Nitrate Reagent Research Articles

Overcoming Challenges in O-Nitration: Selective Alcohol Nitration Deploying N,6-Dinitrosaccharin and Lewis Acid Catalysis.

Nitrate esters hold pivotal roles in pharmaceuticals, energetic materials, and atmospheric processes, motivating the development of efficient synthesis routes. Here, we present a novel catalytic method for the synthesis of nitrates via the direct O-nitration of alcohols, addressing limitations of current traditional methods. Leveraging bench-stable and recoverable N,6-dinitrosaccharin reagent, our catalytic strategy employs magnesium triflate to achieve mild and selective O-nitration of alcohols, offering broad substrate scope and unprecedentedly large functional group tolerance (e.g. alkenes, alkynes, carbonyls). DFT mechanistic studies reveal a dual role of the magnesium catalyst in the activation of both the nitrating reagent and the alcohol substrate. They also unveil a barrierless proton transfer upon formation of a widely-accepted - yet elusive in solution - nitrooxonium ion intermediate. Overall, our work contributes to the development of mild, selective, and sustainable approaches to nitrates synthesis, with potential applications in drug discovery, materials science, and environmental chemistry.

Overcoming Challenges in O‐Nitration: Selective Alcohol Nitration Deploying N,6‐Dinitrosaccharin and Lewis Acid Catalysis

Nitrate esters hold pivotal roles in pharmaceuticals, energetic materials, and atmospheric processes, motivating the development of efficient synthesis routes. Here, we present a novel catalytic method for the synthesis of nitrates via the direct O‐nitration of alcohols, addressing limitations of current traditional methods. Leveraging bench‐stable and recoverable N,6‐dinitrosaccharin reagent, our catalytic strategy employs magnesium triflate to achieve mild and selective O‐nitration of alcohols, offering broad substrate scope and unprecedented large functional group tolerance (e.g. alkenes, alkynes, carbonyls). DFT mechanistic studies reveal a dual role of the magnesium catalyst in the activation of both the nitrating reagent and the alcohol substrate. They also unveil a barrierless proton transfer upon formation of a widely‐accepted — yet elusive in solution — nitrooxonium ion intermediate. Overall, our work contributes to the development of mild, selective, and sustainable approaches to nitrates synthesis, with potential applications in drug discovery, materials science, and environmental chemistry.

Preparation of a benziodazole-type iodine(III) compound and its application as a nitrating reagent for synthesis of furazans via a copper-catalyzed cascade process

The existing hypervalent I(III) reagents bearing ONO2 group are limited in types and their applications primarily focused on the nitrooxylation reactions featuring a fully-exo fashion. Herein, a benziodazole-type O2NO-I(III) compound was prepared and its reaction with β-monosubstituted enamines in the presence of CuI could trigger a radical nitration/cyclization/dehydration cascade to provide a series of less explored but biologically interesting furazan heterocycles. Mechanistically, the benziodazole-type O2NO-I(III) compound acts as a nitrating reagent and incorporates its NO moiety into the final furazan product in a fully-endo model, a process of which was proposed to involve nitration, cyclization and dehydration.

Deselenylative Acylation and Nitration of Monoselenides.

A deselenylative protocol that enables the construction of the C-C and C-N bonds has been disclosed. By using acyl chloride/AgOTf as an efficient acylation reagent, diarylselenides smoothly undergo deselenylative acylation to produce a series of aroyl compounds. In addition, deselenylative nitration can be enabled by a mild nitration reagent consisting of TsCl and AgNO3, furnishing a diverse array of nitroaromatic compounds.

Simplifying Nitration Chemistry with Bench-stable Organic Nitrating Reagents.

Nitro compounds play a crucial role in academia and industries, serving as building blocks for the synthesis of drugs, agrochemicals, and materials. Nitration, a fundamental process in organic synthesis, has undergone significant evolution since the 19th century. While electrophilic nitration dominates historically, recent decades have seen a focus on new reagents and their reactivity modes for achieving mild and robust synthesis of nitro compounds. Our group has a longstanding interest in developing cost-effective, readily available, recyclable nitrating reagents derived from organic scaffolds. These reagents serve as a controllable source of nitryl radical and nitronium ion species, enabling mild and practical nitration of hydrocarbons with exceptional functional group tolerance. This account details the development of nitrating reagents and their diverse applications in catalytic nitration across various classes of organic molecules.

DNDMH-mediated direct nitration of aryl alkenes.

N-nitro type reagents have been demonstrated as mild nitration tools in recent years. This work presents an exploration of direct nitration of aryl alkenes mediated by DNDMH, a novel N-nitro type reagent developed in our previous study. It exhibits herein a new property of DNDMH as an effective direct nitration reagent for aryl alkenes, through probably the delivery of nitro radicals with the aid of TEMPO and Cu(OAc)2.

Regioselectivity in the Nitration of Eugenol Is Independent of Inorganic Reagents: An Experimental and Theoretical Investigation with Synthetic and Mechanistic Implications.

In this study, we reinvestigated the straightforward nitration of eugenol using traditional reagents and bismuth nitrate. NMR analysis of the obtained products revealed that the regioselectivity of eugenol nitration was independent of the inorganic nitrating reagent used, consistently resulting in the formation of 6-nitroeugenol. This contradicts previous literature reports because the elusive synthesis of 5-nitroeugenol using Bi(NO3)3·5H2O was not achievable through straightforward methods; instead, this isomer could only be prepared via the well-established three-step synthesis. Theoretical investigations using DFT calculations, considering both the dielectric constant of the medium and explicit water molecules, substantiated this regioselectivity. It was found that hydration water played a critical role in the formation of a Zundel cation, shifting the thermodynamic equilibrium toward the exclusive production of 6-nitroeugenol. These results imply that all biological studies involving eugenol derivatives synthesized via direct nitration with Bi(NO3)3·5H2O should be reviewed, as they dealt with 6-substituted eugenol derivatives rather than the previously assumed 5-substituted eugenol.

Process safety evaluation of the nitration synthesis process of Pendimethalin

In this research, pendimethalin was synthesized by a two-step reaction with N-(1-Ethylpropyl)− 3,4-dimethylaniline as raw material and nitric acid as nitration reagent. The research focused on the second-step reaction, which was far more dangerous than the first-step. The effects of reaction temperature (Tp), feeding time (t), stirring rate (SR) and nitric acid concentration (φ) on the yield and thermal hazard of the second step reaction were explored by experiments. The optimal process conditions were obtained. In addition, concentration variation of each component during the reaction were monitored by using HPLC for intermediate sampling. Combined with the theoretical calculation, the possible reaction mechanism was deduced. The reaction can be divided into two main paths according to the sequence of nitro substitution. In one of these paths the nitro group replaced the H first at position 2 and then at position 6, while in the other path it was completely reversed. Both paths eventually produced pendimethalin. Finally, the thermal hazard was analyzed by Stoessel criticality diagram. The risk levels for the two-step reaction were level 1 and level 3, respectively. This study provides theoretical support for the safe production of the nitration and synthesis of pendimethalin.

Formation of Highly Oxidized Organic Compounds and Secondary Organic Aerosol from α-Thujene Ozonolysis.

We conducted laboratory chamber experiments to probe the gas- and particle-phase composition of oxidized organics and secondary organic aerosol (SOA) formed from α-thujene ozonolysis under different chemical regimes. The formation of low-volatility compounds was observed using chemical ionization mass spectrometry with nitrate (NO3-) and iodide (I-) reagent ions. The contribution of measured low-volatility compounds to particle growth was predicted using a simple condensational growth model and found to underpredict the measured growth rates in our chamber (on the order of several nm min-1). The yields of low-volatility compounds and SOA mass were similar to those of other monoterpene ozonolysis systems. While semivolatile compounds C10H14-16O3-7 were measured most abundantly with I- reagent ion, a large fraction of products measured with NO3- were C5-7 fragments with predicted intermediate volatility. Additionally, particle composition was measured with ultrahigh-performance liquid chromatography with high-resolution mass spectrometry and compared to particle composition from α-pinene ozonolysis. Structural isomers were identified from tandem mass spectrometry analysis of two abundant product ions (C8H13O5-, C19H27O7-). Our results indicate that although this system efficiently generates low-volatility organics and SOA under the conditions studied, fragmentation pathways that produce more highly volatile products effectively compete with these processes.

Trifluoromethanesulfonic Acid Promoted Controllable Electrophilic Aromatic Nitration.

In this work, we developed a facile and controllable electrophilic aromatic nitration method with commercially available 68% HNO3 as the nitrating reagent and trifluoromethanesulfonic acid (HOTf) as the catalyst in hexafluoroisopropanol or under solvent-free conditions. The electrophilic nitration products of different arenes can be obtained in almost quantitative yields by tuning the loading of HOTf. The strong acidity and water absorbing property of HOTf allowed this transformation to reach completion in a short time at room temperature.

Formation of highly oxygenated organic molecules from the oxidation of limonene by OH radical: significant contribution of H-abstraction pathway

Abstract. Highly oxygenated organic molecules (HOMs) play a pivotal role in the formation of secondary organic aerosol (SOA). Therefore, the distribution and yields of HOMs are fundamental to understand their fate and chemical evolution in the atmosphere, and it is conducive to ultimately assess the impact of SOA on air quality and climate change. In this study, gas-phase HOMs formed from the reaction of limonene with OH radicals in photooxidation were investigated with SAPHIR (Simulation of Atmospheric PHotochemistry In a large Reaction chamber), using a time-of-flight chemical ionization mass spectrometer with nitrate reagent ion (NO3--CIMS). A large number of HOMs, including monomers (C9–10) and dimers (C17–20), were detected and classified into various families. Both closed-shell products and open-shell peroxy radicals (RO2) were identified under low NO (0.06–0.1 ppb) and high NO conditions (17 ppb). C10 monomers are the most abundant HOM products and account for over 80 % total HOMs. Closed-shell C10 monomers were formed from a two peroxy radical family, C10H15Ox⚫ (x=6–15) and C10H17Ox⚫ (x=6–15), and their respective termination reactions with NO, RO2, and HO2. While C10H17Ox⚫ is likely formed by OH addition to C10H16, the dominant initial step of limonene plus OH, C10H15Ox⚫, is likely formed via H abstraction by OH. C10H15Ox⚫ and related products contributed 41 % and 42 % of C10 HOMs at low and high NO, demonstrating that the H-abstraction pathways play a significant role in HOM formation in the reaction of limonene plus OH. Combining theoretical kinetic calculations, structure–activity relationships (SARs), data from the literature, and the observed RO2 intensities, we proposed tentative mechanisms of HOM formation from both pathways. We further estimated the molar yields of HOMs to be 1.97-1.06+2.52 % and 0.29-0.16+0.38 % at low and high NO, respectively. Our study highlights the importance of H abstraction by OH and provides the yield and tentative pathways in the OH oxidation of limonene to simulate the HOM formation and assess the role of HOMs in SOA formation.

Dinitro-5,5-Dimethylhydantoin: An Arene Nitration Reagent.

The development of a new N-nitro type compound, dinitro-5,5-dimethylhydantoin (DNDMH), has been reported as an arene nitration reagent. The exploration demonstrated that arene nitration with DNDMH exhibited good tolerance with diverse functional groups. It is notable that, among the two N-nitro units of DNDMH, only the N-nitro unit on N1 was delivered to the nitroarene products. The N-nitro type compound with a single N-nitro unit on N2 cannot promote the arene nitration.

Eco-friendly nitration of acetanilide over MCM-41-supported CeCuCoOx catalyst: A solid acidic catalysis strategy

The development of solid acidic catalyst is of great significance to the safe, controllable, efficient and environment-friendly nitration of aromatics. Herein, a series of trimetallic supported catalysts were obtained by the equivalent-volumetic impregnation method. In the as-prepared Ce4Cu6Co0.5Ox/MCM-41 catalyst with strong acidic sites, the metal oxide particles mainly distributed in a form of nanowires in MCM-41 molecular sieve channels. And, the Ce4Cu6Co0.5Ox/MCM-41 catalyst exhibited an excellent catalytic performance for the nitration of acetanilide with equivalent dilute nitric acid as a nitration reagent. Surprisingly, 91% conversion of acetanilide with 91.6% selectivity to mono-nitroacetanilide was achieved. The nitration of acetanilide obviously exhibited a typical ortho-para nitration effect of the aromatics. Furthermore, an excellent stability and acceptable reusability proved a potential to replace the nitration system of concentrated acid in chemical industry. The Lewis acid sites of Ce4Cu6Co0.5Ox/MCM-41 solid acid catalyst can act a similar role to a strong protic acid in mixed acid system, which can polarize nitric acid molecules to form active NO2+ reagents. Meanwhile, the abundant strong acidic sites of solid acidic Ce4Cu6Co0.5Ox in MCM-41 channels are significantly conducive to the sorption and activation of the reactants. The present work provides a prospective strategy for constructing a solidic acid catalyst with an eco-friendly nitration of aromatics.

Nitration of Pyrrolo[2,1-a]isoquinolines

We have successfully modified a series of pyrrolo[2,1-a]isoquinolines via direct nitration under mild reaction conditions. Easily accessible nitrates including CAN, Cu(NO3)2·H2O, and Fe(NO3)3·9H2O all can serve as effective nitrating reagents for functionalizing pyrrolo[2,1-a]isoquinolines. Various nitro-bearing pyrrolo[2,1-a]isoquinolines have been efficiently prepared in acceptable to good yields.

L-ergothioneine reduces nitration of lactoferrin and loss of antibacterial activity associated with nitrosative stress

Lactoferrin (LF) is a multifunctional antimicrobial, anti-inflammatory, and antioxidant protein that occurs naturally in mammals, most notably in exocrine gland tissues and fluids, such as in the eye. Nitrosative stress can promote changes to tyrosine and other amino acid residues of the protein, which also reduces the activity of LF. l-ergothioneine (ET) is a potent anti-inflammatory antioxidant present in the eye and other tissues through nutrition or supplementation and that may play a role in the prevention or treatment of a variety of diseases. Here we investigated the ability of ET to reduce 3-nitrotyrosine (NTyr) formation using two separate substrates, with the goal of determining whether ET can protect the antibacterial function of LF and other proteins when exposed separately to peroxynitrite and tetranitromethane as nitrating reagents. Native human LF was used as a simple protein substrate, and lamb corneal lysate was chosen as one example of mammalian tissue with a more complex mixture of proteins and other biomolecules. Nitration was monitored by absorbance and fluorescence spectroscopy as well as sandwich (nitrated LF) and direct NTyr (corneal lysate) enzyme-linked immunosorbent assays (ELISAs). We found that pretreatment with ET reduced chemical modification of both native LF and corneal lysate samples and loss of antibacterial LF function due to exposure to the nitrating reagents. These initial results suggest that ET, raised to sufficiently elevated levels, could be tailored as a therapeutic agent to reduce effects of nitrosative stress on LF and in turn sustain the protein activity.

Nitryl Radical‐Triggered Semipinacol‐Type Rearrangement, Lactonization, and Cycloetherification of Olefins

AbstractWe report the development of a practical photocatalytic strategy to access various nitro‐containing cyclic compounds from olefins via semipinacol‐type rearrangement, cycloetherification, and lactonization reactions, employing N‐nitrosuccinimide as a bench‐stable, non‐metal‐based nitrating reagent. Mechanistic insights suggest that this light‐driven process occurs via NO2 radical pathway mediated by a photoredox catalyst, which triggers an N−N bond fragmentation. Subsequent Giese‐type addition of nitryl radicals to activated olefins takes place, leading to the formation of nitro‐containing β‐functionalized ketones, lactones and cycloethers. The reaction proceeds under mild reaction conditions and tolerates a wide range of functional groups and structural variations.

Copper-catalyzed nitration of electron-deficient BN-naphthalene.

Under Cu-catalysis, a regioselective nitration of 1,8-dihalogenated BN-naphthalene (ABN) compounds (4a-4c) has been established with the use of tert-butyl nitrite as the nitrating reagent. The syntheses of dihalo-ABN nitro products (6a-6c; halo = Cl, Br and I) were case-studied in conjunction with the first synthesis and characterization of diiodo-ABN compound 4c. The molecular structures of these compounds have been spectroscopically characterized and further confirmed by X-ray single crystal diffraction experiments. This method allows direct regioselective nitration of electron-deficient ABN systems, providing a step-economical entry to novel nitro-ABN structural motifs with potential applications in agrochemicals, materials sciences, and the medicinal and pharmaceutical industries.

The Effect of Power on Nitrate Synthesis and The Emission Intensities of Reactive Species Using Anodic Plasma Electrolysis

Nitrates are used as fertilizer to fulfill nutrients for plants. Anodic plasma electrolysis technology can be an effective and environmentally friendly solution in nitrogen fixation into nitrate compounds. This research aimed to determine the effect of controlling voltage and power in nitrate synthesis using plasma electrolysis with air as the raw material injected at the anode. The material used is an electrolyte solution of 0.02 M K2SO4, the electrodes used are in the form of tungsten and stainless steel, and a nitrate reagent is used for the nitrate test. The results of the study showed that at 400 W, the optimal rate was 0.8 L men-1 with 1889 mg L-1 of nitrate formed. While at 500 W and 600 W, the optimal rate of 1 L men-1 with nitrate formed was 2213 mg L-1 and 2453 mg L-1. The emission intensities of reactive species N, N2*, N2+,•OH, •H, and •O at an optimal rate of 0.8 L men-1 400 W 700 V in 20139 au, 28540 au, 18023 au, 30863 au, 12547 au, 49800 au. The addition of air injection will increase the oxygen input into the plasma zone, which can produce reactive species •O and nitrogen produces reactive species N, N2*, N2+ forms NO. The formed NO compounds can be oxidized to NO2, and the reaction between NO2 and reactive species •OH forms nitrates.

Rediscovering N‐Methyltetranitropyrrole – A Versatile High Energy Material via Facile Two‐step Eco‐friendly Synthetic Approach

AbstractA highly efficient 2‐step method, where three nitro groups could be directly introduced upon pyrrole moiety in a single step, was developed as an environmentally benign process for the synthesis of N‐methyltetranitropyrrole (1) employing metal nitrate/conc. sulphuric acid as the nitrating reagent. This method resulted 1 in high purity having higher thermal stability (273 °C) along with reduced sensitivity (impact sensitivity >40 J; fricition sensitivity >360 N), which makes it a versatile high energy material. An over‐oxidized new product 1‐methyl‐3,3,4,4‐tetranitropyrrolidine‐2,5‐dione (4) was also isolated during optimization, whose energetic properties are similar to those of RDX.

From N-H Nitration to Controllable Aromatic Mononitration and Dinitration-The Discovery of a Versatile and Powerful N-Nitropyrazole Nitrating Reagent.

Nitroaromatics are tremendously valuable organic compounds with a long history of being used as pharmaceuticals, agrochemicals, and explosives as well as vital intermediates to a wide variety of chemicals. Consequently, the exploration of aromatic nitration has become an important endeavor in both academia and industry. Herein, we report the identification of a powerful nitrating reagent, 5-methyl-1,3-dinitro-1H-pyrazole, from the N-nitro-type reagent library constructed using a practical N–H nitration method. This nitrating reagent behaves as a controllable source of the nitronium ion, enabling mild and scalable nitration of a broad range of (hetero)arenes with good functional group tolerance. Of note, our nitration method could be controlled by manipulating the reaction conditions to furnish mononitrated or dinitrated product selectively. The value of this method in medicinal chemistry has been well established by its efficient late-stage C–H nitration of complex biorelevant molecules. Density functional theory (DFT) calculations and preliminary mechanistic studies reveal that the powerfulness and versatility of this nitrating reagent are due to the synergistic “nitro effect” and “methyl effect”.