节点文献
新型过渡金属配合物的合成、表征及应用研究
Study on the Synthesis, Characterization and Application of Novel Transition Metal Complexes
【作者】 刘善斌；
【作者基本信息】 中国海洋大学 ， 海洋化学工程与技术， 2011， 博士
【摘要】 氨基酸类衍生物及希夫碱过渡金属配合物在材料、医药生物、催化等领域具有广泛的应用,成为当前配位化学研究热点之一。合成新的配体及过渡金属配合物、研究其性质及应用,对配位化学的发展有重要的意义。L-半胱氨酸是一种具有生理活性的α-氨基酸。它在医药、食品及化妆品等生产中有着广泛的应用。在医药方面,它可作为预防和治疗放射性伤害的物质,是治疗肝炎、肝中毒及锑中毒等的解毒剂,其衍生物在医药上也有着广泛的用途。研究L-半胱氨酸衍生物的金属配合物及生物活性是生命科学中重要的研究课题。本文合成了4个系列21种过渡金属配合物及4个希夫碱配体及配合物的单晶。这些配合物是以L-半胱氨酸缩邻香草醛、L-半胱氨酸缩香草醛、L-半胱氨酸缩3,4-二羟基苯甲醛和4,4’-二氨基二苯甲烷缩邻香草醛为配体合成的。采用元素分析、红外光谱、紫外光谱、XRD单晶衍射、核磁共振、摩尔电导率及热重分析对配体及配合物进行了表征。对部分配合物与DNA的相互作用、抗肿瘤活性及4,4’-二氨基二苯甲烷缩邻香草醛希夫碱被用作检测Zn（Ⅱ）的荧光探针的应用进行了研究。具体内容如下:1.合成了L-半胱氨酸缩邻香草醛配体及它的4种过渡金属配合物,配合物的组成为:[M2（C）11H13NO4S)2（CH3COO）2] [M=Cu（Ⅱ）, Co（Ⅱ）, Zn（Ⅱ）, Mn（Ⅱ）]。2.合成了L-半胱氨酸缩香草醛配体及它的5种过渡金属配合物,各配合物的组成分别为:[Cu（C）11H12NO4S)（CH3COO）（H2O）]、[Co（C）11H12NO4S)（CH3COO） （H2O）3]、[Cd（C）11H12NO4S) （CH3COO）（H2O）]·2H2O]、[Zn（C）11H12NO4S)（CH3COO） （H2O）]·2H2O、[Mn（C）11H12NO4S) （CH3COO） （H2O）2]。3.合成了L-半胱氨酸缩3,4-二羟基苯甲醛配体及它的5种过渡金属配合物,配合物的组成为:[M(C10H11NO4S)2] [M=Cu（Ⅱ）, Co（Ⅱ）, Cd（Ⅱ）, Zn（Ⅱ）, Mn（Ⅱ）]。4.合成了4,4’-二氨基二苯甲烷缩邻香草醛希夫碱配体及它的7种过渡金属配合物,配合物的组成为:[M2(C58H58N4O8)2],[M= Cu（Ⅱ）, Co（Ⅱ）, Ni（Ⅱ）, Cd（Ⅱ）,Zn（Ⅱ）, Mn（Ⅱ）, Fe（Ⅱ）]。培养得到了该配体及其铜配合物的单晶,晶体结构测试表明:4,4’-二氨基二苯甲烷缩邻香草醛希夫碱（L）配体晶体属正交晶系,Fdd2空间群,化学式C29H26N2O4,M = 466.5。晶胞参数:a = 24.433（2） （?）,b=38.886（3） （?）,c =4.7896（6） （?）,α= 90°,β= 90°,γ= 90°,Z = 8, V=4736.8（8）（?）3,T = 293（2） K,Dc = 1.308g·cm-3,R1 = 0.046,wR2 = 0. 0712 [I>2σ（I）],F（000） =1968。晶体结构显示,羟基上氢原子与希夫碱的氮原子形成了分子间氢键。4,4’-二氨基二苯甲烷缩邻香草醛希夫碱Cu（Ⅱ）配体物晶体属三斜晶系,P-1空间群,化学式C125H127Cu4N11O25,M =2437.5。晶胞参数:a =13.697（13）) （?）,b=14.181（15） （?）,c =18.6859（19）（?）,α= 69.56°,β=70.07°,γ= 81.63°,Z = 1, V=3195.9（6）（?）3,T = 298 K,Dc = 1.267g·cm-3,R1 =0.0756,wR2 = 0. 0.1920 [I>2σ（I）],F（000） =1270。晶体结构显示,配合物为双核配合物,Cu（Ⅱ）为四配位,分别位于扭转四面体的中心。5.利用Achar的微分法和Coats-Redfern的积分法计算程序,分别对30种热分解动力学进行了拟合,对部分配合物进行了非等温热分解动力学处理,得出了配合物某步热分解反应机理、热分解动力学方程、相应的动力学参数及活化熵变△S≠和吉布斯自由能变△G≠。[Cu （C）11H12NO4S)2（CH3COO）]·H2O第2步热分解反应机理:动力学函数符合反应方程:f（α）=1/4（1-α）[-ln（1-α）]-3,热分解动力学方程为:dα/dt = A·e-E/RT·f（α） = A·e-E/RT·1/4（1-α）[-ln（1-α）]-3,E = 349.5 kJ·mol-1,lnA = 73.74,r = 0.9900,△S≠= 363.6 J·mol-1·K,△G≠= 161.2 kJ·mol-1。[Zn2L2]第2步热分解反应机理:动力学函数符合二级反应方程:f（α）=（1-α）2,其热分解动力学方程为:dα/dt = A·e-E/RT·f（α） = A·e-E/RT·（1-α）2,E = 390.5 kJ·mol-1,lnA = 66.68,r = 0.9884,△S≠= 242.2 J·mol-1·K,△G≠= 287.0 kJ·mol-1。[Cu2（C）11H13NO4S)2（CH3COO）2]、[Cu(C10H11NO4S)2]、[Cu2L2]及[Cd2L2]的热分析数据略。6.合成了4-[（E）-（2-甲氧基）亚甲氨基]-N,N-二甲基苯和1,5-二甲基-2-苯基-4-{[（E）-3,4,5-三甲氧基苯亚甲基]亚氨基}-1H-吡唑-3（2H）-酮2种希夫碱配体,并得到了其单晶。晶体结构测试表明:4-[（E）-（2-甲氧基）亚甲氨基]-N,N-二甲基苯胺的晶体属正交晶系,空间点群Pna21,化学式C16H18N2O,M =254.3,晶胞参数为a =15.182（8）（?）,b=11.756（6） （?）,c = 7.809（4）（?）,α=90.000°,β= 90.000°,γ= 90.000°,V = 1393.813)（?）3,Z = 4,F（000） = 544.0,Dc = 1.212 Mg·m -3,R1 = 0.0433,wR2 = 0.1006 [I>2σ（I）]。1,5-二甲基-2-苯基-4-{[（E）-3,4,5-三甲氧基苯亚甲基]亚氨基}-1H-吡唑-3（2H）-酮晶体属正交晶系,空间点群P21/c,化学式C21H23N3O4,M =381.4,晶胞参数为a =12.3644 （12）（?）,b=14.0075（16）（?）,c = )11.2682（）11)（?）,α=90.000（?）,β= 90.000（?）,γ= 90.000（?）,V = )1393.8（）13)（?）3,Z = 4,F（000） = 544.0,Dc = 1.2)12 Mg·m -3,R1 = 0.0433,wR2 = 0.1006 [I>2σ（I）]。采用密度泛函理论（DFT）B3LYP方法,对4-[（E）-（2-甲氧基）亚甲氨基]-N,N-二甲基苯胺和1,5-二甲基-2-苯基-4-{[（E）-3,4,5-三甲氧基苯亚甲基]亚氨基}-1H-吡唑-3（2H）-酮希夫碱晶体的分子构型、前沿轨道能量、自然电荷布局、自然键轨道进行了计算。计算结果表明,实验值与计算值基本吻合,并预测了它们的化学性质。7.本文探讨了4,4’-二氨基二苯甲烷缩邻香草醛希夫碱（L）被用作检测Zn（Ⅱ）的荧光探针的特性,并考察了金属阳离子、常见阴离子、溶液pH及溶剂对荧光探针性能的影响。研究表明,4,4’-二氨基二苯甲烷缩邻香草醛希夫碱在450-650 nm范围内没有荧光,当有Zn（Ⅱ）离子存在时,在525nm处的荧光强度明显增强。配体可在DMF,DMSO,四氢呋喃,甲苯及三氯甲烷中对Zn（Ⅱ）离子进行检测,pH范围为6-14,且Na（I）, Mg（Ⅱ）, Ca（Ⅱ）, Al（Ⅲ）, Cu（Ⅱ）, Co（Ⅱ）, Ni（Ⅱ）, Cd（Ⅱ）, Mn（Ⅱ）, Sn（Ⅱ）, Pb（Ⅱ）, Cr（Ⅲ）, Fe（Ⅲ）, La（Ⅲ）, Yb（Ⅲ）, Er（Ⅲ） and Pr（Ⅲ）等离子的存在对体系的荧光强度没有影响。以DMF为溶剂,在Zn （Ⅱ）离子浓度在1.0×10-7 mol·L-1 - 1.2×10-5 mol·L-1浓度范围内,Zn （Ⅱ）离子浓度与荧光强度呈很好的线性关系,I = 45.86c+18.12, R2=0.9991（I为荧光强度,c为Zn （Ⅱ）离子浓度）。4,4’-二氨基二苯甲烷缩邻香草醛希夫碱可被用作检测Zn（Ⅱ）的荧光探针。8.采用紫外可见光谱、荧光光谱,EB-DNA猝灭实验和粘度法等方法对4种配体的Cu（Ⅱ）配合物与DNA作用方式进行了研究。结果表明:[Cu2（C）11H13NO4S)2（CH3COO）2]、[Cu （C）11H12NO4S)2（CH3COO）]·H2O和[Cu2L2]配合物与DNA的作用方式为插入作用,而[Cu(C10H11NO4S)2]与DNA的作用方式为静电结合。9.本文以蛋白酶体为靶点,对部分配合物的抗肿瘤活性进行了研究。通过MTT法对18种配合物进行了初步筛选,发现L-半胱氨酸缩邻香草醛Cu（Ⅱ）配合物、4,4’-二氨基二苯甲烷缩邻香草醛希夫碱Cu（Ⅱ）配合物和4,4’-二氨基二苯甲烷缩邻香草醛希夫碱Fe（Ⅱ）配合物可以抑制前列腺癌细胞（PC-3）的增长。通过对配合物与糜蛋白酶体（CT-like）和半胱氨酸蛋白酶（Caspase-3）作用的研究表明,4,4’-二氨基二苯甲烷缩邻香草醛希夫碱Fe（Ⅱ）配合物对糜蛋白酶体活性有抑制作用,并且对Caspase-3的增殖作用明显。说明该配合物可以通过抑制糜蛋白酶体活性和激活Caspase-3的方法,诱导PC-3细胞的凋亡。
【Abstract】 Transition metal complexes of amino acid derivative and Schiff base are widely used in the fields of material, medicine and catalysis etc. Thus, studies on the synthesis of novel complexes, studing their properties and application are significant the development of coordination chemistry.L-cysteine isα-amino Acids which has strong biological activity. It is widely used in medicine, food and cosmetic areas. It can prevent and treat the radioactivity. L-cysteine is an antidote of hepatotoxicity and stibialism. The study of synthetization and bioactivity of metal complex, which is derived from L-cysteine derivative, is an important research topic in life science.In this paper, three ligands derived from L-cysteine （L-cys） , vanillin（vani）, o-vanillin（ovani）, 3,4-dihydroxybenzaldehyde（3,4DHD） and a Schiff base ligand derived from 4,4`-diaminodiphenylmethane and o-vanillin were prepared. And twenty-one coordination compounds of transition metal were synthesized. Four crystals of these ligands or complexes were prepared. These ligands and complexes were characterized by elemental analysis, 1H NMR, IR spectroscopy, UV spectroscopy, single-crystal X-ray diffraction, TG-DTG analysis and molar conductance analysis. The binding mode of some complexes with DNA, anticancer activity and a fluorescent probe based on Schiff Base which derived from 4,4`-diaminodiphenylmethane and o-vanillin, for the detection of Zinc （Ⅱ） . The details of contents are as follow:（1） The ligand and 4 transition metal complexes derived from L-cysteine and o-vanillin were synthetized. The compositions of the complexes are confirmed to be [M2 （C）11H13NO4S) 2（CH3COO） 2] [M=Cu （Ⅱ）, Co （Ⅱ）, Zn （Ⅱ）, Mn （Ⅱ）].（2） The ligand and 5 transition metal complexes derived from L-cysteine and vanillin were synthetized. The compositions of the complexes are confirmed to be [Cu （C）11H12NO4S) （CH3COO） （H2O）], [Co （C）11H12NO4S) （CH3COO） （H2O） 3], [Cd（C）11H12NO4S)（CH3COO）（H2O）]·2H2O,[Zn（C）11H12NO4S)（CH3COO）（H2O）]·2H2O, [Mn（C）11H12NO4S) （CH3COO） （H2O）2].（3） The ligand and 5 transition metal complexes derived from L-cysteine and 3,4-dihydroxybenzaldehyde were synthetized. The compositions of the complexes are confirmed to be [M (C10H11NO4S) 2] [M=Cu （Ⅱ）, Co （Ⅱ）, Cd （Ⅱ）, Zn（Ⅱ）, Mn（Ⅱ）].（4） The ligand and 7 transition metal complexes derived from 4,4`-diaminodiphenylmethane and o-vanillin were synthetized. The compositions of the complexes are confirmed to be [M2(C58H58N4O8)2], [M=Cu（Ⅱ）, Co（Ⅱ）, Ni（Ⅱ）, Cd（Ⅱ）, Zn（Ⅱ）, Mn（Ⅱ）, Fe（Ⅱ）]. The crystals of Schiff base and its Cu （Ⅱ） were obtained.X-ray crystallography shows that the crystal derived from 4,4`-diaminodiphenylmethane and o-vanillin [L] crystallizes in the orthorhombic, Fdd2 space group, molecular formula: C29H26N2O4, M= 466.5. Unit cell parameter: a = 24.433（2） （?）, b=38.886（3） （?）, c =4.7896（6） （?）,α= 90°,β= 90°,γ= 90°, Z = 8, V=4736.8（8） （?）3, T = 293（2） K, Dc = 1.308 g·cm -3, R1 = 0.046, wR2 = 0.0712 for I>2σ（I）, F（000） =1968. The crystal structure shows that the H atom of hydroxybenzene and N atom of Schiff base formed intramolecular hydrogen bond.The crystal of Cu（Ⅱ） complex with Schiff base ligand derived from4,4`-diaminodiphenylmethane and o-vanillin（Cu2L2） belongs to orthorhombic, Fdd2 space group, molecular formula: C)125H127Cu4N)11O25,M =2437.5.Unit cell parameter: a =13.697（）13 （?）,b=14.181（15） （?）,c =18.6859（19）（?）,α= 69.56°,β=70.07°,γ= 81.63°,Z = 1, V=3195.9（6）（?）3,T = 298 K,Dc = 1.267 g·cm-3,R1 =0.0756,wR2 = 0. 0.1920 for I>2σ（I）,F（000） =)1270. The structure of Cu2L2 shows that the complex is bi-nuclear. The Cu （Ⅱ） ion is in a four-coordinate, located in center of a distorted tetrahedron.（5） Combinating Achar differential and Coats-Redfern integral method which fits the thirty kinetic equations, the calculating program of some step of thermal decomposition for complexes was designed. The kinetic equations of corresponding kinetic parameters were obtained. The kinetic parameters include E, A, order of reaction and correlation coefficient etc. The activation entropy△S≠and activation free-energy△G≠for some thermal decomposition steps were also calculated.The thermal decomposition kinetic function of [Cu （C）11H12NO4S)2（CH3COO）]·H2O in step（2） may be expressed as f（α）=1/4（1-α）[-ln（1-α）]-3, and the kinetic equation of thermal decomposition may be expressed as dα/dt = A·e-E/RT·f（α） = A·e-E/RT·1/4（1-α）[-ln（1-α）]-3,E = 349.5 kJ·mol-1, lnA = 73.74, r = 0.9901,△S≠= 363.6 J·mol-1·K,△G≠= 161.2 kJ·mol-1.The thermal decomposition kinetic function of [Zn2L2] in step（2） may be expressed as f（α） =（1-α）2, and the kinetic equation of thermal decomposition may be expressed as dα/dt = A·e-E/RT·f（α） = A·e-E/RT·（1-α）2, E = 390.5 kJ·mol-1, lnA = 66.68, r = 0.9884,△S≠= 242.2 J·mol-1·K,△G≠= 287.0 kJ·mol-1.TG-DTG analysis data of [Cu(C10H11NO4S)2] , [Cu2L2] , [Cd2L2] and [Cu2（C）11H13NO4S)2（CH3COO）2] were omitted.（6） The crystals of 4-[（E）-（2-Methoxyphenyl）iminomethyl]-N,N-dimethylaniline and 1,5-Dimethyl-2-phenyl-4-{[（E）-3,4,5-Tri methoxy benzylidene]amino}-1H -pyrazol-3（2H）-one were obtained. The measurement of crystal structure showed that:The crystal 4-[（E）-（2-Methoxyphenyl）iminomethyl]-N,N-dimethylaniline belongs to orthorhombic, Pna21 space group, molecular formula: C16 H18 N2 O, M =254.3.Unit cell parameter: a =15.182（8）（?）,α=90.000（?）,b=)11.756（6）（?） ,β= 90.000（?）, c = 7.809（4）（?）,γ= 90.000（?）, V = )1393.8（）13)（?）3, Z = 4, F（000） = 544.0, Dc = 1.2)12 Mg·m-3, R1 = 0.0433, wR2 = 0.1006 for I>2σ（I）.The crystal 1, 5-Dimethyl-2-phenyl-4-{[（E）-3,4,5-Tri methoxy benzylidene] amino}-1H-pyrazol-3（2H）-one belongs to monoclinic, P21/cspace group, molecular formula: C21H23N3O4,M =381.4.Unit cell parameter: a =)12.3644 （）12)（?）, b=14.0075（16）（?）, c = )11.2682（）11)（?）,α=90.000（?）,β= 90.000（?）,γ= 90.000（?）, V = 1393.813（?）3,Z = 4, F（000） = 544.0, Dc = 1.212 Mg·m-3, R1 = 0.0433, wR2 = 0.1006 for I>2σ（I）.The crystals of 4-[（E）-（2-Methoxyphenyl）iminomethyl]-N,N-dime-thylaniline and 1,5-Dimethyl-2-phenyl-4-{[（E）-3,4,5-Tri methoxy benzylidene]-amino}-1H- Pyrazol-3（2H）-one were calculated using the density functional theory （DFT） with the gradient corrected B3LYP method. The crystal structure of the compound is totally optimized. The energies and components of molecular orbital （HOMO and LUMO）, natural population, NBO and stabilization energy were calculated. All data obtained from the calculations are consistent with those gained from the determination, which means the calculation model is stabilized. The chemical property of two Schiff bases was illustrated.（7） In this paper, the character of fluorescent probe （L） derived from 4,4`-diaminodiphenylmethane and o-vanillin for detection of Zn （Ⅱ） cation was studied. The metal ion, negative ion, effect of pH and solution of the fluorescent probe （L） were studied.The results showed that: the Schiff base （L） derived from 4,4`-diaminodiphenylmethane and o-vanillin, has no fluorescence intensity in a range of 450-650 nm, but its fluorescence spectrum shows enhancement in the intensity of the signal at 525 nm on binding with the Zn（Ⅱ） cation. This Schiff base can be used in N, N-dimethylformamide （DMF）, tetrahydrofuran （THF）, toluene, and dimethylsulfoxide （DMSO）, at pH 6 to 14, and Na（I）, Mg（Ⅱ）, Ca（Ⅱ）, Al（Ⅲ）, Cu（Ⅱ）, Co（Ⅱ）, Ni（Ⅱ）, Cd（Ⅱ）, Mn（Ⅱ）, Sn（Ⅱ）, Pb（Ⅱ）, Cr（Ⅲ）, Fe（Ⅲ）, La（Ⅲ）, Yb（Ⅲ）, Er（Ⅲ） and Pr（Ⅲ） ion has no effect to the fluorescence intensity of Zn-L system. Dissolved in DMF, Fluorescence intensity is linear with concentration of Zn （Ⅱ） cation in a range from 1.0×10-7 mol·L-1 to 1.2×10-5 mol·L-1 atλem=538 nm. I=45.86c+18.12, R2=0.9991. [I: fluorescence intensity; c: concentration of Zn （Ⅱ）]. Schiff base derived from 4, 4`-diaminodiphenylmethane and o-vanillin, can be used as a fluorescent probe for detection of Zn （Ⅱ） cation.（8） The DNA binding modes of the four Cu （Ⅱ） complexes were investigated by electronic absorption spectra, EB-DNA displacement experiment and viscosity measurement. The experimental evidences indicated that: [Cu2（C）11H13NO4S)2（CH3COO）2], [Cu （C）11H12NO4S)2（CH3COO）]·H2O and [Cu2L2] could interact with DNA through intercalation, and [Cu(C10H11NO4S)2] binds to DNA through an electrostatic interaction mode.（9） In this paper, the anticancer activity of complexes was studied using protease for targets. 3 complexes were sifted from 18 complexes using MTT method. It was found that complexes of No.6 [Cu （Ⅱ） complex derived from L-cysteine and ovanillin], NO.14 [Cu （Ⅱ） complex derived from 4,4`-diaminodiphenylmethane and o-vanillin] and No.18 [Fe（Ⅱ） complex derived from 4,4`-diaminodiphenylmethane and o-vanillin] showed high anticancer activity. The study of the impact of complexes to CT-like （chymotrypsin-like activity） and Caspase-3 showed that No.18 complex could inhibit proteasome and activate Caspase-3 to induce apoptosis in prostate cancer PC-3.
【Key words】 L-cysteine； complex； DNA； fluorescent probe； anticancer；