SYNTHESIS, STRUCTURAL AND REACTIVITY STUDIES OF COPPER COMPLEXES

Abstract

Copper is physiologically bioessential element required for the growth and survival ofmany living organism. Mono, di and multinuclear copper complexes are used to mimics the synthetic models of the active sites of many metalloproteins for example cytochrome C-oxidase, azurin, blue copper protein (plastocyanin), hemocyanin, superoxide dismutase and nitrite reductase and also plays an important role in the endogenous oxidative DMA damage associated with aging and cancer. Nitrogen heterocycle such as pyrrole and indole along with imidazole and pyrazole has been widely used in the field of chemistry. The pyrazole nucleus both thermally and hydrolytically is very stable and occupies a position similar to that of pyridine or ammonia in spectrochemical series. As a ligand, it coordinates to metals and metalloids as well as act as a base and can react efficiently with both organic as well as inorganic acids. The nucleophilicity of the nitrogen and their steric accessibility may be varied through appropriate substitution. The pyrazole with various substituents at 3 or 5 positions is an excellent candidate for the engineering of structures. Due to these attractive features, the coordination and supramolecular chemistry of pyrazole and its derivatives have attracted much attention. For the sake of convenience, the work embodied in the thesis is presented in the following chapter: The first chapter of the thesis is the general introduction and presents an up to date survey of literature related to the various metal complexes used for the DNA interaction and cleavage study. The different types of copper complexes related to the present research have been posed in the context ofthe cited work. The second chapter of the thesis deals with the synthesis of [Cu(Im eH)3Cl2], lk2(tmtBu)2CuCl2], [Cu(Pz'Pr2H)2(u-Cl)(Cl)]2, [Cu(PztBu,PrH)2(u-Cl)(Cl)]2, [Cu(Pzph'MeH)2(u-Cl)(Cl)]2, [Cu(PzCum<MeH)2(u-Cl)(Cl)]2, [Cu(ImH)4](N03)2, [Cu(PzH)4(N03)2], [Cu(Pz'Pr2H)3(N03)](N03), [Cu(PztBuiPrH)3(N03)](N03), [Cu(Pzph'MeH)2(OH)(N03)2]-.Pzph'MeH2+.CH3CN, [Cu(PzCuMeH)(N03)2] and [Cu(Pzph2H)(N03)2], where ImH, imidazole; ImMeH, methylimidazole; tmt_Bu, N-tertbutyl- 2-thioimidazole; PzH, pyrazole; Pz'Pr2H, 3,5-diisopropylpyrazole; PztBl ,PrH, 3-tertbutyl- 5-isopropylpyrazole; PzPh'MeH, 3-phenyl-5-methylpyrazole; Pzph2H, 3,5- diphenylpyrazole and pzCumMeH represents 3-cumenyl-5-methylpyrazole as supporting ligand. These complexes have been characterized by different methods including X-ray crystallography and further used for the DNA interaction. DNA interaction study reveals that the two cis-chloro group of the [Cu(ImMeH)3Cl2] covalently binds with N7 of guanines of DNA in major groove; at the same time complex [k2(tmtBu)2CuCl2] being tetrahedral does not bind with the DNA. The covalent interaction of [Cu(PzCuMeH)(N03)2] and [Cu(PzPh2H)(N03)2] is less than [Cu(ImMeH)3Cl2] because of the presence of less labile nitro group as compared to chloro group and also the steric hindrance on pyrazole do to allow to bind these complexes to DNA comfortably. Thus controlled change ofthe anion as well as ligand brings about a significant change in the structure and help in getting the desired structure for particular activity. The synthesis of mono, bi and tetranuclear copper complexes viz., [Cu(PziPr2H)(u,-d) "") •Qx-o)} [^(Pz^'^^aj^l^Aro), [c^Pz^^Hx^a),,]^^^ *> |Cu(Pz,Pr2H)2(u-OCH3)]2(N03)2, [Cu(PztBuiPrH)2(^OCH3)]2(N03)2.2CH3OH, [Cu(Pz'Pr2H)3(N03)(p-Cl-OBz)].CH3CN, [Cu(PztBu'lPrH)3(N03)(p-Cl-OBz)], [Cu(p-CH3- OBz)2(PzlPr2H)]2.2CH3CN, [Cu(^-CH3-OBz)2(PztBu'PrH)]2, [Cu(p-OCH3- OBz)2(CH3CN)]2.2CH3CN, [Cu(/?-CN-OBz)(CH3CN)]2 has been presented in third chapter of the thesis. These complexes have also been characterized by different techniques including X-ray crystallography and further used for theDNA interaction. The low temperature magnetic measurements were also presented. DNA binding characteristics studies of these complexes were performed through UV absorption titration, viscosity and gel electrophoresis. The cleavage studies show that it is the hydroxyl radical which is involved in the mechanism of DNA cleavage and the DNA cleavage property increases with increase in the nuclearity The chapter four of the thesis deals with the preparation of pyrazole based ionic salts with both organic as well as inorganic acids. The reaction ofphenylphosphonic acid with different substituted ditopic pyrazole (PzH, PzMe2H, PzPhMeH and Pz,Pr2H) gave neutral salts. In case of plane pyrazole and 3,5-dimethylpyrazole, diamond shaped and triangular cavity has been formed. As the substitution increases at 3 and 5 position of pyrazole, the cavity disappears. The different copper phosphonate complexes have been synthesized hydrothermally. Further attempts have been made to prepare hydrochloric salts of variety of ditopic pyrazoles PzPh'McI I2+-CF, PzPh2PI2+-Cl\ PzCum'MeH2+-Cl\ The treatment of 3,5- diphenylpyrazole with different acids afford salt viz., Pzph2H2+-H2P04", Pz H2+-N03" .H20, 8Pzph2H2+.4HS04\2S04\3H20, Pzph2H2+-C104\H2O.CH3OH. The presence of different anion leads to the change in packing which involves change in number and type of interaction and the orientation of the molecules in the three dimensional space. In another set of experiment isostructural co-crystals of adenosine [Ade] with a variety of 5- halouracil (5X-Ura where X= F, CI, Br and I) in 1:1 ratio have been prepared. The antitumor and DNA cleavage activity shows depressed activity of flouro and chlorouracil in presence of adenosine. Theoretical studies suggested that the structure remain the same in both solid and gaseous phase and the hydrogen bond interaction energy largely depend on the substituents in different salts and co-crystals. The material reagents, synthetic procedures, experimental details, theoretical calculation, molecular modeling and different type of spectroscopic measurements for DNA interactions are described in chapter five of the thesis. Methods for the preparation of different type of ligands and their complexes with Copper (II) and also synthesis of salt and co-crystals have been reported.