Formation and nucleophilic capture of &lt;i&gt;N&lt;/i&gt;-nitrosiminium ions

Chahoua, Latifa; Vigroux, Alain; Chiang, Y.; Fishbein, James C.

doi:10.1139/cjc-77-5-6-1148

Cited by 3 publications

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“…This was observed previously with both the piperidino and pyrrolidino analogues, and the leveling effect of concentration was ascribed to a competing general base-catalyzed hydration reaction, as indicated in the mechanism of eq 3 ,,− , Fitting of the data to the appropriate equation 30 results in the fits indicated by the lines in Figure using values of the ratios of the rate constants reported in Table . These values are of reasonable magnitude compared to those of the other two systems studied.…”

Section: Discussionsupporting

confidence: 70%

“…To further study the chemistry of the metabolite 3 , a stable source is of interest, and the α-acetoxynitrosamine 7 is an obvious candidate. α-Acetoxynitrosamines are widely used as presumed equivalents to the α-hydroxynitrosamines. ,, Unadorned cyclic and acyclic α-acetoxynitrosamines generally decompose by S N 1 solvolysis via short-lived N -nitrosiminium ion intermediates that, upon hydration with attack on carbon, give rise to the α-hydroxy compounds, as hypothetically indicated for 7 in Scheme . − Attack on the cation at the nitroso nitrogen can be competitive with attack at carbon, and consequent denitrosation instead yields the imine with no diazonium ion-generating potential. Attack on the nitrogen atom of the nitrosiminium ion is generally a minor reaction, the extent varying, but not predictably, with structure.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Aqueous Chemistry of α-Acetoxy-N-nitrosomorpholine: Reactive Intermediates and Products

2005

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[reaction: see text] Alpha-acetoxy-N-nitrosomorpholine (7) has been synthesized starting by the anodic oxidation of N-acetylmorpholine in methanol. The 55% yield of N-nitrosomorpholinic acid, after cyanide-for-methoxy group exchange and hydrolysis, is an improvement of approximately 10-fold over our original 10-step method, and this is readily converted to 7. A study of the kinetics of decomposition of 7 in aqueous media at 25 degrees C and 1 M ionic strength was conducted over the pH range from 1 to 12. The reaction exhibited good first-order kinetics at all values of pH, and a plot of the log of k0, the buffer-independent rate constant for decomposition, against pH indicated that a pH-independent reaction dominates in the neutral pH region whereas acid- and base-catalyzed reactions dominate in the low and high pH regions, respectively. Reaction at neutral pH in the presence of increasing concentrations of acetate ion results in a decrease in the value of k(obsd), to an apparent limiting value consistent with a common-ion inhibition by the capture, and competing base-catalyzed hydration of, an N-nitrosiminium ion intermediate. The 100-fold smaller reactivity of 7 at neutral pH compared with its carbon analogue, alpha-acetoxy-N-nitrosopiperidine, is also consistent with the electronic effects expected for such a reaction. The dinitrophenylhydrazones derived from pH-independent and acid-catalyzed reactions are identical in kind and quantity, within experimental error, to those observed in the decay of alpha-hydroxy-N-nitrosomorpholine. Decay of 7 in the presence of benzimidazole buffer results in the formation of 2-(2-(1H-benzo[d]imidazol-1-yl)ethoxy)acetaldehyde (12) and 2-(1H-benzo[d]imidazol-1-yl)ethanol (13). Independent synthesis and study of 12 indicates that it is stable at 80 degrees C in 0.1 M DCl, but it slowly decomposes to 13 in neutral and basic media in a reaction that is stimulated by primary and secondary amines, but not by tertiary amines and carbonate buffer. The benzimidazole trapping studies and those of the stability of 12 indicate the possibility that metabolic activation of N-nitrosomorpholine by hydroxylation alpha to the nitroso nitrogen can result in the deposition of a metastable ethoxyacetaldehyde adduct on the heteroatoms of DNA.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Synthesis and Aqueous Chemistry of α-Acetoxy-N-nitrosomorpholine: Reactive Intermediates and Products

2005

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“…This addition most likely proceeds by acid catalysis to generate NO + , regioselective electrophilic addition of NO + to the imine to form N -nitrosoiminium ions 4 − 6 , and subsequent water addition and deprotonation. The ions 4 − 6 are of interest in their own right because they are thought to be the reactive species in acid-catalyzed conversion of α-acetoxy- N -nitrosamines to the respective alcohols. , …”

Section: Resultsmentioning

confidence: 99%

“…N- Nitrosamines are latent carcinogens and require cytochrome P450 mediated α-oxidation for their conversion into the active carcinogens, the α-hydroxy- N -nitrosamines . The decomposition pathways of alkyl- N -nitrosamines have been intensively studied both experimentally and theoretically, and cyclic N -nitrosamines have received increasing attention. − In this context, we focus here on the elucidation of the possible role of nitrosation of compounds with CN double bonds in the generation of cell-damaging electrophiles. We recently reported on the nitrosation of the CN bonds of acyclic secondary and tertiary amidines …”

Section: Introductionmentioning

confidence: 99%

Nitrosation Chemistry of Pyrroline, 2-Imidazoline, and 2-Oxazoline: Theoretical Curtin−Hammett Analysis of Retro-Ene and Solvent-Assisted C−X Cleavage Reactions of α-Hydroxy-N-Nitrosamines

Loeppky

Glaser

2005

J. Org. Chem.

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The results are presented of a theoretical study of the nitrosation chemistry of pyrroline 1 (X = CH2), imidazoline 2 (X = NH), and 2-oxazoline 3 (X = O). Imines 1-3 are converted to the alpha-hydroxy-N-nitrosamines 7-9 via the N-nitrosoiminium ions 4-6. The NN-cis isomers of 7-9 may undergo retro-ene reactions to the delta-oxoalkyl diazotic acids 10-12. With the opportunity for microsolvation, C-X cleavage becomes possible for 8 and 9 and leads to the formation of N-(2-aminoethyl)- and N-(2-hydroxyethyl)-N-nitrosoformamides 15 and 16, respectively. The NN-isomerization barriers are comparable to the barriers for the ring-opening reactions, and the consideration of two Curtin-Hammett scenarios is required: CH-I for the NN-trans-rotamers of 7-9 to undergo C-X cleavage or NN-isomerization and CH-II for the NN-cis-rotamers to undergo C-X cleavage, C-N cleavage, or NN-isomerization. We determined all stereoisomers of the substrates, the products, and of all transition states structures for the retro-ene reactions of 7-9, the C-X cleavages of microsolvated 8 and 9, and the NN-isomerizations of 8 and 9. The potential energy surfaces were explored at the B3LYP/6-31G level, and the results are discussed with emphasis on the comparison of the kinetics and thermodynamics of C-N versus C-X cleavage. The study shows all decompositions to be very fast with activation barriers below 21 kcal.mol(-1), and the comparative analysis predicts that the chemical toxicologies of 1 and 3 should be similar and remarkably different from that of 2.

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The reaction of nitrosodicyclohexylamine with organolithiums

Vázquez

Rodríguez

Nudelman

2008

J of Physical Organic Chem

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The detailed study of the reaction of N‐nitrosamines with organolithium compounds, under different reaction conditions, allowed the development of a useful methodology for the synthesis of substituted hydrazones and trialkyl hydrazines. The reaction proved to be very sensitive to the reaction conditions, and different main products can be obtained by fine tuning of several variables. With the purpose of searching into the reaction mechanism, a careful isolation, characterization, and quantitative determination of several minor products was carried out. N,N‐ dicyclohexylamine, N‐cyclohexylidencyclohexyl amine, and N,N,N′‐dicyclohexylalkylhydrazines, were the main side products identified after the work up of the reaction mixtures. With the same aim, the kinetics of the reaction of N‐nitrosodicyclohexylamine with n‐BuLi, was determined at temperatures in the range 0 °C room temperature. Under the conditions leading to the trialkyl hydrazine, the results show an abrupt slowdown of the reaction rate, after a short reaction time. This result, together with other observations, such as the recovering of hydrazone even when using high [RLi], is indicative of equilibrium involving different species in the reaction mixture. The isolation of reduction products, as well as additional experiments carried out with lithium dialkylamides and NO, allowed suggestion of an overall mechanistic scheme for the complex consecutive and parallel reactions, that is consistent with the afforded evidences. Copyright © 2008 John Wiley & Sons, Ltd.

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Formation and nucleophilic capture of <i>N</i>-nitrosiminium ions

Cited by 3 publications

References 0 publications

Synthesis and Aqueous Chemistry of α-Acetoxy-N-nitrosomorpholine: Reactive Intermediates and Products

Synthesis and Aqueous Chemistry of α-Acetoxy-N-nitrosomorpholine: Reactive Intermediates and Products

Nitrosation Chemistry of Pyrroline, 2-Imidazoline, and 2-Oxazoline: Theoretical Curtin−Hammett Analysis of Retro-Ene and Solvent-Assisted C−X Cleavage Reactions of α-Hydroxy-N-Nitrosamines

The reaction of nitrosodicyclohexylamine with organolithiums

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