【作者】 张凯；

【导师】 陆嘉星；

【作者基本信息】 华东师范大学 ， 物理化学， 2011， 博士

【摘要】 由于传统化学工业对人类赖以生存的地球环境的污染严重性,绿色化学日益兴起。绿色化学要求从本源上杜绝或减少废液、废气、废渣排放,包括消除有害物质、生产环境友好的产品以及生产过程的绿色化等。CO2是最主要的温室气体,将其活化利用不仅可以控制温室气体排放,减缓环境污染,而且可以利用廉价而且丰富的C1资源合成重要的化工产品。但由于CO2热力学性质稳定,如何将其活化成为了研究利用的难点。电化学合成反应是通过反应物在电极上得失电子实现的,不用额外添加氧化剂与还原剂,减少了物质消耗,从本质来说,有机电合成很有可能会消除传统有机合成产生环境污染的根源,是一种新型的“绿色”合成方法。α-羟酸类化合物是一类重要的非兹消炎镇痛药物合成中间体,关于它们电合成的研究报道虽然很多,但普遍存在着羧化产物产率不高、使用有害汞、铅电极材料或价钱较高的Pt电极等缺点。氨基酸作为构成生物体蛋白质并同生命活动有关的最基本的物质,其传统的合成方法有斯瑞克法、赫尔-乌尔哈-泽林斯基α-溴化法、盖布瑞尔法、丙二酸酯法,合成过程相对复杂繁琐,有时还需要在封管或高压釜内进行,不符合“绿色化学”的合成宗旨。共轭双烯与CO2分子的电羧化交联反应报道很少,此类羧化反应的特点同时也是难点在于产物结构分布规律很不明显。由于得失电子本身不具备手性,通过电化学手段有选择性的活化固定二氧化碳分子从理论上讲是不可能的,从而必须借助额外的诱导手段,通常情况下,采用手性溶剂和支持电解质诱导时所需手性物质剂量比较多,而采用吸附型手性电极、共价键型手性或者聚合物薄膜手性修饰电极诱导时只需要催化剂量的手性诱导剂。不对称电羧化反应具有极大的挑战性,到目前为止,只有少数几例成功依靠底物分子自身手性结构诱导完成的不对称电羧化反应。将电化学这一绿色方法直接用于活化固定温室气体CO2合成α-羟酸酯、双酸酯、N-取代α氨基酸衍生物等有机化合物相对于传统有机合成方法具有条件温和、步骤简单易控、选择性高等优势,特别是利用手性电极诱导方式以芳香酮等潜手性物质为底物进行不对称电羧化反应的研究在国内外几乎处于空白状态,因而具有非常好的应用前景。本论文的主要内容如下：(1)含碳氧不饱和双键芳香族化合物的电羧化反应研究在0.1molL-1TEABF4-DMF溶液中,采用GC-Pt-Ag/AgI/0.1mol L-1 TBAI三电极体系对系列芳香族羰基化合物包括苯甲醛、对甲氧基苯甲醛、苯乙酮、对甲基苯乙酮、对甲氧基苯乙酮、对氰基苯乙酮、苯丙酮、对甲基苯丙酮、二苯甲酮的循环伏安行为进行了比较研究,通过计算比较各底物电化学行为参数,讨论了取代基效应影响规律。在一室型电解池中,以Mg为牺牲阳极,不锈钢、钛、铜、镍和银为工作电极,以对甲氧基苯乙酮为原料,通过电化学方法活化固定二氧化碳合成了重要的有机合成中间体2-羟基-2-(4-甲氧基苯基)-丙酸甲酯。实验中考察了各个反应条件包括支持电解质种类、电极材料、电流密度、电解电量和反应温度对电羧化反应的影响。在饱和了CO2的DMF溶液中,0.1mol L-1TEABr为支持盐,不锈钢电极为工作电极,控制温度为25℃,恒定电流密度为5.0 mA cm-2的条件下电解至理论电量产率达到63%。在玻碳电极上,运用循环伏安法研究了对甲氧基苯乙酮的电化学行为,推测其电羧化过程符合ECE(电子传递反应-化学反应-再电子传递反应)反应机理。在一室型电解池中,以对甲基苯丙酮为底物,常压下采用电化学方法活化固定CO2合成了2-羟基-2-对甲苯基-丁酸甲酯。在恒电位电解的条件下首先考察了溶剂和支持电解质种类对电羧化反应的影响,进而又在恒电流电解条件下考察了电极材料、电流密度(电解电位)、通电量、温度对羧化产率的影响。以廉价镍为工作电极,在0.1molL-1TEABr-DMF溶液体系中恒定电流密度为5.0mA cm-2电解至电量为2.8F mol-1,反应温度控制在-10℃,羧化产率高达97%。在玻碳电极上,运用循环伏安法研究了对甲氧基苯乙酮的电化学行为,推测其电羧化过程符合ECE(电子传递反应-化学反应-再电子传递反应)反应机理。(2)不饱和碳氧双键化合物的不对称电羧化反应研究利用Chiralpak AD-H手性柱建立了四种重要的解热镇痛药物合成中间体苯羟乙酸(扁桃酸)、2-苯基-2-羟基丙酸(阿卓乳酸)、2-羟基-2-(4-甲氧基苯基)丙酸、2-羟基-2-(4-甲基苯基)丁酸的高效液相色谱手性拆分方法。以正己烷-乙醇-三氟乙酸(TFA)为流动相体系,通过调整正己烷与乙醇的比例、改变醇的种类以及TFA的含量着重探讨了待测组分与手性固定相(CSP)之间的作用以及分离规律,同时也实现了四种α-羟酸对映异构体的完全分离。在一室型电解池中,在辛可尼定和辛可宁两种生物碱的诱导作用下,以潜手性的苯乙酮为原料一步法即合成了分别以R和S构型为主的具有光学活性的医药合成中间体2-羟基-2-苯基丙酸(阿卓乳酸)。根据生物碱在阴极表面吸附作用的不同,实验中首先考察了不锈钢、铂及铜三种电极材料对苯乙酮不对称电羧化反应的影响,进而在辛可尼定和辛可宁两种生物碱的诱导下,考察了生物碱与辅助剂正丁醇比例、反应溶剂、支持电解质种类、温度、电流密度和通电量对不对称电羧化产率及光学收率的影响,其中正丁醇对有效完成不对称诱导作用意义重大。根据分析比较加入诱导剂及辅助剂前后苯乙酮的电化学行为,对苯乙酮不对称电羧化反应可能的诱导机理进行了推导。(3)脂肪族共轭双烯类化合物的电羧化研究在温和条件下,首先研究了山梨酸甲酯双烯结构活化固定常压CO2的电羧化反应,分离得到的三种产物产率受到溶剂、电极材料、电流密度、电解电量、反应温度等各个实验条件的影响。采用不锈钢为工作电极,镁为牺牲阳极,在0.1mol L-1TBAP-DMF溶液体系中控制电流密度为5.0mA cm-2,电解至理论电量,温度为-10℃,反应总产率最高可达47%,同时羧化产率达到26%。在山梨酸甲酯优化条件基础上,又对其它含有不同取代基团的共轭双烯结构3-甲基-1,3-戊二烯、2,4-二甲基-1,3-戊二烯、2,5-二甲基-2,4-己二烯进行了电羧化研究比较,结果3-甲基-1,3-戊二烯电羧化产物唯一,2,4-二甲基-1,3-戊二烯电羧化得到两种难以完全分离的同分异构体,2,5-二甲基-2,4-己二烯由于其强大的推电子效应几乎不能被还原。以玻碳为工作电极,采用循环伏安法对四种共轭双烯结构在通入二氧化碳前后的电还原行为进行了研究,并且对不同的共轭双烯结构电羧化可能的机理进行了推导,同时,采用Guassian03W软件对产物进行了半经验模拟能量计算,为推导的机理进一步提供了理论佐证。(4)对甲氧基亚苄基胺乙酸甲酯的电羧化反应研究以饱和了CO2的DMF为溶液,Mg为牺牲阳极,首次研究了不饱和C=N双键中氮原子被脂肪族乙酸甲酯基取代之后的对甲氧基亚苄基胺乙酸甲酯的电羧化反应。该反应得到C-羧酸化、N-羧酸化、C,N-羧酸化三种产物,其产率分布受到各个反应条件的影响,包括支持电解质种类、电极材料、电流密度、电解电量、反应温度等。在初步优化反应条件下,总羧化产率达到33.5%,同时C-羧化,N-羧化,C,N-羧化产物比例为14.1：5.7：13.8。以玻碳为工作电极,运用循环伏安法对甲氧基亚苄基胺乙酸甲酯的电化学还原行为进行了研究,推测了其电羧化生成三种羧酸化产物的机理。更多还原

【Abstract】 In order to avoid the severe pollution caused by the traditional chemical industry to the human-reliable earth environment, the green chemistry gradually becomes more and more promising. Because green chemistry is in principle based on the abatement of the waste of solution, gas and solid including all the harmful trashes and production of environmental benign compounds together with a green process. Carbon dioxide is the most dominating greenhouse gas. However, it can be propsed as the most abundant and cheapest C1 building block in the organic synthesis from an opposite view. Therefore great effort has been placed toward fixation of CO2 to reduce the greenhouse effect and improve the catastrophic events. However, owing to the high thermodynamic stability of CO2, effective activation of it has become a problem. Electrochemistry can work this out by the electron transfer between the electrode and substrates without additional redox reagents. Essentially, organic electrosynthsis would probably eliminate the environmental pullation from the source to be a new "green" synthetic technology.a-Hydroxy acids (AHAs) has been widly used to synthesize one impartant class of nonsteroidal anti-inflammatory pharmaceutical. There have been many reports about electrosynthesis of AHAs, however, the carboxyaltion yields are not always very satisfying and need of using highly toxic mercury/lead or the costly platinum cathode material makes this process less attractive and somewhat troublesome from the view point of industry. Amino acids are used as an elementary substrate to compose the necessary protein to biological movement which could be synthesized via traditional organic reactions such as Hell-Volhard-Zelinsky reaction, Gabriel reaction or using propanedioic acid eater as the reactant. The synthetic procedures are comparatively complex and fussy and some of the reactions need performing in a close vessel or autoclave which definitely goes against the principles of green chemistry. There are only a few examples of electrocarboxylation of conjugated dienes in the presence of CO2, the difficulty and characteristic of which is the disorder of the distribution law of aimed products.Asymmetric electrochemical carboxylation has been challenging for many years due to the diffculty in selective fixation of the small molecule of carbon dioxide since it has been known that enantioselective electron transfer is not possible in principle and the electron cannot possess chirality. Usually, chiral solvents and supporting electrolytes need large amounts of optically active materials inherently. By contrast, only catalytic amounts of chiral materials are necessary when chiral electrodes including chiral electrode suface-active materials, chiral chemically modified electrodes and optically active polymer-coated electrodes are used as the chiral auxiliary. As far as we hnow, only a few asymmetric electrochemical carboxylation was reported up to now.The study on electrochemical activation and fixation of greenhouse gas of carbon dioxide to a-hydroxy acids, dicarboxylated acid ester, N-substituted amino acid derivative, etc. possess series of advantaged of mild conditions, simple operation, high selectivity compared to traditional ouganic synthesis. Specially, application of the chiral electrode in asymmetric electrocarboxylation of prochiral sustrate is particularly new all over the world with a very promising prospect.The details are given as follows:(1) Electrocarboxylation of unsaturated aromatic compounds including C=O bondComparative electrochemical behavior of series of aromatic aldehyde or ketone including benzaldehyde,p-methoxybenzaldehyde, acetophenone, p-methoxyacetophenone,p-methylacetophenone,4-cyanoacetophenone, propiophenone,p-methylpropiophenone, benzophenone were studed by cyclic volmmetry in the solution of 0.1 mol L-1 TEABF4-DMF in a conventional three-electrode cell with the glassy carbon disk as the working electrode, a platinum spiral as the counting electrode and Ag/AgI/O.1mol L-1 TBAI as the reference electrode. Potential law was then investigated by calculating respective electrochemical parameters of various substrated influenced by distinct substitution effects.In one compartment electrochemical cell equipped with magnesium as the sacrificial anode, stainless steel (Ss), titanium (Ti), copper (Cu), nickel (Ni), silver(Ag) as the cathode and in the DMF solution saturated with carbon dioxide, the aimed product 2-hydroxy-2-(4-methoxy-phenyl)-propionic acid methyl ester was electrosynthesized via electrochemical fixation of carbon dioxide. Under the various controlled current conditions, electrocarboxylation of p-methoxylacetophenone was measured as a function of supporting electrolytes, cathode materials, the current density, passed charge and temperatures. After systematic optimization, the maximal yield of 63% was achieved when the electrolysis was carried out at a controlled current density of 5.0 mA cm-2 until theoretical charge passed through the cell. Furthermore, the electrochemical behavior of p-methoxylacetophenone was studied in a three-electrode system, with a glassy carbon as the working electrode (d=3.0 mm), a platinum spiral (Pt) as the counter electrode and Ag/AgI/0.1 mol L-1 TBAI in DMF as the reference electrode. The possible electrocarboxylation mechanism was put forward accordingly, which suggested a typical ECE (one electron reduction chemical reaction-another electron reduction) process.In one compartment electrochemical cell 2-hydroxy-2-p-tolyl-butyric acid methyl ester was electrosynthesized by electrochemical carboxylation of p-methylpropiophenone in the presence of carbon dioxide. By potentiostatic electrolysis, the electrocarboxylation was first studied by varying the solvent and the kind of supporting electrolyte. Then other conditions including cathode materials, the current density, passed charge and temperatures were further studied under galvanostatic control. As a result, the excellent yield of 97% was obtained when the electrolysis was carried out in DMF-0.1 mol·L-1 tetraethylammonium bromide (TEABr) solution using cheap and environmentally benign nickel as the cathode under a controlled current density of 5.0 mA·cm-2 until 2.8 F·mol-1 charge passed through the cell at-10℃. The electrochemical behavior of p-methoxylacetophenone was studied on the glassy carbon electrode by cyclic voltammetry and the probable mechanism was proposed accordingly, which suggested a typical ECE (one electron reduction-chemical reaction-another electron reduction) process.(2) Asymmetric electrocarboxylation of unsaturated aromatic ketone including C=O bondThe chiral HPLC methods were established for the enantiomeric separation of four kinds of important anti-inflammatory medical intermediates: phenylhydroxyacetic acid (mandelic acid) 2-hydroxy-2-phenyl propanoic acid (atrolactic acid),2-hydroxy-2-(4-methoxyphenyl) propanoic acid,2-hydroxy-2-(4-methylphenyl) butyric acid. Based on the mobile phase consisting of n-hexane, ethanol and trifluoroacetic acid (TFA), the functionary law and separation rules between the separated enantiomers and the chiral stationary phase were specially discussed by varying the ratio of n-hexane/ethanol, the kind of alcohol and different proportions of trifluoroacetic acid additive. Furthermore, the corresponding enantiomers of the four kinds ofα-hydroxy acids were completely separated on the chiralpak AD-H column with optimal chromatographic profiles.A novel method of selective fixation of carbon dioxide was developed in this work. In an undivided cell the pharmaceutically active 2-hydroxy-2-phenylpropionic acid (atrolactic acid) has been produced from prochiral acetophenone in the presence of two kinds of chiral alkaloids, cinchonidine and cinchonine, acting as the inductors which were inclined to afford R and S products respectively. Since the alkaloid has a strong tendency to adsorb to the surface of the cathode, three different cathode materials (stainless steel, platinum, copper) were applied in the process of asymmetric electrochemical carboxylation. Using cinchonidine and cinchonine as the inductors, the electrocarboxylation yield as well as the ee value of the aimed 2-hydroxy-2-phenylpropionic acid was also measured as a function of the concentration ratio of the alkaloid to the cocatalyst of butanol, supporting electrolyte, temperature, charge passed, current density, solvent. In particular, the butanol may play a critical role of helping to accomplish the asymmetric electrocarboxylation induction. From further analysis of cyclic voltammograms of acetophenone before and after addition of the alkaloid and butanol, a possible induction mechanism was put forward accordingly. (3) Electrocarboxylation of aliphatic conjugated dienes including C=C bondUnder mild condtions, electrocarboxylation of methyl sorbate chosen as the. modal diene was first investigated by activation and fixation of greenhouse gas of atmospheric carbon dioxide. The yields of three isolated products were influenced by various experimental conditions including solvent, cathode material, current density, passed charge and temperature. After initiall optimization, the overall yield of 47% with the 26% carboxylated yield could be achieved when the electrolysis was carried out in the 0.1 mol L-1 TBAP-DMF at a controlled current density of 5.0 mA cm-2 until theoretical charge passed through the cell at-10℃using stainless steel as the working electrode and sacrificial magnesium as the anode.On the basis of optimized condition of electrocarboxylation of methyl sorbate electrochemical carboxylation of three other conjugated diene strutures including 3-methyl-1,3-pentadiene,2,4-dimethyl-1,3-pentadiene,2,5-dimethyl-2,4-hexadiene with different substitution effect was comparatively studied. As a result, electrocarboxylation of 3-methyl-1,3-pentadiene gave exclusive product, electrocarboxylation of 2,4-dimethyl-1,3-pentadiene gave two isomeric carboxylated compounds which were hard to isolate and electrocarboxylation of 2,5-dimethyl-2,4-hexadiene even could not be realised due to its strong electron-danating effect.The electrochemical behavior of four conjugated dienes was then studied on the glassy carbon electrode by cyclic voltammetry and the probable mechanisms were proposed accordingly. Furthermore, some gas-phase geometry optimizations and semiempirical calculations have been done using Gaussian03W program, which definitely offered some corroboration to the speculated mechanism.(4) Electrocarboxylation of [(4-methoxy-benzylidene)-amino]-acetic acid ester including C=N bondIn the undivided cell, electrocarboxylation of [(4-methoxy-benzylidene)-amino]-acetic acid ester, in which the nitrogen atom of the C=N was substituted by the aliphatic group was investigated for the first time in the DMF solution saturated with CO2 using magnesium rod as the sacrificial anode. Finally, C-carboxylated, N-carboxylated and C,N-carboxylated products were obtained whose yields were influenced by various reaction conditions including the supporting electrolyte, cathode material, current density, charge passed and temperature. After preliminary optimization, the total carboxylation yield of 37.3% could be achieved with a ratio between the three products of 14.1:5.7:13.8. Using glassy carbon as the working electrode, the electrochemical behavior of the [(4-methoxy-benzylidene)-amino]-acetic acid ester was studied by cyclic voltammetry. Based on the character in the absence of presence of carbon dioxide, the possible electrocarboxylation scheme was postulated accordingly.更多还原