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Article

Synthesis Comparative Electrochemistry and Spectroelectrochemistry of Metallocenyl β-Diketonato Dicarbonyl Complexes of Rhodium(I)—Cytotoxicity of [Rh(FcCOCHCOCF3)(CO)2]

by
Eleanor Fourie
1,
J. W. (Hans) Niemantsverdriet
2 and
Jannie C. Swarts
1,*
1
Department of Chemistry, University of the Free State, Bloemfontein 9300, South Africa
2
Syngaschem, Valeriaanlaan 16, 5672 XD Nuenen, The Netherlands
*
Author to whom correspondence should be addressed.
Inorganics 2024, 12(12), 321; https://doi.org/10.3390/inorganics12120321
Submission received: 6 November 2024 / Revised: 2 December 2024 / Accepted: 9 December 2024 / Published: 11 December 2024
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Abstract

:
The metallocenyl-containing β-diketonato rhodium(I) dicarbonyl complexes of [Rh(FcCOCHCOR)(CO)2] where R = CF3, 10; Fc = ferrocenyl = FeII(C5H5)(C5H4), 11; Rc = ruthenocenyl = RuII(C5H5)(C5H4), 12; and Oc = osmocenyl = OsII(C5H5)(C5H4), 13 were synthesized. Complexes 10–13 were then subjected to an electrochemical study utilizing cyclic voltammetry (CV), square wave voltammetry (SWV), and linear sweep voltammetry (LSV) in the non-coordinating solvent/supporting electrolyte medium CH2Cl2/0.1 mol dm−3 [N(nBu)4][B(C6F5)4]. The formal reduction potential for the electrochemical reversible Fc0/+ couples in 10–13 was identified in the range 0.156 ≤ Eo′ ≤ 0.328 V while the electrochemically irreversible osmocenyl and ruthenocenyl oxidations were observed at peak anodic potentials of Epa = 0.640 V and Epa = 0.751 V, respectively. Resolution between the closely overlapping CV-determined Fc0/+ and RhI/II couples was too poor for unambiguous measurement of the RhI/II redox potential, but square wave voltammetry allowed estimates of Eo′ (RhI/II) in the range 0.156 ≤ Eo′ ≤ 0.398 V. FT-IR spectroelectrochemistry confirmed the one-electron oxidation of RhI by the appearance of CO vibrational bands at stretching frequencies, which are associated with rhodium(II) and not rhodium(III). Cytotoxicity tests on 10 (IC50 = 19.2 µM) showed it to be substantially less cytotoxic than the free β-diketone, FcCOCH2COCF3, and [Rh(FcCOCHCOCF3)(cod)].

Graphical Abstract

1. Introduction

Rhodium(I) complexes are of interest inter alia because of their medical [1] and catalytic properties [2,3,4] as well as its use as a mirror in the ITER (International Thermonuclear Experimental Reactor) [5]. The properties of rhodium that make its use so attractive include several relatively stable oxidation states (0, +1, +2, +3), a variety of coordination numbers, rich and tuneable redox properties [6], and diverse redox and ligand exchange kinetics. For example, ligands with electron-withdrawing molecular fractions on them, such as the CF3 group, increase the rate of substitution reactions [7], while those with electron-donating molecular fragments (e.g., the ferrocenyl group) increase the rate of oxidative addition reactions for rhodium complexes [6]. Rhodium also has a low oxophilicity [1], implying that this noble metal and its complexes display a tolerance to many functional groups and have good water stability, provided that the ligands co-ordinated to them are aqueous-stable.
In terms of dicarbonyl rhodium(I) complexes, the Monsanto catalyst [Rh(CO)2(I)2]− is probably the best known compound [8], but β-diketonato rhodium(I) dicarbonyl complexes, [Rh(β-diketonato)(CO)2], are mostly only fleetingly mentioned and discussed as precursors towards β-diketonato rhodium(I) monophosphine monocarbonyl complexes [9,10]. One of the only available electrochemical and crystallographic studies on [Rh(β-diketonato)(CO)2] complexes highlighted the redox potential tuneability of both the rhodium and ferrocenyl centres in complexes where β-diketonato = FcCOCHCOR− and R = CF3 and CH3 and Ph, and Fc = FeII(C5H5)(C5H4) = ferrocenyl [11]. Electrochemical studies were performed in acetonitrile containing [N(nBu)4][PF6] as a supporting electrolyte. RhI was found to be oxidized to RhIII in this medium and CH3CN coordinated to the Rh centre. In contrast, in dichloromethane as a solvent and in the presence of bulky non-coordinating supporting analyte anions like B{C6H3(CF3)2}4− [12] or B(C6F5)4− [13] rather than the usual PF6− or ClO4− supporting analyte anions, rhodium(I) may be oxidized in a one-electron quasi-reversible process to rhodium(II), and the ruthenocenyl and osmocenyl groups may be oxidized reversibly.
The ease of ferrocenyl-containing ligand synthesis, their stability, the electrochemical reversible behaviour of the ferrocenyl group [14,15,16], and the antineoplastic [6,17] and antimalarial [18] properties it possesses are some of the reasons why ferrocenyl-containing systems are also often used as catalytic or otherwise active components [19,20,21]. Other group 8 metallocenes are much less studied, probably because it becomes more difficult to synthesize complexes of them as one moves from iron to ruthenium to osmium. With respect to this study, the cytotoxicity of ruthenocene is documented [22] and the relative ease of synthesizing ferrocenyl [23], ruthenocenyl [24], osmocenyl [25], and cobaltocenium [26] derivatives may be evaluated by comparing the synthetic conditions to obtain phosphine ligands containing these groups.
In this paper, we discuss the synthesis of new metallocene-containing rhodium(I) dicarbonyl complexes, [Rh(FcCOCHCOR)(CO)2], with R = Rc = ruthenocenyl, 12, and R = Oc = osmocenyl, 13, as well as the previously reported [11] complexes [Rh(FcCOCHCOCF3)(CO)2], 10, and [Rh(FcCOCHCOFc)(CO)2], 11. The ruthenocenyl and osmocenyl complexes are of value as knowledge of these two metallocenes are very scarce compared to that of ferrocene. We also describe an in-depth study of the electrochemistry of rhodium(I) dicarbonyl complexes 10–13 in a non-coordinating electrolyte and solvent system, which allowed the unambiguous detection of RhII species for the first time in these complexes. FT-IR is employed in a spectroelectrochemical study to identify the generated rhodium(II) species and the cytotoxicity of 10 is compared to those of its synthetic precursors, the free β-diketone FcCOCH2COCCF3 and [Rh(FcCOCHCOCCF3)(cod)]. The observation of the CO stretching frequencies of electrochemically generated rhodium(II) complexes of 11–13 on a normal laboratory timescale is very unique as this rhodium oxidation state is normally so unstable that its existence is often indirectly deduced rather than directly measured.

2. Results and Discussion

2.1. Synthesis

The formation of the osmocene-containing β-diketone 5 under basic conditions according to Scheme 1 by Claisen condensation in 31% yield was, as for ferrocene [27], accompanied by the formation of OcCOCH=C(CH3)Oc, the aldol self-condensation product of acetyl osmocene, 1. To minimize the formation of this unwanted and difficult-to-remove side product, the added base, lithium diisopropylamide (LDA), was added marginally in excess over acetyl osmocene, so that the latter is the limiting reagent. A careful optimization of the reaction time before the addition of the ester helps to minimize acetyl osmocene self-condensation. In our hands, the best results were obtained by allowing LDA to react with acetyl osmocene to generate the nucleophilic species, OsCOCH2−, for no more than 30 min before the addition of the appropriate ester, here, methyl ferrocenoate. All β-diketones were orange-red solids, stable in air and having a long shelf life (>3 years).
The synthesis of electron-rich rhodium(I) dicarbonyl complexes was performed in two steps from the rhodium-chloro-cyclooctadiene dimer [Rh2Cl2(cod)2], as shown in Scheme 2. Although they can also be obtained in one step from [Rh2Cl2(CO)4], we found this precursor to be more suitable for a reaction with electron-poor β-diketones possessing electron-withdrawing side groups, e.g., H3CCOCH2COCF3. The appropriate β-diketone, 2, 3, 4, or 5, was reacted with [Rh2Cl2(cod)2] to form a rhodium(I) β-diketonato cyclooctadiene complex. Care was taken to ensure that all starting materials were of very high purity, in order to simplify the purification of the rhodium β-diketonato complexes. Bubbling of CO gas, at a pressure of approximately 1300 Pa above atmospheric pressure, through a solution of this [Rh(β-diketonato)(cod)] complex in acetone, led to the formation of the desired [Rh(β-diketonato)(CO)2] complex. The displacement of cod by CO is an equilibrium process and quick precipitation and isolation through centrifugation led to high yields. Two new compounds, [Rh(FcCOCHCORc)(CO)2] 12 and [Rh(FcCOCHCOOc)(CO)2] 13, were synthesized, as well as the previously reported [11] [Rh(FcCOCHCOFc)(CO)2] 11 and [Rh(FcCOCHCOCF3)(CO)2] 10. All dicarbonyl rhodium complexes were orange-red and stable in air but had a much shorter shelf life than the free β-diketones (seldom more than 1 year).

2.2. Electrochemistry

The cyclic, square wave and linear sweep voltammetry of compounds 10–13 in a CH2Cl2 solution containing 0.1 mol dm−3 [N(nBu)4][B(C6F5)4] are shown in Figure 1. Reported potentials (Table 1 at a scan rate of 100 mV s−1 and Figure 1) are relative to FcH/FcH+ while decamethylferrocene, Fc*, was used as an internal standard to prevent overlap of free ferrocene as an internal standard with ferrocenyl groups of 10–13. Under the conditions of this study, the reversible Fc*/Fc*+ redox couple is at Eo′ = −607 mV vs. FcH/FcH+.
Wave 1 shows the one-electron redox couple for the oxidation of the ferrocenyl centre of the β-diketone of all four complexes. The formal reduction potential, Eo′ = ½(Epa + Epc), of the CF3 complex 10 is 328 mV while those of complexes 11–13 are between 156 and 171 mV. ΔEp = Epa − Epc for the normally reversible ferrocenyl redox process, wave 1, was found to be between 60 and 84 mV at a scan rate of 100 mVs−1, but electrochemical reversible redox processes should in theory exhibit ΔEp values of 59 mV. However, wave 2, the RhII/RhI couple, is largely overlapping with wave 1 and the poor resolution between these two redox processes leads to a broadening of wave 1. This explains the larger than expected ΔEp values observed for the ferrocenyl wave, and we conclude that the Fc0/+ couples of complexes 10–13 are indeed reversible at slow scan rates.
That a second one-electron redox process is buried under the one-electron Fc0/+ redox process of wave 1 is clear when one compares the peak anodic current, ipa, of the internal standard, Fc*, with ipa of wave 1, and also ipa of wave 1 with ipa of wave 3. For example, for 10 and 11, which contain equimolar amounts of Fc* and 10, or Fc* and 11, the ratio of (ipa,wave 1 + ipa,wave 2 overlapping)/ipa,Fc* = 1.93 or 1.92. Since both the Fc* group and the ferrocenyl group are one-electron transfer processes, it follows that the submerged wave 2 below wave 1 also represents a one-electron transfer process; otherwise, the ratio (ipa,wave 1 + ipa,wave 2 overlapping)/ipa,Fc* cannot approach 2. Likewise, the ratio (ipa,wave 1 + ipa,wave 2 overlapping)/ipa,wave 3 for 11, 12, and 13 is 1.95, 2.06, and 1.90, respectively (currents are from Table 1). If one bares in mind that both the Rc0/+ and Oc0/+ couples should be one-electron transfer processes under the conditions employed, we conclude that CV wave 2 superimposed onto CV wave 1 represents a one-electron transfer process and is associated with the RhII/RhI couple. The RhII/RhI couple of wave 2 is further highlighted hereafter in the spectroelectrochemical discussion.
The third wave in the CV of compounds 11, 12, and 13 shows the redox couple of the second metallocene attached to the β-diketonato ligand. Complex 11 with R = Fc shows the second quasi-reversible ferrocenyl wave (ΔEp = 84 mV) at an Eo′ value of 295 mV. Note that the two Fc groups of 11 are spectroscopically equivalent but not electrochemically. When the first Fc group is oxidized to Fc+, it converts from an electron donor with group electronegativity 1.87 to an electron-withdrawing group with group electronegativity 2.82 [11]. This is almost as strong electron withdrawing as a CF3 group with group electronegativity 3.01 [11]. Since good communication exists between the two pendent ferrocenyl groups, it follows that the second ferrocenyl group of 11 with Eo′ = 295 mV is almost as difficult to oxidize as the Fc group of 10 with Eo′ = 328 mV, Table 1. The result is that the two Fc groups of 11 behave as two distinctly different redox centres, each one being involved in a separate one-electron transfer process [11]. Compounds 12 (R = Rc) and 13 (R = Oc) show irreversible oxidation waves for the oxidation of the ruthenocenyl or osmocenyl centre at Epa values of 751 and 640 mV, respectively.
By using square wave (SW) and linear sweep (LSV) voltammetry, we were able to identify the RhII/RhI couple associated with wave 2, which are buried beneath wave 1 more clearly. Due to the nature of the ferrocenyl and rhodium redox processes, the ferrocenyl being a fast electrochemically reversible process and the RhII/RhI couple being a slow quasi-reversible or electrochemically irreversible process, square wave voltammetry at a frequency of 50 Hz was able to partially separate these two poorly resolved CV peaks better, Figure 1. For this reason, wave 2 was observed in the case of 10, 12, and 13 at a slightly larger potential than in the CV, while the ferrocenyl formal reduction potential was independent of SW frequency. The RhII/RhI couple, wave 2, is buried under each CV, but the SW voltammograms at 50 Hz clearly showed wave 2 to the right at slightly larger potentials of wave 1. These potentials are also listed in Table 1.
A final observation in the SWVs of 12 and 13 relates to the separation of the broadish CV wave 3 into two sharper SWV components, waves 3 and 4. These are associated with the monomeric and dimeric forms, respectively, of the oxidized ruthenocenium species [28], i.e., Rc+ and Rc+–Rc+, and oxidized osmocenium species Oc+ and Oc+–Oc+ [29]. The oxidized ferrocenium group, Fc+, does not undergo this dimerization. Only the oxidized ruthenocenium monomer and dimer of free ruthenocene have been studied electrochemically in detail before [28].
The LSV confirmed the interpretation of the RhII/RhI couple as being poorly resolved from the Fc+/Fc0 couple by identifying the combined relative number of electrons present in wave 1 and 2 as two. The LSV of compounds 11, 12, and 13 also shows that the electrons transferred during wave 1 and 2 combined are double that of wave 3, the one-electron metallocene oxidation wave. For compound 10, the LSV also shows two electrons being transferred for wave 1 and 2 if one compares the LSV current to the one-electron redox process of an equimolar amount of the internal standard, decamethylferrocene (Fc*). The CV, LSV, and SWV results are therefore all mutually consistent with a one-electron oxidation of the rhodium(I) centre overlapping the one-electron oxidation of the β-diketonato ferrocenyl group of 10–13.
The RhII/RhI couple in DCM and [N(nBu)4][PF6] was also previously reported by Smith, Bezuidenhout, and co-workers [30]. These researchers synthesized cyclo-octadiene and dicarbonyl rhodium complexes similar to our complexes 6–13 but having the bidentate β-diketonato ligand replaced with a chloro and ferrocenyl Fisher carbene ligand, i.e., [Rh(cod)Cl{C(OEt)Fc}] and [Rh(CO)2Cl{C(OEt)Fc}]. This ligand system is more electron-donating than our metallocenyl β-diketonato ligand system and therefore should also stabilize electrochemically generated rhodium(II) intermediates substantially. Although no LSV data are available, the RhI/RhII and RhII/RhIII couples are observed for the cod complex at 0.193 and 0.413 V vs. FcH/FcH+. No data are reported for the dicarbonyl complex. We did not observe RhII/RhIII couples for our dicarbonyl compounds as these fell outside the potential window of the solvent, but our RhI/RhII couples fell in the potential range of 0.156 ≤ Eo′ ≤ 0.398 V vs. FcH/FcH+ and correspond well with Smith’s cod complex potentials [30].

2.3. Spectroelectrochemistry

To more clearly understand the rhodium redox process buried beneath the ferrocenyl redox couple in CV wave 1, spectroelectrochemistry was performed. IR spectra were recorded for the dicarbonyl complex as the applied potential was systematically increased in 0.1 V increments from 0 V inside an Ottle cell. These experiments were performed at concentrations three times higher than that of the electrochemistry experiments, to increase the observability of the IR peaks. By focusing on the IR carbonyl peaks, it is possible to identify changes in the redox state of the rhodium centre as the potential is increased. Rhodium oxidation state changes in rhodium carbonyl complexes from RhI to RhII typically lead to CO stretching frequency (υ(CO)) and increases for the two observed CO bands (Figure 2 and Table 2) of 10–30 cm−1 while oxidation state changes from RhI to RhIII typically lead to CO stretching frequency increases of 80–120 cm−1 [11].
IR spectra obtained from spectroelectrochemistry of rhodium(I) dicarbonyl complexes 10–14 are shown in Figure 2 and IR peak values of the Rh(I) and the oxidized Rh(II) carbonyl peaks, as well as the potential of maximum Rh(II) IR peak values, are listed in Table 2. At a resting potential of 0 V, two carbonyl peaks, A1 and B1, of the original RhI species are observable. As the potential is increased, these two carbonyl peaks disappear, together with the appearance of two new carbonyl peaks, A2 and B2. The newly formed peaks reach a maximum in size at a potential just larger than the CV observed wave 1 potential and can be attributed to the Rh(II) species formed upon oxidation at wave 1. As the potential is further increased, the Rh(II) carbonyl peaks quickly disappear again and at a potential of ca. 1.6 V, they are completely gone. This indicates the decomposition of the rhodium complex, due to loss of the CO ligands.
Spectroelectrochemistry by virtue of the small υ(CO) increases (much less than 80–120 cm−1) thus gives further proof that the RhI centre of 10–13 undergoes oxidation to a RhII species at wave 2, but according to CV measurements, this oxidation is closely overlapped by the oxidation of the β-diketonato ferrocenyl ligand.
The RhI IR carbonyl stretching frequencies reported in Table 2 correlate very well with the υ(CO) values reported by Smith [30] for [Rh(CO)2Cl{C(OEt)Fc}] (2001 and 2084 cm−1), but these authors did not report any RhI υ(CO) values.
The combined insight of CV and spectroelectrochemistry of rhodium(I) dicarbonyl complexes can be summarized schematically as shown in Scheme 3.

2.4. Cytotoxicity of 10

The antineoplastic activity of complex 10, [Rh(FcCOCHCOCCF3)(CO)2], was probed against a cervical cancer HeLa cell line. Figure 3 is a cell survival curve showing cell growth expressed as a percentage of the control’s growth (in essence, this is cell growth inhibition) as a function of drug concentration in μM. The mean concentration needed for 50% cell growth inhibition was obtained from three triplicated experiments and estimated by extrapolation as IC50 = 19.2 ± 0.1 µM. In comparison, under identical conditions, the IC50 of cisplatin was found to be 0.5 ± 0.1 µM.
The antineoplastic activity of the two synthetic precursors to 10, namely the free β-diketone FcCOCH2COCF3 and [Rh(FcCOCHCOCCF3)(cod)], were determined against a malignant human prostate epithelium (1542T); IC50 values of 4.52 and 4.14 μM, respectively, were found [31]. The presence of two bound CO groups in the structure of 10 did not make it more cytotoxic than either FcCOCH2COCF3 or [Rh(FcCOCHCOCCF3)(cod)]. The mechanism of action of the ferrocenyl group is known to involve electron transfer [17] but for rhodium, it is not yet clear. It may involve oxidative addition reactions (also a form of electron transfer), or substitution, or DNA intercalation. Further research is required to understand the mechanism of action of the rhodium centre.

3. Materials and Methods

3.1. General Information

Solid reagents, solvents and dissolved reactants (Aldrich, Johannesburg, South Africa) were used without any further purification. Organic solvents were dried and distilled directly prior to use where specified; water was double-distilled. The rhodium-chloro-cyclooctadiene dimer [Rh2Cl2(cod)2] [32]; free β-diketones FcCOCH2COR with R = CF3, 2 [33] and Fc, 3 [34] as well as Rc, 4 [35]; rhodium complexes [Rh(FcCOCHCOR)(cod)] with R = CF3, 6 and Fc, 7 [11]; and [Rh(FcCOCHCOR)(CO)2] with R = CF3, 10 and Fc, 11 [11] were synthesized as described before. [N(nBu)4][B(C6F5)4] was synthesized utilizing a published procedure [14]. 1H NMR spectra at 20 °C were recorded on a Bruker Advance DPX 300 NMR spectrometer (Bruker, Johannesburg, South Africa) at 300 MHz with chemical shifts presented as δ values referenced to SiMe4 at 0.00 ppm, utilizing CDCl3 as a solvent, and 13C NMR was recorded on a Bruker Advance II 600 NMR spectrometer (Bruker, Johannesburg, South Africa), also utilizing CDCl3 as a solvent. The CDCl3 was made acid-free by passing it through basic alumina immediately before use. An elemental analysis was conducted by the Analytical Chemistry group of the Chemistry Department of the UFS on a Leco TruSpec Micro instrument (Leco, Pretoria, South Africa).

3.2. Synthesis of New Complexes

The procedure and data reported are reproduced from the PhD thesis of E. Fourie [36] with permission from the UFS.

3.2.1. 1–Ferrocenyl–3–osmocenylpropane–1,3–dione, FcCOCH2COOc, 5

This ligand was synthesized as shown in Scheme 1. Acetyl osmocene 1 (0.25 g, 0.71 mmol) [37] was dissolved in the minimum dry THF (1.5 mL) and the system was degassed with N2. It was cooled to 0 °C, added to LDA (0.45 mL of 1.8 M, 0.73 mmol, 1 eq.) under N2, and stirred for 30 min. Methyl ferrocenoate [35] (0.17 g, 0.71 mmol, 1 eq.) was added to the reaction mixture under N2. The reaction mixture was allowed to warm to room temperature and stirred overnight. Ether (30 mL) was added until a precipitate was formed, and filtered. The precipitate was suspended in 1 M HCl (50 mL) and extracted with ether. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to yield a pure product as an orange-red powder. Yield 31% (0.12 g, 0.21 mmol). Melting point = 194 °C. υ(C=O) = 1652 cm−1. δH (300 MHz, CDCl3)/ppm: 5.83 (s; 1H; enol CH); 5.37 (t; 2H; keto 0.5 × C5H4; Oc, J = 1.9 Hz); 5.35 (t; 2H; enol 0.5 × C5H4; Oc, J = 1.9 Hz); 5.00 (m; 4H; keto 0.5 × C5H4; Oc; enol 0.5 × C5H4); 4.92 (t; 2H; enol 0.5 × C5H4; Fc, J = 2.0 Hz); 4.81 (s; 5H; keto C5H5; Oc); 4.78 (t; 2H; keto 0.5 × C5H4; Fc); 4.74 (s; 5H; enol C5H5; Oc); 4.58 (t; 2H; keto 0.5 × C5H4; Fc, J = 2.0 Hz); 4.50 (t; 2H; enol 0.5 × C5H4; Fc, J = 2.0 Hz); 4.24 (s; 5H; keto C5H5; Fc); 4.16 (s; 5H; enol C5H5; Fc); 3.89 (s; 2H; keto CH2). Elemental anal. (%): calc. for C23H20O2FeOs (574.5): C, 48.09; H, 3.51; found: C, 48.0; H, 3.5.

3.2.2. [Rh(β-diketonato)(cod)] and [Rh(β-diketonato)(CO)2] Complexes

These complexes were synthesized as shown in Scheme 2. Complexes 8, 9, 12, and 13 are new; synthetic details follow hereafter.

[Rh(FcCOCHCORc)(cod)] 8 and [Rh(FcCOCHCOOc)(cod)] 9

The synthesis of 8 may serve as an example. Solid 4 (0.09 g, 0.18 mmol, 2 eq.) was added to a solution of [Rh2Cl2(cod)2] (0.04 g, 0.09 mmol) in DMF (1 mL). The mixture was stirred for 1 h and the product precipitated with an excess of water (20 mL). The product was filtered off and dissolved in ether and the organic layer was washed with water. The ether was dried over Na2SO4 and evaporated under reduced pressure to yield pure 8 as an orange-red solid. Yield 87% (0.06 g, 0.09 mmol). Melting point = 176 °C. δH (300 MHz, CDCl3)/ppm: 5.88 (s; 1H; CH), 5.06 (t; 2H; 0.5 × C5H4, Rc, J = 1.9 Hz), 4.68 (t; 2H; 0.5 × C5H4, Rc, J = 1.9 Hz), 4.65 (t; 2H; 0.5 × C5H4, Fc, J = 2.0 Hz), 4.58 (s; 5H; C5H5, Rc), 4.34 (t; 2H; 0.5 × C5H4, Fc, J = 2.0 Hz), 4.25 (m; 4H; 4CH), 4.16 (s; 5H; C5H5, Fc); 2.52 (m; 4H; 0.5 × 4CH2), 1.77 (m; 4H; 0.5 × 4CH2). Elemental anal. (%): calc. for C31H31O2RhFeRu (695.4): C, 53.5; H, 4.5; found: C, 53.4; H, 4.5.
Synthetic quantities and characterization data of 9: Solid 5 (0.1 g, 0.17 mmol, 2 eq.) was added to a solution of [Rh2Cl2(cod)2] (0.04 g, 0.09 mmol) in DMF (1 mL). Yield: 77% (0.05 g, 0.06 mmol) as an orange-red solid. Melting point = 183 °C. δH (300 MHz, CDCl3)/ppm: 5.80 (s; 1H; CH), 5.21 (t; 2H; 0.5 × C5H4, Oc, J = 1.9 Hz); 4.87 (t; 2H; 0.5 × C5H4, Oc, J = 1.9 Hz), 4.77 (s; 5H; C5H5, Oc), 4.63 (t; 2H; 0.5 × C5H4, Fc, J = 2.0 Hz), 4.33 (t; 2H; 0.5 × C5H4, Fc, J = 2.0 Hz); 4.15 (s; 5H; C5H5, Fc), 4.08 (m; 4H; 4CH), 2.52 (m; 4H; 0.5 × 4CH2), 1.87 (m; 4H; 0.5 × 4CH2). Elemental anal. (%): calc. for C31H31O2RhFeOs (784.6): C, 47.5; H, 4.0: found: C, 47.6; H, 4.0.

[Rh Rh(FcCOCHCORc)(CO)2] 12 and [Rh(FcCOCHCOOc)(CO)2] 13

The synthesis of 13 may serve as an example. [Rh(FcCOCHCOOc)(cod)], 9 (0.1 g, 0.13 mmol) was dissolved in 40 mL acetone. Carbon monoxide gas was bubbled through the solution by passing it through a sintered glass tube. The CO (g) pressure was maintained at approximately 1300 Pa above atmospheric pressure for 30 min. Cold water (60 mL) was added to precipitate the product, and the mixture was stirred for a further 15 min, then centrifuged. The precipitate was washed with water, with care being taken not to allow liberated cod to get in contact with the precipitate; filtered; and dried in a desiccator. Yield 81% (0.08 g, 0.11 mmol) as an orange solid. Melting point = 191 °C. υ(C=O) = 2069 and 2006 cm−1. δH (300 MHz, CDCl3)/ppm: 6.02 (s; 1H; CH), 5.33 (t; 2H; 0.5 × C5H4, Oc, J = 1.9 Hz); 4.95 (t; 2H; 0.5 × C5H4, Oc, J = 1.9 Hz), 4.78 (s; 5H; C5H5, Oc), 4.76 (t; 2H; 0.5 × C5H4, Fc, J = 2.0 Hz), 4.44 (t; 2H; 0.5 × C5H4, Fc, J = 2.0 Hz), 4.15 (s; 5H; C5H5, Fc). 13C{1H}-NMR (CDCl3, δ, ppm): 68.7 (s, 0.5 × C5H4, Fc); 70.3 (s, C5H5, Fc); 70.4 (s, 0.5 × C5H4, Oc); 71.3 (s, 0.5 × C5H4, Fc); 72.2 (s, C5H5, Oc); 72.7 (s, 0.5 × C5H4, Oc); 80.9 (s, Cq/C5H4, Fc); 85.6 (s, Cq/C5H4, Oc); 94.8 (s, CH/β-dik); 181.7 (s, CO/β-dik); 183.1 (s, CO/β-dik); 183.9 (s, CO); 184.4 (s, CO). Elemental anal. (%): calc. for C25H19O4RhFeOs (732.4): C, 41.0; H, 2.6; found: C, 41.3; H, 2.7.
Synthetic quantities and characterization data of 12: [Rh(FcCOCHCORc)(cod)], 8 (0.2 g, 0.29 mmol) was dissolved in 80 mL acetone. Yield = 85% (0.12 g, 0.19 mmol) as an orange-red solid, m.p. = 185 °C. IR: υ(C=O) = 2068 and 2006 cm−1. 1H-NMR (CDCl3, δ, ppm): 6.10 (s; 1H; CH); 5.18 (t; 2H; 0.5 × C5H4, Rc, J = 1.9 Hz); 4.77 (m; 4H; 0.5 × C5H4, Rc; 0.5 × C5H4, Fc); 4.57 (s; 5H; C5H5, Rc); 4.45 (t, 2H, 0.5 × C5H4, Fc, J = 2.0 Hz); 4.16 (s; 5H; C5H5, Fc). 13C{1H}-NMR (CDCl3, δ, ppm): 68.7 (s, 0.5 × C5H4, Fc); 70.3 (s, C5H5, Fc); 70.4 (s, 0.5 × C5H4, Rc); 71.3 (s, 0.5 × C5H4, Fc); 72.2 (s, C5H5, Rc); 72.7 (s, 0.5 × C5H4, Rc); 80.9 (s, Cq/C5H4, Fc); 85. 6 (s, Cq/C5H4, Rc); 94.8 (s, CH/β-dik); 181.6 (s, CO/β-dik); 183.4 (s, CO/β-dik); 183.9 (s, 1 × CO); 184.4 (s, 1 × CO). Elemental anal. (%): calc. for C25H19O4RhFeRu (643.2): C, 46.7; H, 3.0; found: C, 46.6; H, 33.0.

3.3. Electrochemistry

Measurements on ca. 1.0 mmol dm−3 solutions of the complexes in dry air free dichloromethane containing 0.10 mol dm−3 tetrabutylammonium tetrakis(pentafluorophenyl)-borate, [N(nBu)4][B(C6F5)4], as a supporting electrolyte, were conducted under a blanket of purified argon at 25 °C, utilizing a BAS 100 B/W electrochemical workstation (Analytical Science Technology, Cape Town) interfaced with a personal computer. A three-electrode cell, which utilized a Pt auxiliary electrode, a glassy-carbon working electrode (surface area: 0.0707 cm2), and an in-house-constructed Ag/Ag+ reference electrode (a silver wire, immersed in 0.01 mol dm−3 AgNO3 with a vycor tip (Analytical Science Technology, Cape Town)), was used. Successive experiments under the same experimental conditions showed that all formal reduction and oxidation potentials were reproducible within 5 mV. Results are referenced against ferrocene, utilizing decamethylferrocene (Fc*) [38,39] as an internal standard. To achieve this, each experiment was first performed in the absence of ferrocene and decamethylferrocene, and then repeated in the presence of ca. 1 mmol dm−3 decamethylferrocene. A separate experiment containing only ferrocene and decamethylferrocene was also performed. Data were then manipulated on a spreadsheet to set the formal reduction potentials of the FcH/FcH+ couple to 0 V. Under our conditions, the Fc*/Fc*+ couple was at −607 mV vs. FcH/FcH+, while the FcH/FcH+ couple was at 220 mV vs. the Ag/Ag+ reference electrode.

3.4. Spectroelectrochemistry

Spectroelectrochemistry was performed in a Specac Omni Ottle Cell P/N 1800 (Merck, Johannesburg, South Africa, Ottle = Optically Transparent Thin-Layer Electrochemical), attached to a BAS CV-27 (Analytical Science Technology, Cape Town) electrochemical workstation interfaced with a personal computer. The Ottle cell was placed inside a Bruker Tensor 27 Fourier transform infrared (FT-IR) spectrometer (Bruker, Johannesburg, South Africa) to obtain IR spectra. Measurements were carried out on ca. 3.0 mmol dm−3 solutions of the complexes in dry dichloromethane, containing 0.30 mol dm−3 tetrabutylammonium tetrakis-(pentafluorophenyl)borate as a supporting electrolyte, at 25 °C. IR spectra were taken at regular intervals, as the potential was increased in 0.05–0.1 V increments, from 0 V to ca. 1.6 V.

3.5. Cytotoxic Tests

Compounds were dissolved in DMSO to give stock concentrations of 10 mg cm−3 and diluted in the appropriate growth medium (EMEM+), which contains components such as essential amino acids, vitamins, inorganic salts, hormones, metabolites, and nutrients, supplemented with fetal calf serum (FCS) to give final DMSO concentrations not exceeding 0.5% and drug concentrations of 1–3000 μg cm−3 prior to cell experiments. The human cervix epithelioid cancer cell line, HeLa (ATCC CCI-2, American Type Culture Collection), was grown as a monolayer culture in MEM. The growth medium was incubated at 37 °C under 5% CO2 and fortified with 10% FCS and 1% penicillin and streptomycin. Appropriate solvent control systems were included. Cells were seeded at 500 cells/well for 7-day incubation experiments and in 96-well microtiter plates in a final volume of 200 μL of the growth medium in the presence or absence of different concentrations of experimental drugs. Wells without cells and with cells but without drugs were included as controls. After incubation at 37 °C for 7 days, cell survival was measured by means of the colourimetric 3-(4,5-dimethylthiazol-2-yl)-diphenyl tetrasodium bromide (MMT) assay [40].

4. Conclusions

Although the functionalization of free ruthenocene and especially free osmocene is much more difficult to achieve than the functionalization of free ferrocene, for example, the synthesis of acetyl ruthenocene and acetyl osmocene compared to acetyl ferrocene as precursors to β-diketonato ligands, once the metallocene-containing β-diketonato ligand has been obtained, coordination reactions to synthesize [Rh(FcCOCHCOR)(CO)2] complexes with R = CF3, 10; Fc, 11; Rc, 12; and Oc, 13 proceed easily and smoothly, especially via the [Rh(FcCOCHCOR)(cod)] intermediate. Complexes 11–13 can also be obtained from the tetracarbonyl dimer [Rh2Cl2(CO)4] but in lower yields as this route is better suited to ligand substitution with more electron-withdrawing ligands such as H3CCOCH2COCF3.
All compounds showed the reversible Fc0/+ couple in the potential range 0.156 ≤ Eo′ ≤ 0.328 V vs. FcH/FcH+ while the electrochemically irreversible osmocenyl and ruthenocenyl oxidations were observed at peak anodic potentials of Epa = 0.640 V and Epa = 0.751 V vs. FcH/FcH+, respectively. The oxidation of RhI to RhII occurred at potentials that overlapped with the ferrocenyl couple and only the stronger resolving capability of square wave voltammetry allowed estimates of the RhI/II redox couple at slightly larger potentials than the Fc0/+ couple: 0.398 V for 10 (R = CF3), 0.156 V for 11 (R = Fc), 0.159 V for 12 (R = Rc), and 0.171 V for 13 (R = Oc). The electrochemistry as well as spectroelectrochemistry of these rhodium(I) dicarbonyl complexes were mutually consistent in showing that rhodium(I) is oxidized in CH2Cl2 containing [NnBu4][B(C6F5)3] in a one-electron transfer process to rhodium(II). All RhII complexes were very unstable and very quickly decomposed, probably to RhIII complexes bearing no carbonyl groups. Especially the spectroelectrochemistry identification of RhII is unique in this study, as the rhodium(II) oxidation state is usually so unstable, it seldom is possible to obtain normal laboratory timescale physical proof of it. Measurements of the carbonyl stretching frequencies, υ(CO), of electrochemically generated [RhII(FcCOCHCOR)(CO)2] compounds were possible because of the use of the non-coordinating solvent and supporting electrolyte system consisting of dry dichloromethane containing tetrabutylammonium tetrakis(pentafluorophenyl)borate, [N(nBu)4][B(C6F5)4]. It also enabled the chance observation of both the monomeric and dimeric forms of the highly unstable oxidized ruthenocenyl and osmocenyl groups, namely Rc+ and Rc+–Rc+ and also Oc+ and Oc+–Oc+.
Finally, the antineoplastic activity of [Rh(FcCOCHCOCF3)(CO)2], 10, was found to be much less than those of its synthetic precursors [Rh(FcCOCHCOCCF3)(cod)] or FcCOCH2COCF3.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/inorganics12120321/s1, 1H and 13C NMR spectra of 10–13 as well as CV electrochemical data of 10–13 at scan rates of 100, 200, 300, 400, and 500 mV s−1. Figure S1: 1H NMR spectrum of [Rh(FcCOCHCORc)(CO)2] 12; Figure S2: 1H NMR spectrum of [Rh(FcCOCHCOOc)(CO)2] 13; Figure S3: 1H NMR spectrum of [Rh(FcCOCHCOFc)(CO)2] 11; Figure S4: 1H NMR spectrum of [Rh(FcCOCHCOCF3)(CO)2] 10; Figure S5: 13C NMR spectrum of [Rh(FcCOCHCORc)(CO)2] 12; Figure S6: 13C NMR spectrum of [Rh(FcCOCHCOOc)(CO)2] 13; Figure S7: 13C NMR spectrum of [Rh(FcCOCHCOFc)(CO)2] 11; Figure S8: 13C NMR spectrum of [Rh(FcCOCHCOCF3)(CO)2] 10; Table S1: Full electrochemical data for complexes 10–13 in CH2Cl2/0.1 mol dm−3 [NnBu4][B(C6F5)], at all scan rates and T = 25 °C.

Author Contributions

Conceptualization, J.W.N. and J.C.S.; Funding acquisition, J.W.N. and J.C.S.; Investigation, E.F.; Supervision, J.C.S.; Writing—original draft, E.F.; Writing—review and editing, E.F., J.W.N. and J.C.S. All authors have read and agreed to the published version of the manuscript.

Funding

The authors acknowledge the Central Research Fund of the University of the Free State, Bloemfontein, South Africa (J.C.S. and E.F.), for financial support. Funding is also acknowledged from Synfuels China Technology Co., Ltd., Beijing–Huairou, P.R. China (J.W.N.), and Syngaschem BV, The Netherlands (J.C.S., E.F.).

Institutional Review Board Statement

The cytotoxic component of this study involved no humans. It was conducted in accordance with the Declaration of Helsinki and approved by the Environment and Biosafety Research Ethics Committee of the University of the Free State (UFS-ESD2023/0015/23; approved on 6 April 2023) for studies involving in this case purchased cell cultures.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

Author J. W. (Hans) Niemantsverdriet is the owner of the company Syngaschem. All the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Inorganics 12 00321 sch001
Scheme 1. Synthetic route to FcCOCH2COOc, 5; LDA = lithium diisopropylamide.
Scheme 1. Synthetic route to FcCOCH2COOc, 5; LDA = lithium diisopropylamide.
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Inorganics 12 00321 sch002
Scheme 2. Synthetic route towards rhodium dicarbonyl complexes 10–13; cod = 1,5-cyclooctadiene.
Scheme 2. Synthetic route towards rhodium dicarbonyl complexes 10–13; cod = 1,5-cyclooctadiene.
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Figure 1. Cyclic voltammograms (CVs) of 1 mmol dm−3 solutions of compounds 10–13 in dichloromethane containing 0.1 mol dm−3 [N(nBu)4][B(C6F5)4] at 100 mV s−1 on a glassy-carbon working electrode and at 25 °C. Linear sweep voltammograms (LSVs) at 2 mV s−1 are shown below the CV of each compound, while square wave voltammograms (SWVs at 50 Hz) are shown above the CVs. The peak labelled Fc* is that of the internal standard decamethylferrocene. Numbers 1–4 are wave numbers. Wave 4 in the SWVs of 12 and 13 is associated with dimeric 12 and 13; they were difficult to observe in the CVs of these complexes.
Figure 1. Cyclic voltammograms (CVs) of 1 mmol dm−3 solutions of compounds 10–13 in dichloromethane containing 0.1 mol dm−3 [N(nBu)4][B(C6F5)4] at 100 mV s−1 on a glassy-carbon working electrode and at 25 °C. Linear sweep voltammograms (LSVs) at 2 mV s−1 are shown below the CV of each compound, while square wave voltammograms (SWVs at 50 Hz) are shown above the CVs. The peak labelled Fc* is that of the internal standard decamethylferrocene. Numbers 1–4 are wave numbers. Wave 4 in the SWVs of 12 and 13 is associated with dimeric 12 and 13; they were difficult to observe in the CVs of these complexes.
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Figure 2. IR spectra of rhodium(I) dicarbonyl complexes 10, 11, 12, and 13 at a concentration of 0.003 mol dm−3, at regular potential increases, in CH2Cl2/0.3 mol dm−3 [N(nBu4)][B(C6F6)], T = 25 °C. No changes in IR spectra were observed at wavenumbers below 1950 cm−1. After 10 min or at an oxidation potential of 1.6 V, the peaks A2 and B2 were completely gone, indicating that the oxidized RhII products of 11–13 are unstable and decomposed quickly and at high potentials with CO loss, most probably ultimately with RhIII generation. Arrows indicate the direction of peak intensity change.
Figure 2. IR spectra of rhodium(I) dicarbonyl complexes 10, 11, 12, and 13 at a concentration of 0.003 mol dm−3, at regular potential increases, in CH2Cl2/0.3 mol dm−3 [N(nBu4)][B(C6F6)], T = 25 °C. No changes in IR spectra were observed at wavenumbers below 1950 cm−1. After 10 min or at an oxidation potential of 1.6 V, the peaks A2 and B2 were completely gone, indicating that the oxidized RhII products of 11–13 are unstable and decomposed quickly and at high potentials with CO loss, most probably ultimately with RhIII generation. Arrows indicate the direction of peak intensity change.
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Scheme 3. Schematic representations of electrochemical reactions of metallocene-containing rhodium(I) dicarbonyls 10–13 with Mc = Fc, Rc, or Oc. CV waves 1 and 2 are poorly resolved but from SWV, wave 2 is at slightly larger potentials than wave 1. For wave 3, only the Mc = Fc reaction is reversible; for M = Rc or Oc, it is irreversible. Within ca. 10 min or at large potentials, the CO peak pairs of all complexes disappear (Figure 2).
Scheme 3. Schematic representations of electrochemical reactions of metallocene-containing rhodium(I) dicarbonyls 10–13 with Mc = Fc, Rc, or Oc. CV waves 1 and 2 are poorly resolved but from SWV, wave 2 is at slightly larger potentials than wave 1. For wave 3, only the Mc = Fc reaction is reversible; for M = Rc or Oc, it is irreversible. Within ca. 10 min or at large potentials, the CO peak pairs of all complexes disappear (Figure 2).
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Figure 3. Effect of [Rh(FcCOCHCOCCF3)(CO)2], 10, on cell growth inhibition of HeLa cells incubated for 7 days from triplicate experiments.
Figure 3. Effect of [Rh(FcCOCHCOCCF3)(CO)2], 10, on cell growth inhibition of HeLa cells incubated for 7 days from triplicate experiments.
Inorganics 12 00321 g003
Table 1. Cyclic voltammetric data at 100 mV s−1 a (potentials vs. FcH/FcH+) of ca. 1 mmol dm−3 solutions of [Rh(FcCOCHCOR)(CO)2] complexes 10–13 in CH2Cl2 containing 0.1 mol dm−3 [N(nBu)4][B(C6F5)4] supporting electrolyte at 25 °C.
Table 1. Cyclic voltammetric data at 100 mV s−1 a (potentials vs. FcH/FcH+) of ca. 1 mmol dm−3 solutions of [Rh(FcCOCHCOR)(CO)2] complexes 10–13 in CH2Cl2 containing 0.1 mol dm−3 [N(nBu)4][B(C6F5)4] supporting electrolyte at 25 °C.
Comp.; RWave Epa
(mV)		Eo’ (Eo’wave 2) b
(mV)		∆Ep
(mV)		ipa
(μA)		ipc/ipaWaveEpa
(mV)		Eo′
(mV)		∆Ep
(mV)		ipa
(μA)		ipc/ipa
10; R = CF31, Fc0/+371328 (ca. 398)843.910.99------
11; R = Fc1, Fc0/+193156 (–)754.440.983, Fc0/+337295842.280.98
12; R = Rc1, Fc0/+206159 (ca. 233)824.000.973, Rc0/+751--1.94-
13, R = Oc1, Fc0/+201171 (ca. 255)603.890.963, Oc0/+640--2.05-
a Supplementary Data provide details for 10 and 13 at scan rates 100–500 mV s−1. b The first formal reduction potential comes from the CV potential peaks using the formula Eo′ = ½(Epa + Epc) and relates to the Fc0/+ couple (wave 1). The second potential in brackets was estimated from the peak potential observed in the square wave voltammogram for wave 2 at a frequency of 50 Hz and relates to the RhII/RhI couple.
Table 2. Spectroelectrochemical data obtained for 0.003 mol dm−3 rhodium(I) dicarbonyl complexes [Rh(FcCOCHCOR)(CO)2] dissolved in CH2Cl2 containing 0.3 mol dm−3 [N(nBu)4][B(C6F5)4], at T = 25 °C.
Table 2. Spectroelectrochemical data obtained for 0.003 mol dm−3 rhodium(I) dicarbonyl complexes [Rh(FcCOCHCOR)(CO)2] dissolved in CH2Cl2 containing 0.3 mol dm−3 [N(nBu)4][B(C6F5)4], at T = 25 °C.
CompoundRh(I), υ(CO)/cm−1Applied
E/V vs. Ag(m)		Rh(II), υ(CO)/cm−1
A1B1A2B2
13: [Rh(FcCOCHCOCOc)(CO)2]207920101.0520892037
12: [Rh(FcCOCHCOCRc)(CO)2]208620211.0020982037
11: [Rh(FcCOCHCOCFc)(CO)2]207720080.8020942040
10: [Rh(FcCOCHCOCCF3)(CO)2]207920080.8020902036
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Fourie, E.; Niemantsverdriet, J.W.; Swarts, J.C. Synthesis Comparative Electrochemistry and Spectroelectrochemistry of Metallocenyl β-Diketonato Dicarbonyl Complexes of Rhodium(I)—Cytotoxicity of [Rh(FcCOCHCOCF3)(CO)2]. Inorganics 2024, 12, 321. https://doi.org/10.3390/inorganics12120321

AMA Style

Fourie E, Niemantsverdriet JW, Swarts JC. Synthesis Comparative Electrochemistry and Spectroelectrochemistry of Metallocenyl β-Diketonato Dicarbonyl Complexes of Rhodium(I)—Cytotoxicity of [Rh(FcCOCHCOCF3)(CO)2]. Inorganics. 2024; 12(12):321. https://doi.org/10.3390/inorganics12120321

Chicago/Turabian Style

Fourie, Eleanor, J. W. (Hans) Niemantsverdriet, and Jannie C. Swarts. 2024. "Synthesis Comparative Electrochemistry and Spectroelectrochemistry of Metallocenyl β-Diketonato Dicarbonyl Complexes of Rhodium(I)—Cytotoxicity of [Rh(FcCOCHCOCF3)(CO)2]" Inorganics 12, no. 12: 321. https://doi.org/10.3390/inorganics12120321

APA Style

Fourie, E., Niemantsverdriet, J. W., & Swarts, J. C. (2024). Synthesis Comparative Electrochemistry and Spectroelectrochemistry of Metallocenyl β-Diketonato Dicarbonyl Complexes of Rhodium(I)—Cytotoxicity of [Rh(FcCOCHCOCF3)(CO)2]. Inorganics, 12(12), 321. https://doi.org/10.3390/inorganics12120321

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