【作者】 魏星跃；

【导师】 秦圣英；

【作者基本信息】 四川大学 ， 有机化学， 2004， 博士

【摘要】 模拟酶的主要目的之一,是用化学方法来设计合成能高效专一地催化普通化学反应的、非大分子肽骨架的、但含有类似酶反应活性位点的小分子化合物。人工酶,即模拟天然酶的局部结构和功能,它通常应具有结合部位和催化部位。常作为第一代仿酶基体的冠醚,是一类由外侧亲脂的多个亚乙基和内侧亲水的杂原子构筑的环状化合物,它能包络多种客体分子,模拟和调控酶活性中心周围的微环境。因此,将功能分子冠醚化,设计合成性能更加优异的人工酶模型化合物,是近年来冠醚化学和仿生化学研究中的重要内容。但迄今为止,键连冠醚的Schiff碱仿酶模型还较少,特别是将具有一定刚性的苯并氮杂冠醚挂接在Schiff碱金属配合物中作为仿单加氧酶、水解酶则更未见到。为了充分发挥具有特定空间构型和功能的苯并氮杂冠醚对人工酶活性中心周围微环境的调控作用,本文从苯并-10-氮杂-15-冠-5出发,设计合成了氮杂冠醚取代的单、双和不对称水杨醛亚胺Schiff碱配体及其过渡金属配合物;深入系统地研究了配体中冠醚环取代基及其键连部位、配合的碱金属离子对二氧亲合性、仿单加氧酶和水解酶性能的影响,并探索其中的规律性,获得了一系列具有重要理论意义和应用前景的创新结果,为仿单加氧酶和水解酶新模型的设计合成提供理论依据。本文利用苯并-10-氮杂-15-冠-5和吗啉环上仲氨基的活性和Schiff碱易于修饰的特点,设计合成了以苯并-10-氮杂-15-冠-5或吗啉基作悬吊基的三个系列共29个新的水杨醛亚胺Schiff碱配体及其58个相应的Co(II)、Mn(II)过渡金属配合物,并以IR、1HNMR、MS、和元素分析表征。模拟生物氧载体,深入系统地研究了配体结构,键连的氮杂冠醚及其键连位置对Co(II)配合物氧合性能的影响。在-5oC ~ 25 oC范围内测定了它们在二甘醇二甲醚溶液中的氧合反应平衡常数Ko2和计算了热力学参数ΔHo、ΔSo;考察了添<WP=8>加碱金属盐增大二氧亲合性能的结果表明:1冠醚取代的Co(II)配合物的二氧亲和性均大大优于相应的吗啉基取代的类似物, 其中尤以双Schiff碱双冠醚的品种为最佳,其活性顺序有:双冠醚取代的双Schiff碱>单冠醚取代的双Schiff碱>单冠醚取代的单Schiff碱>吗啉基取代的Schiff碱>简单Schiff碱钴(II)配合物,具有明显的大环效应。2.冠醚环在配体中的键连部位对载氧性能影响明显。3.挂接的苯并氮杂冠醚能充分协调好配体的π-授予性、疏水性、大环效应、空间位阻和氢键力对活性中心的有效调控作用,提高载氧性能。4 由氧合反应液的EISMS谱确证,添加碱金属盐KNO3的氧合反应体系中存在Co(II)/K(I)异双核夹心络合物,表现出类似生物酶中的协同效应。冠环中配合的碱金属离子能大大提高钴(II)配合物的二氧亲性,其中以K+最佳。模拟细胞色素P-450单加氧酶,以PhIO 、NaClO 为氧源,系统地研究了在常温常压下它们的锰(III)配合物对苯乙烯的催化环氧化。结果表明,与非冠醚化类似物比较,氮杂冠醚-Schiff碱合锰(III)的催化活性均大大高于前者, 且有:双冠醚取代的双Schiff碱>单冠醚取代的双Schiff碱>单冠醚取代的单Schiff碱>吗啉基取代的Schiff碱>简单Schiff碱锰(III)配合物的催化活性顺序。这与载氧活性顺序一致,其中尤以双(苯并-10-氮杂-15-冠-5)Mn(III)salophen(MnLd3Cl)最佳:反应转化率(1小时)79.5%, 选择性95.8%,TOF(转化频率) 38.1。以动力学方法考察了配体结构对环氧化反应的影响,表明该催化反应具有典型的酶促反应动力学特征。但与氧合反应不同,冠醚环配合的碱金属离子对催化反应无影响。然而,当以NaClO为氧源的水/烃两相反应体系中,含冠醚的锰(III)配合物却同时具有相转移催化的双功能作用,使苯乙烯转化率达91.6%,为吗啉基取代品种的8倍。首次研究了它们的过渡金属配合物作为水解酶人工模型,催化酯(PNPP)水解反应动力学,提出了动力学数学模型, 探讨了反应机理。结果表明:悬挂的两个冠醚环构建的空穴效应除有利于PNPP接近活性中心外,并借助于氢键力协同中心金属离子激活配位的水分子,加速水解反应。其中以双(苯并-10-氮杂-15-冠-5)Mn(III)salen (MnLd1Cl)催化活性最高,水解反应表观速率常数6.61×10-2 (s-1), 为PNPP自水解速率的5000倍,非冠醚类似物的120倍。选择4个典型冠醚取代的Schiff碱配体培养出单晶,测定了晶体结构。通过结构方面的信息,对仿酶催化作用作出了合理的解释。证实了具有一定刚性的苯<WP=9>并氮杂冠醚能充分协调好对活性中心周围的微环境和空间位阻的作用,同时也进一步确证了合成的产物与其预期结构完全一致。更多还原

【Abstract】 One of the chief purpose of enzyme-mimic researches is to design and synthesize low molecular weight compound which have no peptide bone of the macromolecule, but possess reactive site similar to that of enzyme and can catalyze common chemical reaction with high capability and selectivity. Synzymes are a kind of compound to mimic partial structure and function of enzyme, they generally possess both associate site and catalytic site within the molecule. Crown ethers, as the first generation of enzyme-mimic base compounds, are a category of cyclic compounds which are constructed by hydrophobic outer ethylene groups and hydrophilic inner oza or aza atoms. They can associate with many guest molecules, mimic and control the microenviroment around the reactive site to improve the reactivity of synzymes. Thus, to design and synthesis crown ether substituted functional molecule is a trend of current Crown Chemistry and Biomimetic Chemistry. However, by now the crown ether substituted Schiff base-type enzyme-mimic models remain rather seldom. The report of benzoaza crown-Schiff bases as monooxygenase-mimic and hydrolase-mimic have not been found yet. For the purpose to employ the cooperativity of the azacrown ethers in enzyme-mimic aspects, we design and synthesis benzo-10-aza-15-crown-5 substituted mono, bis and asymmetric salicylaldimine Schiff bases and their transition-metal complexes, and systematically study the influences of azacrown ether substituentes as well as their bonding sites, and the alkali metal ions complexed with the crown ethers on the dioxygen affinities, monooxygenase-mimic and hydrolase- mimic performances of these complexes, and moreover, discover some regulations among them. As a result, we have gained a series of new results which will supply <WP=11>many valuable information for the design an synthesis of new monooxygenase- mimic and hydrolase-mimic models. Considering that the reactivity of the N atom of the crown ether or morpholino ring and the modifiability of the Schiff base ligand, 3 series of benzo- 10-aza-15-crown-5 or morpholino substituted new salicylaldimine Schiff bases and their transition-metal [Co(II), Mn(III)] complexes have been designed and successfully synthesized. Thy all have been characterized by IR、1HNMR、MS、and elemental analyse.The Co(II) complexes have been employed as synthetic oxygen carriers. Their equilibrium constants Ko2 and thermodynamic parameters ΔHo and ΔSo for oxygenation in the presence of diethyleneglycol dimethy ether (as solvent) and pyridine (as axial lingand) over a range of –5oC to 25 oC have been determined and calculated. The results indicate that: 1. the dioxygen affinities of all the crown ether-Schiff base Co(II) complexes are superior to their crown-free analogues, and the former also obviously possess macrocyclic effect. The dioxygen affinities are follow the order: double azacrown ether substituted bis-Schiff base > single azacrown ether substituted bis-Schiff base > single azacrown ether substituted mono-Schiff base> morpholino substituted species> the simple analogues. 2. the bonding sites of the crown ether in the complexes visibly influence the dioxygen affinities of the complexes. 3. the benzoaza crown ether substituted species can attune well many factors of the ligands such as π-donating ability, hydrophobicity, steric block and hydrogen bond between azacrown ether and nearby hydroxyl to effectively control the reactive center and improve the dixygen affinities. 4.The ESIMS spectra confirm the existence of K(I)/Co(II) dinuclear sandwich type complexes in the oxygenation reaction, which can much enhance the O2-binding abilities of the complexes.The Mn(III) complexes have been employed as cytochrome P-450 artificial models to catalyze epoxidation of styrene under ambient temperature and pressure using PhIO and NaClO as oxygen source. The results reveal that, as compared with the crown-free analogues, the crown ether substituted species show much higher catalytic <WP=12>activities. Their catalytic capabilities also follow a更多还原