Coordination chemistry and solution behaviour of gold (I) complexes
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Date
2007-11
Authors
Sam, Zolisa Agnes
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University of the Free State
Abstract
English: The aim of this study was to extend the knowledge base of gold(I) coordination chemistry and investigate the substitution behaviour of these complexes with sulphurdonor ligands. The water-soluble and air-stable ligand 1,3,5-triaza-7- phosphatricyclo[3.3.1.13,7]decane (PTA) with low steric demand was employed in the synthesis of the various complexes in this study. The [Au(PTA)Cl] complex was reacted with S-donor ligands such as SCN¯, thiourea and methyl thiourea and the equilibrium constant determination was done using 31P NMR by monitoring the chemical shift change when stoichiometric amounts of the ligand are added to the [Au(PTA)Cl] solution. The equilibrium constants obtained were 0.070(6), 4.191(1) and 6.734(3) for SCN¯, thiourea and methyl thiourea as entering ligands, respectively. The X-ray crystal structure of the inclusion of the PTA ‘guest’ molecule into the ‘host’ b- cyclodextrin (b-CD) was determined. The PTA-b-CD·8H2O inclusion compound crystallises in the monoclinic space group P21 with eight solvent water molecules in an asymmetric unit and was refined to a final R value of 4.35%. The packing within the PTA-b-CD·8H2O inclusion compound is of a ‘herring-bone’ type motif. An attempt to include auranofin {[Au(PEt3)(Sgluc)]; Sgluc = thioglucose} into the cavity of the b- cyclodextrin resulted in only auranofin crystallising without being included. However, since the data collection for the auranofin compound was done at 100 K, careful observations in parameters such as selected torsion and bond angles were noted to have 1-4° changes as compared to the known auranofin structure investigated at room temperature, which clearly indicated a phase change and a new polymorph at 100 K. The pure auranofin compound investigated in this study crystallises in the monoclinic space group P21 and was refined to a final R value of 1.59%. Further study of the interactions of b-cyclodextrin with PTA and related ligands and gold(I) complexes in this study was investigated with NMR spectroscopy. This was done by the determination of the equilibrium constant when these complexes are included into the b-cyclodextrin. The equilibrium constants calculated for PTA, (PTAMe)+ and PPh3 were 8.7(1) x 102 and 23(4) and 10(6) M-1, respectively, while for the [Au(PTAMe)Cl] and [Au(dppe)2]Cl equilibrium constants of 23(5) and 6(1) M-1 were obtained. The PTA ligand clearly showed the largest ‘host-guest’ stability. The solubility of the phenyl compounds, following the inclusion, was not improved that much as compared to the PTA compounds which may be due to steric hindrance and orientation of the phenyl groups being too large to be incorporated into the b-cyclodextrin. This phenomenon is also noted in the unsuccessful incorporation of auranofin which may be due the orientation of the ethyl groups into b-cyclodextrin. In an attempt to increase the solubility of these gold(I) complexes, bidentate P-donor ligand systems with a bridging ferrocene group, functionalised by hydrophilic moieties, were synthesised. These complexes were unambiguously characterised by X-ray crystallography. The following dinuclear gold(I) crystal structures are reported, with their general crystal data reported in parenthesis: [(AuCl)2(m-dppf-CH(CH3)N(CH3)2)] (Monoclinic, P21/n, R = 4.94%) [(AuSCN)2(m-dppf-CH(CH3)N(CH3)2)] (Triclinic, P 1 , R = 5.76%) [(AuCl)2(m-dppf-CH(CH3)OAc)] (Orthorhombic, Pbca, R = 4.09%) [(AuSCN)2(m-dppf-CH(CH3)OAc)] (Triclinic, P 1 , R = 4.36%) [(AuSCN)2(m-dppf)] (Monoclinic, C2/c, R = 2.36%) The SCN¯ ligand in the thiocyanato gold(I) dppf structures coordinated to the soft Au(I) metal centre via the softer S atom. An interesting factor was the isomorphism identified for the two [(AuSCN)2(m-dppf-CH(CH3)N(CH3)2)] and [(AuSCN)2(m-dppf-CH(CH3)OAc)] structures while the structure for the [(AuSCN)2(m-dppf)] compound was interlinked by short Au…Au contacts of 2.9798(7) Å of which none were observed for the other structures. Auranofin and its derivative compounds such as PTA-auranofin, PTAMe-auranofin and triethylarsine-auranofin were utilised and tested for biological activity against cancer cell lines. Furthermore, a preliminary chemiluminescence assay was done with the compounds at three different concentrations (0.3, 3.1 and 12.5 mM for each compound) to determine their effect on the chemiluminescence of isolated blood neutrophils. The auranofin compound was included in the investigations as reference. The A2780 human ovarian cancer cell lines are the most sensitive to all derivatives while the arsine-auranofin compound showed good activity against A2780 human ovarian cancer cell lines with an IC50 of only about 0.0076 mg/mL. Generally, auranofin and arsineauranofin gave results closely related to each other with arsine-auranofin having higher toxicity to other cells whereas PTA-auranofin and PTAMe-auranofin showed more correlation to each other and had less activity. For the preliminary chemiluminescence assays it can be mentioned that for all auranofin derivatives, at low concentrations the compounds act as stimulants to the neutrophil chemiluminescence activity and at higher concentrations the compounds act as inhibitors to neutrophil activity. Complex substitution behaviour was observed for selected gold(I) dinuclear {[(AuCl)2(m- dppf-CH(CH3)OAc)]} and mononuclear systems {[Au(PX)Cl]; X = Ph3 or Ph2Fc} when the chloride is substituted with ligands such as L-cysteine and SCN¯ as studied by UVVis and 31P NMR. Furthermore, fast reaction kinetics for the chloride substitution with ligands such as SCN¯ and dimethylthiourea from the mononuclear [Au(PPh3)Cl] complex was investigated with stopped-flow techniques. The overall rate constants for the substitutions from [Au(PPh3)Cl] with SCN¯ and dimethyl thiourea representing the forward reactions were obtained as k1 = 13(1) and 2.17(1) x 103 M-1s-1 respectively. Thus, it was concluded that chloride substitution reactions on linear gold(I) systems are extremely fast reactions.
Afrikaans: Die doel van hierdie ondersoek was om die kennis tov die koordinasiechemie van goud(I) komplekse uit te brei deur die substitusiegedrag van ‘n reeks komplekse met swaweldonoratoomligande te ondersoek. Die wateroplosbare en lugstabiele ligand, 1,3,5-triaza-7-fosfatrisiklo[3.3.1.13,7]dekaan (PTA) wat ‘n klein steriese parameter het, is gebruik om enkele monomeriese komplekse te berei. Die [Au(PTA)Cl] kompleks is met S-donorligande soos SCN￣, tioureum en metieltioureum gereageer en die ewewigskonstantes vir die chloriedsubstitusie is mbv 31P NMR bepaal deur die verandering in chemiese verskuiwing as ‘n funksie van bygevoegde ligand te bepaal. Ewewigskonstantes van 0.070(6), 4.191(1) en 6.734(3) is onderskeidelik vir SCN￣, tioureum en metieltioureum as inkomende ligande, verkry. Die X-straalkristalstruktuur van die insluiting van die PTA gasentiteit in die b- siklodekstrien (b-CD) gasheer, is bepaal. Die PTA-b-CD·8H2O insluitingkompleks kristalliseer in die monokliniese ruimtegroep met agt solvaatwatermolekule in ’n asimmetriese eenheid en het verfyn na ’n R-waarde van 4.35%, met ’n visgraattipe pakkingspatroon. In ’n poging om ook die auranofin {[Au(PEt3)(Sgluk)]; Sgluk = tioglukose} binne die b-siklodekstrien as inslutingsproduk te verkry was onsuksesvol, en slegs die auranofinmolekuul het gekristalliseer. Nadat die kristaldata-opname by 100 K gedoen is, het dit geblyk dat daar betekenisvolle verskille in sekere bindingsparameters, van 1 tot 4° in sekere gevalle van die kamertemperatuuropname verskil, bestaan, en het bevestig dat ‘n nuwe polimorf van auranofin by 100 K bestaan. Die suiwer auranofin hier genoem kristalliseer in die monokliniese ruimtegroep P21 en het verfyn tot ‘n finale R-waarde van 1.59%. Verdere interaksies van die b-siklodekstrien met PTA, verwante ligande en goud(I) komplekse, is met behulp van KMR spektroskopie ondersoek deur die ewewigskonstantes van hierdie prosesse te bepaal. Waardes van 8.7(1) x 102, 23(4) en 10(6) M-1 vir PTA, (PTAMe)+ en PPh3 onderskeidelik verkry, terwyl die [Au(PTAMe)Cl] en [Au(dppe)2]Cl ewewigskonstantes van 23(5) en 6(1) M-1 gelewer het. Die PTA insluitingskompleks was dus duidelik die stabielste. Die oplosbaarheid van die verbindings is nie noemenswaardig deur die byvoeging van die sikliese suiker verbeter nie, moontlik as gevolg van steriese faktore en gepaardgaande swak interaksie met die b-siklodekstrien, terwyl die etielgroepe in auranofin waarskynlik soortgelyke afstotende eienskappe vertoon. In ‘n poging om die oplosbaarheid van hierdie fosfienkomplekse te verbeter, is bimetaalkomplekse met ferroseenbrugligande gesintetiseer. Hidrofiliese wateroplosbare entiteite is aan die ferroseengroep geheg. Hierdie komplekse is eenduidig met behulp van X-straalkristallografie gekarakteriseer, en is soos volg (algemene kristaldata in hakies): [(AuCl)2(u-dppf-CH(CH3)N(CH3)2)] (Monoklinies, P21/n, R = 4.94%) [(AuSCN)2(u-dppf-CH(CH3)N(CH3)2)] (Triklinies, P 1 , R = 5.76%) [(AuCl)2(u-dppf-CH(CH3)OAc)] (Ortorombiies, Pbca, R = 4.09%) [(AuSCN)2(u-dppf-CH(CH3)OAc)] (Triklinies, P 1 , R = 4.36%) [(AuSCN)2(u-dppf)] (Monoklinies, C2/c, R = 2.36%) Die SCN￣ ligand in die tiosianato goud(I) dppf strukture koordineer aan die sagte Au(I) metaalsenter via die sagte swawelatoom. ‘n Interessante waarneming is dat die twee [(AuSCN)2(u-dppf-CH(CH3)N(CH3)2)] en [(AuSCN)2(u-dppf-CH(CH3)OAc)] structure isomorf aanmekaar is, terwyl die [(AuSCN)2(u-dppf)] verbinding intermolekulêre Au…Au kontakafstande van 2.9798(7) Å, wat nie in enige van die ander structure bestaan nie, toon. Auranofin en sy derivate soos die genoemde PTA-auranofin, PTAMe-auranofin en trietielarsienauranofin se biologiese aktiwiteit teen kankerselle is bepaal. Hierdie verbindings se chemiluminisensie is by drie konsentrasies (0.3, 3.1 en 12.5 uM vir elke verbinding) ook evalueer om die effek van inhibering op geïsoleerde bloedneutrofiele te bepaal met auranofin as verwysing. Die A2780 menslike ovariumkanker sellyne was die mees sensitiefste en die arsien-auranofin het baie goeie aktiwiteit getoon met ‘n IC50 van slegs 0.0076 ug/mL. In die algemeen het auranofin en arsien-auranofin soortgelyke resultate gelewer, maar die arsienkompleks het groter toksisiteit teen ander selle getoon. PTA-auranofin en PTAMe-auranofin, aan die ander kant, het baie laer aktiwiteit getoon. In die chemiluminesensiemetings het al die auranofi nverbindings by lae konsentrasies as neurofiliese stimulante opgetree maar as inhibeerders by hoër konsentrasies. Komplekse substitusiegedrag van die chloriedligand is waargeneem vir geselekteerde goud(I) bimetaal {[(AuCl)2(u-dppf-CH(CH3)OAc)]} en monokernige {[Au(PX)Cl]; X = Ph3 of Ph2Fc} komplekse met ligande L-sisteïn en SCN￣ soos deur UV-sigbare en 31P KMR bestudeer. Baie vinnige reaksietempo’s is vir die chloriedsubstitusie van die [Au(PPh3)Cl] kompleks met ligande soos SCN￣ en dimetieltioureum met behulp van stopvloeispektrofotometrie waargeneem. Die tempokonstantes vir die voorwaartse reaksies vir hierdie chloriedsubstitusie deur SCN￣ en dimetieltioureum is k1 = 13(1) en 2.17(1) x 103 M-1s-1 onderskeidelik, bepaal. Dit is dus duidelik dat hierdie tipe reaksies baie vinnig plaasvind.
Afrikaans: Die doel van hierdie ondersoek was om die kennis tov die koordinasiechemie van goud(I) komplekse uit te brei deur die substitusiegedrag van ‘n reeks komplekse met swaweldonoratoomligande te ondersoek. Die wateroplosbare en lugstabiele ligand, 1,3,5-triaza-7-fosfatrisiklo[3.3.1.13,7]dekaan (PTA) wat ‘n klein steriese parameter het, is gebruik om enkele monomeriese komplekse te berei. Die [Au(PTA)Cl] kompleks is met S-donorligande soos SCN￣, tioureum en metieltioureum gereageer en die ewewigskonstantes vir die chloriedsubstitusie is mbv 31P NMR bepaal deur die verandering in chemiese verskuiwing as ‘n funksie van bygevoegde ligand te bepaal. Ewewigskonstantes van 0.070(6), 4.191(1) en 6.734(3) is onderskeidelik vir SCN￣, tioureum en metieltioureum as inkomende ligande, verkry. Die X-straalkristalstruktuur van die insluiting van die PTA gasentiteit in die b- siklodekstrien (b-CD) gasheer, is bepaal. Die PTA-b-CD·8H2O insluitingkompleks kristalliseer in die monokliniese ruimtegroep met agt solvaatwatermolekule in ’n asimmetriese eenheid en het verfyn na ’n R-waarde van 4.35%, met ’n visgraattipe pakkingspatroon. In ’n poging om ook die auranofin {[Au(PEt3)(Sgluk)]; Sgluk = tioglukose} binne die b-siklodekstrien as inslutingsproduk te verkry was onsuksesvol, en slegs die auranofinmolekuul het gekristalliseer. Nadat die kristaldata-opname by 100 K gedoen is, het dit geblyk dat daar betekenisvolle verskille in sekere bindingsparameters, van 1 tot 4° in sekere gevalle van die kamertemperatuuropname verskil, bestaan, en het bevestig dat ‘n nuwe polimorf van auranofin by 100 K bestaan. Die suiwer auranofin hier genoem kristalliseer in die monokliniese ruimtegroep P21 en het verfyn tot ‘n finale R-waarde van 1.59%. Verdere interaksies van die b-siklodekstrien met PTA, verwante ligande en goud(I) komplekse, is met behulp van KMR spektroskopie ondersoek deur die ewewigskonstantes van hierdie prosesse te bepaal. Waardes van 8.7(1) x 102, 23(4) en 10(6) M-1 vir PTA, (PTAMe)+ en PPh3 onderskeidelik verkry, terwyl die [Au(PTAMe)Cl] en [Au(dppe)2]Cl ewewigskonstantes van 23(5) en 6(1) M-1 gelewer het. Die PTA insluitingskompleks was dus duidelik die stabielste. Die oplosbaarheid van die verbindings is nie noemenswaardig deur die byvoeging van die sikliese suiker verbeter nie, moontlik as gevolg van steriese faktore en gepaardgaande swak interaksie met die b-siklodekstrien, terwyl die etielgroepe in auranofin waarskynlik soortgelyke afstotende eienskappe vertoon. In ‘n poging om die oplosbaarheid van hierdie fosfienkomplekse te verbeter, is bimetaalkomplekse met ferroseenbrugligande gesintetiseer. Hidrofiliese wateroplosbare entiteite is aan die ferroseengroep geheg. Hierdie komplekse is eenduidig met behulp van X-straalkristallografie gekarakteriseer, en is soos volg (algemene kristaldata in hakies): [(AuCl)2(u-dppf-CH(CH3)N(CH3)2)] (Monoklinies, P21/n, R = 4.94%) [(AuSCN)2(u-dppf-CH(CH3)N(CH3)2)] (Triklinies, P 1 , R = 5.76%) [(AuCl)2(u-dppf-CH(CH3)OAc)] (Ortorombiies, Pbca, R = 4.09%) [(AuSCN)2(u-dppf-CH(CH3)OAc)] (Triklinies, P 1 , R = 4.36%) [(AuSCN)2(u-dppf)] (Monoklinies, C2/c, R = 2.36%) Die SCN￣ ligand in die tiosianato goud(I) dppf strukture koordineer aan die sagte Au(I) metaalsenter via die sagte swawelatoom. ‘n Interessante waarneming is dat die twee [(AuSCN)2(u-dppf-CH(CH3)N(CH3)2)] en [(AuSCN)2(u-dppf-CH(CH3)OAc)] structure isomorf aanmekaar is, terwyl die [(AuSCN)2(u-dppf)] verbinding intermolekulêre Au…Au kontakafstande van 2.9798(7) Å, wat nie in enige van die ander structure bestaan nie, toon. Auranofin en sy derivate soos die genoemde PTA-auranofin, PTAMe-auranofin en trietielarsienauranofin se biologiese aktiwiteit teen kankerselle is bepaal. Hierdie verbindings se chemiluminisensie is by drie konsentrasies (0.3, 3.1 en 12.5 uM vir elke verbinding) ook evalueer om die effek van inhibering op geïsoleerde bloedneutrofiele te bepaal met auranofin as verwysing. Die A2780 menslike ovariumkanker sellyne was die mees sensitiefste en die arsien-auranofin het baie goeie aktiwiteit getoon met ‘n IC50 van slegs 0.0076 ug/mL. In die algemeen het auranofin en arsien-auranofin soortgelyke resultate gelewer, maar die arsienkompleks het groter toksisiteit teen ander selle getoon. PTA-auranofin en PTAMe-auranofin, aan die ander kant, het baie laer aktiwiteit getoon. In die chemiluminesensiemetings het al die auranofi nverbindings by lae konsentrasies as neurofiliese stimulante opgetree maar as inhibeerders by hoër konsentrasies. Komplekse substitusiegedrag van die chloriedligand is waargeneem vir geselekteerde goud(I) bimetaal {[(AuCl)2(u-dppf-CH(CH3)OAc)]} en monokernige {[Au(PX)Cl]; X = Ph3 of Ph2Fc} komplekse met ligande L-sisteïn en SCN￣ soos deur UV-sigbare en 31P KMR bestudeer. Baie vinnige reaksietempo’s is vir die chloriedsubstitusie van die [Au(PPh3)Cl] kompleks met ligande soos SCN￣ en dimetieltioureum met behulp van stopvloeispektrofotometrie waargeneem. Die tempokonstantes vir die voorwaartse reaksies vir hierdie chloriedsubstitusie deur SCN￣ en dimetieltioureum is k1 = 13(1) en 2.17(1) x 103 M-1s-1 onderskeidelik, bepaal. Dit is dus duidelik dat hierdie tipe reaksies baie vinnig plaasvind.
Description
Keywords
X-ray crystal structure, Auranofin, Ferrocenyl phosphine, Equilibrium constant, S-donor ligands, Substitution, 1-3-5-triaza-7-phosphatricyclo[3.3.1.13-7]decane, ß-cyclodextrin, Gold(I) complexes, Gold compounds, Ligands, Coordination compounds, Thesis (Ph.D. (Chemistry))--University of the Free State, 2007