【作者】 朱荣秀；

【导师】 刘成卜；

【作者基本信息】 山东大学 ， 物理化学， 2007， 博士

【摘要】 不对称催化是当今化学发展最为活跃的领域之一，是开发手性药物、材料及香料等化学品的强大理论基础和学术依据。其中金属络合物是研究最为普遍的化学催化剂，并且取得世人瞩目的成就，2001年的诺贝尔化学奖授予了该领域做出突出贡献的三位科学家。在金属络合物催化蓬勃发展的同时，近年来，不含金属的有机小分子催化越来越受到关注，正在成为化学领域继金属催化剂之后研究的另一热点。不对称有机催化(Enantioselective Organocatalysis)作为二十一世纪新出现的概念，因其高效性和高选择性，成为构建分子骨架的重要工具，在有机合成及制药工业中发挥着巨大作用，为医药、化学、材料和生物学的发展提供了广阔的应用前景。不对称有机催化的实验研究及理论研究，不仅能丰富有机化学学科内容，还能造福于人类，具有重要的理论与实际意义。开展不对称有机催化反应的理论研究，从分子水平上研究不对称催化反应的机理，不仅有助于了解有机小分子催化反应的反应历程，解释和说明实验结果，而且可以用来设计实验，预测实验中反应中间体和过渡态的结构及稳定性，以及不对称催化反应的立体选择性等。本论文运用量子化学方法研究了胺类双官能团催化剂催化的五个不对称反应体系，从微观角度研究了不对称催化反应的机理，揭示了双官能团有机催化作用的微观本质，重点阐明了反应的立体选择性和区域选择性的本质，旨在获得一个对胺类双官能团催化剂催化不对称有机反应机理的全面、深入的认识，从而为新型、高效催化剂的研发以及手性合成的发展提供一定的理论指导。本工作对胺类双官能团催化的微观机理、催化剂的双官能团在不对称催化反应中的作用、控制对映选择性的因素以及电子效应、立体效应等对催化剂活性和选择性的影响做了较系统的研究。主要研究内容及结论归纳如下：1．概括了不对称有机催化的实验和理论研究现状，总结了不对称有机催化的通用机理(共价键合和非共价相互作用)。国内外对有机催化的研究主要侧重于实验方面的工作，对于催化剂的合成、结构优化以及催化反应的机理等方面，已有大量的文献报道。新的不对称催化反应不断被发现，高效、高选择性和高普适性的有机催化剂不断被研发，不对称有机催化正处于蓬勃发展的黄金时期。2．用密度泛函理论，采用反应模型研究了双官能团(硫)脲催化的1，3-二羰基化合物与偶氮二甲酸酯的不对称α-氨基化反应。计算结果表明：(1)双官能团(硫)脲催化的反应机制首先是催化剂对亲核试剂和亲电试剂的双活化：亲核试剂的活化是通过催化剂的叔氨基夺取1，3-二羰基化合物上的活泼氢实现的。亲电试剂的活化是通过底物与催化剂之间形成多重氢键网达到的：接着发生Michael加成，两个反应底物之间形成C-N键；最后质子从催化剂的叔氨基转移到加合物上，伴随着氢键配合物的解离释放出产物和催化剂。(2)催化反应有四条竞争反应通道，它们对应着EH的两个异构体EH1和EH2与DMAD的四种不同的配合方式。(3)催化氨基化反应的速控步骤是C-N键的形成，同时也是决定对映选择性的关键步骤。计算结果确证了催化剂的(硫)脲基在催化反应中起着至关重要的作用，并从理论上解释了该不对称催化反应的对映选择性。总之，通过DF了计算提供了详细的催化不对称α-氨基化反应的机制，充分解释了实验现象。3．用密度泛函理论研究了叔胺-(硫)脲双官能团催化剂催化的1，3-二羰基化合物和硝基烯烃的不对称Michael加成反应。采用模型催化剂和模型化合物成功验证了实验预测的反应机理，并提供了详细的催化反应过程及控制反应对映选择性的因素。计算结果表明：(1)双官能团(硫)脲催化的反应机制首先是亲核试剂和亲电试剂的活化，亲核试剂的活化是通过催化剂的叔氨基夺取1，3-二羰基化合物上的活泼氢实现的，亲电试剂的活化是通过底物与催化剂之间形成多重氢键网达到的；接着发生Michael加成，形成新的C-C键；最后质子从催化剂的叔氨基转移到加合物上，伴随着氢键配合物的解离释放出产物和催化剂。(2)催化反应有四条竞争反应通道，它们对应着两种反应底物与催化剂不同的配合方式以及反应过程中氢质子不同的转移过程，其中对应R-型产物、涉及氢直接转移的通道是最佳反应通道。(3)计算结果发现决定对映选择性的关键步骤是C-C键的形成，而速控步骤是第二次质子的转移，即质子从催化剂的叔氨基转移到Michael加合物上。计算结果从理论上解释了催化剂的叔氨基的作用：即对反应速率影响很大，但对选择性影响较小，并理论预测了催化反应的立体选择性。总之，通过DFT计算提供了详细的1，3-二羰基化合物和硝基烯烃催化不对称Michael加成反应的机制，充分解释了实验现象。4．理论研究了双官能团叔胺-(硫)脲催化剂催化α，β-不饱和亚胺和丙二腈的不对称Michael反应。计算结果表明：(1)催化反应经C-C键的形成和氢质子的转移两个过程得到最终的产物。(2)催化反应沿两条反应通道最终得到两个产物异构体。(3)催化反应的决速步骤是C-C键形成的过程，同时它也是控制不对称催化反应的立体选择性的关键步骤。另外，由相对反应速率理论，推测了的催化反应的ee值，计算结果与实验值相吻合，说明DFT方法应用于该领域的计算研究是可信的。5．聚乳酸(PLA)类材料由于具有良好的生物相容性和生物降解性，是目前医用可降解材料领域中最重要的材料之一。PLA主要通过催化LA(丙交酯)开环聚合得到，而有机催化剂合成生物降解聚合物是最具开创性的研究工作。采用密度泛函理论(DFT)，用模型化合物，在B3LYP／6-31G(d)水平上研究了双官能团胺-硫脲催化丙交酯聚合反应链引发机理。通过几何构型全优化，得到了链引发阶段的反应物、产物、中间体和过渡态的最可几何构型。讨论了催化聚合反应链引发反应的两条可能路径：反应路径A(质子转移和开环同步进行)和反应路径B(质子转移和开环分步进行)。通过对这两条路径进行了分析和比较，表明反应沿路径A在能量上最为有利。另外，总结了催化剂的双官能团在催化开环过程中所起的作用，即氨基活化引发剂，(硫)脲活化单体，通过两个基团共同作用，完成催化开环。计算结果表明催化聚合的链引发反应的决速步骤是反应的第二步，即甲醇上的氢转移到催化剂的叔胺上，同时环打开的过程。6．用密度泛函理论在B3LYP／6-31G(d)水平上研究了脯氨酸衍生物催化的硝基苯与环己酮烯胺不对称串联的亚硝基醛醇-迈克尔反应。串联反应有两条反应通道被详细描述，它们分别对应氧选择性的醛醇反应(Channel A)和氮选择性的醛醇反应(Channel B)。计算结果发现Channel A比Channel B在能量上更有利，通过详细的理论分析弄清了决定区域选择性的关键因素是质子在四唑酸及亚硝基之间的转移，而速控步骤是串联反应的分子内Michael加成。计算结果还发现在ChannelA中，分子内Michael加成在热力学及动力学的角度都是可行的，这样就从理论上解释了实验现象，即串联反应得到了氧亚硝基型的D-A产物。总之，通过DFT计算提供了详细的催化不对称O-nitroso aldol／Michael反应的机制，充分解释了实验现象。本论文的创新点表现在三个方面：1)首次用量子化学方法研究了胺类双官能团催化的机理，解释了实验上不能解决的问题，如：催化剂的双官能团在催化过程中的角色。控制对映选择性的因素，详细催化机理等，有关结果对于催化剂的设计、开发具有一定的指导作用。2)探讨了有机催化剂结构与性能的关系，总结了胺类双官能团有机催化的微观本质，弄清控制对映选择性的关键因素，从而为相关实验研究提供一定的理论依据，并为设计与开发新的不对称有机催化提供新的思路。3)运用相对反应速率理论，预测了胺类双官能团催化反应的ee值，计算结果与实验值相吻合，说明DFT方法应用于该领域的计算研究是可信的，从而提供了一种理论预测ee值的可靠手段。与金属络合物催化相比，有机催化剂的种类以及被研究的有机催化反应数量还非常有限。目前的大部分有机催化反应对反应底物依赖性比较大，底物结构稍有改变就有可能导致产率和对映选择性的大大下降。如何使催化剂更具有普遍适用性，提高基团的兼容性，提高催化选择性(包括化学选择性、区域选择性、立体选择性)，仍然是面临的挑战性问题。本文的研究取得了许多具有理论价值的创新性成果，对实验研究及不对称有机催化的进一步研究有重要的理论指导意义。更多还原

【Abstract】 Asymmetric catalysis represents one of the major challenges in modern organic chemistry. It plays a key role in drug discovery and Pharmaceuticals. In the last decade, more attention has been paid to transition metal catalysis, and the success in this field led to the Nobel Prize in Chemistry in 2001. However, in recent years, many chemists are getting acquainted with the advantages of organic catalysts, and organocatalysis has received considerable attention. Great progress in organocatalysis has been made theoretically and experimentally. Organocatalysis as a new concept emerged at the 21st century has been developing within organic chemistry into its own subdiscipline, and its Golden Age has already dawned.The term "organocatalysis" describes the acceleration of chemical reactions through the addition of a substoichiometric quantity of an organic compound. The interest in this field has increased spectacularly in the last few years as result of both the novelty of the concept and, more importantly, the fact that the efficiency and selectivity of many organocatalytic reactions meet the standards of established organic reactions. Organocatalytic reactions are becoming powerful tools in the construction of complex molecular skeletons.The advantages of organocatalysts include their lack of sensitivity to moisture and oxygen, and their ready availability, low cost, and low toxicity, which confers a huge direct benefit in the production of pharmaceutical intermediates when compared with transition metal catalysts. Moreover, the design and use of synergic systems and bifunctional organocatalysts, which have two distinct functionalities （e.g. a Lewis base and a Bronsted acid） within the same molecule, is becoming more and more common.As realization grows that organic molecules not only are green and easy to manipulate but also can be very efficient and remarkably enantioselective catalysts, asymmetric organocatalysis gradually catch up with the spectacular advancements of transition metal catalysis. Despite thorough experimental investigations and possible catalytic mechanism proposal, relative little is understood about the intricacies of organocatalysis, a situation that needs to be addressed to enable catalyst design to advance on a rational basis. Therefore, further thorough investigations on organocatalysis will be of important theoretical and practical values.Theoretical studies of reaction mechanism by computational methods have been greatly facilitated by innovation of computer technology and development of the methods. Recently, B3LYP methods have been applied for non-metal small molecular catalytic reaction and have achieved the considerable results.In this dissertation, we studied the bifunctional amine catalysis with density functional theory （DFT） calculations. Our purposes are to a) shed light on the mechanistic details of the bifunctional amine catalysis and hence obtain a better interplay between theory and experiment, b) understand the roles of bifunctional group of the catalyst and the origin of enantioselectivity for the catalyzed reaction, and c) provide a general profile of the catalytic reaction by bifunctional amine catalysts. Our results provide detailed information on the transition states of bifunctional amine catalyzed organic reaction and should be helpful for the designing the new efficient bifunctional catalyst examples.The valuable results in this dissertation can be summarized as follows:1. The research history and current state on organocatalysis have been briefly reviewed. A number of asymmetric organocatalytic reactions have recently been developed, and new asymmetric reactions are constantly being reported. Most organocatalysts used currently are bifunctional, commonly with a Br（?）msted acid and a Lewis base center. These compounds activate both the donor and the acceptor, thus resulting in a considerable acceleration of the reaction rate. Moreover, the general mechanisms of organocatalysis have been illustrated: covalent bonded interactions and non-covalent bonded interactions.2. A general profile of the Michael reaction of 1, 3-Dicarbonyl compounds and nitroolefins catalyzed by bifunctional-urea catalyst has emerged clearly via the DFT calculations on the prototype reaction between the malonate and nitroolfins. Four reaction channels, corresponding to the approach modes of the nitroolfins to chiral scaffold and the second proton transfer processes, have been characterized in detail. It is found that the enantioselectivity of the catalyzed Michael reaction is controlled by the C-C bond-formation step, while the rate determining step is the proton transfer from the amino group of catalyst to α-carbon of nitronate. Our calculated results confirm the amino group has a significant effect on the reaction rate, but only slight effect on the enantioselectivity. The present DFT study well explains the experimental finding and provides the details of the reaction mechanisms.3. The α-amination reaction of cyclic 1, 3-dicarbonyl compounds with azodicarboxylate catalyzed by a urea-based chiral bifunctional organocatalyst is investigated using density functional theory （DFT） calculations. The predicted mechanism involves first nucleophile activation via protonation of the amino group and electrophile activation through substrate binding to urea; then C-N bond formation between these two activated components; and finally, the proton transfer from the protonated amino group to adduct, followed by the dissociation of the H-bonded complex to give amination product along with the catalyst. The structures of the catalyst and two substrates as well as the catalyst-substrate complexes have been discussed in detail. Four reaction channels have been shown for the C-N bond-forming. The rate determining step is the nucleophilic center of the enolate anion attacks the electron-deficient dimethyl azodicarboxylate （DMAD）. The calculations show that the amino group activates 1, 3-dicarbonyl compounds via deprotonation, while the urea and amine moieties stabilize the intermediates throughout the reaction via the multiple hydrogen bonds between the catalyst and substrates. The origin of enantioselectivity for the investigated reaction is also discussed. Our calculated results confirm the urea moiety of the catalyst has a significant effect on the title reaction. The present DFT study well explains the experimental findings and provides the details of the mechanisms.4. The Michael reaction of malononitrile to α, β-unsaturated imides in the presence of bi-functional thiourea catalyst has been investigated by DFT calculations. The computational results support the proposed mechanism, which involves: （i） The conjugate hydrogen bonding interactions of α, β-unsaturated imides and catalyst. （ii） A plausible transition state in which imide derivatives and the anion of tautomer of malononitrile coordinates to the thiourea moiety and the tertiary amine group, respectively. The rate determining step is nucleophilic carbon of the anion of tautomer of malononitrile attacking α, β-unsaturated imides. The enantioselectivity for the investigated reaction is originated from the different coordination modes of α, β-unsaturated imides to catalyst. The calculated results show that the reaction prefers R-configurational products, which is consistent with the experimental results.5. Design and synthesis of biodegradable polymers have attracted considerable attention due to the rapid development of the biomedical science and engineering. One of the most promising and practical materials is polylactide （PLA）. Because of its bioresorbability and biocompatibility, PLA is recognized as an important material for medical and pharmaceutical applications as well as for industrial applications such as food packaging and paper. PLA is obtained from the corresponding monomers by ring opening polymerization （ROP）. Hedrick detailed an organocatalytic approach to the living ROP of lactide with bifunctional thiourea catalysts. In this dissertation a computational DFT study with the B3LYP method on the mechanism of the thiourea-catalyzed ROP has been performed. All the structures are optimized completely at the B3LYP/6-31G（d） level. The catalysis property of bifunctional amine catalyst is notable. That is catalysis proceeds by bifunctional activation of the carbonyl of a lactide monomer via hydrogen bonding to the thiourea group and of the initiating/propagating alcohol by the Bronsted basic （tertiary amino） group of the catalyst. Nucleophilic ring-opening of the lactide leads to propagation, whereby the ring-opened lactide forms the propagating alcohol for the subsequent addition of monomer.6. The tandem O-nitroso aldol/Michael reaction between nitrosobenzene and cyclohexenone catalyzed by pyrrolidine-based catalyst in gas phase and solution is studied using density functional theory, to determine the detailed mechanism and key factors controlling the regioselectivity. Two regioselective channels （0- and N-selective） have been characterized in detail. The rate determining step is the Michael reaction, and the corresponding barriers for 0- and N-selective channels are 14.05 and 31.96 kcal mol^-1, respectively. The key factor controlling the selectivity is the proton transfers between the tetrazolic acid and the nitroso group. It was found that the Michael reaction along the O-selective channel is both thermodynamically and kinetically feasible, which corroborates the early experimental findings. Finally, our calculations show that solvent effects stabilize all relevant stationary points, but do not change the profile of the PES.Although substrate dependence remains an important issue in many of the reactions discussed, more and more transformations now meet the standards of established asymmetric reactions. Despite the considerable progress that has been made in the elucidation of transition states, we are only beginning to understand the basic factors that control reactivity and selectivity in these reactions, and the rational design of catalysts remains in most cases a dream. The number of organocatalytic （non-asymmetric） reactions is steadily increasing, which provides a solid basis for the development of novel enantioselective reactions. New asymmetric reactions are constantly being reported. Although creativity and persistence will certainly remain the major factors in the success of this research, the increasing use of automatization and computational techniques may facilitate both the discovery of novel catalyst structures and the screening of reactions for catalysts of the next generations.In this dissertation, the valuable results have provided reliable verification and theoretical guide for further studying of bifunctional amine catalysis even for the development of organocatalysis.更多还原