肼与羰基化合物的固相反应及其机理研究

【作者】 于淑媛；

【导师】 刘奉岭；

【作者基本信息】 山东师范大学 ， 有机化学， 2004， 硕士

【摘要】 肼与羰基化合物生成腙及其成环化合物，这是有机合成中的一类重要的反应。其产物由于具有广泛的生物活性和药理活性，而备受人们的关注。如吡唑衍生物有降血压、抗菌、消炎、抗癌等特性；1，3，4-噻二唑杂环类衍生物有抗菌、杀虫、除草、调节植物生长、消炎止痛等广泛的生理活性；近年来，各种α，β-不饱和酮的Mannich反应研究极为活跃，与其相应的苯腙已被用作抗白血病的药；同时，酰腙也是一种很好的配体。因此，该反应的研究具有重要的实际意义。虽然此反应已被广泛的研究，但大多用的是传统的方法：把二者混合，加入乙醇或乙酸，回流一定时间，即可生成腙或其成环化合物。在有机溶液中进行的反应，混合均匀，能量交换稳定，但有机溶剂一般易挥发、有毒、难以提纯、污染环境，给生态环境带来了沉重的负担，不符合“绿色化学”的要求。而固相合成的方法不仅避免了因使用溶剂而造成的能耗高，节约了溶媒，避免了环境的污染、毒害、爆炸等，提高了反应的空间效率；而且它的操作简单：加热、研磨、振荡、微波及超声波辐射都可加速反应，是一种绿色环保的实验方法，也符合当今经济可持续发展战略的要求。因此，我们对肼与羰基化合物的反应进行了固相合成的研究。迄今为止，固相合成此类反应的报道还不多见，采用的固体催化剂或载体也仅限于粘土、氧化硅，氧化铝，分子筛等。就我们所知，关于该反应机理的量子化学研究到目前尚未见到。本文从实验上和理论上对肼与羰基化合物的反应进行了一些探讨，希望对此类反应的深入研究提供实验和理论上的依据。 本文的主要研究内容如下： 1．寻找符合“绿色化学”要求的催化剂或载体 实验上，我们以对硝基苯甲醛（p-O₂N-C₆H₄CHO）和氨基硫脲（NH₂NHCSNH₂）的反应、对硝基苯甲醛（p-O₂N-C₆H₄CHO）和苯甲酰肼（PhCONHNH₂）的反应为研究对象，以不同的物质为催化剂，采用了固相合成的方法，以研磨为合成手段，对反应进行了研究，寻找符合“绿色化学”要求的催化剂或载体。我们发现，除了以上介绍的几种催化剂以外，NH₄OAc、KF，K₂CO₃等也可以催化此反应，而且催化效果不错。同时，我们对改变催化剂的酸碱度会对反应有何影响也作一定的研究。 2．芳香醛中苯环上的取代基对反应有何影响 我们以p-R-C₆H₄CHO（R=NO₂、HO、N（CH₃）₂）分别与氨基硫脲（NH₂NHCSNH₂）、 苯甲酰肼（PhCONHNH2）的反应为研究对象，采用了固相合成的方法，以研磨为合 成手段，对无催化剂时、以NH40Ac和HOAc为催化剂时的反应分别进行了研究。 发现当对位上有吸电子基时，有利于反应的进行；而对位上有供电子基时，则不 利于反应的发生。同时空间效应对反应也有一定的影响。山东师范大学硕士学位论文3.甲醛与甲酞麟的反应机理研究 甲醛与甲酞麟的反应是拨基化合物与酞麟的反应中最简单的，因此我们先对它的反应进行了理论上的研究。 在无催化剂的条件下，本文采用量子化学从头计算的HF/6一31G（D，P）、B3LYpz6一3一。（D，P）[’4]方法，详细研究了甲醛似eoH)和甲酞阱（NHZNHCOH）的反应。在得到产物酞膝的同时，也得到了一个中间体和两个过渡态（见图l）。并通过振动频率的计算，对各平衡构型和过渡态的构型进行了确证。同时，我们在计算得到的反应过渡态的基础上，采用琅C方法，确证了过渡态与反应物、产物的对应关系（见图2）。整个反应过程中，由于活化能EaZ>Eal，所以第二步反应，即由中间体峥产物这一步是整个反应的决定步骤。 在催化剂存在条件下，计算方法与上类似，我们对催化剂的作用过程和反应机理作了合理的推测。在HF水平上，用6一31G..基组计算发现，反应同样存在一个中间体和两个过渡态（图5），基本构型与无催化剂时类似。对各构型进行了优化，并对各过渡态构型进行了琅C计算以确证与反应物及生成物连接的正确性。同样，中间体峥产物这一步是整个反应的决定步骤。4.芳香醛与酞麟的机理研究 前面，我们从实验上对芳香醛与酞麟的的固相反应进行了研究，但它们的反应机理并不清楚，因此，在甲醛与甲酞脐反应的基础上，我们采用AMI、IIF/6一31G**的方法，对无催化剂和有催化剂时，p一R-C6H4CHO（R=N02、H、HO、N（CH3）2）分别与氨基硫脉（NHZNHCS卜任12）、苯甲酞麟（P hcONHNHz）反应的机理进行了研究。发现它们的反应历程与甲醛与甲酞麟的反应历程类似:在得到产物酞踪构型的同时，也得到了一个稳定的中间体和两个过渡态的构型（见图9、13、17、20），并对各过渡态构型进行了琅C计算以确证它们与反应物及生成物连接的正确性。同样，中间体峥产物这一步是整个反应的决定步骤。5.酞膝的异构化反应的理论研究 酞踪存在酮式和烯醇式两种互变异构，可以作为分子开关的模型化合物:如当酞踪处于酮式结构时，分子开关处于“开”状态:当处于烯醇式结构时，则使开关处于“关”状态。可以通过控制酞膝的酮式和烯醉式两种结构的互变实现分子开关的“开”和“关”状态。因此，我们在HF水平上，用6一31G**基组对酞踪的异构化反应进行了研究。计算了异构化反应的过渡态的能量。 全部量子化学计更多还原

【Abstract】 The reaction of the hydrazine with the aldehyde (or ketone) always leads to the formation of a hydrazone, which is an important compound because of its activation in biology and pharmacology. For example, 1,2,4-Triazines have been associated with diverse pharmacological activities such as antihypertension and inhibition of platelets, antileukemic, antiinflammatory, and are potent neuro-protective agents. So this reaction has attracted wide interest. The most common synthetic method of this reaction is the traditional method-reactants react in solution. In this case the reaction may cause many problems because of the present of the organic solvent, such as the environmental pollution. For avoiding the problems, solid-state synthesis are used to sythesize hydrazone in this thesis.Since solid-state synthesis has many advantages, such as manipulating easily and less pollution to environment, it develops very quickly. Recently, several new techniques, such as microwave, accelerate the development of the solid-state synthesis. In one word, solid-state synthesis is a g ood method and accords with the demand of "Green Chemistry".Althought there are many reports with regarding to the sythesis of hydrazone, to the best of our knowledge theoretical studies of the mechanism of this reaction has never b een r eported yet. In t his t hesis, t he s olid-state s ynthesis h as b een u sed t o t he reaction of the hydrazine with the aldehyde, and the mechanism of this reaction has been studied by using the ab initio and the density function methods. The thesis consists of five parts.1. Search some sood satalysts that are accord with the demand of "Green Chemistry".In the experiment, we introduced a method of solid-state synthesis: grinding the two solid reactants and catalyst together in a cornelian mortar. The reactants are p-O2N-C6H4CHO, NH2NHCSNH2, PhCONHNH2. We find some good catalysts such as NH4OAc, KF, K2CO3 except AhOs, silical gel, kaoline and so on, some of them have been reported.2. The influence of the group in phenyl to the reactionThe reactants are p-R-C6H4CHO (R=NO, H, HCK N(CH3)2) and NH2NHCSNH2, PhCONHNH2. We have studied the reaction at several condition of without catalyst or not. The results showed that the group in phenyl is great influence to the reaction.3. The mechanism of the reaction of HCHO and HCONHNH2The mechanism of the reaction of HCHO and HCONHNH2 without catalyst hasbeen examined in detail by ab initio method at HF/6-31G** level and DFT method at B3LYP/6-31G** level, obtained a stable intermediate (3) and two transition states (6 and 7). The theoretical analysis indicated that the intermediate geometry (3) is a stable structure and the transitions state (6 and 7) are all right. The potential profile for this reaction was obtained by the calculation of IRC. And we conclude that the second process is a key process of the whole reaction,At the same time, the mechanism of the reaction of HCHO and HCONHNH2 with catalyst has been also examined by ab initio method at HF/6-31G** level too, and a stable intermediate (8) and two transition states (9 and 10) have been obtained. The theoretical results have proved that the catalyst can reduce the activation energy and can accelerate the reaction. NKiAc is the best catalyst among all of catalysts we researched.4. The mechanism of the reaction of p-R-C6H4CHO(R=NO2, H, HO, N(CH3)2), and NH2NHCSNH2 or PhCONHNH2.The mechanism of the reaction of p-R-CeRtCHO (R=NO2, H, HO, N(CH3)2), and NH2NHCSNH2 or PhCONHNH2 with the catalysts or not have been studied at AMI level. The result shows that its mechanism is similar to the mechanism of the reaction of HCHO and HCONHNH2’. a stable intermediate and two transition states. The theoretical analysis also indicated that the group of phenyl has some influence at certain extent.5. The theoretical study of the isomerization of p-R-C6H4CH=NNHCSNH2 and p-R-C6H4CH=NNHCOPh (R=NO2, H, HO, N(CH3)2)The mechanism of the isomerization of p-R-C<sH4CH=NNHCSNH2 and p-R-C6H4CH=NNHCOPh (R=NO2, H, HO, N(CH3)2 ) have be更多还原