【作者】 陈梓湛；

【导师】 邹新琢；

【作者基本信息】 华东师范大学 ， 有机化学， 2010， 博士

【摘要】 旨在合理使用化学品、减少危险物质及环境污染的绿色化学于20世纪下半叶迅速兴起,成为了当前化学研究的热点和前沿。在此背景下,人们有必要以新的视角重新审视和思考有机化学中研究历史最悠久的基础反应之一——有机卤代反应。一方面,有机卤代物是一类有用的化合物,它们被广泛应用、发挥着重要作用。另一方面,尽管有机化学家已经做出了不懈的努力,但在众多有机化学家、政府安全生产管理部门、化工企业乃至普通大众看来,卤代反应往往是最不符合绿色化学要求的有机化学反应之一。一些卤代反应常用的反应试剂、进行卤代反应研究和生产的场所往往是政府安全生产管理部门的重点监控对象。因此,开展各种绿色有机卤代反应的研究,有重要的学术和实际意义。本文从绿色化学的角度出发,以低毒、廉价的通用商品——二卤(溴和氯)海因作为卤代试剂,以苯乙酮等化合物为主要反应底物,系统考察羰基化合物α位的溴代和氯代反应。在以上溴代和氯代反应的基础上,进一步考察α-氟代苯乙酮的绿色合成方法,探索用亲核氟化策略打通一条用苯乙酮类化合物或α-卤代苯乙酮绿色合成α-氟代苯乙酮类化合物的新通道。本文希望为绿色有机卤代反应的学术研究和应用提供一些理论和实际参考。全文共分四个章节,具体内容如下：第一章,首先简述了绿色化学中的基本内容及其在“试剂绿色化”、“高选择性反应”、“高效合成方法”和“绿色反应介质”四个方面的研究进展；然后按照不同的试剂,对溴代、氯代和氟代反应的现状和研究进展进行了部分综述。在此基础上,阐明了本文思路。第二章,较系统地考察了二溴海因在多种绿色反应条件下对羰基化合物的溴代反应。首先,将对甲苯磺酸-甲醇溴代体系的应用范围拓展至脂肪族酮类化合物和β-酮酯类化合物。然后,发展了水-醇-酸可重复利用的溴代反应体系,该体系可用于酮类和部分芳香族化合物的溴代反应,有助于减少强酸性物质的排放。之后,发展了在四丁基溴化铵与对甲苯磺酸配制而成的新低共熔物中进行的溴代反应,以75～80%的产率得到α-一溴代苯乙酮类化合物。其后,发展了以离子交换树脂为催化剂无溶剂状态下的溴代反应。接着,在硅胶-甲醇条件下实现了非酸条件下的溴代,快速地以90～96%的高产率直接得到一溴代产物。最后,在分析比较各种绿色溴代反应的基础上,利用低共熔物中的溴代反应,进行重要抗菌剂噫醚唑的合成,以97%的高产率直接得到中间体4-(4’-氯苯氧基)-2-氯-α-溴苯乙酮,成功地替代了液溴的的使用,在此基础上,经过5步合成反应,成功得到最终产物嗯醚唑。第三章,利用二氯海因,通过比较接近绿色化学要求的反应条件,发展高选择性氯代反应。首先,利用氯化胆碱与对甲苯磺酸配制而成的新低共熔物,考察了低共熔物中苯乙酮类化合物的α-一氯代反应反应,以75～82%的产率得到一氯代苯乙酮类化合物。然后,在低共熔物一氯代反应的基础上,发展了快速、高效的羰基化合物α,α-二氯代反应,该反应仅需45分钟就以86～96%的高产率、高选择性地得到相应的二氯代物。其后,利用硅胶为催化剂,甲醇为溶剂发展了快速、高效的羰基化合物a-一氯代反应,以92～98%的高产率、高选择性地直接得到α-一氯代苯乙酮类化合物,该反应的机理可能与带有0-C1结构的中间体形式有关。本章发展的低共熔物催化二氯代反应与硅胶催化一氯代反应互为补充,形成了一套解决氯代选择性问题的绿色方案。最后,水相溴代反应的基础上,发展了水相中和普通无机盐催化下的三个苯环氯代反应,取得了良好的结果,三种方法互为补充可以使二氯海因应用于不同活性的芳香族化合物,是一套有效的、成本低廉的、比较接近绿色化学要求的芳香族化合物氯代方案。第四章,利用含氟盐,以亲核氟化反应为基础,发展了一组包括一锅法在内的氟化方法。首先,以聚乙二醇-400为催化剂,利用KF,在乙腈中成功地合成了α-氟代苯乙酮类化合物。然后,提出了以TBAF·3H20/ZnF2/KF为混合氟源的亲核氟化方法,以60～90%的产率得到氟代苯乙酮类化合物。接着,在亲核氟化反应的基础上,利用氯化胆碱与对甲苯磺酸配制而成的新低共熔物,实现了从苯乙酮类化合物直接合成α-氟代苯乙酮类化合物,氯代与氟代反应在同一个反应瓶内进行,以亲核的策略实现了通常需要亲电氟化试剂才能完成的α位直接氟代。其后,以溴代缩酮类化合物为底物,进行亲核氟化反应,可直接得到α-氟代苯乙酮类化合物,并进一步发展了新低共熔物帮助下的苯环亲核氟化反应；最后,利用氯化胆碱与对甲苯磺酸配制而成的新低共熔物,合成了苯乙酮的亚胺和α-氟代苯乙酮的亚胺,这两种物质是医药、农药的开发中两个重要的化合物。更多还原

【Abstract】 In the second half of the20th century, green chemistry, that aims to improve the reasonable usage of chemicals and reduce hazardous substances and environmental pollution, rised rapidly and became the focus and cutting edge of chemical research. Based on this background, it is necessary for people to re-think and re-examine the organic halogenation from a new point of view, which is one of the oldest basic reactions in the research history of organic chemistry. On one hand, organic halides are a class of useful compounds that are extensively used to play important roles in many fields. On the other hand, halogenation is viewed as one of the reactions that can not meet the requirements of green chemistry by many organic chemists, governmental safety management, chemical companies and the general public. Some reagents that are usually used in the halogenation and some places where halogenation reactions are carried out for research or manufacturing are the key monitoring targets of the governmental safety department. So it has academic and practical significance to research various kinds of green halogenations.From the point of view of green chemistry, a-brominations and chlorinations of carbonyl compounds are systematically studied in this dissertation.1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) and1,3-dichloro-5,5-dimethylhydantoin (DCDMH) that are cheap general merchandises with low toxicity are used as halogenating reagents and acetophenones are selected as the main tested substrates in this study. On the basis of the brominations and chlorinations mentioned above, green methods to prepare a-fluoroacetophenones are also studied to find a new way of conversion of acetophenones or a-bromoacetophenones to a-fluoroacetophenones. This dissertation may provide some theoretical and practical references for academic research and application of green halogenations.This dissertation is divided into four chapters and the details are as follows:Chapter One:firstly, the basic elements of green chemistry are outlined and the research progresses in four fields that are green reagents, high selective reactions, high efficient reactions and green media are described. Secondly, the current situation and research progresses of brominations, chlorinations and fluorinations are partly introduced according to the different types of halogenating reagents. On this basis, the main idea of this dissertation is clarified.Chapter Two:the brominations of carbonyl compounds using DBDMH in various green media are systematically studied. Firstly, aliphatic ketones and β-ketoesters are tested to extend the application scope of the p-TsOH-CH3OH brominating system. Secondly, a reusable brominating system that makes use of water, methanol and acid is developed and some carbonyl compounds and aromatic compounds are tested. This system can reduce the emissions of strong acids. Thirdly, a bromination reaction that is carried out in a new deep eutectic solvent (DES) that prepared from tetrabutyl ammonium bromide (TBAB) is developed and the yields of a-bromoacetophenones are75-80%. Fourthly, a no-solvent bromination reaction catalyzed by an ion exchange resin is developed. Fifthly, a rapid non-acid brominating reaction is realized, in which silica gel and methanol are used and the brominated products are obtained with the yields of90～96%. Finally, on the basis of analysis of these green brominations, the bromination in DES is used in the synthesis of an important antimicrobial, difenoconazole. The intermediate,1-(4-(4-chlorophenoxy)-2-chlorophenyl)-2-bromoethanone is obtained in high yield of97%by the new method that replaces the usage of elemental bromine. On the basis of this new method, difenoconazole is finally prepared by a five-step routine.Chapter Three:Some chlorination reactions with high selectivity that are close to the requirements of green chemistry are developed by DCDMH. Firstly, a-monochlorination of acetophenones in a new DES that is prepared from choline chloride and p-TsOH is studied and a-chloroacetophenones are obtained in the yields of75～82%. Secondly, on the basis of the a-monochlorination in DES, rapid α,α-dichlorination with high efficiency is developed and after only45min, a,a-di chloroacetophenones are obtained in high yields of86～96%with high selectivity. Thirdly, a rapid a-monochlorination of carbonyl compounds with high efficiency is developed, in which silica gel is used as catalyst and methanol is used as solvent, and a-chloroacetophenones are obtained in high yields of92～98%with high selectivity. The intermediate with O-Cl structure may involve in the mechanism of this a-mono chlorination. The a,a-dichlorination catalyzed by DES and a-mono chlorination catalyzed by silica gel are complementary and they forms a set of solutions for the selectivity of chlorination. Finally, on the basis of bromination in water, three chlorinations of aromatic compounds that are carried out in water or catalyzed by common salt are developed and the yields of chlorinated compounds are not bad. These three chlorinations are also complementary and they are also an effective, cheap and green set of solutions for aromatic chlorination.Chapter Four:on the basis of nucleophilic fluorination, a group of fluorinations that include a one-pot method are developed using fluoride salt. Firstly, a fluorination is realized using PEG-400as co-solvent, KF as nucleophilic source and acetonitrile as solvent and a-fluoroacetophenones are obtained. Secondly, a new nucleophilic fluorinating method that use TBAF-3H2O/ZnF2/KF as mixed fluorinating source is realized and a-fluoroacetophenones are obtained in the yields of60～90%. Thirdly, on the basis of the two nucleophilic fluorinations mentioned above, a new method in DES that formed between choline chloride and p-TsOH is realized and a-fluoro acetophenones are obtained directly from acetophenones by nucleophilic strategy. The chlorination and fluorination are carried out in just one flask, which is commonly realized by electrophilic reagents. Fourthly,1-(2-bromo-1,1-dimethoxyethyl) benzenes are tested in the nucleophilic fluorination and a-fluoroacetophenones are obtained directly. Further, an aromatic fluorination in a new DES is also developed. Finally, N,N’-bis(1-phenylethylidene)ethane-1,2-diamines and N-(2-fluoro-l-phenyl ethylidene)-1-phenylethanamine are prepared by DES that formed between choline chloride and p-TsOH. These two compounds are important in the R&D of medicine and pesticide.更多还原