achieving the bioactive compound nitroxynil.

Engineering Cytochrome P450BM3 Enzymes for Direct Nitration of Unsaturated Hydrocarbons

AbstractApplications of the peroxidase activity of cytochrome P450 enzymes in synthetic chemistry remain largely unexplored. We present herein a protein engineering strategy to increase cytochrome P450BM3 peroxidase activity for the direct nitration of aromatic compounds and terminal aryl‐substituted olefins in the presence of a dual‐functional small molecule (DFSM). Site‐directed mutations of key active‐site residues allowed the efficient regulation of steric effects to limit substrate access and, thus, a significant decrease in monooxygenation activity and increase in peroxidase activity. Nitration of several phenol and aniline compounds also yielded ortho‐ and para‐nitration products with moderate‐to‐high total turnover numbers. Besides direct aromatic nitration by P450 variants using nitrite as a nitrating agent, we also demonstrated the use of the DFSM‐facilitated P450 peroxidase system for the nitration of the vinyl group of styrene and its derivatives.

Engineering Cytochrome P450BM3 Enzymes for Direct Nitration of Unsaturated Hydrocarbons.

Applications of the peroxidase activity of cytochrome P450 enzymes in synthetic chemistry remain largely unexplored. We present herein a protein engineering strategy to increase cytochrome P450BM3 peroxidase activity for the direct nitration of aromatic compounds and terminal aryl-substituted olefins in the presence of a dual-functional small molecule (DFSM). Site-directed mutations of key active-site residues allowed the efficient regulation of steric effects to limit substrate access and, thus, a significant decrease in monooxygenation activity and increase in peroxidase activity. Nitration of several phenol and aniline compounds also yielded ortho- and para-nitration products with moderate-to-high total turnover numbers. Besides direct aromatic nitration by P450 variants using nitrite as a nitrating agent, we also demonstrated the use of the DFSM-facilitated P450 peroxidase system for the nitration of the vinyl group of styrene and its derivatives.

Heterogeneous Catalysis as an Efficient Tool for Selective Hydrogenation of Oximes to Amines and Hydroxylamines

The synthesis of many biologically active compounds is not complete without transforming the carbonyl group into an amino group, carried out by the reaction of nucleophilic substitution with hydroxylamine at the carbonyl carbon atom and further reduction of the C–N and N–O bonds. This method eliminates nitrating agents that exhibit oxidizing properties and may cause undesirable effects on other structural fragments of complex molecules. Selective hydrogenation of oximes over heterogeneous catalysts is still one of the most useful and challenging reactions in synthetic organic chemistry to obtain amines and hydroxylamines since the 1920s when the Adam’s catalyst was first used for this reaction. In this review, we focused on the application of heterogeneous catalysts for the hydrogenation of oximes in relation to the methods applied for pharmaceutical synthesis.

Synthesis of Nitro- and Acetyl Derivatives of 3,7,10-Trioxo-2,4,6,8,9,11-hexaaza[3.3.3]propellane.

Here, we report the study results of the nitration of 3,7,10-trioxo-2,4,6,8,9,11-hexaaza[3.3.3]propellane (THAP) by different nitrating agents such as nitric acid, mixed nitric/sulfuric acids, nitric anhydride, and mixed concentrated nitric acid/acetic anhydride to furnish 3,7,10-trioxo-2-nitro-2,4,6,8,9,11-hexaaza[3.3.3]propellane and 3,7,10-trioxo-2,8-dinitro-2,4,6,8,9,11-hexaaza[3.3.3]propellane, whereas a lactam-lactim rearrangement was found to take place upon vigorous cooling to give 10-hydroxy-2,4,6,8,9,11-hexaazatricyclo[3.3.3.01,5]undec-9-ene-3,7-dione. The two competing reactions, lactam-lactim rearrangement, and nitration were found to take place. The acylation of 3,7,10-trioxo-2,4,6,8,9,11-hexaaza[3.3.3]propellane was examined and the formation conditions of 2,6-di- and 2,6,9-triacetyl-substituted and 3,7,10-trioxo-2,4,6,8,9,11-hexaacetyl-2,4,6,8,9,11-hexaaza[3.3.3]propellane were established. The acetyl derivatives were found to be instable in an acidic medium and to undergo deacylation. The obtained findings correlate well with the quantum-chemical calculations.

Regioselective nitration of toluene to para‐nitrotoluene with NO2 over dealumination Hβ zeolite: Comparison of organic and inorganic acids

AbstractThis work presents a novel heterogeneous catalytic system for the preparation of para‐nitrotoluene (p‐NT) with nitrogen dioxide (NO2) as a nitrating agent in the presence of oxygen (O2). By applying dealuminated Hβ zeolite treated with oxalic acid (Hβ‐Ox) as a catalyst, p‐NT can be obtained with high conversion (90.5%) and selectivity (72.6%). In addition, it can be recycled at least five times without a significant decrease in catalytic activity. This result demonstrates that the catalyst has high efficiency, good stability, and regenerability. Meanwhile, the characteristics of pristine Hβ and different dealuminated Hβ zeolites modified with organic and inorganic acids were systematic contrastive studied using X‐ray diffraction (XRD), nitrogen (N2) adsorption‐desorption, Fourier‐transform infrared (FT‐IR), scanning electron microscope (SEM), temperature‐programed desorption of ammonia (NH3‐TPD), pyridine adsorption infrared (Py‐FT‐IR), and solid state 27Al nuclear magnetic resonance (27Al MAS‐NMR). Finally, the higher conversion and para‐selectivity over Hβ‐Ox also give a reasonable explanation in this paper.

Identification and Structure Analysis of an Unusual Halohydrin Dehalogenase for Highly Chemo-, Regio- and Enantioselective Bio-Nitration of Epoxides.

We report the discovery of an unusual halohydrin dehalogenase, HHDHamb, that can work under relatively low acidic conditions and extremely low temperatures for the bio-nitration of epoxides using nitrite as a nitrating agent. The bio-nitration strategy exhibits high chemo-, regio-, and enantioselectivity, catalyzing the kinetic resolution of various epoxides to enantiopure β-nitroalcohols with nitro-bearing stereocenters in up to 41 % isolated yield and >99 % enantiomeric excess (ee). Additionally, the bio-nitration method displays a high reaction efficiency and can be performed on a gram scale. We also solved the crystal structure of HHDHamb to understand the possible structural determinants of chemoselectivity control in the bio-nitration reaction.

Identification and Structure Analysis of an Unusual Halohydrin Dehalogenase for Highly Chemo‐, Regio‐ and Enantioselective Bio‐Nitration of Epoxides

AbstractWe report the discovery of an unusual halohydrin dehalogenase, HHDHamb, that can work under relatively low acidic conditions and extremely low temperatures for the bio‐nitration of epoxides using nitrite as a nitrating agent. The bio‐nitration strategy exhibits high chemo‐, regio‐, and enantioselectivity, catalyzing the kinetic resolution of various epoxides to enantiopure β‐nitroalcohols with nitro‐bearing stereocenters in up to 41 % isolated yield and >99 % enantiomeric excess (ee). Additionally, the bio‐nitration method displays a high reaction efficiency and can be performed on a gram scale. We also solved the crystal structure of HHDHamb to understand the possible structural determinants of chemoselectivity control in the bio‐nitration reaction.

Protein Tyrosine Nitration in Plant Nitric Oxide Signaling.

Nitric oxide (NO), which is ubiquitously present in living organisms, regulates many developmental and stress-activated processes in plants. Regulatory effects exerted by NO lies mostly in its chemical reactivity as a free radical. Proteins are main targets of NO action as several amino acids can undergo NO-related post-translational modifications (PTMs) that include mainly S-nitrosylation of cysteine, and nitration of tyrosine and tryptophan. This review is focused on the role of protein tyrosine nitration on NO signaling, making emphasis on the production of NO and peroxynitrite, which is the main physiological nitrating agent; the main metabolic and signaling pathways targeted by protein nitration; and the past, present, and future of methodological and strategic approaches to study this PTM. Available information on identification of nitrated plant proteins, the corresponding nitration sites, and the functional effects on the modified proteins will be summarized. However, due to the low proportion of in vivo nitrated peptides and their inherent instability, the identification of nitration sites by proteomic analyses is a difficult task. Artificial nitration procedures are likely not the best strategy for nitration site identification due to the lack of specificity. An alternative to get artificial site-specific nitration comes from the application of genetic code expansion technologies based on the use of orthogonal aminoacyl-tRNA synthetase/tRNA pairs engineered for specific noncanonical amino acids. This strategy permits the programmable site-specific installation of genetically encoded 3-nitrotyrosine sites in proteins expressed in Escherichia coli, thus allowing the study of the effects of specific site nitration on protein structure and function.

Organophotoredox Catalyzed Stereoselective Nitration of Olefins with tert‐Butyl Nitrite under Air

AbstractAn efficient method for the E‐selective synthesis of nitroolefins is developed by employing DDQ as the organophotoredox catalyst in combination with tert‐BuONO (TBN) as a nitrating agent under visible‐light irradiation. This green transition metal‐free approach utilizes aerial oxygen as the terminal oxidant and occurs at room temperature. Following the established protocol, 41 different olefines containing broad diversity of substituents were nitrated in good to excellent yields. Mechanistic experiments and photophysical studies revealed the probable mechanism.

Facile and Efficient Nitration of 4‐Aryl‐1(2H)‐Phthalazinone Derivatives Using Different Catalysts

AbstractDifferent nitration methods were investigated on 4‐(4‐mthoxy‐3‐methyl phenyl)‐1(2H)‐phthalazinone and its derivatives using HNO3 as a nitrating agent with different catalysts. LC–MS/MS has been used to determine the product‘s structure. The results showed that the most suitable catalyst was P2O5 at room temperature to introduce an ortho mono‐nitrated group for the phthalazinone derivatives bearing donating groups on the phenyl ring. In contrast, 4‐halophenyl phthalazinone derivatives gave a high yield of mono‐nitrated products using H2SO4 as a catalyst. All mono‐nitrated products were separated with good to excellent yields, and their structures were confirmed by FT‐IR, NMR, LC‐MS/MS and elemental analyses.