Znorg. Chem. 1993, 32, 2506-2517
2506
Synthesis, Structure, and Electronic Spectroscopy of Neutral, Dinuclear Gold(1) Complexes. Gold(1)-Gold(1) Interactions in Solution and in the Solid State Ratnavathany Narayanaswamy,lPMichelle A. Young,ln Erica Parkhurst,tJPMichelle Ouellette,zJ* Margaret E. Kerr,lP Douglas M. Ho,lbJcRichard C. Elder,*JbAlice E. Bruce,'JPand Mitchell R. M. Bruce*Ja Departments of Chemistry, University of Maine, Orono, Maine 04469, and University of Cincinnati, Cincinnati, Ohio 45221
Received August 7, 1992 A series of neutral, dinuclear gold(1) complexes containing phosphine and thiolate ligands have been synthesized and characterized by elemental analysis and by 'H and 31PNMR and UV-visible spectroscopy. Crystal structures of two of the complexes are reported. [Auz@-tc)2(dppb)] (4) crystallizes in the triclinic space group Pi ( Z = 2) with unit cell dimensions a = 10.757(2) A, b = 13.177(2) A, c = 14.630(3) A, a = 82,23(1)O, /3 = 83.16(1)O, and y = 75.42(1)O; R = 0.0286. [A~~@-tc)~(dpppn)] (5) crystallizes in the monoclinic spacegroup P2,/n ( Z = 4) with unit cell dimensions a = 12.007(1) A, b = 25.292(5) A, c = 13.421(2) A, and /3 = 94.92(1)'; R = 0.0432. The structures of 4 and 5 are similar; each has linear, two-coordinate gold atoms connected via a bridging bis(phosphine) to form an open-chain dinuclear complex. The dinuclear units are then connected via short intermolecular gold(1)gold(1) interactions to form polymeric chains. The intermolecular Au-Au distances for 4 and 5 are 3.094(1) and 3.200( 1) A, respectively. Other similar complexes include [A~~@-tc)~(dppm)] (l),[Au2@-tc)2(dppe)] (2), and [A~~(p-tc)~(dppp)] (3). Cyclic dinuclear gold(1) complexes with bridging bis(phosphine) and dithiolate ligands are also reported: [Au(dppe)(pdt)AuI (6), [Au(dppp)(pdt)AuI (71, [Au(dppb)(pdt)Aul (8), [Au(dpepn)(pdt)Au1(9), and [Au(dppe)(tdt)Au] (10). The following abbreviations are used: dppm = bis(dipheny1phosphino)methane; dppe = 1,2-bis(diphenylphosphino)ethane; dppp = 1,3-bis(diphenylphosphino)propane; dppb = 1,4-bis(diphenyIphosphino)butane; dpppn = 1,5-bis(diphenylphosphino)pentane;PMe3= trimethylphosphine; PPh3 = triphenylphosphine; p-tc = p-thiocresol; pdt = 1,3-propanedithiol; tdt = 3,4-toluenedithiol. Spectral features of the dinuclear gold complexes are compared to those of the mononuclear complexes Au(PPhj)@-tc) (11) and Au(PMe3)@-tc) (12). Analysis of the electronic absorption spectra from Gaussian band spectral fitting, comparison to free ligand spectra, studies of solvatochromism, and alterations of the phosphine and thiolate ligands indicate that the two lowest energy transitions in 1-9, 11, and 12 are LMCT (S Au) transitions. The spectra for the open-chain complexes, 2-5 in which the length of the bis(phosphine) backbone successively increases by 1, are very similar and show no absorption bands below 3.0 X lo4cm-I. However, the lowest energy transition for the smallest member of this series, 1 (which is yellow), is significantly red shifted, occurring a t 2.8 X lo4 cm-I. A similar trend is observed for the two smallest members of the cyclic series, 6 and 7 compared to 8 and 9. Variable-temperature NMR experiments reveal the presence of dynamic processes for 1,6, and 9. The activation energy, determined by line shape analysis, is approximately 10 kcal/mol for 1 and 9 and less than 10 kcal/mol for 6. The observed red shift in the LMCT transitions and the variable-temperature behavior are consistent with the presence of intramolecular gold(1)-gold(1) interactions in solution for 1 and 6-9. The implications of these results for biological systems are considered.
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Introduction Gold(1) thiolate complexes have been used for the treatment of rheumatoid arthritis for over 60 years, despite the fact that the mechanism by which these drugs affect the course of the disease is not well understood.2 Water-soluble, injectable gold drugs such as Myochrysine [gold(I) sodium thiomalate] and Solganol [gold(I) thioglucose] are anionic and exist as gold-thiolate
* Corresponding authors. Comments concerning the crystal structure should be addressed to R.C.E. Upward Bound student. 3 Project SEED student. (1) (a) University of Maine. (b) University of Cincinnati. (c) Present address: Department of Chemistry, Princeton University, Princeton, +
NJ 08544. (2) (a) Walz, D. T. Mechanisms of Action of Gold Salts in Rheumatoid Arthritis. In Advances in Inflammation Research; Otterness, I., Capetola, R., Wong, S . , Eds.; Raven Press: New York, 1984; Vol. 7, p 239. (b) Brown, D. H.; Smith, W. E. Chem. SOC.Rev. 1980, 9, 217. (c) Shaw, C. F., 111. Inorg. Persprcr. B i d . Med. 1979, 2, 287. (d) Sadler, P. J. Srruct. Bonding (Berlin) 1976, 29, 17 1. (3) (a) Elder, R. C.; Ludwig, K.; Cooper, J. N.; Eidsness, M. K. J. Am. Chrm. SOC.1985, 107, 5024. (b) AI-Sa'ady, A. K. H.; Moss, K.; McAuliffe, C. A,; Parish, R. V. J . Chem. Soc., Dalton Trans. 1984, 1609. (c) Isab, A. A.; Sadler, P. J. J. Chem. Soc., Dalron Trans. 1981, 1657. (d) Isab, A. A.; Sadler, P. J. J . Chem. Soc., Chem. Commun. 1976, 1051.
oligomers in ~olution.~ In contrast, the orally administered drug Auranofin [(tetraacetylthioglucse)(triethylphosphine)gold(I)], approved for use in the 1980s, is a neutral, mononuclear gold complex composed of phosphine as well as thiolate ligand^.^ In addition to the importance of thiolate ligands in the formulation of gold drugs, binding of gold(1) to thiolate functions in proteins is expected to play a key role in the molecular pharmacology of gold. For example, it is well established that gold circulates in the bloodstream bound to cysteine-34 in the protein albumin, and facile thiolate exchange reactions have been proposed to account for transport of gold from the bloodstream to joints and organs throughout the body.5 An intriguing phenomenon in gold chemistry which has received attention in both theoretical and experimental studies is the propensity for weak bonding interactions between closed shell, (4) (a) Sutton, B. M.; McGusty, E.; Walz, D. T.; DiMartino, M. J. J . Med. Chem. 1972, 15, 1095. (b) Hill, D. T.; Sutton, 9. M. Crysf.Srrucr. Commun. 1980, 9, 679. (c) See ref 3a. (5) (a) Shaw, C. F., 111; Coffer, M. T.; Klingbeil, J.; Mirabelli, C. K. J . Am. Chem.SOC.1988,110,729. (b) Coffer, M. T.;Shaw,C. F., 111; Eidsness, M. K.; Watkins, J. W., 11; Elder, R. C. Inorg. Chem. 1986,25,333. (c) Isab, A. A,; Sadler, P. J. J . Chem. Soc., Dalron Trans. 1982, 135. (d) Snyder, R. M.; Mirabelli, C. K.; Crooke, S . T. Biochem. Pharmacol. 1986, 35, 923.
0020-1669/93/1332-2506$04.00/0 0 1993 American Chemical Society
Neutral, Dinuclear Gold(1) Complexes dI0 gold(1) atoms.6 In the solid state, evidence for a weak bond between gold atoms is providedby Au(1)-Au(1) separations(2.783.25 A), which are less than the van der Waals radii for g0ld.7 Schmidbaur et al. have estimated the strength of gold-gold interactions on the order of 5-15 kcal/mol.6a This estimate is based upon the observation that coordinationof a bis(phosphine) molecule to two Au(I)-Cl fragments alters the ground-state conformation of the phosphine ligand as a result of a gold(1)gold(1) interaction (eq 1).* The energiesof gold(1)-gold(1) bonds
are the same order of magnitude as those of hydrogen bonds, which are important factors for determining protein structure and function. An interesting question to consider is whether goldgold interactionscan form under biological conditions and, if so, whether they can influence protein conformation and function. We are investigatingseveral seriesof neutral,dinuclear gold(1) complexes containing phosphine and thiolate ligands, in which the length of the bridging bis(phosphine) backbone is systematically changed (see Table I). In 1-5, the number of methylene groups in the bis(phosphine) backbone increases from 1 to 5, forming an increasingly larger series of open-chain, dinuclear gold complexes. The same series of bis(phosphines) are used in 69; however use of an aliphatic dithiolate is expected to create an increasinglylarger series of cyclic, dinuclear gold complexes. Finally, by using an aromatic dithiolate, a more rigid, cyclic dinuclear gold complex should be formed (10). Our short-term goals are (1) to investigate the structure and bonding (in the solid state and solution) in these dinuclear gold complexes, with the specificaim of determiningwhether gold(1)-gold(1) interactions occur and (2) to determine if the Occurrence of gold(1)-gold(1) interactions can be correlated with ring size (which is directly related to the number of methylene units in the bis(phosphine) backbone) or rigidity of the complex. Our longer term goals are to use the information obtained from studies on model complexes to investigatethe occurrence of gold(1)-gold(1) interactions under more biologically relevant conditions.
Experimental Section Reagents. All manipulations were performed under nitrogen, employing standard Schlenk and glovebox techniquesag Phosphines were obtained from Aldrich or Strem and used as received. HAuC14.3H20, p-thiocresol (CH$&SH), 1,3-propanedithiol [HS(CH&SH], 3,4tohenedithiol [CH3C6H3(SH)2],3,4dichlorobenzenethiol [ (C1)2C6H$H], and ethanolamine ( H ~ N C H ~ C H Z O were H ) purchased from Aldrich. Solvents were reagent grade and were used without further purification. Mononuclear and dinuclear gold phosphine chloride complexes were prepared as described in the literature.I0 Instrumental Details. The NMR data were obtained on a Varian XL-200 FT-NMR spectrometer operating at 200 MHz for IH and 81 MHz for j l P N M R . Phosphoruschemicalshiftsarereferencedtoextemal 85% H3PO4. Variable-temperature 31P(lH)N M R data were obtained for 1 (0.035 and 0.069 M), 4 (0.07 M), 6 (saturated solution), 9 (saturated (a) For a recent review see: Schmidbaur, H. Gold Bull. 1990, 23, 11. (b) Pyykk6, P.; Zhao, Y. Angew. Chem., Int. Ed. Engl. 1991, 30, 604. (c) Balch, A. L.;Fung, E.Y.; Olmstead, M. M. J. Am. Chem. SOC.1990, 112,5181. (d) Raptis,R.G.; Fackler, J. P.,Jr.;Murray, H. H.;Porter, L. C. Inorg. Chem. 1989, 28,4057. (e) King, C.; Wang, J.-C.; Khan, M. N. 1.; Fackler, J. P., Jr. Inorg. Chem. 1989, 28,2145. (f) Jiang, Y.; Alvarez, S.;Hoffmann, R. Inorg. Chem. 1985, 24, 749. Bondi, A. J . Phys. Chem. 1964,68, 441. Schmidbaur, H.; Graf, W.; Mfiller, G. Angew. Chem., Int. Ed. Engl. 1988, 27, 417. Shriver, D. F.; Drezdon, M. A. The Manipulation of Air-Sensitive Compounds, 2nd 4.;Wiley: New York, 1986. (a) Mann, F. G.; Wells, A. F.; hrdie, D. J . Chem. SOC.1937, 1828. (b) Mirabelli, C.K.;Hill, D. T.; Faucette, L. F.; McCabe, F. L.;Girard, G. R.; Bryan, D. 9.; Sutton, 9. M.; Bartus, J. 0.;Crooke, S. T.; Johnson, R. K. J . Med. Chem. 1987, 30, 2181.
Inorganic Chemistry, Vol. 32, No. I I, I993 2507 solution), and 11 (0.05 M) in CD2Cl2 from +20 to -80 OC. Variabletemperature ' H NMR data were obtained for 1(0.02 M) in CD2C12 from t 2 0 to-80 "C. Carbon and hydrogen elemental analyses were performed by Galbraith Laboratories, Knoxville, TN. UV-Visible Spectra and Spectral Fits. Electronic absorption spectra were measured in 1.O-cm quartz cuvettes using a Hewlett Packard 8452 diode array spectrophotometer. Typically, four dilutionsof eachcomplex were prepared in the concentration range (0.12-1.9) x 10-4 M. No deviations from Beer's law behavior were observed for any complex. Spectra Calc (Galactic Industries) was used to manipulate, spectrally fit, and plot allelectronicabsorptionspectra. The peakmaximaandextinction coefficients were estimated for all clearly discernible peaks. The number and approximate positions of shoulders were estimated from the first derivative of the absorption spectra. Derivative spectra were examined at several concentrations to prevent including a false positive signal that may originate from noise in an absorption spectrum. The estimates of peak positions and extinction coefficients were used as input parameters for the spectral fitting program Curvefit (Spectra Calc) in which a set of Gaussian bands is iteratively fit to theexperimental absorptionspectrum. The spectral fit was considered complete when the change in x2between successive iterations was small (15 kcal/m01).~~On the basis of the similarities in AGt for 1 ( 5 1) Binsch, G. In Dynamic Nuclear Magnetic Resonance Spectroscopy;
Jackman, L. M., Cotton, F. A., Eds.; Academic Press: New York,1975; p 49. (52) (a) Equal populationsofdifferent 3iPsitescandisplaydifferentintensities due to different T I values and NOEsjKaHowever, line shape analysis was also carried out using the graphical method of Shanan-Atidi and Bar-Eli for unequal population of sites.S2bBy using this method, the calculated AG? is also 10 kcal/mol. (b) Shanan-Atidi, H.; Bar-Eli, K. H. J . Phys. Chem. 1970, 74, 961. (53) Schmidbaur, H.; Deschler, U.; Milewski-Mahrla. B. Chem. Ber. 1983, 116, 1393.
Inorganic Chemistry, Vol. 32, No. 11, 1993 2517 and 9, a likely alternative is that the dynamic process originates from equilibria between gold(1)-gold(1) bonded and nonbonded conformations. Summary. Intermolecular gold-gold interactions occur in the solid-state structures of the two largest, open-chain molecules 4 and 5 [Au-Au = 3.094( 1) and 3.200( 1) A, respectively]. All of the open-chain and cyclic dinuclear gold complexes are white, with the exception of 1, which is yellow. The lowest energy electronic transitions for complexes 1-9,11, and 12 are assigned as LMCT (S Au) transitions. The absorption spectra of the open-chain complexes 2-5 (in which n successively increases from 2 to 5) are nearly superimposable. However in complex 1, where n = 1, the lowest energy band is significantly red shifted (by 2.5 X lo3cm-I relative to that of 5). In the cyclic dinuclear gold(1) complexes a similar trend is found: the lowest energy band in 6 is red-shifted by 1.0 X lo3 cm-l relative to that of 8. We hypothesize that two factors contribute to the red shifts: gold(1)gold(1) interactions and repulsive interactions between sulfurcentered HOMO orbitals. Variable-temperature IH and 3lP NMR studies indicate the presence of fluxional processes for complexes 1, 6, and 9 but not for 4. Together, the UV-visible and variable-temperature NMR studies suggest that in solutions of 1 and 6-9 there are equilibria between fntramolecular goldgold bonded and nonbonded conformational isomers. The results of this study may have biological implications for the neutral phosphine gold(1) thiolate complexes used in the treatment of rheumatoid arthritis. It is well established that gold(1) phosphines bind to cysteine sulfur in proteins. Our study suggests that it may be possible for two Au-cysteine sites to interact via gold-gold bonds but only if the two sites are closely situated. Thus, knowledge of a protein's three-dimensional structure may provide a way of evaluating possible candidates for gold(1)-gold(1) interactions. In addition, gold-gold interactions may promote gold redox chemistry since interacting transition metals can alter redox behavi0r.~6 A lowering of the oxidation potential, for example, may lead to the generation of toxic Au(II1) complexes. Another possible site of redox activity is a disulfide bridge, where Au(1) -Au(III) oxidation may couple with disulfide reduction. Studies are now underway to evaluate these possibilities. We are also investigating gold(1)-gold( I) interactions by EXAFS spectroscopy,emission spectroscopy,and cyclicvoltammetry. These studieswill be reported in forthcoming papers.
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Acknowledgment, A.E.B. and M.R.M.B. gratefully acknowledge financial support from the National Institutes of Health (Grant AR39858) and the University of Maine BRSG funds. We thank Dr. R. Anderegg (Glaxo, Inc.) for kindly providing FAB-MS data. We are grateful to Professors J. P. Fackler, Jr., J. Nagle, G. Parkin, and J. L. Templeton for helpful discussions. Private communication of unpublished results from Professor Fackler is also acknowledged. Mr. L. Lester (at UM) is acknowledged for technical assistance. SupplementaryMaterial Available: Absorption and derivative spectra and spectral fits for 6,8, and 11(Figures A-C) and tables listing complete details of the structure determination, H atom coordinates and isotropic displacement parameters, anisotropictemperature parameters, and bond distances and angles for 4 and 5 (23 pages). Ordering information is given on any current masthead page.
(54) Hyperchem molecular modeling software by Autodesk, 2320 Marinship Way, Sausalito, CA 94965. ( 5 5 ) See ref 51, p 604. (56) (a) Downard, A. J.; Honey, G. E.; Phillips, L. F.;Steel, P. J. Inorg. Chem. 1991,30,2260. (b) Auburn, P. R.;Lever, A. B. P. Inorg. Chem. 1990, 29, 2551. (c) Koley, A. P.; hrohit, S.;Ghosh, S.;Prasa, L. S.; Manoharan, P. T. J. Chem. SOC.,Dalton Trans. 1988, 2607.
