The Journal of organic chemistry

Synthesis and aqueous chemistry of alpha-acetoxy-N-nitrosomorpholine: reactive intermediates and products.

PMID 16388636


[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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