Synthesis by ligand exchange and electrochemistry of ruthenocenyl-containing β-diketonato complexes of titanocene. Structure of [TiCp2(RcCOCHCOCH3)][ClO4]

Journal of Organometallic Chemistry xxx (2016) 1e9

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Synthesis by ligand exchange and electrochemistry of ruthenocenylcontaining b-diketonato complexes of titanocene. Structure of [TiCp2(RcCOCHCOCH3)][ClO4] Elizabeth Erasmus a, Alfred J. Muller b, Uwe Siegert a, Jannie C. Swarts a, * a b

Department of Chemistry, University of the Free State, Bloemfontein, 9300, South Africa Department of Chemistry, University of Johannesburg, Auckland Park, Johannesburg, 2006, South Africa

a r t i c l e i n f o

a b s t r a c t

Article history: Received 27 December 2015 Received in revised form 6 May 2016 Accepted 9 May 2016 Available online xxx

A new synthetic route involving ligand exchange towards a series of ruthenocenyl-containing b-diketonato titanocene complexes of the type [TiIV(C5H5)2(RcCOCHCOR)][ClO4] with Rc ¼ RuII(C5H5)(C5H4) and R ¼ C10F21 (1), CF3 (2), C6F5 (3), C10H21 (4), CH3 (5), Rc (6) and Fc ¼ FeII(C5H5)(C5H4) (7) are described. The complex [TiIV(C5H5)2(RcCOCHCOCH3)][ClO4], 5, (Z ¼ 4) crystallised in the monoclinic space group P21/n. A cyclic voltammetric electrochemical study in CH2Cl2/0.1 M [NBu4][B(C6F5)4] showed the one-electron transfer redox processes of the TiIII/TiIV and Rc/Rcþ couples exhibited irreversible electrochemical behaviour. In CH3CN/0.1 M [N(nBu)4][PF6], the ruthenocenyl couple switched to an electrochemically and chemically irreversible two-electron transfer redox couple, Rc/Rc2þ, involving the RuIV redox centre. The 0 redox potentials of the TiIII/TiIV, Rc/Rcþ and Rc/Rc2þ couples were in the range 642 < Eo < 1479 mV 0 0 (both solvents), 1016 mV < Eo < 1034 mV (CH2Cl2) and 609 mV < Eo < 832 mV (CH3CN) vs. the free ferrocene couple, FcH/FcHþ, respectively. The Fc/Fcþ redox process associated with 7 was observed at 0 Eo ¼ 0.259 (CH3CN) and 0.235 V (CH2Cl2). The cytotoxicity of [TiIV(C5H5)2(RcCOCHCOCF3)][ClO4], 2, against CoLo DM320 and HeLa cells, IC50 ¼ 10.2 and 9.7 mmol dm3 respectively, was found to be in the same order of magnitude as those of the free ligand, RcCOCH2COCF3. © 2016 Elsevier B.V. All rights reserved.

Keywords: Titanocene Ruthenocene b-diketonates Cyclic voltammetry Crystal structure Cytotoxicity

1. Introduction Metal complexes of b-diketones have been the interest of many kinetic [1], electrochemical [2], structural [2], catalytic [3] and medical studies [4]. Incorporation of the ferrocenyl group into the b-diketonato ligand imposed interesting properties on the ligand and their associated metal complexes which have been studied extensively [5]. Our group recently described the synthesis and properties of ruthenocenyl-containing b-diketones [6]. The electrochemical behaviour of the ruthenocenyl-containing b-diketones has proven to be very complex [6], similar to its parent compound, ruthenocene [7]. When the ruthenocenyl-containing b-diketones are investigated in a coordinating solvent/electrolyte system such as CH3CN/[N(nBu)4][PF6], an irreversible two electron process involving a RuII/RuIV couple is often observed [6a]. However, investigations in the non-coordinating solvent/electrolyte system [8]

* Corresponding author. E-mail address: [email protected] (J.C. Swarts).

CH2Cl2/[NBu4][B(C6F5)4], may involve an irreversible one-electron RuII/RuIII couple followed by, in analogy to ruthenocene itself [7], dimerization of the 17-electron RuIII species to regain an 18 electron configuration [6b]. This behaviour was also detected for the structurally related ruthenocenyl-containing chalcones, RcCOCH] CHR, [9]. The electrochemical behaviour of a ruthenocenylcontaining b-diketone coordinated to a transition metal has not yet been reported. It has been shown that for ruthenocene-free complexes of the type [Ti(C5H5)2(CH3COCHCOZ)][ClO4] with Z ¼ CF3, OCH3, C6H5, CH3 and Fc, the TiIII/TiIV redox couple exhibits chemical and electrochemical reversible cyclic voltammetric behaviour in CH3CN/ [N(nBu)4][PF6] [2c]. The formal reduction potential of the TiIII/TiIV couple increases as the group electronegativity, cR, of the R group of the b-diketonato ligand increases. The influence of an additional redox active centre on this TiIII/TiIV couple is, however, unexplored. The synthesis of titanium(IV) complexes is usually based on an anion metathesis reaction which is driven by precipitation of one of the products. Doyle and Tobias prepared titanocene(IV)-b-diketonato complexes via this procedure [10].

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E. Erasmus et al. / Journal of Organometallic Chemistry xxx (2016) 1e9

In this study a new, high yielding, ligand exchange synthetic protocol for the ruthenocenyl-containing b-diketonato titanocene complexes is reported and the single crystal structure of [Ti(C5H5)2(RcCOCHCOCH3)][ClO4], 5, was solved. The electrochemical properties of [Ti(C5H5)2(RcCOCHCOR][ClO4] complexes 1e7 in CH2Cl2/0.1 M [NBu4][B(C6F5)4] or CH3CN/0.1 M [N(nBu)4] [PF6] highlighted the influence of the TiIV/TiIII and Rc/Rcþ (or Rc/ Rc2þ) redox centres on each other. The cytotoxic properties of [TiIV(C5H5)2(RcCOCHCOCF3)][ClO4], 2 is also reported and compared with that of the free ligand, RcCOCH2COCF3. 2. Experimental 2.1. General procedures and instruments Titanocene dichloride, silver perchlorate and other solid reagents (Strem, Aldrich) were used without further purification. Liquid reactants and solvents were distilled prior to use, water was double distilled. Ruthenocenyl-containing b-diketones RcCOCH2COR with R ¼ C10F21, CF3, C6F5, C10H21, CH3, Rc and Fc were synthesized according to published procedures [6] with care being taken to separate it from the Aldol product, RcCOCH]C(CH3)Rc, during workup as described for ferrocene [11]. The titanocenyl complex [Ti(C5H5)2(CH3COCHCOCH3)][ClO4], 8, was prepared as described before [2c,10]. CAUTION: All ClO 4 salts should be handled with care as they are explosive. Melting points were determined with a Reichert Thermopan microscope with a Koffler hot-stage and are uncorrected. Elemental analysis was performed by the Analytical Chemistry Section of the UFS on a Leco TruSpec Micro instrument. 1H NMR measurements were recorded on a Bruker Avance DPX 300 NMR spectrometer. Chemical shifts are reported as d values relative to SiMe4 (0 ppm). The ruthenocenyl and ferrocenyl cyclopentadienyl signals that are split into pseudotriplets are labled “pt”. IR spectra were recorded from neat samples on a Digilab FTS 2000 Fourier transform spectrometer utilizing a He-Ne laser at 632.6 nm. 2.2. Synthesis 2.2.1. 1-Ruthenocenyl-3-methylprop-1,3-dionatobis(cyclopentadienyl)titanium(IV) perchlorate, (5) Two methods were utilized to obtain this complex. Method (a) is an adaption of Doyle’s metathesis method to obtain 5 while Method (b) represents a general example of the procedure used to obtain complexes 1e7 via the ligand exchange method. 2.2.1.1. Method (a). Doyle’s metathesis method was adopted as follows to obtain 5: Titanocene dichloride (15 mg, 0.63 mmol) was suspended at room temperature in 1 ml air-free water and stirred for an hour. Silver perchlorate (26 mg, 1.26 mmol) was added and the mixture was stirred for a further hour. The precipitate that formed, silver chloride, was filtered off and the appropriate bdiketone, here 1-ruthenocenylbutane-1,3-dione (20 mg, 0.63 mmol) dissolved in 2 ml THF/water (1:1), was added dropwise while stirring. The solution was left to stand for 2 days after which the precipitate was filtered off and washed with water and diethyl ether. The residue was recrystallized from chloroform and heptane to give 10 mg (27%) of clean 5, M.p. ¼ 135e136  C. dH (300 MHz, CDCl3)/ppm: 2.24 (s; 3H; CH3); 4.55 (s; 5H; C5H5 from Rc); 4.80 (pt; 2H; 0.5 x C5H4 from Rc); 5.18 (pt; 2H; 0.5 x C5H4 from Rc); 6.21 (s; 1H; CH); 6.72 (s; 10H; 2 x C5H5 from the titanocenyl group). dH (300 MHz, acetone-d6)/ppm: 2.24(s; 3H; CH3); 4.76 (s; 5H; C5H5 from Rc); 5.04 (pt; 2H; 0.5 x C5H4 from Rc); 5.39 (pt; 2H; 0.5 x C5H4 from Rc); 6.56 (s; 1H; CH); 6.89 (s; 10H; 2 x C5H5 from the titanocenyl group). 13C{1H} NMR (150 MHz, CDCl3): d 26.3

(CH3); 71.1 (C5H4Ru); 72.8 (C5H5Ru), 75.0 (C5H4Ru); 81.9 (Ci, C5H4Ru); 101.8 (CH); 121.7 (C5H5)2Ti); 189.9 (CO); 191.0 (CO). Anal. Calc, for C24H23O6ClRuTi: C, 58.4, H,4.5. Found: C, 58.1, H, 4.3%. 2.2.1.2. Method (b). The general procedure for the synthesis of 1e7 via the new ligand exchange method is elucidated with the synthesis of 5 which was as follows: 2,4-Pentanedionato-bis(cyclopentadienyl)titanium(IV) perchlorate (14 mg, 0.037 mmol) and 1ruthenocenyl-3-methylprop-1,3-dione (10 mg, 0.037 mmol) was dissolved in 10 ml acetonitrile and refluxed for 3 h. The solvent’s volume was reduced to ca. 2 ml before 15 ml water was added to precipitate the product. The precipitate was filtered off and washed with diethyl ether to produce 18 mg (82%) of clean 5. Characterisation data is the same as reported in 2.2.1. 2.3. Characterisation data of 1e4, 6 and 7 obtained by method (b), par 2.2.1.2 2.3.1. 1-Ruthenocenyl-3-perfluoroundecylprop-1,3-dionatobis(cyclopentadienyl)titanium(IV) perchlorate, 1 Yield 61%, m.p. ¼ 70e72  C. dH (300 MHz, CDCl3)/ppm: 4.61 (s; 5H; C5H5 from Rc); 4.92 (pt; 2H; 0.5 x C5H4 from Rc); 5.22 (pt; 2H; 0.5 x C5H4 from Rc); 6.06 (s; 1H; CH); 6.60 (s; 10H; 2 x C5H5 from the titanocenyl group). dH (300 MHz, acetone-d6)/ppm: 4.66 (s; 5H; C5H5 from Rc); 5.02 (pt; 2H; 0.5 x C5H4 from Rc); 5.42 (pt; 2H; 0.5 x C5H4 from Rc); 6.41 (s; 1H; CH); 6.65 (s; 10H; 2 x C5H5 from the titanocenyl group). Anal. Calc, for C33H20O6F21ClRuTi: C, 39.7, H, 2.1. Found: C, 39.4, H, 1.8%. 2.3.2. 1-Ruthenocenyl-3,3,3-trifluorobutane-1,3dionatoebis(cyclopentadienyl)titanium(IV) perchlorate, 2 Yield 100%, m.p. ¼ 140e141  C. dH (300 MHz, CDCl3)/ppm: 4.79 (s; 5H; C5H5 from Rc); 5.16 (pt; 2H; 0.5 x C5H4 from Rc); 5.44 (pt; 2H; 0.5 x C5H4 from Rc); 6.43 (s; 1H; CH); 6.84 (s; 10H; 2 x C5H5 from the titanocenyl group). 13C{1H} NMR (150 MHz, CDCl3): d 70.9 (C5H4Ru); 72.9 (C5H5Ru); 74.1 (C5H4Ru); 83.1 (Ci, C5H4Ru); 94.0 (CH); 121.7 (C5H5)2Ti); 189.9 (CO); 191.0 (CO). Anal. Calc, for C24H20O6F3ClRuTi: C, 52.7, H, 3.9. Found: C, 52.9, H, 4.2%. 2.3.3. 1-Ruthenocenyl-3-(2,3,4,5,6-pentafluorophenyl)prop-1,3dionato -bis(cyclopentadienyl)titanium(IV) perchlorate, (3) Yield 90%, m.p. ¼ 85e86  C. dH (300 MHz, CDCl3)/ppm: 4.62 (s; 5H; C5H5 from Rc); 4.81 (pt; 2H; 0.5 x C5H4 from Rc); 5.18 (pt; 2H; 0.5 x C5H4 from Rc); 6.30 (s; 1H; CH); 6.82 (s; 10H; 2 x C5H5 from the titanocenyl group). Anal. Calc, for C29H20O6F5ClRuTi: C, 53.9, H, 3.3. Found: C, 54.1, H, 3.4%. 2.3.4. 1-Ruthenocenyl-3-undecylprop-1,3-dionatobis(cyclopentadienyl)titanium(IV) perchlorate, (4) Yield 55% m.p. ¼ 74e76  C. dH (300 MHz, CDCl3)/ppm: 0.90 (m; 3H; CH3); 1.30 (m; 14H; 7 x CH2); 2.06 (s; 2H; CH2); 2.40 (s; 2H; CH2); 4.70 (s; 5H; C5H5 from Rc); 4.95 (pt; 2H; 0.5 x C5H4 from Rc); 5.25 (pt; 2H; 0.5 x C5H4 from Rc); 6.10 (s; 1H; CH); 6.74 (s; 10H; 2 x C5H5 from the titanocenyl group). dH (300 MHz, acetone-d6)/ppm: 0.86 (m; 3H; CH3); 1.28 (m; 14H; 7 x CH2); 1.74 (s; 2H; CH2); 2.54 (s; 2H; CH2); 4.75 (s; 5H; C5H5 from Rc); 5.05 (pt; 2H; 0.5 x C5H4 from Rc); 5.40 (pt; 2H; 0.5 x C5H4 from Rc); 6.55 (s; 1H; CH); 6.86 (s; 10H; 2 x C5H5 from the titanocenyl group). Anal. Calc, for C33H41O6ClRuTi: C, 63.9, H, 6.8. Found: C, 63.3, H, 6.4%. 2.3.5. 1,3-Diruthenocenylprop-1,3-dionato-bis(cyclopentadienyl) titanium(IV) perchlorate, (6) Yield 63%, m.p. ¼ 80e81  C. dH (300 MHz, CDCl3)/ppm: 4.66 (s; 10H; 2 x C5H5 from Rc); 4.94 (pt; 4H; 2 x 0.5 x C5H4 from Rc); 5.18 (pt; 4H; 2 x 0.5 x C5H4 from Rc); 6.24 (s; 1H; CH); 6.70 (s; 10H; 2 x

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E. Erasmus et al. / Journal of Organometallic Chemistry xxx (2016) 1e9

C5H5 from the titanocenyl group). 13C{1H} NMR (150 MHz, CDCl3): d 70.8 (C5H4Ru); 72.7 (C5H5Ru), 74.1 (C5H4Ru); 82.8 (C5H4Ru); 92.8 (CH); 121.5 (C5H5)2Ti); 187.3 (CO). Anal. Calc, for C33H29O6ClRu2Ti: C, 55.8, H, 4.3. Found: C, 55.5, H, 4.6%. 2.3.6. 1-Ruthenocenyl-3-ferrocenylprop-1,3-dionatobis(cyclopentadienyl)titanium(IV) perchlorate, (7) Yield 56%, m.p. ¼ 78  C. dH (300 MHz, CDCl3)/ppm: 4.31 (s; 5H; C5H5 from Fc)); 4.68 (s; 5H; C5H5 from Rc); 4.72 (pt; 2H; 0.5 x C5H4 from Fc); 4.89 (pt; 2H; 0.5 x C5H4 from Fc); 4.98 (pt; 2H; 0.5 x C5H4 from Rc); 5.22 (pt; 2H; 0.5 x C5H4 from Rc); 6.32 (s; 1H; CH); 6.74 (s; 10H; 2 x C5H5 from the titanocenyl group). dH (300 MHz, acetoned6)/ppm: 4.40 (s; 5H; C5H5 from Fc); 4.75 (s; 5H; C5H5 from Rc); 4.77 (pt; 2H; 0.5 x C5H4 from Fc); 5.02 (pt; 2H; 0.5 x C5H4 from Fc); 5.12 (pt; 2H; 0.5 x C5H4 from Rc); 5.46 (pt; 2H; 0.5 x C5H4 from Rc); 6.78 (s; 1H; CH); 6.92 (s; 10H; 2 x C5H5 from the titanocenyl group). 13 1 C{ H} NMR (150 MHz, CDCl3): d 70.7 (C5H5Fe); 70.9 (C5H4Ru); 72.7 (C5H5Ru); 73.4 (C5H4Fe); 73.7 (C5H4Fe); 74.4 (C5H4Ru); 83.2 (Ci, C5H4Ru); 98.1 (CH); 121.7 (C5H5)2Ti); 196.7(CO); 197.3 (CO). Anal. Calc, for C33H29O6ClRuFeTi: C, 59.7, H, 4.6. Found: C, 59.2, H, 4.4%.

3

electrode, but results are presented referenced against ferrocene as an internal standard as suggested by IUPAC [20]. To achieve this, each experiment was performed first in the absence of ferrocene (FcH) and then repeated in the presence of <1 mmol dm3 ferrocene. Data were then manipulated on a Microsoft excel worksheet to set the formal reduction potentials of FcH/FcHþ couple at 0 V. Under our conditions, the FcH/FcHþ couple has a formal reduction 0 potential of Eo ¼ 421 mV vs. Ag/AgCl with a DE ¼ 77 mV and ipc/ ipa ¼ 0.99. 2.6. Cytotoxicity test The cytotoxicity tests of 2 was determined as described before [21] utilizing the HeLa cell line from the ATCC CCL-2, American Type Culture Collection, Manassas, Virginia, USA. Cell survival was measured by means of the colourimetric 3-(4,5-dimethylthiazol-2yl)-diphenyltetrazolium bromide (MTT) assay. 3. Results and discussion 3.1. Synthesis and spectroscopic characterisation

2.4. X-ray crystal structure determination for (5) Crystals of [Ti(C5H5)2(RcCOCHCOCH3)][ClO4], 5, was obtained by recrystallization from dichloromethane: n-hexane (1:1 by volume) and mounted on a glass fibre for the X-ray crystallographic analysis. The X-ray intensity data were measured on a Bruker SMART 1K CCD diffractometer area detector system equipped with a graphite monochromator and Mo Ka fine-focus sealed tube (l ¼ 0.71073 Å) operated at 1.5 KW power (50 KV, 30 mA). The detector was placed at a distance of 4.0 cm from the crystal. Data collection was conducted at room temperature. The initial unit cell and data collection were achieved by use of Bruker SMART software [12]. A total of 1315 frames were collected at exposure times of 30 s.frame1 and a 0.3 scan width in u. The first 50 frames were recollected at the end of each data collection to check for decay; none was found. All reflections were merged and integrated using SAINT [13] and were corrected for Lorentz, polarization and absorption effects using SADABS [14]. The structures were solved by the direct methods package SIR97 [15] and refined using the WinGX software package [16] incorporating SHELXL [17]. All non-H atoms were refined with anisotropic displacement parameters, while the H atoms were constrained to parent sites by means of a riding model. The DIAMOND [18] Visual Crystal Structure Information System software was used for the graphics. The final refinement showed only minor alerts with online IUCr checkcif routines, mostly relating to atomic displacement parameters. Further refinement, such as disorder treatment of the solvent, was not investigated for the purpose of this study. 2.5. Electrochemistry Measurements utilizing scan rates of 100, 200, 300, 400 and 500 mV s1 on ca. 2.0 mmol dm3 solutions of the complexes in either dry air free dichloromethane containing 0.10 mol dm3 tetrabutylammonium tetrakis(pentafluorophenyl)borate or acetonitrile containing 0.10 mol dm3 tetrabutylammonium hexafluorophosphate as supporting electrolyte were conducted under a blanket of purified argon at 25  C utilizing a BAS 100 B/W electrochemical workstation interfaced with a personal computer. A three electrode cell, which utilized a Pt auxiliary electrode, a glassy carbon working electrode of surface area 7.07 mm2 and an in-house constructed Ag/AgCl reference electrode [19] were employed. Temperature was kept constant within 0.5  C. Experimentally potentials were referenced against the Ag/AgCl reference

The two titanium complexes [Ti(C5H5)2(CH3COCHCOCH3)] [ClO4], 8, and [Ti(C5H5)2(RcCOCHCOCH3)][ClO4], 5, was synthesized according to the general anion metathesis procedure as described by Doyle and Tobias [10]. The yields of 8 and 5 are 86% and 27% respectively. Since the yield of the ruthenocenyl-containing complex, 5, was so low, an alternative method of synthesizing these ruthenocenyl-containing titanium complexes was investigated. This new synthetic method involved the substitution of the acetylacetonato ligand in [Ti(C5H5)2(CH3COCHCOCH3)][ClO4], 8, with the ruthenocenyl-containing b-diketonato ligand (RcCOCHCOCH3). The yield obtained for 5 with the ligand exchange method was 82%. One would expect that because the Gordy group electronegativity [22] of the ruthenocenyl moiety (cRc ¼ 1.99) is lower than that of the methyl group (cCH3 ¼ 2.34) [23], that the ruthenocenyl-containing b-diketonato ligand is more electron-donating than (CH3COCHCOCH3). Gordy group electronegativity is a measure of the electron-withdrawing power of a group of atoms, like in the ruthenocenyl group (not just one atom like the F atom), on the bonding pair of electrons between that group and the adjacent atom to which it is bonded; a value of 4 indicates strong electron-withdrawing properties, while a value of 2 indicates strong electron-donating properties, see Ref. [22]. This would make it in comparison a better nucleophile, capable of substituting the acetylacetonato ligand. However, when a series of ruthenocenyl-containing b-diketonato titanocene(IV) perchlorate complexes, [Ti(C5H5)2(RcCOCHCOR)][ClO4] with R ¼ C10F21 (1), CF3 (2), C6F5 (3), C10H21 (4), CH3 (5), Rc (6) and Fc (7), were synthesized according to this new ligand exchange procedure (Scheme 1), yields showed a different-than-expected trend. Except for R ¼ C10H21 and C10F21, an increase rather than a decrease in yield was associated with an increase in the Gordy group electronegativity, cR, of the Rgroup (see Table 1). It appears that removal of the substituted volatile CH3COCH2COCH3 b-diketone is important to obtain the desired product. By refluxing the reaction mixture, the exchanged volatile CH3COCH2COCH3 b-diketone is removed from the reaction mixture. This would shift the exchange equilibrium position in the exchange reaction to favour the desired product. The reason why R ¼ C10H21 and C10F21 did not follow this trend is probably associated with the length of the C10 side chains. It is envisaged that these long chains will at least hamper access of these b-diketones to the titanium centre of 8, making them sluggish to react. The Ti-Ru bimetallic complexes 1e5 and trimetallic complexes (6, Ti-Ru-Ru and 7, Ti-Fe-Ru) are soluble in polar organic solvents

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E. Erasmus et al. / Journal of Organometallic Chemistry xxx (2016) 1e9

O

+ ClO4-

CH3

O

Ti

+ O

O R

Ru

O

CH3CN

+ ClO4-

R

Ti O

CH3

Ru 8 R = C10F21 (1), CF3 (2), C6F5 (3), C10H21 (4), CH3 (5), Rc (6) and Fc (7). Scheme 1. Synthesis of [Ti(C5H5)2(RcCOCHCOR)][ClO4] complexes 1e7 via 8.

Table 1 Gordy scale group electronegativities, yields and 1H NMR resonance position shifts of important resonances of [Ti(C5H5)2(RcCOCHCOR)][ClO4] complexes 1e7 in moving from chloroform-d1 to acetone-d6 as solvent. R Group

cR a

1: 2: 3: 4: 5: 6: 7:

3.04 61% 3.01 100% 2.46 90% 2.43 55% 2.34 82% 1.99 63% 1.87 56%

a

C10F21 CF3 C6F5 C10H21 CH3 Rc Fc

Yield (%) nCO Vibration (cm1) 1574 1584 1552 1544 1540 1502 1502

1

H NMR shift for C5H5 of Fcb

1

H NMR shift for C5H5 of Rcb

-c -c -c -c -c -c 0.09

0.05 -d -d 0.05 0.21 -d 0.07

1

H NMR shift for CH of betab

1

H NMR shift for C5H5 of Tib

0.35 -d -d 0.45 0.35 -d 0.46

0.05 -d -d 0.12 0.17 -d 0.18

cR ¼ Gordy scale apparent group electronegativity values.

H NMR shifts ¼ (1H NMR resonance position of peak in chloroform-d1) e (1H NMR resonance position of peak in acetone-d6); beta ¼ b-diketonato ligand. Complex has no ferrocenyl group. Not determined.

b 1 c d

such as THF, acetone and acetonitrile, less soluble in less polar solvents such as dichloromethane and chloroform, but, even though they are charged, are insoluble in water. Especially 6 and 7 decomposed quickly in dichloromethane and chloroform if these solvents were not passed through basic alumina to remove any photochemically generated HCl. In the solid state they are stable for months. In the IR region of electromagnetic frequencies, the free bdiketones exhibit prominent nCO vibrations in the range 1620e1710 cm1 [24]. The titanocene complexes 1e7 exhibit these vibrations at ca.120 cm1 smaller wave numbers; in the range 1500e1590 cm1. These vibrational wave numbers are typical for chelate-bonded b-diketonates in transition metal chemistry [25]. Other prominent IR absorptions for 1e7 included nC]C (1410e1440 cm1) vibrations, and a distinguished absorption at ca. 3000 cm1 which is associated with CH stretching bands. The 1H NMR spectra of 1e7 are unique in that resonances for unsubstituted cyclopentadienyl ligands coordinated to up to three metal centres, TiIV, RuII and FeII, are observed. Those coordinated to the TiIV centre were found the furthest downfield in the range 6.60e6.90 ppm. Those coordinated to the RuII centre resonated in the range 4.55e4.79 ppm and the unsubstituted C5H5 ligand associated with the ferrocenyl group of complex 7 resonated at 4.31 ppm. The observed systematic upfield shift of these resonances follows a reciprocal trend compared the Allen atomic electronegativities of Fe (1.80), Ru (1.54) and Ti(1.38) as well as the ionisation energies (IE) of FeII (2nd IE: 1561 kJ mol1) and RuII (2nd IE: 1620 kJ mol1) and TiIV (4th IE: 4174 kJ mol1). More interesting though, is the downfield shift in resonance positions when the NMR solvent changes from chloroform-d1 to acetone-d6. The ruthenocenyl C5H5 signal moved with 0.05e0.21 ppm, the ferrocenyl C5H5 signal moved by 0.09 ppm, the titanocenyl C5H5 signal with 0.05e0.18 ppm, and the b-diketonato methine (CH) signal moved with 0.35e0.46 ppm to lower fields, see

experimental. These downfield shifts are calculated as follows: (1H NMR shifts) ¼ (resonance position of peak in chloroform-d1) e (NMR resonance position of peak in acetone-d6). The calculated “shifts” in signal resonances is the direct consequence of solventcomplexþ interaction (each complex is a cation, see Scheme 1) with CDCl3e(complex)þ interactions being the weakest and (CD3)2C]Ocomplexþ interactions being the strongest. The smallest shifts were observed for the C10H21 and C10F21 complex. They are also the most hydrophobic in the series 1e7 which means their interaction with hydrophilic (CD3)2C]O will be minimal. This means the acetoned6-complexþ interactions for these two complexes will resemble the chloroform-d1-complexþ interactions the closest, hence the relative smaller shifts. Results are summarised in Table 1. The larger the measured “shifts” are, the more acetone compatible is the complex. Solvent-complex (or electrolyte-complex) interactions also cause big differences in electrochemical behaviour of complexes. For example, ruthenocene, RcH, can be oxidised in a one-electron process to RcHþ in a CH2Cl2/[NBu4][B(C6F5)4] solvent-electrolyte medium [7]. However, in CH3CN/[N(nBu)4][PF6], due to solventcomplexþ and (electrolyte anion)-complexþ interactions, RcHþ is not formed. Over oxidation to a Rc2þ species inevitably occurs [2c,7]. Consequences of this weak versus strong solvent-complexþ interactions are further investigated and described in the electrochemical study of complexes 1e7 below. 3.2. Single crystal-ray structure of 5 A perspective view of the molecular structure of 5 showing atom labelling is presented in Fig. 1. Crystal data of 5 are summarised in Table 2, selected bond lengths and angles may be found in Table 3. The full set of bond lengths and angles is available from the cif file (Supporting Information. Perspective views highlighting the eclipsed conformation of the cyclopentadienyl ligands is also

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Fig. 1. Perspective view showing atom labelling of the molecular structure of [Ti(C5H5)2(RcCOCHCOCH3)][ClO4], 5.

5

provided). The titanium atom displays a distorted tetrahedral geometry. Bond angles around Ti were between 86.9 and 133.4 . The angle O(1)-Ti-O(2) is 86.9(1)º and falls in the predicted range of 85e88 [26]. Upon defining cent ¼ centroid of the indicated cyclopentadienyl carbon atoms, then the other angles around Ti are cent(31e35)-Ti-cent(41e45) ¼ 133.4 , O(1)-Ticent(31e35) ¼ 104.8 , O(1)-Ti-cent(41e45) ¼ 105.8 , O(2)-Ticent(31e35) ¼ 106.4 and O(2)-Ti-cent(41e45) ¼ 105.4 . They differ at most with 23.9 from 109.47, the angle for a regular tetrahedron. The average Ti-C bond distance for 5 are 2.368 Å and 2.348 Å for the two cyclopentadienyl rings respectively while the Ti-O(1) and Ti-O(2) bond lengths are 1.964(2) and 1.957(2) Å respectively. The difference in Ti-O bond lengths (0.007 Å) is within four times the error in bond distances (i.e. within 4s(I) values) and is small. Comparison of the TiIV centre bond distances and angles of the ionic complex [Ti(C5H5)2(RcCOCHCOCH3)][ClO4], 5, with those of a previously reported [27] neutral complex having a TiIII centre, [TiIII(C5H5)2(CH3COCHCOCH3)], highlights differences as a result of the change in titanium redox state in the absence of a coordination sphere change. The TiIII complex has a OeTieO angle of 84.3 [27]; this is 2.6 smaller than the 86.9(1)º found for the present tita-

Table 2 Crystal data and structure refinement for [Ti(C5H5)2(RcCOCHCOCH3)][ClO4], 5. Empirical formula

C24 H23 O6 Cl Ti Ru

F(000)

1192

Molecular weight Crystal size/mm3 Temperature/K Wavelength/Å Crystal system Space group Unit cell dimensions

646.097 0.34  0.18  0.03 293(2) 0.71073 Monoclinic P21/n a ¼ 9.973(2) Å b ¼ 20.176(4) Å c ¼ 11.509(2) Å a ¼ 90 b ¼ 97.32(3) g ¼ 90 . 2296.9(8) 4 1.711

Absorption coefficient/mm1 Absorption correction q range for data collection/o Index ranges Reflections collected Independent reflections Completeness to q ¼ 28.30 Max. and min. transmission Refinement method Data/restraints/parameters Goodness-of-fit on F2 Final R indices [I > 2s(I)] R indices (all data) Largest Diff. Peak and hole/e Å3

1.160 Semi-empirical from equivalents 2.02e28.30 8h  13, 26  k  26, 14  l  15 15804 5656 [R(int) ¼ 0.0396] 99.2% 0.9660 and 0.6937 Full-matrix least-squares on F2 5656/0/299 1.016 R1 ¼ 0.0380, wR2 ¼ 0.0759 R1 ¼ 0.0776, wR2 ¼ 0.0889 0.387 and 0.346 e.Å3

Volume/Å3 Z Density (calc.)/Mg m3

Table 3 Bond lengths (Å) and angles (º) for [Ti(C5H5)2(RcCOCHCOCH3)][ClO4], 5. Atoms

Bond length

Atoms

Angle

TieO(2) TieO(1) O(1)eC(1) O(2)eC(3) C(1)eC(2) C(2)eC(3) C(3)eC(4) C(1)eC(11) C(11)eC(12) C(11)eC(15) C(21)eC(22) C(31)eC(32) C(41)eC(42) RueC(11) RueC(23) TieC(33) TieC(42) CleO(3) CleO(4) CleO(5) CleO(6)

1.957(2) 1.964(2) 1.285(3) 1.297(4) 1.407(4) 1.372(4) 1.497(4) 1.458(4) 1.433(4) 1.429(4) 1.388(6) 1.377(6) 1.380(6) 2.178(3) 2.169(4) 2.345(4) 2.373(4) 1.406(3) 1.391(3) 1.377(4) 1.410(3)

cent(31e35)-Ti-cent(41e45)a O(1)-Ti-cent(31e35)a O(1)-Ti-cent(41e45)a O(2)-Ti-cent(31e35)a O(1)-Ti-cent(41e45)a O(2)-Ti-O(1) C(1)-O(1)-Ti C(3)-O(2)-Ti O(1)-C(1)-C(2) O(1)-C(1)-C(11) O(2)-C(3)-C(2) O(2)-C(3)-C(4) C(2)-C(3)-C(4) C(1)eC(2)eC(3) C(2)eC(1)eC(11) C(1)eC11)eC(12) C(1)eC(11)eC(15) C(12)eC(13)eC(14) C(11)eC(15)eC(14) O(3)eCle(O(6) O(3)eCleO(5)

133.37 104.84 105.75 106.41 105.42 86.9(1) 127.9(2) 125.4(2) 122.3(3) 116.2(3) 123.7(3) 114.9(3) 121.3(3) 124.3(3) 121.5(3) 127.4(3) 124.4(3) 109.(3) 107.3(3) 107.0(2) 109.6(3)

a

nium(IV) species, 5. The average TiIVeO bond length, 1.961(2) Å, is almost 0.1 Å shorter than the reported TiIIIeO distance of 2.068(5) Å for [TiIII(C5H5)2(CH3COCHCOCH3)] [27]. The TiIII complex has an average TieC distance of 2.375 Å; this is 0.017 Å longer than those of 5 which averages 2.358 Å. All these differences clearly demonstrate that the TiIV centre is noticeably more electrophilic than the TiIII centre. The above described bond lengths and angles are similar to values found for other titanocene(III) [28] and titanocene(IV) derivatives [29]. In terms of the b-diketonato ligand, the bond length C(3)eC(2) (1.372(4) Å) is slightly shorter than that of C(1)eC(2) (1.407(4) Å) and implies the b-diketonato ligand is asymmetrically bound to Ti. The angles O(1)-C(1)-C(2) [122.3(3)º], C(3)-C(2)-C(1) [124.3(3)º] and O(2)-C(3)-C(2) [123.7(3)º] are slightly larger than the theoretical value of 120 expected for the sp2 hybridization. This means that the pseudo-aromatic ring is distorted and intramolecular electronic communication between the Ti centre, the b-diketonato CH3-group and the ruthenocenyl group are not optimum. This observation explains the non-linear relationship observed between Epa for the Rc group and the Gordy group electronegativity of the R0 group of the b-diketonato ligand, cR, as well as between Eo for the

Cent ¼ centroid of the indicated cyclopentadienyl carbon atoms in brackets.

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Ti4þ/Ti3þ couple and cR that is described in the electrochemical section below. The cyclopentadienyl rings of the ruthenocenyl group are in the eclipsed conformation and orientated parallel to one another (Fig. 1S in Supporting Information). The torsion angle O(1)-C(1)C(11)-C(15) of 3.2(4)o indicate the b-diketonato plane is almost parallel to the cyclopentadienyl planes as well (Fig. 1S, Supporting Information). The average CeC bond length of the substituted cyclopentadienyl ring of the ruthenocenyl group is 1.419 Å, while for the unsubstituted ring it is 1.386 Å. For the titanocenyl group average CeC bond lengths are 1.363 (atoms 31e35) and 1.379 (atoms 41e45). 3.3. Electrochemistry The cyclic voltammetric behaviour of the b-diketonato titanocenyl complexes 1e7 were studied in CH3CN/0.1M [N(nBu)4][PF6] as example of a medium that allows interactions [6,7] with analytes, as well as in CH2Cl2/0.1 M [N(nBu)4][B(C6F5)4], a medium that interacts so little with analytes that it is known to allow detection of the ruthenocenium radical cation [7]. Cyclic voltammograms (CV’s) are shown in Fig. 2 while data from these CV’s is tabulated in Table 4. The oxidation potential of the Rc/Rc2þ couple and reduction potential of the Ti4þ/Ti3þ couple, unlike the free b-diketones, exhibits no linear dependence on the Gordy group electronegativity of the R-group although a general trend is that as the R-group electronegativity increases, the oxidation potential of the Rc/Rc2þ

couple and reduction potential of the Ti4þ/Ti3þ couple becomes more positive. Just as for the free b-diketones [6a], in CH3CN/[NBu4] [PF6], the ruthenocenyl moiety’s oxidation is assigned to be a twoelectron transfer process in which the Ru(II) centre of the Rc moiety is converted to Ru(IV) to generate Rc2þ. The electrochemically generated Rc2þ specie formed during the oxidation of the ruthenocenyl moiety binds with the solvent (CH3CN), which in analogy with free ruthenocene [7,8], osmocene [7] and the free ligand, RcCOCH2COR [6a], may have the formula [Ti(C5H5)2{RuIV(C5H5)(C5H4COCHCOR)(CH3CN)}]3þ. The peak anodic currents for 1e7 of the Rc/Rc2þ couple (wave 2) were not equal in size. The shape of these waves, especially the CV of 6, is attributed to substrate adsorption on, or at least association with the working electrode (because there is still an ip e (scan rate)1/2 dependency that indicates a solution-based species). For complexes 2, 4 and 5, the fully oxidised species is a cation of charge 3þ, for 7 the cation has a charge of 4 þ while for 6 it has a charge of 5þ. These charges would certainly enhance a lower solubility in the solvent, here to promote in the cases of especially 2, 5 and 6 deposition on or association with the electrode, and the observed current fluctuations are attributed to this. [Ti(C5H5)2(RcCOCHCOCF3)][ ClO4], 2, exhibits two reduction peaks (1a and 1b). The reversibility of wave 1a leads us to assign this wave as the important redox process associated with TiIV reduction of 2. The source of wave 1b is at this stage not fully understood although it may be associated with compound adsorption (or association with the surface of the electrode. Other researchers [30] explained a similar peak splitting of titanocene dichloride,

Fig. 2. Cyclic voltammgrams of 2.0 mmol dm3 solutions of [Ti(C5H5)2(RcCOCHCOR)][ClO4] complexes (4 mmol dm3 for 4) in CH3CN/0.1 mol dm3 [N(nBu)4][PF6] (left) or CH2Cl2/ 0.1 mol dm3 [N(nBu)4][B(C6F5)4] (right) at a glassy carbon-working electrode at 25  C and a scan rate of 200 mV s1. CV’s for [Ti(C5H5)2(RcCOCH2COFc)][ClO4] (7) were at scan rates of 100, 200, 300 and 400 mV s1. a) In CH3CN/[N(nBu)4][PF6]: The electrochemistry of 2 and 4e7 in CH3CN/[N(nBu)4][PF6] revealed chemical and electrochemical irreversible behaviour for the Rc/Rc2þ couple, while the Ti4þ/Ti3þ couple of 2, 4 and 5 approached electrochemical and chemical reversibility with 74 < DE < 94 and ipc/ipa z 1. Theoretically, electrochemically and chemically reversible processes are characterised by DE ¼ 56 mV and ipc/ipa ¼ 1 [8]. However, for the two metallocene-containing compounds 6 and 7, the Ti4þ/Ti3þ couple was chemically and electrochemically irreversible at all scan rates. The Fc/Fcþ couple of 7 showed chemical and electrochemical reversible behaviour with DE ¼ 64 mV and ipc/ipa z 1.

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7

Table 4 Cyclic voltammetry data of ca. 2.0 mmol dm3 solutions of [Ti(C5H5)2(RcCOCHCOR)][ClO4] complexes 1e7 in CH3CN containing 0.1 mol dm3 [N(nBu)4][PF6] and, in parentheses and italics, CH2Cl2 containing 0.1 mol dm3 [N(nBu)4][B(C6F5)4] as supporting electrolyte at 25  C and 200 mV s1 scan rate. Peak current ratios are always (ireverse scan/(iforward scan). Wavea

Compound

IV

1: R ¼ C10F21

2: R ¼ CF3

3: R ¼ C6F5 4: R ¼ C10H21e 5: R ¼ CH3 6: R ¼ Rc; 7: R ¼ Fc;

a b c d e

Epc or Epa/mV III

a

1a, Ti /Ti 1b, TiIV/TiIII 2; Rc/Rcþ 1a, TiIV/TiIII 1b, TiIV/TiIII 2a; Rc/Rcþ 2b; Rc/Rcþ 1, TiIV/TiIII 2; Rc/Rcþ 1, TiIV/TiIII 2; Rc/Rcþ 1, TiIV/TiIII 2; Rc/Rcþ 1, TiIV/TiIII 2; Rc/Rcþ 1, TiIV/TiIII Fc/Fcþ 2; Rc/Rcþ

Epc, - ; (1450) Epc, -a; (1244) Epa, - a; (975) Epc, 899; (875) Epc, 642; (691) Epa, 650d; (850) Epa, 832d; (1003) Epc, -a; (1479) Epa, -a; (890) Epc, 945; (981) Epa, 609d; (1160) Epc, 890; (1016) Epa, 722d; (719) Epc, 902; (994) Epa, 602d; (933) Epc, 900; (973) Epa, 291; (310) Epa, 714d; (813)

0

DEp/mV a

Eo /mV

- ; (228) -a; (206)c -a; (82) 74; (96) 68; (124)c -b; ()b -b; ()b -a; (316) -a; ()b 94; ()b -b; (252) 64; ()b -b; ()b -b; (144)c -b; ()b -b; ()b 64; (150) -b; ()b

a

- ; (1338) -a; (1141)c -a; (1016) 862; (827) 608; (629) -b; ()b -b; ()b -a; (1321) -a; ()b 898; ()b -b; (1034) 858; ()b -b; ()b -b; (922)c -b; ()b -b; ()b 259; (235) -b; ()b

ipc or ipa/mA a

ipc, - ; (6.9) ipc, -a; (3.8) ipa, -a; (4.6) ipc, 2.9; (1.9) ipc, 3.6; (5.5) ipa, 5.4; (3.0) ipa, 4.5; (2.6) ipc, -a; (2.2) -a; (1.9) ipc, 13.7; (9.7) ipa, 14.6; (10.4) ipc, 2.2; (13.0) ipa, 23.7; (3.4) ipc, 5.3; (3.9) ipa, 59.0; (4.1) ipc, 2.4; (3.7) ipa, 2.7; (2.7) ipa, 2.6; (2.2)

Peak current ratios ipa/ipc, -a; (0.9) ipa/ipc, -a; (<0.05) ipc/ipa, -a; (0.3) ipa/ipc, 0.9; (0.2) ipa/ipc, 0.2; (0.9) ipc/ipa, 0.0; (0.0) ipc/ipa, 0.0; (0.0) ipa/ipc, -a; (0.7) ipc/ipa, -a; (0.0) ipa/ipc, 0.9; (0.0) ipc/ipa, 0.0; (0.4) ipa/ipc, 0.9; (0.0) ipc/ipa, 0.0; (0.0) ipa/ipc, 0.0; (0.2) ipc/ipa, 0.0; (0.0) ipa/ipc, 0.0; (0.0) ipc/ipa, 1.0; (0.9) ipc/ipa, 0.0; (0.0)

Experiment not performed in CH3CN containing 0.1 mol dm3 [N(nBu)4][PF6]. No Epc (or Epa) wave detected. Estimate only due to poor resolution or current intensity. A Rc/Rc2þ couple in the CH3CN/[N(nBu)4][PF6] solvent electrolyte system. The concentration of 4 was ca. 4 mmol dm3.

Red Cp2TiCl2 + sol

Cp2TiCl(sol)+ + Cl-

Ox

Red

Cp2TiCl2- + sol

Cp2TiCl(sol) + Cl-

Ox

Scheme 2. Square scheme30 explaining the observed electrochemistry of titanocene dichloride, Ti(C5H5)2Cl2; sol ¼ solvent, here CH3CN.

Ti(C5H5)2Cl2 by the involvement of solvent, here CH3CN, according to Scheme 2. Although not completely impossible, we do not favour a similar scheme to explain the peak splitting of [Ti(C5H5)2(RcCOCHCOCF3)] [ClO4], 2, because neither the cyclopentadienyl ligands of 2 nor the bidentate b-diketonato ligand of 2 would be prone to substitution by CH3CN to invoke Scheme 2 as a possible electrochemical pathway for the reduction of TiIV. A third possible explanation for the observed peak splitting may be the presence of both symmetric, bidentate betadiketonato coordinated and asymmetric mono-

Scheme 3. Redox events observed in the electrochemistry of 2, 4 and 5 in CH3CN. For 6 and 7 wave 1 does not represent a reversible process, 6 shows a second irreversible ruthenocenyl oxidation overlaying the first one (wave 2), and 7 exhibits also a reversible Fc/Fcþ couple before wave 2.

coordinated b-diketonato ligands to the titanium core of 2. A plausible redox scheme explaining the observed redox events for these complexes are shown in Scheme 3. b) In CH2Cl/[N(nBu)4][B(C6F5)4]: The electrochemistry of 1e7 was also studied in the non-coordinating solvent and electrolyte system CH2Cl2/[N(nBu)4][B(C6F5)4] [7,8], to establish if the generation of a 17e ruthenocene species, IV III [Ti (C5H5)2(Ru (C5H5)(C5H4eCOCH2COR)]2þ specie could be verified. Cyclic voltammograms of 1e7 in CH2Cl2/[N(nBu)4] [B(C6F5)4] at a scan rate of 200 mV s1 are shown in Fig. 2, right. The electrochemical data resulting from these cyclic voltammograms are summarised in Table 4. Except for 1 and 4 with R ¼ C10F21 and C10H21 respectively, all complexes showed an electrochemical and chemically irreversible Rc/Rcþ couple at wave 2, Table 4. Only for 1 and 4 was the ruthenocenium, Rcþ, reduction half wave observable albeit very weak with ipc/ipa < 0.4; this indicated the stability of the electrochemically generated Rcþ species is very low, even on cyclic voltammetric time scale utilizing a scan rate of 500 mV s1 (Fig. 2 shows 200 mV s1 scans). Complex 1 exhibited an electrochemically reversible Rc/Rcþ couple with DE ¼ 82 mV (theoretically DE ¼ 59 mV is predicted) at slow scan rate. Although the reduction half wave of the Rcþ fragment could not be identified for 2, 3 and 5e6, in analogy to 1 and 4, it is assumed Rcþ also formed during the anodic half wave of the redox process associated with wave 2 of the cyclic voltammograms of these complexes, Fig. 2, Table 4. In addition, all of the complexes 1e7, exhibited an electrochemical irreversible Ti4þ/Ti3þ couple (wave 1) with 96 < DE < 316 mV. Except for 1, 2 and 3, the current of the oxidation half waves of this couple was very small, Table 4. This led to poor ipa/ipc values for wave 1. This time, substrate adsorption (or association) onto the working electrode by virtue of larger than expected ipc currents was more prevalent at the cathodic process of wave 1, and the observed deviations of current ratios from unity (Table 4) are attributed to this. Of course, because the currents associated with the TiIII/TiIV redox process are not associated with a thermodynamic reversible

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processes obeying Nernstian conditions, they may also be smaller than expected which will also lead to poor current ratios. As in CH3CN, the voltammogram of 2 exhibited an “a” and “b” component at wave 1 in CH2Cl2/[NBu4][B(C6F5)4]. As in CH3CN, wave 1a is regarded as the main redox contribution due to enhanced electrochemical reversibility (DEwave 1a ¼ 96 mV, DEwave 1b ¼ 124 mV). As for CH3CN, the source of these two components could include substrate deposition, ligand dissociation or mixtures of symmetric bidentate and asymmetric monodentate b-diketonato coordination to the titanium core of 2. No meaningful linear relationship could be found between Epc values of Ti4þ/Ti3þ couple or the Epa values of Rc/Rcþ couple and cR, 0 most likely because Epa and Epc, unlike Eo , is not a thermodynamic quantity. Epa and Epc is only that potential where the kinetics of oxidation or reduction is just the fastest. Scheme 4 shows the redox processes associated with 1e7.

3.4. Cytotoxicity evaluation of 2 Complex 2, [Ti(C5H5)2(RcCOCHCOCF3)][ClO4], was subjected to cytotoxicity evaluations against CoLo 320DM (a human colorectal cell line) and HeLa cells (a human cervix epithelioid cancer cell line). Fig. 3 is a survival curve that indicates percentage HeLa cell survival, plotted as a function of drug dose with concentration expressed in mmol dm3. IC50 values (drug dose required for 50% cell death) were estimated by extrapolation. They were found to be IC50 ¼ 10.2 mmol dm3 for CoLo DM320 cells and 9.7 mmol dm3 for HeLa cells. Complex 2 were not as effective as cisplatin [21] (IC50(CoLo) ¼ 3.0 mmol dm3; IC50(HeLa) ¼ 5.6 mmol dm3) in killing cancer cells. However, cisplatin has many side effects including extreme nephrotoxicity. Known titanium complexes like titanocene dichloride exhibit much less side effects. The present class of compounds may therefore also have less toxic side effects. This is currently under investigation. The cytotoxicity of complex 2 were almost the same as those of the free ligand [21], RcCOCH2COCF3 (IC50(CoLo) ¼ 8.2 mmol dm3; IC50(HeLa) ¼ 9.0 mmol dm3) This shows that the presence of the titanocenyl moiety, -Ti(C5H5)2 has no beneficial or synergistic effect with the ruthenocenyl group or trifluoromethyl group of the ligand. This is surprising because by combining more than one type of anti-cancer active moiety in the same molecule, here titanium and ruthenium, enhanced anticancer activity is often observed [31].

Fig. 3. Plot of percentage HeLa cell survival against concentration (mmol dm3) of [Ti(C5H5)2(RcCOCHCOCF3)][ClO4], 2.

4. Conclusion Seven new tetrahedral ruthenocenyl-containing b-diketonato titanocenyl(IV) complexes of the type [Ti(C5H5)2(RcCOCHCOR)] [ClO4] with R ¼ C10F21, 1, CF3, 2, C6F5, 3, C10H21, 4, CH3, 5, Rc, 6 and Fc, 7, were obtained either via a metathesis reaction from Ti(C5H5)2Cl2 or via (CH3COCHCOCH3) substitution from [Ti(C5H5)2(CH3COCHCOCH3)][ClO4] with the desired ruthenocenyl-containing b-diketone. The ligand substitution route is the higher yielding synthetic method. The crystal structure for the R ¼ CH3 complex showed a distorted tetrahedral configuration around the titanium centre and the ruthenocene-containing b-diketonato ligand were asymmetrically bound to the titanium metal centre. Distortions in the structure from optimum bond angles are at the root of poor intramolecular communication between structural fragments and manifested in, for example, in poor electrochemical relationships. Electrochemical data for the Ti4þ/Ti3þ couple in the CH3CN/[NBu4] [PF6] solvent/electrolyte system highlighted reversible behaviour for all complexes except the electron-rich complexes 6 and 7. The ruthenium(II) ion of the ruthenocenyl moiety were in this solvent system oxidised to a RuIV species, but in CH2Cl2/[NBu4][B(C6F5)4] a one-electron oxidation to Rcþ bearing a RuIII species was observed. The stability of the Rcþ species was low; even on CV time scale at a scan rate of 200 mV s1 only the long-chain complexes 1 and 4 bearing either a C10F21 or C10H21 b-diketonato fragment allowed detection of the cathodic half wave of the Rcþ species. In general, in CH3CN/[NBu4][PF6] the redox potentials of the Rc/Rc2þ and the Ti4þ/Ti3þ couples became more positive as the Gordy group electronegativity of the R-group increased. Cytotoxic studies revealed that [Ti(C5H5)2(RcCOCHCOCF3)][ClO4] are less cytotoxic than cisplatin, but as cytotoxic as the free ligand, RcCOCHCOCF3. No synergistic effects could be detected between the cytotoxic titanocenyl, ruthenocenyl and trifluoromethyl moieties. Acknowledgements JCS and EE acknowledge generous financial support from NRF under grant 2054243 and the University of the Free State during the course of this study. AJM acknowledges the University of Johannesburg for funding. Prof. C.E.J. Medlen from the Department of Pharmacology at the University of Pretoria is acknowledged for assisting with the cytotoxicity tests. Appendix A. Supplementary data

Scheme 4. Redox events observed in the electrochemistry of 1 inCH2Cl2. For 2e7, the TiIII/TiIV couple associated with wave 1 does not represent a reversible process, while wave 2 is only reversible for 4 as well. For 2, 3, 6 and 7 wave 2 represents an irreversible Rc/Rcþ couple. Complex 6 shows a second irreversible ruthenocenyl oxidation wave unresolved from the first one, and 7 exhibits also a reversible Fc/Fcþ couple before wave 2.

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