KINETICS AND MECHANISM OF THE DECOMPOSITION IN AQUEOUS-SOLUTIONS OF 2-(HYDROXYAMINO)IMIDAZOLES
KINETICS AND MECHANISM OF THE DECOMPOSITION IN AQUEOUS-SOLUTIONS OF 2-(HYDROXYAMINO)IMIDAZOLES
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DOI：
10.1021/ja00203a018
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发表时间：
1989-10-11
影响因子：
15
通讯作者：
MCCLELLAND, RA
中科院分区：
文献类型：
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作者：
BOLTON, JL;MCCLELLAND, RA
本文报道了1-X-2-（羟氨基）咪唑2在水溶液中转化为1-X-2-氨基-4,5-二氢-4,5-二羟基咪唑离子的动力学研究，取代基为X = H （2a）、CH3 （2b）、CH2CH2Br （2c）、CH2CHOHCH2OCH3 （2d）、CH2CONHCH2CH2OH （2e）和CH2CHOHCH2NC5H10 （2f）。提出了一种中性形式的咪唑作为动力学活性物质，在没有催化（OH-作为离去基）和水合氢离子和缓冲酸的催化下进行N-O键的限速裂解的机制。这些反应产生共振稳定的咪唑鎓离子7，它与水和加入的亲核试剂反应生成产物。与机理一致的观察结果包括以下方面：(i) 1,3-二甲基-2-（羟氨基）咪唑离子是一种不能转化为活性中性形式的质子化2的模型，是非活性的。（ii）在98%的产物与添加的亲核试剂谷胱甘肽（GSH）反应的条件下，速率常数没有变化。（iii） 2b-2e的速率-pH曲线具有高pH和低pH区域，其中速率常数与pH无关，这是机理所要求的。（iv）动力学分析得到的2bH+的酸度常数与核磁共振波谱法得到的酸度常数相同。(v) N-1取代基的作用与缺电子中间体的形成一致。（vi）溶剂极性降低导致N-O非催化异裂解速率常数降低，m值约为。0.5. 提出的机制是n -苯基羟胺到对氨基酚的班贝格重排的杂环类似物。然而，2-咪唑体系的反应性更强，这一特征可以根据。sigma来预测。+值为该组。通过类比缩醛水解，一个稳定的阳离子中间体的产生被认为是负责一般酸催化的存在。氮离子7b与谷胱甘肽阴离子和水的反应比kGS:kw为5倍。105 m - 1。这意味着kw必须小于104s -1，因为与硫醇阴离子的反应不能比扩散发生得快。与其他氮离子和碳离子的kw值比较表明，咪唑氮离子是一种寿命特别长的离子。已知大多数2-硝基咪唑药物的还原会导致与DNA的共价结合以及细胞内谷胱甘肽的消耗；在本调查结果的背景下，考虑了氮离子负责的可能性。
A kinetic study is reported of the reaction in aqueous solution whereby 1-X-2-(hydroxyamino)imidazoles 2 are converted into 1-X-2-amino-4,5-dihydro-4,5-dihydroxyimidazolium ions, with substituents X = H (2a), CH3 (2b), CH2CH2Br (2c), CH2CHOHCH2OCH3 (2d), CH2CONHCH2CH2OH (2e), and CH2CHOHCH2NC5H10 (2f). A mechanism is proposed with the neutral form of the imidazole as the kinetically active species, undergoing rate-limiting cleavage of the N-O bond with no catalysis (OH- as leaving group) and with catalysis by the hydronium ion and by buffer acids. These reactions produce a resonance-stabilized imidazolenitrenium ion 7, which reacts with water and added nucleophiles leading to products. Observations consistent with the mechanism include the following: (i) The 1,3-dimethyl-2-(hydroxyamino)imidazolium ion, a model of protonated 2 that cannot be converted to the reactive neutral form, is unreactive. (ii) Under conditions where 98% of the products are due to reaction with the added nucleophile glutathione (GSH), there is no change in rate constant. (iii) The rate-pH profiles for 2b-2e have regions at high pH and low pH where the rate constants are independent of pH, as required by the mechanism. (iv) The acidity constant for 2bH+ obtained through kinetic analysis is the same as that obtained by NMR spectroscopy. (v) Effects of the N-1 substituents are consistent with the formation of an electron-deficient intermediate. (vi) Decreasing solvent polarity results in a decrease in the rate constant of the uncatalyzed N-O heterolysis, with an m value of .apprx. 0.5. The proposed mechanism is a heterocyclic analog of the Bamberger rearrangement of N-phenylhydroxamine to p-aminophenol. The 2-imidazole system is however more reactive, a feature shown to be predictable on the basis of the .sigma.+ value for this group. Through analogy with acetal hydrolysis, the production of a stabilized cationic intermediate is suggested to be responsible for the presence of general acid catalysis. The ratio kGS:kw for reactions of the nitrenium ion 7b with glutathione anion and water is 5 .times. 105 M-1. This implies that kw must be less than 104 s-1, since the reaction with the thiol anion cannot occur faster than diffusion. A comparison with kw values for other nitrenium ions and carbenium ions shows that the imidazolenitrenium ion is an exceptionally long-lived species. Most reduction of 2-nitroimidazole drugs is known to result in covalent binding to DNA as well as in depletion of intracellular glutathione; the possibility that the nitrenium ion is responsible is considered in the context of the results of this investigation.