金属盐催化合成喹唑啉衍生物的反应机理研究

发布时间：2018-05-27 06:15

本文选题：密度泛函理论 + 羧化偶合　；参考：《山西师范大学》2017年硕士论文

【摘要】：喹唑啉是含有两个氮原子的苯并杂环化合物,是许多药物分子中重要的结构单元。喹唑啉衍生物,通常可用作制备α-肾上腺素接收器、抗痉挛药、抗菌药以及精神镇静剂等药物,在抗癌、抗肿瘤、抗菌、消炎等方面显示出较强的药理活性。基于喹唑啉类衍生物在医药学领域非常广阔的发展前景,因此探索相关类的实验方法已成为化学家关注的焦点。本论文采用密度泛函方法M06对金属盐催化合成喹唑啉衍生物的反应机理进行了详细的理论研究,其中分别选用铯盐和铜盐作为高效催化剂,研究了相应的催化机制,主要内容如下:第一部分介绍了实验上合成喹唑啉类物质的多种方法,以及课题的研究背景和实用意义。第二部分简要介绍了本文进行反应机理研究所用到的计算方法的理论知识,包括从头算自洽方法、密度泛函理论、过渡态理论以及计算软件的应用。第三部分对碳酸铯催化二氧化碳与2-氨基苄腈偶合反应的机理进行了详细的研究。通过密度泛函方法计算研究,这个反应体系有两种可能的反应机理,即碳酸铯先与2-氨基苄腈发生配位(机理一)或者二氧化碳先与2-氨基苄腈发生配位(机理二)。通过能量计算及结构分析,这个反应的最优路径为机理一,主要包括羧化偶合和分子重排两部分。从最优路径中我们可以发现,羧化偶合生成的中间体5b对于后续分子重排反应的顺利进行至关重要,因此被视为关键的活性中间体。在最优路径中,整个催化循环的决速步为4→5b,该步需要经过过渡态TS4-5,即氢迁移和亲核环化同时发生的协同振动六元环构型。这个过程需要克服的能垒最高,为38.0 kcal/mol。本文详细阐述了碳酸铯作为多功能的高效催化特性。此外,本文还对实验中所测得反应体系的最佳反应条件进行了理论验证。第四部分描述了CuI催化邻溴苄胺和苯甲酰胺发生乌尔曼偶联和芳构化等系列串联反应的详细反应机理,最终确定了最优的反应路径。在乌尔曼偶联反应过程中,主要通过置换反应、氧化加成、还原消除等三部分成功构建了C-N键,生成中间体22。在整个乌尔曼偶联催化循环反应中,氧化加成过程(21→15→TS(15/3b)→3b)需要克服的能垒最高,为29.5 kcal/mol,因此我们认为这一步是构建C-N键偶联反应的速控步。活性物质22在碱K_2CO_3作用下,发生去质子环化、芳构化等系列反应,最终生成目标产物2-取代的喹唑啉衍生物。在这部分中,芳构化氧化脱氢过程(29→TS(29/Product)→Product)中,需要克服的活化能最高,为41.0 kcal/mol,因此,我们认为这步即为去质子环化、芳构化等系列反应的速控步。在整个催化循环中,金属盐CuI和碱K_2CO_3共同促进了反应的顺利进行,极大的降低了所需要的活化能。
[Abstract]:Quinazoline is a benzo heterocyclic compound containing two nitrogen atoms and is an important structural unit in many drug molecules. Quinazoline derivatives are usually used to prepare 伪-adrenergic receptors, antispasms, antimicrobials, and mental tranquilizers, showing strong pharmacological activities in anticancer, antitumor, antimicrobial and anti-inflammatory aspects. Based on the broad prospect of quinazoline derivatives in the field of medicine and pharmacy, it has become the focus of chemists to explore the experimental methods of related classes. In this paper, the mechanism of the synthesis of quinazoline derivatives catalyzed by metal salts was studied in detail by density functional method (DFT) M06, in which cesium salt and copper salt were used as high efficient catalysts, respectively, and the corresponding catalytic mechanisms were studied. The main contents are as follows: in the first part, various methods of synthesizing quinazoline are introduced, and the research background and practical significance are also discussed. The second part briefly introduces the theoretical knowledge of the calculation methods used in the study of reaction mechanism, including the self-consistent method from the beginning, density functional theory, transition state theory and the application of calculation software. In the third part, the mechanism of coupling reaction between carbon dioxide and 2-aminobenzylonitrile catalyzed by cesium carbonate was studied in detail. According to the density functional method, there are two possible reaction mechanisms in this reaction system, namely, the coordination of cesium carbonate with 2-aminobenzene nitrile (mechanism one) or the coordination of carbon dioxide with 2-aminobenzene nitrile (mechanism II). Through energy calculation and structure analysis, the optimal path of this reaction is the first mechanism, which mainly includes carboxylation coupling and molecular rearrangement. From the optimal path, we can find that the intermediate 5b generated by carboxylation coupling is very important for the subsequent molecular rearrangement, so it is regarded as the key active intermediate. In the optimal path, the critical velocity step of the whole catalytic cycle is 4 ~ 5b, which requires the transition state TS4-5, that is, the coordinated vibrational six-member ring configuration of hydrogen migration and nucleophilic cyclization. The highest energy barrier to overcome is 38.0 kcal / mol. In this paper, the catalytic properties of cesium carbonate as a multi-functional catalyst are described in detail. In addition, the optimal reaction conditions of the reaction system are theoretically verified. In the fourth part, the mechanism of series of Ulmann coupling and aromatization of o-bromobenzylamine and benzoamide catalyzed by CuI is described in detail, and the optimal reaction path is determined. In the process of Ulmann coupling reaction, C-N bond was successfully constructed by substitution reaction, oxidation addition and reduction elimination. In the whole Ulmann coupling catalytic cycle reaction, the oxidation addition process has the highest energy barrier of 29.5 kcal / mol, which is 29.5 kcal / mol, which is the highest energy barrier to be overcome in the oxidation addition process. Therefore, we consider this step to be the rapid control step for the construction of C-N bond coupling reaction. A series of reactions such as deproton cyclization and aromatization of active substance 22 were carried out under the action of alkali K_2CO_3, and the target product, 2-substituted quinazoline derivative, was finally formed. In this part, in the process of oxidative dehydrogenation of aromatization, the activation energy needed to be overcome is the highest, which is 41.0 kcal / mol. Therefore, we think that this step is a rate-controlled step for a series of reactions, such as deproton cyclization, aromatization and so on. In the whole catalytic cycle, metal salt CuI and alkali K_2CO_3 promote the smooth progress of the reaction and greatly reduce the required activation energy.
【学位授予单位】：山西师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O626;TQ460.1

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