- The Use of Potassium/Sodium Nitrite as a Nitrosating Agent in the Electrooxidative N-Nitrosation of Secondary Amines
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We report herein on the electrochemical N-nitrosation of secondary amines using widely available sodium/potassium nitrite as a nitrosating agent. This approach not only eliminates the need for using a combination of sodium/potassium and a strong acid but also has good functional group tolerance. The reaction is compatible with the late-stage modification of pharmaceutical compounds and could be conducted in gram scale with a high reaction efficiency. Preliminary mechanistic studies indicate that the N-nitrosation occurs via the anodic oxidation of KNO2 into an NO2 radical which is then transformed into an NO+ cation.
- Chen, Zuxing,Gao, Meng,Lu, Cuifen,Ma, Chao,Ruan, Mengyao,Wang, Feiyi,Wang, Ying,Yang, Guichun,You, Shiqi
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- Oxone-sodium nitrite mediated N-nitrosamines formation under mild conditions from secondary amines
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Herein, we report an efficient synthesis of N-nitrosamines from cyclic, aliphatic, benzylic, and aromatic secondary amines via a novel straightforward, efficient, and mild chemical process using sodium nitrite and Oxone in methanol as a solvent at 0–5 °C. The demonstrated methodology accounts well for the parameters like cost-effective, short reaction time, clean and safe handling along with good to excellent yields.
- Gaur, Pinki,Banerjee, Shaibal
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- Synthesis and properties of 2-hydroxyethyl derivatives of methylene-bis(1-oxy-3, 3-dialkyl-1-triazene 2-oxides)
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Synthetic approach to 2-hydroxyethyl derivatives of methylene-bis(1-oxy-3, 3-dialkyl-1triazene 2-oxides), promising NO donors, which can release NO in living organisms was developed. Some transformations of the hydroxyethyl moiety of the synthesized compounds were studied.
- Smirnov,Nikitin,Gordeev,Pokhvisneva,Ternikova,Luk’yanov
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- The mild N-nitrosation of secondary amines with trichloro nitromethane
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Reaction of trichloronitromethane with secondary amine leads to the formation of corresponding carcinogeneous N-nitrosamines under mild conditions.
- Demir,Mahasneh,Aksoy,Gercek
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- THE OXIDATION OF HYDROXYLAMINE BY FREMY'S SALT. PREPARATION OF N-NITROSAMINES AND TETRAZENES
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Treatment of secondary amines with Fremy's salt in aqueous sodium carbonate solution and in the presence of hydroxylamine gives a high yield of either N-nitrosamines or sym-tetrazenes.A mechanism for these conversions is proposed.
- Tato, M. P. Vazquez,Castedo, Luis,Riguera, Ricardo
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- Silica chloride/NaNO2 as a novel heterogeneous system for the nitrosation of secondary amines under mild conditions
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Secondary amines can be readily converted to their corresponding nitroso derivatives with a combination of silica chloride (I), wet SiO2 and sodium nitrite in dichloromethane at room temperature with moderate to excellent yields.
- Zolfigol, Mohammad Ali,Shirini, Farhad,Ghorbani Choghamarani, Arash
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- Synthesis of N,N-dialkylnitramines from secondary ammonium nitrates in liquid or supercritical carbon dioxide
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An efficient explosion-proof method was developed for the preparation of N,N-dialkylnitramines by treatment of dialkylammonium nitrates with a mixture of nitric acid and acetic anhydride in the presence of ZnCl2 in liduid or supercritical carbon dioxide.
- Kuchurov,Fomenkov,Zlotin
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- The use of Nafion-H/NaNO2 as an efficient procedure for the chemoselective N-nitrosation of secondary amines under mild and heterogeneous conditions
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A combination of Nafion-H and sodium nitrite in the presence of wet SiO2 was used as an effective agent for the N-nitrosation of secondary amines under mild and heterogeneous conditions in good to excellent yields.
- Zolfigol, Mohammad Ali,Habibi, Davood,Mirjalili, BiBi Fatemeh,Bamoniri, Abdolhamid
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- N-nitrosation of secondary amines using p-TSA-NaNO2 as a novel nitrosating agent under mild conditions
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A combination of p-toluenesulfonic acid (p-TSA) and sodium nitrite was used as a novel effective nitrosating agent for the N-nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in moderate to excellent yields.
- Borikar, Sanjay P.,Paul, Vincent
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- The reaction of peroxynitrite with morpholine (secondary amines) revisited: The overlooked hydroxylamine formation
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The reaction of peroxynitrite/peroxynitrous acid with morpholine as a model compound for secondary amines is reinvestigated in the absence and presence of carbon dioxide. The concentration- and pH-dependent formation of N-nitrosomorpholine and N-nitromorpholine as reported in three previous papers ([25] [26] [14]) is basically confirmed. However, 13C-NMR spectroscopic product analysis shows that, in the absence of CO2, N-hydroxymorpholine is, at pH≥7, the major product of this reaction, even under anaerobic conditions. The formation of N-hydroxymorpholine has been overlooked in the three cited papers. Additional (ring-opened) oxidation products of morpholine are also detected. The data account for radical pathways for the formation of these products via intermediate morpholine-derived aminyl and α-aminoalkyl radicals. This is further supported by EPR-spectrometric detection of morpholine-derived nitroxide radicals, i.e., morpholin-4-yloxy radicals. N-Nitrosomorpholine, however, is very likely formed by electrophilic attack of peroxynitrite-derived N2O4. 15N-CIDNP Experiments establish that, in the presence of CO2, N-nitro- and C-nitromorpholine are generated by radical recombination. The present results are in full accord with a fractional (28±2% ) homolytic decay of peroxynitrite/peroxynitrous acid with release of free hydroxyl and nitrogen dioxide radicals.
- Kirsch, Michael,Korth, Hans-Gert,Wensing, Angela,Lehnig, Manfred,Sustmann, Reiner,De Groot, Herbert
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- Nitrosation of Amines in Nonaqueous Solvents. 2. Solvent-Induced Mechanistic Changes
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We studied the nitrosation of amines (pyrrolidine, piperidine, diethylamine, N-methylpiperazine, N,N′-dimethylethylenediamine, and morpholine) by alkyl nitrites (2-bromoethyl nitrite or 2,2- dichloroethyl nitrite) or by N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in the solvents chloroform, acetonitrile, and dimethyl sulfoxide (DMSO). The mechanism of nitrosation by alkyl nitrites depends on the solvent: in chloroform, all the results were in keeping with formation of a hydrogen-bonded complex between the amine and alkyl nitrite being followed by rate-controlling formation of a tetrahedral intermediate T± that rapidly decomposes to afford the final products; in acetonitrile, a situation intermediate between those obtaining in chloroform and cyclohexane results in the [amine] dependence of the first-order pseudoconstant k0 being qualitatively influenced by temperature and by the identities of both the amine and the alkyl nitrite; in DMSO, the results suggest a mechanism close to the mechanism acting in water. For nitrosation by MNTS, k0 depended linearly on [amine] in all three solvents. The Grunwald-Winstein coefficients correlating the rate constants k for nitrosation by MNTS in the chloroform, acetonitrile, DMSO, dioxane, dichloromethane, and water were l = 0.12 and m = 0.29. Correlation with the Kamlet-Abboud-Taft equation confirmed that k depends largely on the dipolarity of the solvent and, to a lesser extent, its capacity for hydrogen bonding.
- Garcia-Rio,Leis,Iglesias
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- Alumina-methanesulfonic acid (AMA)/NaNO2 as an efficient procedure for the chemoselectivite N-nitrosation of secondary amines
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A combination of alumina/methanesulfonic acid (AMA) and sodium nitrite was used as an effective nitrosating agent for the nitrosation of secondary amines under mild and heterogeneous conditions in good to excellent yields. Copyright Taylor & Francis Group, LLC.
- Niknam, Khodabakhsh,Zolfigol, Mohammad Ali
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- Ph3P/Br2/n-Bu4NNO2 as an efficient system for the preparation of N-nitrosamines and azides
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The combination PPh3/Br2/n-Bu4NNO2 was developed as a new reagent system for the efficient preparation of N-nitrosamines and azides from the corresponding amines and hydrazine derivatives, respectively, at 0 °C to room temperature, in excellent yields.
- Iranpoor, Nasser,Firouzabadi, Habib,Nowrouzi, Najmeh
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- Kinetics of the Aminolysis and Hydrolysis of Alkyl Nitrites: Evidence for an Orbital Controlled Mechanism
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The kinetics of the nitrosation of piperidine by propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl nitrites in 0.1 M NaOH and of the hydrolysis of the nitrite esters were studied spectrophotometrically by monitoring the absorbance of the nitrites at 381 nm. The observed correlation between log k2 and σ* (ρ* = 4.5) shows the reaction to proceed via electrophilic attack by the nitrites; the existence of an isokinetic relationship suggests a single mechanism for the whole series. Comparison of the relative reactivities of the alkyl nitrites (primary > secondary > tertiary) with characteristic parameters of their R groups (vertical ionization potentials and heats of formation of R+) suggests that these reactions are orbital controlled. All hydrolysis reactions were slower than the corresponding aminolysis reactions. This is attributed to a retardation of the former reaction by unfavourable interactions between the lone pairs of the nucleophile and the nitroso nitrogen atom.
- Garcia-Santos,Calle,Gonzalez-Mancebo,Casado
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- Silica sulfuric acid/NaNO2 as a novel heterogeneous system for the chemoselective N-nitrosation of secondary amines under mild conditions
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Neat chlorosulfonic acid reacts with silica gel to give silica sulfuric acid in which sulfuric acid is immobilized on the surface of silica gel via a covalent bond. A combination of silica sulfuric acid and sodium nitrite in the presence of wet SiO2 was used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in excellent yields.
- Zolfigol, Mohammad Ali,Bamoniri, Abdolhamid
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- Molybdate sulfuric acid/NaNO2: A novel heterogeneous system for the N-nitrosation of secondary amines under mild conditions
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Wet molybdate sulfuric acid (=dioxo[bis(sulfato-κO)]molybdenum; MSA), a new solid acid, can be used in combination with sodium nitrite (NaNO 2) to transform a variety of secondary amines to the corresponding N-nitroso compounds under mild, heterogeneous conditions (Table). The process has several advantages: the reagents are inexpensive and non-hazardous, the reaction is clean, fast, and high-yielding, and MSA can be readily removed by filtration and re-used (after treatment with HCl) without loss of activity. Further, only N-nitrosation was observed, but no C- or O-nitrosation.
- Montazerozohori, Morteza,Karami, Bahador
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- Nitrosation of Amines in Non-Aqueous Solvents - Difference between N-N=O and O-N=O Nitroso Donors
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A kinetic study has been carried out on nitroso group transfer from substituted N-methyl-N-nitroso-benzenesulfonamides to different secondary amines: pyrrolidine, piperidine, N-methylpiperazine, and morpholine in cyclohexane. The observed pseudo-first-order rate constant kobs shows a linear and quadratic dependency on the amine concentration with the existence of a primary kinetic isotope effect. Experiments carried out at different temperatures show Arrhenius-type behavior. Addition of isopropylamine (iPrNH2) to the reaction medium produces an increase in k obs. In the presence of a high iPrNH2 concentrations the influence of secondary amine concentration on kobs shows the disappearance of the quadratic dependency of kobs on the secondary amine. These results would be compatible with an addition-elimination mechanism, similar to that observed for the aminolysis of the alkyl nitrites in apolar solvents. The observed behavior in the presence of 18-crown-6 is very different, however. Addition of crown ether catalyses the reaction of aminolysis of alkyl nitrites insofar as it does not alter the rate of the nitroso group transfer from N-nitrososulfonamides. This behavior has been interpreted in terms of a concerted reaction mechanism through cyclical transition states, with four or six centers, involving one or two molecules of secondary amine. Addition of iPrNH2 to the reaction medium causes the appearance of a third reaction path, which emerges through a mixed transition state formed by a molecule of a secondary amine and a molecule of isopropylamine. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Garcia-Rio, Luis,Leis, Jose R.,Moreira, Jose A.,Serantes, David
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- N-nitrosation of secondary amines under mild and heterogeneous conditions
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A combination of potassium monopersulfate and sodium nitrite in the presence of wet SiO2 was used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in excellent yields.
- Zolfigol,Bagherzadeh,Choghamarani,Keypour,Salehzadeh
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- A combined experimental and DFT mechanistic study for the unexpected nitrosolysis of: N -hydroxymethyldialkylamines in fuming nitric acid
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The reaction of dimorpholinomethane in fuming HNO3 was investigated. Interestingly, the major product was identified as N-nitrosomorpholine and a key intermediate N-hydroxymethylmorpholine was detected during the reaction by 1H-NMR tracking which indicates that the reaction proceeds via an unexpected nitrosolysis process. A plausible nitrosolysis mechanism for N-hydroxymethyldialkylamine in fuming nitric acid involving a HNO3 redox reaction is proposed, which is supported by both experimental results and density functional theory (DFT) calculations. The effects of ammonium nitrate and water on the nitrosolysis were studied using different ammonium salts as additives and varying water content, respectively. Observations show the key role of ammonium ions and a small amount of water in promoting the nitrosolysis reaction. Furthermore, DFT calculations reveal an essential point that ammonia, merged from the decomposition of the ammonium salts, acts as a Lewis base catalyst, and the hydroxymethyl group of the substrate participates in a hydrogen-bonding interaction with the NH3 and H2O molecules.
- Zhang, Yu,Zou, Po,Han, Yingbin,Geng, Yongliang,Luo, Jun,Zhou, Baojing
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- Comparative study of nitroso group transfer in colloidal aggregates: Micelles, vesicles and microemulsions
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A kinetic study was carried out on nitroso group transfer from N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) to different secondary amines: morpholine (MOR), piperazine (PIP), dimethylamine (DMA) and piperidine (PIPER) in micelles of dodecyltrimethylammonium bromide (LTABr) and in vesicles of dioxadecyltrimethylammonium chloride (DODAC). Amine nucleophiles were chosen on the basis of their hydrophobicity and basicity. The observed rate constant, kobs, shows opposite behavior in micelles and vesicular systems. kobs for micelle systems decreases as the surfactant concentration increases. This behavior can be interpreted according to the distribution of the reagents among the different pseudophases of the system and the physicochemical properties of the latter. It has been observed that the product of the rate constant in the micellar pseudophase and the distribution constant of the amine, k2mKmR2NH, retains a sequence similar to the reactivity observed in water. The differences observed can be explained on the basis of the different hydrophobicity of the amines and consequently different values of KmR2NH. In all cases a catalytic effect on the addition of vesicles was observed reaching a limiting value of kobs. The kinetic behavior can be explained quantitatively on the basis of a single pseudophase model, k2vKvR2NH in the vesicular systems of DODAC displays a variation which is analogous with the micellar systems but approximately 35 times greater, which in turn indicates the greater hydrophobic character of the vesicles of DODAC by comparison with the micelles of LTABr. In AOT/isooctane/water microemulsions we have found similar behavior where the product is approximately 22 times lower than in vesicles, indicating that the polarity of the interface of the microemulsions is greater than that of the micelles of LTABr and smaller than that of DODAC vesicles. The comparative analysis of the reactivities in the interface of the microemulsion and in an aqueous medium shows that the reactive position in the interface changes as the hydrophobic character of the amine varies.
- Garcia-Rio,Herves,Mejuto,Perez-Juste,Rodriguez-Dafonte
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- Cyclodextrins as enzyme models in nitrosation and in acid-base- catalyzed reactions of alkyl nitrites
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The widely studied cyclodextrin-mediated reactions of esters but not those of alkyl nitrites, together with the marked differences between the chemistry of esters and alkyl nitrites, prompted us to investigate the influence of β-cyclodextrin (β-CD) on the reactions of alkyl nitrites. Due to the particular characteristics of alkyl nitrite reactions, the system β- cyclodextrin-alkyl nitrites allows us to explore cyclodextrin's behavior under several experimental conditions, contrary to the case of esters. Therefore, general acid-base-catalyzed hydrolysis and nitrosation of amines by alkyl nitrites are studied. Alkyl nitrites of a particular structure have been chosen to clearly evidence the mimicry of enzyme catalysis by β-CD. Addition of β-CD strongly inhibits the acid hydrolysis of alkyl nitrites (a very fast reaction in water), except in the case of ethoxyethyl nitrite, where no effect is detected. The retardation of the reaction is attributed to a separation of the reagents: β-CD and alkyl nitrites form host-guest 1:1 inclusion complexes, but simple cations, such as H3O+ in the present case, did not prove to include into the β-CD cavity. In fact, at constant β-CD concentrations, addition of dodecyltrimethylammonium bromide monomers (DTABr), which strongly compete with alkyl nitrites for the hydrophobic β- CD cavity and, thus, expel the alkyl nitrites, catalyzes the reaction. On the contrary, in alkaline medium, when a secondary hydroxy group of β-CD is ionized, addition of β-CD to the reaction medium strongly catalyzes the basic hydrolysis of alkyl nitrites (an extremely slow reaction in water). The degree of catalysis depends on the alkyl nitrite structure, varying from a factor higher than 100 in the case of 3-phenyl-1-propyl nitrite, to 0 (no reaction is observed) in the case of 2-phenyl-2-propyl nitrite. The effective molarities calculated for the catalysis evidence a base-catalyzed mechanism for the reaction. The strong catalysis observed with 1-phenyl-1-propyl nitrite upon the addition of DTABr is indicative of an example of allosteric activation. Finally, the nitrosation of pyrrolidine, piperidine, and cyclohexylamine by ethoxyethyl nitrite is slightly catalyzed by the presence of β-cyclodextrin. The degree of the observed catalysis depends on both the amine concentration and the structure.
- Iglesias, Emilia
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- Thermal Decomposition of Nitramines: Dimethylnitramine, Diisopropylnitramine, and N-Nitropiperidine
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Kinetics and activation parameters of the solution thermolysis of nitramines dimethylnitramine, diisopropylnitramine, and N-nitropiperidine were determined over the temperature range 200-300 deg C.Each formed the corresponding nitrosamine as the only, or major, condensed-phase product.For dimethylnitramine the products were completely characterized.The observations of a large positive activation volume in the thermolysis of dimethylnitramine and of the slowing of the decomposition reaction with increased solvent viscosity both suggest that the rate-determining step is homolysis, the N-NO2 bond being the most obvious point for this.Nitrosamines could be produced by this route; however, when doubly 15N-labeled dimethylnitramine was heated with unlabeled dimethylnitramine, little scrambling of the label in the reactant was observed.Label scrambling was observed in the nitrosamine but could have resulted from subsequent N-NO homolysis.Scrambling of the label in the product gases and the observation of a kinetic isotope effect when perdeuterated dimethylnitramine was decomposed were explained in terms of a second decomposition route involving transfer of hydrogen from the α carbon to one of the NO2 oxygens.
- Oxley, J. C.,Hiskey, M.,Naud, D.,Szekeres, R.
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- Transfer of the Nitroso Group in Water/AOT/Isooctane Microemulsions: Intrinsic and Apparent Reactivity
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The kinetics of the transfer of the nitroso group from N-methyl-N-nitroso-p-toluenesulfonamide to each of seven secondary amines (piperazine, N-methylbenzylamine, piperidine, dimethylamine, morpholine, pyrrolidine, and diisopropylamine) was studied using a wide variety of water/AOT/isooctane microemulsions as reaction media.The diverse kinetic behavior of the various amines can be explained quantitatively on the basis of a single model taking into account the distribution of the amine among the aqueous and isooctane phases and their mutual interface; the reaction itself always takes place at the interface.The relative reactivities of the amines are discussed in comparison with the order observed in water.
- Garcia-Rio, Luis,Leis, J. Ramon,Pena, M. Elena,Iglesias, Emilia
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- Efficient and chemoselective N-nitrosation of secondary amines under mild and heterogeneous conditions with sodium nitrite and oxalic acid two hydrate
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Secondary amines can be quantitatively converted to their corresponding nitroso derivatives with a combination of oxalic acid and sodium nitrite in dichloromethane at room temperature.
- Zolfigol, Mohammad Ali
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- Selective N-nitrosation of amines, N-alkylamides and N-alkylureas by N2O4 supported on cross-linked polyvinylpyrrolidone (PVP-N2O4)
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N2O4 was supported on the cross-linked polyvinylpyrrolidone (PVP) to afford a solid, stable and recyclable nitrosating agent. This reagent shows excellent selectivity for N-nitrosation of dialkyl amines in the presence of diaryl-, arylalkyl-, trialkylamines and also for secondary amides in dichloromethane at room temperature under mild and heterogeneous conditions. Also N-nitroso-N-alkyl amides can be selectively prepared in the presence of primary amides and N-phenylamides under similar reaction conditions. Selective N-nitrosation or dealkylation and N-nitrosation of tertiary amines can also be performed by this reagent.
- Iranpoor, Nasser,Firouzabadi, Habib,Pourali, Ali-Reza
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- Nitrosation of Amines in Nonaqueous Solvents, 1. Evidence of a Stepwise Mechanism
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We studied the nitrosation of piperidine, morpholine, pyrrolidine, N-methylpiperazine, N,N′-dimethylethylenediamine and diethylamine by 2-bromoethyl nitrite, 2,2-dichloroethyl nitrite, 2,2,2-trichloroethyl nitrite, or N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in cyclohexane, isooctane, dichloromethane, 1,4-dioxane, or tetrahydrofuran. The dependence of the first-order pseudoconstant k0 on the amine concentration (always in excess) was sigmoid for nitrosation by alkyl nitrites and linear or quadratic for nitrosation by MNTS. The effects on k0 of isotopic substitution, temperature, and base catalysis by a less reactive amine were also determined. The experimental data are in keeping with a reaction mechanism involving a zwitterionic tetrahedral intermediate T± analogous to intermediates postulated for the aminolysis of carboxylic esters in similar solvents: according to this mechanism, T± is formed either directly from the amine and nitrosating agent (in the case of MNTS) or indirectly via a hydrogen-bonded complex between the amine and nitrosating agent (in the case of alkyl nitrites) and decomposes either spontaneously or with the catalytic assistance of a second amine molecule. For alkyl nitrites, the rate-controlling step is the formation of T± at high amine concentrations and its decomposition at low amine concentrations; for MNTS, the rate-controlling step is the formation of T± in more polar solvents and its decomposition in less polar solvents. An alternative mechanism, involving the formation of T± from both monomers and dimers of the amine, is ruled out.
- Garcia Rio,Leis,Iglesias
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- A screening procedure for the formation of nitroso derivatives and mutagens by drug-nitrite interaction
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A general procedure for screening for the formation of nitroso derivatives and/or mutagens by drug-nitrite interaction was established. A test drug (50 mM) was reacted with nitrite (500 mM) at pH 3.0-3.5 and 37°C for 4 h. The residual nitrite in the reaction mixture was decomposed with ammonium sulfamate. The nitrite-free reaction mixture was assayed for both nitroso derivatives and mutagens by colorimetry of Griess reagent-positive substances formed by treatment with hydrogen bromide and by mutagenesis assay using Salmonella typhimurium TA98 and TA100 as tester strains, respectively.
- Takeda,Kanaya
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- In situ generated amine as a Lewis base catalyst in the reaction of 3,7-dinitro-1,3,5,7-tetraazabicyclo[3.3.1]nonane in nitric acid: Experimental and DFT study
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The problem how ammonium nitrate affects the nitrolysis of 3,7-dinitro-1,3,5,7-tetraazabicyclo[3.3.1]nonane (DPT) in nitric acid to prepare 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane (HMX) has puzzled chemists for decades. In this paper, experimental work and theoretical calculation are described to investigate the long-standing challenge. The experiment results showed that ammonium nitrate or alkylammonium chlorides were in favor of the formation of 1-nitroso-3,5,7-trinitro-1,3,5,7-tetraazacyclooctane (MNX) but hindered the conversion of MNX to HMX. A plausible catalytic mechanism was proposed. In which ammonia or amines, in situ generated from the unfavorable balance with their salts, act as Lewis base catalysts. At the same time, the DFT computation results reveal that rigid bicyclic transition states established with 1-hydroxymethyl-3,5,7-trinitro-1,3,5,7-tetraazacyclooctane, ammonia (or amines) and three water molecules lead to very low activation energies. Then, a novel process for the preparation of MNX with excellent yield up to 78.5% was developed, which is free of the use of NaNO2 or N2O4 as nitroso resources.
- Zhang, Yu,Chi, Guoli,He, Ying,Xu, Zishuai,Zhang, Luyao,Luo, Jun,Zhou, Baojing
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- Iodide-catalyzed synthesis of N-nitrosamines via C-N cleavage of nitromethane
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An iodide-catalyzed process to synthesize N-nitrosamines has been developed using TBHP as the oxidant. The mild catalytic system succeeded in cleaving the carbon-nitrogen bond in nitromethane. This methodology uses commercially available, inexpensive catalysts and oxidants and has a wide substrate scope and operational simplicity.
- Zhang, Jie,Jiang, Jiewen,Li, Yuling,Wan, Xiaobing
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- Differences in the activity of neutral and ionized β-cyclodextrin on the nitrosation of amines by phenylpropyl nitrites
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The influence of β-cyclodextrin (β-CD) on the base-catalyzed hydrolysis reaction of 1-phenyl-1-propyl, 2-phenyl-1propyl and 3-phenyl-1-propyl nitrites and on the nitrosation of pyrrolidine, piperidine and N-methylcyclohexylamine by the aforementioned alkyl nitrites (RONO) is studied in aqueous buffers of the amines and in an alkaline medium with [OH-] = 0.20 M. The hydrolysis reaction is catalyzed by the presence of β-CD owing to the formation of reactive 1:1 inclusion complexes between the alkyl nitrite and the ionized β-CD; the addition of potential inhibitors, such as dodecyltrimethylammonium bromide monomers, accelerates the reaction even more. The effect is quite significant in the case of 1-phenyl-1-propyl nitrite and is viewed as a case of allostery. In the presence of neutral β-CD, the nitrosation by 1-phenyl-1-propyl nitrite, either of pyrrolidine or piperidine, is inhibited by β-CD addition; however, the nitrosation reaction of piperidine by 2-phenyl-1-propyl nitrite is catalyzed (passing through a maximum) by β-CD, whereas the nitrosation of pyrrolidine promoted by 3-phenyl-1-propyl nitrite exhibits practically no change upon β-CD addition. In alkaline media (containing ionized β-CD) the nitrosation of pyrrolidine by 1-phenyl-1-propyl nitrite is inhibited by the presence of β-CD; in contrast, the nitrosation of both piperidine and N-methylcyclohexylamine is catalyzed in all cases, but the degree of catalysis depends not only on the alkyl nitrite structure, but also on the type and concentration of the amine. Kinetic results are quantitatively interpreted on the basis of the proposed reaction mechanism in each case, and the kinetic rate constants of the different steps are determined. Comparison of the results obtained in aqueous alkaline media and in aqueous buffers of the amines themselves allows us to establish important characteristics of the transition state of the reaction.
- Iglesias
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- Efficient procedure for chemoselective N-nitrosation of secondary amines with trichloromelamine-NaNO2
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A combination of trichloromelamine and sodium nitrite in the presence of wet silica gel was used as an effective nitrosating agent for the transformation of secondary amines into the corresponding N-nitroso derivatives under mild and heterogeneous conditions in good to excellent yields.
- Bamoniri,Zolfigol,Mirjalili,Fallah
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- Fremy's Salt (Potassium Nitrosodisulphonate): A Nitrosating Reagent for Amines
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Treatment of secondary and tertiary amines with Fremy's salt in aqueous sodium carbonate or pyridine solution gives moderate yields of the corresponding N-nitrosoamines.
- Castedo, Luis,Riguera, Ricardo,Vazquez, M. Pilar
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- Trichloroisocyanuric acid/NaNo2 as a novel heterogeneous system for the N-nitrosation of N,N-dialkylamines under mild conditions
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A combination of trichloroisocyanuric acid and sodium nitrite in the presence of wet SiO2 was used as an effective nitrosating agent for the nitrosation of N,N-dialkyl amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in moderate to excellent yields.
- Zolfigol, Mohammad Ali,Choghamarani, Arash Ghorbani,Hazarkhani, Hassan
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- Visible-Light-Induced Photoaddition of N-Nitrosoalkylamines to Alkenes: One-Pot Tandem Approach to 1,2-Diamination of Alkenes from Secondary Amines
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The generation of aminium radical cation species from N-nitrosoamines is disclosed for the first time through visible-light excitation at 453 nm. The developed visible-light-promoted photoaddition reaction of N-nitrosoamines to alkenes was combined with the o-NQ-catalyzed aerobic oxidation protocol of amines to telescope the direct handling of harmful N-nitroso compounds, where the desired α-amino oxime derivatives were obtained in a one-pot tandem N-nitrosation and photoaddition sequence.
- Patil, Dilip V.,Si, Tengda,Kim, Hun Young,Oh, Kyungsoo
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supporting information
p. 3105 - 3109
(2021/05/05)
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- Electrochemical Nonacidic N-Nitrosation/N-Nitration of Secondary Amines through a Biradical Coupling Reaction
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An acid-free N-nitrosation/nitration of the N?H bonds in secondary amines with Fe(NO3)3 ? 9H2O as the nitroso/nitro source through an electrocatalyzed radical coupling reaction was developed. Cyclic aliphatic amines and N-heteroaromatic compounds were N-nitrosated and N-nitrated, respectively, under mild conditions. Control and competition experiments, as well as kinetic studies, demonstrate that N-nitrosation and N-nitration involve two different radical reaction pathways involving N+ and N. radicals. Moreover, the electrocatalysis method enables the preferential activation of the N?H bond over the electrode and thus provides high selectivity for specific N atoms. Finally, this strategy exhibits a broad scope and provides a green and straightforward approach to generate useful N-nitroso/nitro compounds in good yields. (Figure presented.).
- Zhao, Ji-Ping,Ding, Lu-jia,Wang, Peng-Cheng,Liu, Ying,Huang, Min-Jun,Zhou, Xin-Li,Lu, Ming
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supporting information
p. 5036 - 5043
(2020/07/13)
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- Optimization of biaryloxazolidinone as promising antibacterial agents against antibiotic-susceptible and antibiotic-resistant gram-positive bacteria
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We previously discovered a series of novel biaryloxazolidinone analogues bearing a hydrazone moiety with potent antibacterial activity. However, the most potent compound OB-104 exhibited undesirable chemical and metabolic instability. Herein, novel biaryloxazolidinone analogues were designed and synthesized to improve the chemical and metabolic stability. Compounds 6a-1, 6a-3, 14a-1, 14a-3 and 14a-7 showed significant antibacterial activity against the tested Gram-positive bacteria as compared to radezolid and linezolid. Further studies indicated that most of them exhibited improved water solubility and chemical stability. Compound 14a-7 had MIC values of 0.125–0.25 μg/mL against all tested Gram-positive bacteria, and showed excellent antibacterial activity against clinical isolates of antibiotic-susceptible and antibiotic-resistant bacteria. Moreover, it was stable in human liver microsome. From a safety viewpoint, it showed non-cytotoxic activity against hepatic cell and exhibited lower inhibitory activity against human MAO-A compared to linezolid. The potent antibacterial activity and all these improved drug-likeness properties and safety profile suggested that compound 14a-7 might be a promising drug candidate for further investigation.
- Wu, Yachuang,Ding, Xiudong,Yang, Yifeng,Li, Yingxiu,Qi, Yinliang,Hu, Feng,Qin, Mingze,Liu, Yajing,Sun, Lu,Zhao, Yanfang
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- Substrate promiscuity of ortho-naphthoquinone catalyst: Catalytic aerobic amine oxidation protocols to deaminative cross-coupling and n-nitrosation
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ortho-Naphthoquinone-based organocatalysts have been identified as versatile aerobic oxidation catalysts. Primary amines were readily cross-coupled with primary nitroalkanes via deaminative pathway to give nitroalkene derivatives in good to excellent yields. Secondary and tertiary amines were inert to ortho-naphthoquinone catalysts; however, secondary nitroalkanes were readily converted by ortho-naphthoquinone catalysts to the corresponding nitrite species that in situ oxidized the amines to the corresponding N-nitroso compounds. Without using harsh oxidants in a stoichiometric amount, the present catalytic aerobic oxidation protocol utilizes the substrate promiscuity feature to provide a facile access to amine oxidation products under mild reaction conditions.
- Kim, Hun Young,Oh, Kyungsoo,Si, Tengda
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p. 9216 - 9221
(2019/10/08)
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- Synthesis and antibacterial activity evaluation of novel biaryloxazolidinone analogues containing a hydrazone moiety as promising antibacterial agents
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A series of linezolid analogues containing a hydrazone moiety were designed, synthesized and evaluated for their antibacterial activity. Most compounds exhibited more potent antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens as compared with linezolid and radezolid. Compounds 9a, 9c, 9f, 9g, 10m and 10t were more potent against tested clinical isolates of MRSA, MSSA, VRE and LREF as compared to linezolid. Compound 9a exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome. The most promising compound 9a showed remarkable antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens with MIC value of 0.0675 mg/mL, respectively, which was 15- to 30-fold more potent than linezolid.
- Wu, Yachuang,Ding, Xiudong,Ding, Liang,Zhang, Yongsheng,Cui, Lei,Sun, Lu,Li, Wei,Wang, Di,Zhao, Yanfang
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p. 247 - 258
(2018/09/18)
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- An efficient synthesis of: N -nitrosamines under solvent, metal and acid free conditions using tert -butyl nitrite
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Synthesis of various N-nitroso compounds from secondary amines is reported using tert-butyl nitrite (TBN) under solvent free conditions. Broad substrate scope, metal and acid free conditions, easy isolation procedure and excellent yields are few important features of this methodology. The acid labile protecting groups such as tert-butyldimethylsilyl (TBDMS) and tert-butyloxycarbonyl (Boc) as well as sensitive functional groups such as phenols, olefins and alkynes are found to be stable under the standard reaction conditions. Besides N-nitrosation, TBN is also found to be an efficient reagent in few other transformations including aryl hydrazines to aryl azides and primary amides to carboxylic acids under mild conditions.
- Chaudhary, Priyanka,Gupta, Surabhi,Muniyappan, Nalluchamy,Sabiah, Shahulhameed,Kandasamy, Jeyakumar
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supporting information
p. 2323 - 2330
(2016/05/19)
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- Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine
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Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine-iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both α-iodo- and α,α-diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I+ under O2. In particular, evidence supports α,α-diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion.
- Li, Jing,Lear, Martin J.,Kwon, Eunsang,Hayashi, Yujiro
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p. 5538 - 5542
(2016/04/20)
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- Bismuth chloride-sodium nitrite: A novel reagent for chemoselective N-nitrosation
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Bismuth(III) chloride-sodium nitrite was used as a mild and efficient reagent for N-nitrosation of various tetrazoles, secondary amines, and amides under ambient conditions. Nitrosation took place chemoselectively at the nitrogen atom, giving corresponding N-nitroso derivatives in good to excellent yield. Copyright Taylor & Francis Group, LLC.
- Chaskar, Atul C.,Langi, Bhushan P.,Deorukhkar, Amol,Deokar, Hrushikesh
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experimental part
p. 604 - 612
(2009/07/04)
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- Dinitrogen tetroxide-impregnated charcoal (N2O 4/charcoal): Selective nitrosation of amines, amides, ureas, and thiols
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Efficient N-nitrosation of amines, amides, and ureas, and also S-nitrosation of thiols were performed with dinitrogen tetroxide impregnated on activated charcoal (N2O4/charcoal) in CH 2Cl2 at room temperature. High selectivity was observed for N-nitrosation of dialkyl amines, N-alkylamides and N-alkylureas. Dealkylation and N-nitrosation of trialkylamines were also performed by this reagent. Copyright Taylor & Francis, Inc.
- Iranpoor, Nasser,Firouzabadi, Habib,Pourali, Ali Reza
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p. 1517 - 1526
(2007/10/03)
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- Controlled photochemical release of nitric oxide from O2-naphthylmethyl- and O2-naphthylallyl-substituted diazeniumdiolates
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The photochemistry of O2-naphthylmethyl- and O2-naphthylallyl-substituted diazeniumdiolates has been investigated. Electron-donating methoxy group substitution is shown to have a significant effect on the observed photochemistry, with the appropriate substitution pattern resulting in efficient diazeniumdiolate photorelease. Observed nitric oxide release rates from these photoprecursors are consistent with those expected for normal thermal dissociation of the diazeniumdiolate in aqueous solutions and show the same pH dependence. Copyright
- Bushan, K. Mani,Xu, Hua,Ruane, Patrick H.,D'Sa, Raechelle A.,Pavlos, Christopher M.,Smith, Joseph A.,Celius, Tevye C.,Toscano, John P.
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p. 12640 - 12641
(2007/10/03)
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- Chemoselective N-nitrosation of secondary amines under mild and heterogeneous conditions via in situ generation of NOCI
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A combination of inorganic chloride salts [e.g. WCl6, AlCl3 and ZnCl2] and sodium nitrite in the presence of wet SiO2 were used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in moderate to excellent yields.
- Zolfigol,Shirini,Choghamarani,Taqian-Nasab,Keypour,Salehzadeh
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p. 420 - 422
(2007/10/03)
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- Reactivity of nitrogen nucleophiles towards S-nitrosopenicillamine
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We report the results of a kinetic study of the reactions of a number of nitrogen nucleophiles with the nitrosothiol S-nitrosopenicillamine (SPEN). The range of nucleophiles includes primary, secondary and tertiary aliphatic amines, together with hydrazine, hydroxylamine, azide ion, ammonia, semicarbazide, thiomorpholine and S-methylcysteine. Secondary amines form N-nitrosamines quantitatively. As expected, reaction occurs via the free base forms of the nucleophiles and consequently most of the reactions take place readily only at relatively high pH. Experiments were carried out with [nucleophile] ? [RSNO], and for many reactions, plots of the first order rate constant vs. [nucleophile] were linear. For ammonia and the primary amines, however, this plot tended to level off at high [nucleophile] and an explanation is offered involving the reversible formation of an inactive RSNO-amine complex, for which there is spectral evidence, in parallel with the main reaction. For the secondary amines there is a reasonably good Broensted plot with a β value of ~0.2. The much greater reactivities of S-methylcysteine and thiomorpholine, compared to those of primary amines and morpholine respectively are consistent with initial attack at the sulfur atom, followed by an internal rearrangement. Over the whole range of nucleophiles studied there is a reasonable correlation with the Ritchie N+ parameter, and not with the Pearson n scale. Comparisons are made with the corresponding reactions of alkyl nitrites and N-methyl-N-nitrosotoluene-p-sulfonamide (MNTS).
- Munro, Andrew P.,Williams, D. Lyn H.
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p. 1989 - 1993
(2007/10/03)
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- Mechanisms of Nitramine Thermolysis
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The thermal decomposition of a number of nitramines was studied in dilute solution and in the melt.The nitramines included acyclic mononitramines , cyclic mononitramines , cyclic dinitramines , and 1,3,5-trinitro-1,3,5-triazocyclohexane (RDX), octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), hexanitrohexaazaisowurtzitane (HNIW), and 1,3,3-trinitroazetidine (TNAZ).For the acyclic and cyclic mono- and dinitramines, the corresponding nitrosamines were the only or major condensed-phase product.Kinetics and activation parameters were determined for the thermolysis of dilute solutions (0.01-1.0 wtpercent) over the range 200-300 deg C.The thermolyses were found to be first-order with the rate constants unaffected by the use of deuterated solvent.As the nitramines became more complex than dimethylnitramine (DMN), the rate of decomposition increased and the product distribution became more complex.As the length of the aliphatic chain increased (DMN DEN DPN), the rate of thermolysis increased, yet nitrosamine remained the only observed condensed-phase product.When a secondary carbon was attached to the N-nitramine (DIPN) rather than the primary (DPN), the rate of decomposition increased and a new condensed-phase product was observed.Among the cyclic nitramines, the rate of decomposition increased as the number of NNO2 groups increased (NPIP pDNP; NPyr DNI; mDMP RDX).The position of the nitramine groups affected the decomposition: meta NNO2 groups (mDNP) decomposed faster than para (pDNP).Ring strain decreased stability: mDNP DNI; HMX RDX.In complex nitramines, the increase in decomposition rate, the appearance of new products, and the change in the relative importance of nitrosamine and of N2 and N2O are attributed to new decomposition routes available to them.However, since complex nitramines (e.g.RDX) maintain first-order kinetics and since most have activation energies in the range of 40-50 kcal/mol, it is belived that the triggering mechanism remains N-NO2 homolysis.Intramolecular hydrogen transfer is also considered an important mode of nitramine decomposition.
- Oxley, J. C.,Kooh, A. B.,Szekeres, R.,Zheng, W.
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p. 7004 - 7008
(2007/10/02)
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- Formation of Nitrosamines in Alkaline Conditions: a Kinetic Study of the Nitrosation of Linear and Cyclic Secondary Amines by Nitroalkanes
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A study has been made of the nitrosation of sixteen secondary amines, six alkylamines (dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine) and ten cyclic secondary amines (2-methylaziridine, azetidine, pyrrolidine, piperidine, 2-methylpiperidine, homopiperidine, heptamethyleneimine, piperazine, 1-methylpiperazine and morpholine) by nitropropane and nitrobutane in a strongly basic medium (-> = 0.1 mol dm-3).The nitrites were not formed in situ (i.e. in the actual bulk of the reaction medium) but rather were isolated,purified and used in pure form.The rate equation (i) was found v = k2obs (i).The fitting of the experimental results to the Taft correlation points to a nucleophilic attack on nitrite esters by the amines.Analysis of the log k2/pKa and log k2/Ei(v) correlations indicates orbital control of the reactions studied.These results, together with the fact that the reactivity of the different amines diminishes ostensibly when the values of the 13C-H nuclear spin coupling constant in the series of corresponding cycloalkanes increase, show that the overall hybridization of the nitrogen atom in the cycle changes from sp2 in the triangular nucleophile methylaziridine to sp3 in larger cycles.The results obtained at different temperatures and with water-tetrahydrofuran media, together with a study of isotope effects suggest that these reactions occur through a highly ordered transition state and that the role of solvation should not be overlooked.
- Calle, Emilio,Casado, Julio,Cinos, Jose L.,Mateos, Francisco J. Garcia,Tostado, Manuel
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p. 987 - 991
(2007/10/02)
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- Nitrosamines and Hydrazones of Dinitroformaldehyde from N,N-Disubstituted Hydrazines, a Dialkyl Nitroxide, and Tetranitromethane
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N,N-Disubstituted hydrazines reacted with a mixture of a dialkylnitroxide and tetranitromethane to give nitrosamines and small amounts of hydrazones of dinitroformaldehyde.
- Krishnan, Ashwin M.,Wolford, Lionel T.,Boyer, Joseph H.
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p. 569 - 570
(2007/10/02)
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- Reactions of trifluoroamine oxide: A route to acyclic and cyclic fluoroamines and N-nitrosoamines
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Acyclic secondary fluoroamines and N-nitrosoamines R2NF and R2NNO (R = CH3, C2H5, n-C3H7, i-C3H7, n-C4H9, i-C4H9, c-C6H11) and saturated nonaromatic heterocyclic fluoroamines and N-nitrosoamines R NF and R NNO [R = c-C4H8, c-C5H10, 2,6-(CH3)2-c-C5H8, 2,2,6,6-(CH3)4-c-C5H6] were prepared by reacting trifluoroamine oxide (NF3O) with the respective amine at ≤0 °C in a 1:2 molar ratio. The amine hydrofluoride salts are also formed. Trifluoroamine oxide is a very effective fluorinating and nitrosating reagent and provides an excellent route to >NF- and >NNO-containing compounds. With PF5, 2,2,6,6-(CH3)4-c-C5H6NFgave [CH2CH2CH2C(CH3)2N +=C(CH3)2]PF6-.
- Gupta, Om Dutt,Kirchmeier, Robert L.,Shreeve, Jean'ne M.
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p. 2383 - 2386
(2007/10/02)
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- Decomposition of N-Methyl-N-nitrosotoluene-p-sulphonamide in Basic Media: Hydrolysis and Transnitrosation Reactions
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The decomposition of N-methyl-N-nitrosotoluene-p-sulphonamide (MNTS) has been studied in basic and neutral water-alcohol mixtures.In alkaline media and when OH- was the nucleophile, the known hydrolysis reaction in which OH- attacks the SO2 group was observed; this reaction was first order in both OH- and MNTS.In the presence of ammonia, hydroxylamine, hydrazine, or primary, secondary or tertiary amines, a transnitrosation reaction took place in which the addditional nucleophiles attacked the nitrogen atom of the MNTS N=O group; this reaction was first order in both MNTS and free amine.In particular, MNTS proved to be as efficient as some alkyl nitrites for the nitrosation of secondary amines in neutral or alkaline media, in which conventional nitrosating agents do not exist.Similar reaction rates were observed for the more basic tertiary amines (which gave NO2- among the final products).Primary amines underwent rather slower reactions, with the exception of hydroxylamine and hydrazine, the nucleophilic nature of which is increased by the α effect.We discuss the relative reactivities of the various amines in terms of their basicity and vertical ionization potentials, and we report the effect of the proportion of alcohol in the medium on the rates of both hydrolysis and transnitrosation reactions.
- Castro, Albino,Leis, J. Ramon,Pena, M. Elena
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p. 1861 - 1866
(2007/10/02)
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- Nitrosamines from N,N-Disubstituted Hydrazines Via Hydrazones of Dinitroformaldehyde and Ethyl Nitroglyoxylate
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N,N-Dialkyl, diaryl, and arylalkyl hydrazones of dinitroformaldehyde were obtained from hydrazines and either tetranitromethane (TNM) or iodotrinitromethane (ITM) and gave nitrosamines on irradiation at 350 nm in acetone for several days.Similar N,N-disubstituted hydrazones of ethyl nitroglyoxylate were obtained from the hydrazines and either ethyl dinitroiodoacetate (DNIA) or ethyl dinitrobromoacetate (DNBA) but were neither thermal nor photochemical precursors to nitrosamines, coproducts obtained in minor amounts.Explanations for the formations of the hydrazones and nitrosamines were offered.
- Boyer, Joseph H.,Krishnan, Ashwin M.
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p. 201 - 213
(2007/10/02)
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