ESR studies on the reactions of sulphite radical anion,SO3.̄−, with nitroalkane compounds in aqueous solutions

The reactions of the sulphite radical anion, SO₃^{$\text{.}\text{?}$?} (generated from the Ti³⁺-H₂O₂-Na₂SO₃ system at pH 9), in aqueous solutions with some nitroalkane compounds were investigated by using a rapid-mixing flow technique coupled with electron spin resonance (ESR) which can detect the radicals having a lifetime of 5–100 ms. The SO₃^{$\text{.}\text{?}$?} radical added to the double bond of CN in the nitroalkane aci-anions which are the main form of nitroalkanes in aqueous alkaline solutions. From the observed hyperfine splitting constants of the SO₃^{$\text{.}\text{?}$?} adducts of nitroalkane aci-anions, the preferred conformation of the adducts was deduced.     

Microwave assisted highly efficient one-pot multi-component synthesis of novel 2-(tetrasubstituted-1H-pyrrol-3-yl)-4H-chroman-4-ones catalyzed by heterogeneous reusable silica gel supported polyphosphoric acid (PPA/SiO2)

A solvent-free, eco-friendly and facile approach for the synthesis of highly functionalized tetrasubstituted pyrroles has been reported through one-pot four-component reaction of aldehyde, amine, nitroalkane and 1,3-diketone using silica gel supported polyphosphoric acid (PPA–SiO₂) under microwave condition. The reaction occured through the in situ formation of β-keto enamine and nitrostyrene analog following Michael addition and finally intramolecular annulation affording the products in good yields. The key features of the present method include clean reaction, mild conditions, low catalyst loading, straightforward, high to excellent yields, short reaction time, avoiding use of harmful metal catalyst and organic solvent, environmentally friendly compared to the existing methods, recovery and reusability of catalyst and easy workup procedure.     

I2-catalyzed Michael addition of indole and pyrrole to nitroolefins

An easy and efficient method to generate indolyl nitroalkane 5 and pyrrolyl nitroalkane 7 in high yields using β-nitrostyrene and indole/pyrrole at room temperature in the presence of catalytic amount of iodine is reported. The short reaction times and high yields of product are noteworthy. Molecular iodine promoted Michael addition is operationally simple and efficient method compared to the known Lewis acids or rare earth metal catalysts to generate different indolyl/pyrrolyl nitroalkanes in high yield.     

Iron(III)-catalyzed three-component domino strategy for the synthesis of imidazo[1,2-a]pyridines

An efficient, one-pot, three-component domino strategy has been demonstrated for the synthesis of imidazo[1,2-a]pyridines using a catalytic amount of Fe(III) chloride in high yields in air. A library of imidazo[1,2-a]pyridines was synthesized by the reaction of easily available aldehydes and 2-aminopyridines in a mixture of nitroalkane and DMF (2:1). This transformation presumably occurs by a sequential aza-Henry reaction/cyclization/denitration. The use of readily available chemicals as starting materials, inexpensive metal catalyst, aerobic reaction conditions, tolerance of a wide range of functional groups, and operational simplicity are the notable advantages of this present protocol.     

A new sustainable protocol for the synthesis of nitroaldol derivatives via Henry reaction under solvent-free conditions

A new protocol for the Henry addition of nitroalkanes to aryl- and alkyl-aldehydes promoted by PS-BEMP under solvent-free conditions (SolFC) is presented. The corresponding nitroaldol products were obtained in good yields and short times; furthermore minimization of the reaction waste was achieved by reducing the use of organic solvents. Extension of the protocol was obtained by setting up the tandem Michael-Henry reaction of α,β-unsaturated aldehydes and nitroalkane to yield the corresponding dinitro derivatives.     

Fluorine-induced diastereodivergence discovered in an equally rare enantioselective syn-aza-Henry reaction

Attention to the aza-Henry reaction, particularly over the past two decades, has resulted in a wide range of effective catalysts for the enantio- and diastereoselective versions, driven by the versatility of the β-amino nitroalkane products as precursors to secondary amines and vic-diamines. Despite this broad effort, syn-diastereoselective variants are exceedingly rare. We have discovered a subset of α-fluoro nitroalkane additions that are characterized by an unusual crossover in diastereoselection, often delivering the products with high selectivities. We report here a rigorous comparative analysis of non-fluorinated and α-fluoro nitroalkanes in their additions to azomethines. Both homogeneous and heterogeneous catalysis were applied to probe the possibility that this phenomenon might be more widely operative in the enantioselective additions of fluorine-substituted carbon nucleophiles. A complete correlation within four categories is described that uncovered a clear trend, while revealing a dramatic and distinct reversal of diastereoselection that would normally go undetected.

A comparison of enantioselective aza-Henry reactions with both non-fluorinated and α-fluoro nitroalkanes reveals an unusual reversal of diastereoselection favoring the rare syn-aza-Henry product as a result of fluorine-based diastereodivergence.     

Chiral enhancement in the confined space of zeolites for the asymmetric synthesis of β-hydroxy nitroalkanes

(1S,2S)-N¹,N²-Bis(3-chlorobenzyl)cyclohexane-1,2-diamine 1a′ and (1S,2S)-N¹,N²-bis(4-chlorobenzyl)cyclohexane-1,2-diamine 1b′ were used to prepare chiral Cu(II) complexes Cu-Y-1a, Cu-Y-1b, Cu-mZSM5-1a, and Cu-mZSM5-1b by a flexible ligand method using copper exchanged zeolite Y and mesoporous ZSM-5. The characterization of zeolite supported complexes was performed by microanalysis, IR-, diffuse reflectance spectroscopy (DRS), EPR spectroscopy, specific rotation and thermogravimetric analysis (TGA). The catalytic activity of these supported complexes was explored for the asymmetric nitroaldol reaction of various aldehydes with nitromethane at 0 °C. Excellent yields (up to 99%) of β-hydroxy nitroalkane with an ee of up to 94% were achieved in the case of benzaldehyde as substrate. Significantly, the performance of the supported catalyst was better in terms of enantioselectivity than the complex under homogenous conditions. The supported catalysts were recycled four times with no observable loss in performance and no leaching of the catalytically active complex during the nitroaldol reaction.     

Gas-Phase Fragmentation Analysis of Nitro-Fatty Acids

Nitro-fatty acids are electrophilic signaling mediators formed in increased amounts during inflammation by nitric oxide and nitrite-dependent redox reactions. A more rigorous characterization of endogenously-generated species requires additional understanding of their gas-phase induced fragmentation. Thus, collision induced dissociation (CID) of nitroalkane and nitroalkene groups in fatty acids were studied in the negative ion mode to provide mass spectrometric tools for their structural characterization. Fragmentation of nitroalkanes occurred mainly through loss of the NO₂^- anion or neutral loss of HNO₂. The CID of nitroalkenes proceeds via a more complex cyclization, followed by fragmentation to nitrile and aldehyde products. Gas-phase fragmentation of nitroalkene functional groups with additional γ or δ unsaturation occurred through a multiple step cyclization reaction process, leading to 5 and 6 member ring heterocyclic products and carbon chain fragmentation. Cyclization products were not obtained during nitroalkane fragmentation, highlighting the role of double bond π electrons during NO₂^- rearrangements, stabilization and heterocycle formation. The proposed structures, mechanisms and products of fragmentation are supported by analysis of ¹³C and ¹⁵N labeled parent molecules, 6 different nitroalkene positional isomers, 6 nitroalkane positional isomers, accurate mass determinations at high resolution and quantum mechanics calculations. Multiple key diagnostic ion fragments were obtained through this analysis, allowing for the precise placement of double bonds and sites of fatty acid nitration, thus supporting an ability to predict nitro positions in biological samples.     

Electrophilic addition reactions at multiple bonds

Conclusions A new reaction was discovered when alkoxyalkyl and acyl cations are reacted with alkynes in a nitroalkane medium, which proceeds on the type of a conjugated addition involving the nitroalkane, and leads to the formation of polyfunctional derivatives.See [1] for Communication 6.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 10, pp. 2232–2235, October, 1972.     

Distribution of electronic density in n-mononitroalkanes

In the framework of ??quantum theory of atoms in molecule?? (QTAIM) was distribution of electronic density analyzed and inductive effect studied in trans- and gauche-isomers of n-mononitroalkanes CH₃(CH₂) _n NO₂ with n ?? 8. Influence of NO₂ is demonstrated to spread on the four neighboring NO₂ groups. Association of gauche-effect with the electronic density distribution has been given adequate consideration. Definitions were formulated for the standard NO₂ group and perturbed CH₂ groups. It has been suggested the refinements of additive procedures for properties calculation of n-nitroalkanes as well as of big molecules containing the nitroalkane substituents.     

Substitution of HMPT by the cyclic urea DMPU as a cosolvent for highly reactive nucleophiles and bases

The cyclic urea DMPU (N, N′-dimethyl-N, N′-propylene urea = 1,3-dimethyl-2-oxo-hexahydropyrimidine) is shown to exhibit the same effects HMPT in oxirane-opening with Li-acetylide, in a Wittig olefination, in the double deprotonation of nitroalkane, in the Michael addition of Li-dithiane to cyclohexenone, and in selective generations of certain enolates (Schemes 1–7) DMPU might therefore be as safe substitute of the carcinogenic HMPT as a cosolvent with unique properties in diverse type of reaction.     

The study of reaction mechanism for the transformation of nitronate into nitrile by phosphorus trichloride

Nitronate was generated using β-nitrostyrene and the anion of dimethyl malonate in THF at 0 °C. Subsequent treatment with PCl₃ in the presence/absence of DMAP either in THF or pyridine afforded nitroalkane, chloroxime, and nitrile. Pyridine, THF, and THF-pyridine co-solvent as solvents were investigated under different conditions. With different anions of malonates containing dipolarphiles, cyclic compounds were obtained as major products indicating nitrile oxides were generated during the reaction. Based on the results, compared to that of the one reported in literature, a plausible mechanism involving nitrile oxide intermediate was proposed.     

Asymmetric Henry reactions of aldehydes with various nitroalkanes catalyzed by copper(II) complexes of novel chiral N‐monoalkyl cyclohexane‐1,2‐diamines

A number of novel chiral diamines 3 , (1R,2R)‐N‐monoalkylcyclohexane‐1,2‐diamines, were designed and synthesized from trans‐cyclohexane‐1,2‐diamine and applied to the catalytic asymmetric Henry reaction of benzaldehyde and nitromethane to provide β‐nitroalcohol in high yield (up to 99%) and good enantiomeric excess (up to 89%). By using ligand (1R,2R)‐N¹‐(4‐methylpentan‐2‐yl)cyclohexane‐1,2‐diamine ( 3g ), the reaction was optimized in terms of the metal ion, temperature, solvent and base. Further experiments indicated that the complex, 3g –Cu(OAc)₂, was an efficient catalyst in the asymmetric Henry reaction between different aldehydes and nitromethane, and the desired products have been obtained with high chemical yields (up to 99%) and high enantiomeric excess (up to 93%). The optimized catalyst promoted the diastereoselective Henry reaction of various aldehyde substrates and nitroalkane, which gave the corresponding anti‐selective adduct with up to 99% yield and 83:17 anti/syn selectivity. Upon scaling up to gram quantities, the β‐nitroalcohol was obtained in good yield (96%) with excellent selectivities (93% ee). The chiral induction mechanism was tentatively explained on the basis of a previously proposed transition‐state model. Copyright © 2014 John Wiley & Sons, Ltd.     

Establishing the kinetic competency of the cationic imine intermediate in nitroalkane oxidase

The flavoprotein nitroalkane oxidase catalyzes the oxidation of neutral nitroalkanes to the corresponding aldehydes and ketones. Cyanide inactivates the enzyme during turnover in a concentration-dependent fashion. Mass spectrometry of the flavin from enzyme inactivated by cyanide in the presence of nitroethane or nitrohexane shows that a flavin cyanoethyl or cyanohexyl intermediate has formed. At high concentrations of cyanide, inactivation does not consume oxygen. Rapid reaction studies show that formation of the adduct with 2-(2H2)-nitroethane shows a kinetic isotope effect of 7.9. These results are consistent with cyanide reacting with a species formed after proton abstraction but before flavin oxidation. The proposed mechanism for nitroalkane oxidase involves removal of a proton from the nitroalkane, forming a carbanion which adds to the flavin N(5). Elimination of nitrite from the resulting adduct would form an electrophilic imine which can be attacked by hydroxide. The present results are consistent with cyanide trapping this electrophilic intermediate.     

Synthesis of 3,4-Dihydro-2H-Pyrroles from Ketones,Aldehydes, and Nitro Alkanes via Hydrogenative Cyclization

Syntheses of N-heterocyclic compounds that permit a flexible introduction of various substitution patterns by using inexpensive and diversely available starting materials are highly desirable. Easy to handle and reusable catalysts based on earth-abundant metals are especially attractive for these syntheses. We report here on the synthesis of 3,4-dihydro-2H-pyrroles via the hydrogenation and cyclization of nitro ketones. The latter are easily accessible from three components: a ketone, an aldehyde and a nitroalkane. Our reaction has a broad scope and 23 of the 33 products synthesized are compounds which have not yet been reported. The key to the general hydrogenation/cyclization reaction is a highly active, selective and reusable nickel catalyst, which was identified from a library of 24 earth-abundant metal catalysts.     

Selective retention of explosives and related compounds on gas-chromatographic capillary columns coated with lanthanide(III) β-diketonate polymers

The purpose of this research was to investigate coating capillary columns with lanthanide(III) β-diketonate polymers to provide gas-chromatographic columns with selectivity toward explosives and related compounds. Capillary columns were statically coated with a mixture of a lanthanide(III) β-diketonate polymer, which utilized p-di(4,4,5,5,6,6,6-heptafluoro-1,3-hexanedionyl)benzene (dihed) as a ligand, and SE-30. A novel coating technique was developed that used a methanol-containing azeotrope to provide solubility for both polymers while maintaining a low boiling point compatible with static coating. As based on temperature-programmed retention indices, the experimental columns displayed selective retention of nitroaromatic, nitroalkane, and nitrate ester test probes relative to an appropriate SE-30 control column. Selective retention was more pronounced for strongest Lewis base analyte contained in the test mixture (i.e., cyclohexanone). Relative analyte retention on the La(dihed), Tb(dihed), and Eu(dihed) columns are discussed relative to Lewis acidity and solubility of the polymer in the azeotropic coating solution.     

A new convenient synthesis of Δ2-isoxazolines

²-Isoxazolines were obtained from the reaction of alkenes with nitrile N-oxides, generatedin situ from primary nitroalkane salts in presence of toluenesulfonyl chloride.

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Eine neue, vorteilhafte Synthese von ²-Isoxazolinen (Kurze Mitteilung)

Zusammenfassung Aus der Reaktion von Alkenen mit Nitril-N-oxiden, diein situ aus primären Nitroalkansalzen in Gegenwart von Toluolsulfonylchlorid erzeugt wurden, wurden ²-Isoxazoline erhalten.

     

Bioinspired Nitroalkylation for Selective Protein Modification and Peptide Stapling

Nitroalkanes react specifically with aldehydes, providing rapid, stable, and chemoselective protein bioconjugation. These nitroalkylated proteins mimic key post‐translational modifications (PTMs) of proteins and can be used to understand the role of these PTMs in cellular processes. Demonstrated here is the substrate scope of this bioconjugation by attaching a variety of tags, such as NMR tags, fluorescent tags, affinity tags, and alkyne tags, to proteins. The structure and enzymatic activity of modified proteins remain conserved after labeling. Notably, the nitroalkane group leads to easy characterization of proteins by mass spectrometry because of its distinct fingerprint pattern. Importantly, the nitro‐alkylated peptides provide a new handle for site‐selective fluorination of peptides, thus installing a specific probe to study peptide–protein interactions by ¹⁹F NMR spectroscopy. Furthermore, nitroalkane reagents can be used for the late‐stage diversification of peptides and for the synthesis of peptide staples.     

The role of benzoic acid in proline‐catalyzed asymmetric michael addition: A density functional theory study

In asymmetric Michael addition between ketones and nitroolefins catalyzed by L ‐proline, we observed that it was benzoic acid or its derivatives rather than other proton acid that could accelerate the reaction greatly, and different benzoic acid derivatives brought different yields. To explain the experimental phenomena, a density functional theory study was performed to elucidate the mechanism of proline‐catalyzed asymmetric Michael addition with benzoic acid. The results of the theoretical calculation at the level of B3LYP/6‐311+G(2df,p)//B3LYP/6‐31G(d) demonstrated that benzoic acid played two major roles in the formation of nitroalkane: assisting proton transfer and activating the nitro group. In the stage of enamine formation from imine, the energy profiles of benzoic acid derivatives were also calculated to investigate the reasons why different benzoic acid derivatives caused different yields. The results demonstrated that the pK_a value was the major factor for p‐substituted benzoic acid derivatives to improve the yields, whereas for m/o‐substituted benzoic acid derivatives, both pK_a value and electronic and steric effects could significantly increase the yields. The calculated results would be very helpful for understanding the reaction mechanism of Michael addition and provide some insights into the selection of efficient additives for similar experiments. © 2012 Wiley Periodicals, Inc.     

Comparison of enzymatic and non-enzymatic nitroethane anion formation: thermodynamics and contribution of tunneling

In the reaction of nitroalkane oxidase (NAO), the oxidation of nitroalkanes to the corresponding aldehydes or ketones is initiated by the deprotonation of the neutral nitroalkane. The energetics of nitroethane ionization for both the enzymatic and non-enzymatic reactions have been determined by measuring rate constants as a function of temperature. At 25 degrees C, the rate constant for the acetate-catalyzed reaction is a billionfold smaller than the kcat/Km value for NAO. This corresponds to a difference of 12.3 kcal/mol in the free energy of activation that is largely due to a difference in the activation enthalpy. Analysis of the temperature dependence of the deuterium kinetic isotope effects on the reactions yields similar DeltaEa and AH/AD values for the acetate, phosphate, and NAO-catalyzed reactions that fall within the semiclassical limits, consistent with similar contributions of tunneling to the enzymatic and non-enzymatic reactions.