Cobaltoceniumselenolate Gold(I) Complexes: Synthesis, Spectroscopic, Structural and Anticancer Properties

Abstract Cobaltoceniumselenolate is an unusual, highly air‐sensitive, mesoionic compound containing a very soft anionic selenium donor atom. Here we explore its coordination chemistry with Au(I) metal centers and show that its hetero‐ and homoleptic gold complexes are highly colored, air‐stable compounds, which were characterized by 1H/13C/31P/77Se NMR, IR, UV‐Vis, HR‐MS and single crystal XRD. Cytotoxicity of these polar, water‐soluble complexes was studied against various standard cancer cell lines (A549MDA‐MB‐231, HT‐29) revealing good anticancer activity of all three complexes.

gold(III) complex, and on its cobaltoceniumselenolate derivative CcSe (1) (Scheme 1), [5] that was prepared to evaluate the σdonor character and π-backbonding ability of this unusual redox-responsive organometallic carbene by its 77 Se NMR properties. Cobaltoceniumselenolate (1) is an extremely airsensitive, dark purple compound with a zwitterionic structure composed of an undistorted cationic cobaltocenium moiety with an anionic selenido substituent, as shown by single crystal structure analysis (Scheme 1). [5] Compared to the air-stable selenium derivatives of standard NHCs, cyclic selenoureas, [2] which feature a selenium-carbon double bond, 1 is electronically clearly distinctly different and represents the unusual case of a neutral selenolate ligand. In addition, contrarious steric properties are evident for 1 (axial shielding by the cobaltocenium moiety) and cyclic selenoureas (peripheral shielding by the wingtip substituents). Hence we became interested to investigate Au(I) complexes of 1 in comparison to their cyclic selenourea complexes and for potential applications as new metallodrugs, inspired by current studies in anticancer research on redox-active metal complexes, [6] gold anticancer metallodrugs, [7] and organoselenium anticancer agents. [8] Synthesis: Cobaltoceniumselenolate (1) is available from iodocobaltocenium hexafluoridophosphate [9] by a nucleophilic aromatic substitution with sodium selenide under strictly inert conditions as recently published. [5] In-situ synthesis of 1 followed by oxidation on air led to its dicationic diselenide bis (hexafluoridophosphate) 2 a [CcSeSeCc](PF 6 ) 2 in a satisfying yield of 75 % (Scheme 2). Because it proved quite difficult to obtain suitable single crystals for 2 a, we synthesized also its tetraphenylborate analog 2 b [CcSeSeCc][B(C 6 H 5 ) 4 ] 2 in a similar manner using sodium tetraphenylborate in the work-up procedure (see Supporting Information). As desired, goodquality single crystals of 2 b could be obtained for the XRD analysis discussed below. Reaction of the cobaltoceniumselenolate (1) with (triphenylphosphine)gold chloride afforded either hetero or homoleptic complexes, depending on stoichiometry (Scheme 2). In a 1 : 1 CcSe:Au ratio, heteroleptic [(CcSe)(PPh 3 )Au] PF 6 (3) was obtained (61 % yield), whereas a 2 : 1 CcSe:Au ratio afforded homoleptic [(CcSe) 2 Au]PF 6 (4) in 56 % yield.
Physical, spectroscopic and structural properties (for details and spectra see Supporting Information): Complexes 2 ab, 3 and 4 are air-stable salts with melting points from 135-162°C, soluble in polar solvents like acetonitrile, dimethylformamide, dimethylsulfoxide, acetone, nitromethane, methanol and to a lesser degree in dichloromethane and water. Whereas dicationic diselenides 2 ab are yellow compounds, monocationic gold(I) selenolate complexes 3 and 4 are highly colored dark-red materials, due to their strong selenium-gold charge-transfer absorptions ( Figure 1). 1 H NMR spectra of 2 ab, 3 and 4 showed the typical pattern of monosubstituted metallocenes [s(5H), Cp and 2 × pseudo-t(2H), substituted Cp] in the usual spectral region of cobaltocenium salts (5.3-6.0 ppm), in addition to phenyl-hydrogen signals in the aromatic region for tetraphenylborate salt 2 a and triphenylphosphine complex 3. 13 C NMR spectra of 2 a, 3 and 4 displayed their cobaltocenium signals at 85-89 ppm (Cp and CÀ H carbons of substituted Cp) and those of the substituted carbon resonances at 96.2 (2 a), 104 (3) and 88.6 (4), indicative of the difference in their structure [diselenide 2 a versus heteroleptic 3 and homoleptic 4 CcSe Au(I) complexes). For 3 the 31 P NMR signals were observed at 39.2 ppm [PPh 3 coordinated to Au(I)] and À 143.3 ppm [PF 6 À , septet, 1 J( 19 FÀ 31 P) = 706 Hz]. 77 Se NMR chemical shifts of 2 a and 3 were detected at 429 and 596 ppm versus dimethylselenide as reference. Unfortunately, no signal could be observed for complex 4, even on very long data acquisition periods, probably due to poor relaxation properties. In comparison to the 77 Se signal of the free CcSe ligand [δ( 77 Se) = 258 ppm], [5] the Au(I)coordinated CcSe ligand in complex 3 [δ( 77 Se) = 596 ppm] is highly deshielded by 338 ppm. IR spectra of 2 a, 3 and 4 are rather simple with the most prominent signals at approximately 810 and 550 cm À 1 arising from the strong ν P-F absorptions of the hexafluoridophosphate counterions. The identity of compounds 2 a, 3 and 4 is further corroborated by their high-resolution mass spectra with excellent agreement of experimental with calculated values.
Summary: Starting from the zwitterionic cobaltoceniumselenolate ligand, CcSe, its diselenide oxidation product [CcSeSeCc] 2 + and monocationic hetero/homoleptic [(CcSe)(PPh 3 )Au]PF 6 /[(CcSe) 2 Au]PF 6 gold(I) complexes were obtained. All three compounds are air-stable materials that were fully characterized by spectroscopic techniques (multinuclear NMR, IR, HR-MS, UV-Vis, XRD). Cytotoxic effects were observed with all three complexes against three selected cancer cell lines. Introduction of the gold(I) center significantly increased the cytotoxic activity of the cobaltoceniumselenolates.
Supporting Information (see footnote on the first page of this article): Experimental details, spectra, X-ray and crystallographic refinement details.
Deposition Numbers 2081773 (for 2 b), 2081774 (for 3) and 2081775 (for 4) contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/structures.