Synthesis and aqueous chemistry of alpha-acetoxy-N-nitrosomorpholine: reactive intermediates and products.
Synthesis and aqueous chemistry of alpha-acetoxy-N-nitrosomorpholine: reactive intermediates and products.
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α-乙酰氧基-N-亚硝基吗啉的合成和水化学：反应中间体和产物。
DOI：
10.1021/jo051936z
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Fishbein,JamesC
中科院分区：
文献类型：
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作者：
Zink,CharlesN;Kim,Hyun-Joong;Fishbein,JamesC
以N-乙酰吗啉为原料，在甲醇中阳极氧化合成了α-乙酰氧基-N-亚硝基吗啉（7）。N-亚硝基吗啉酸的产率为55%，经过氰化物交换甲氧基和水解后，比我们原来的10步方法提高了10倍，而且很容易转化为7。在25 °C和1 M离子强度下，在pH 1至12的范围内，对7在水介质中的分解动力学进行了研究。该反应表现出良好的一级动力学在所有的pH值，和图的log ofk 0，缓冲液独立的分解速率常数，对pH值表明，一个pH值独立的反应占主导地位的中性pH值区域，而酸和碱催化的反应占主导地位的低和高pH值区域，分别。反应在中性pH值的存在下，在增加浓度的乙酸根离子的结果中的值ofobsd的减少，到一个明显的限制值一致的共同离子抑制的捕获，和竞争的碱催化水合，一个N-nitrosiazidine离子中间体。在中性pH下，7的反应性比其碳类似物α-乙酰氧基-N-亚硝基哌啶小100倍，这也与这种反应预期的电子效应一致。在实验误差范围内，由非pH依赖性和酸催化反应生成的二硝基苯腙与α-羟基-N-亚硝基吗啉衰变中观察到的二硝基苯腙在种类和数量上相同。在苯并咪唑缓冲液存在下7的衰变导致形成2-（2-（1H-苯并[d]咪唑-1-基）乙氧基）乙醛（12）和2-（1H-苯并[d]咪唑-1-基）乙醇（13）。12的独立合成和研究表明，它在80 °C下在0.1 M DCl中稳定，但在中性和碱性介质中缓慢分解为13，该反应受伯胺和仲胺刺激，但不受叔胺和碳酸盐缓冲液刺激。苯并咪唑捕获研究和12的稳定性研究表明，N-亚硝基吗啉通过α-亚硝基氮的羟基化代谢活化可能导致亚稳态乙氧基乙醛加合物沉积在DNA的杂原子上。
α-Acetoxy-N-nitrosomorpholine (7) has been synthesized starting by the anodic oxidation ofN-acetylmorpholine in methanol. The 55% yield ofN-nitrosomorpholinic acid, after cyanide-for-methoxy group exchange and hydrolysis, is an improvement of ∼10-fold over our original 10-step method, and this is readily converted to7. A study of the kinetics of decomposition of7in aqueous media at 25 °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 ofk0, 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 ofkobsd, to an apparent limiting value consistent with a common-ion inhibition by the capture, and competing base-catalyzed hydration of, anN-nitrosiminium ion intermediate. The 100-fold smaller reactivity of7at neutral pH compared with its carbon analogue, α-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 α-hydroxy-N-nitrosomorpholine. Decay of7in 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 of12indicates that it is stable at 80 °C in 0.1 M DCl, but it slowly decomposes to13in 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 of12indicate the possibility that metabolic activation ofN-nitrosomorpholine by hydroxylation α to the nitroso nitrogen can result in the deposition of a metastable ethoxyacetaldehyde adduct on the heteroatoms of DNA.