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Article

On the Aqueous Solution Behavior of C-Substituted 3,1,2-Ruthenadicarbadodecaboranes

Institute of Inorganic Chemistry, Leipzig University, Johannisallee 29, 04103 Leipzig, Germany
*
Author to whom correspondence should be addressed.
Submission received: 26 June 2019 / Revised: 12 July 2019 / Accepted: 16 July 2019 / Published: 22 July 2019
(This article belongs to the Special Issue Metal Complexes Containing Boron Based Ligands)

Abstract

:
3,1,2-Ruthenadicarbadodecaborane complexes bearing the [C2B9H11]2− (dicarbollide) ligand are robust scaffolds, with exceptional thermal and chemical stability. Our previous work has shown that these complexes possess promising anti-tumor activities in vitro, and tend to form aggregates (or self-assemblies) in aqueous solutions. Here, we report on the synthesis and characterization of four ruthenium(II) complexes of the type [3-(η6-arene)-1,2-R2-3,1,2-RuC2B9H9], bearing either non-polar (R = Me (24)) or polar (R = CO2Me (7)) substituents at the cluster carbon atoms. The behavior in aqueous solution of complexes 2, 7 and the parent unsubstituted [3-(η6-p-cymene)-3,1,2-RuC2B9H11] (8) was investigated via UV-Vis spectroscopy, mass spectrometry and nanoparticle tracking analysis (NTA). All complexes showed spontaneous formation of self-assemblies (108–109 particles mL−1), at low micromolar concentration, with high polydispersity. For perspective applications in medicine, there is thus a strong need for further characterization of the spontaneous self-assembly behavior in aqueous solutions for the class of neutral metallacarboranes, with the ultimate scope of finding the optimal conditions for exploiting this self-assembling behavior for improved biological performance.

Graphical Abstract

1. Introduction

Metallacarborane complexes of the icosahedral type can be roughly divided into two categories: those which feature an exo-polyhedral bond to a metal ion, and those where the metal is coordinated by an approximately planar open face of the carborane cluster, e.g., the C2B3 open face of nido-[C2B9H11]2−, commonly known as “dicarbollide” (see Appendix A for cluster nomenclature) [1]. Complexes belonging to the latter typically show closo structures, formally derived from the parent C2B10H12 clusters by replacement of a BH unit with an isolobal metal complex fragment (Figure 1), which therefore contributes three orbitals to the cluster bonding [2].
One main motivation that pushes investigations on the chemistry and physico-chemical properties of metallacarboranes is the long-known isolobal analogy between the cyclopentadienyl (C5H5, Cp) ligand and the dicarbollide C2B9H112− cluster [3]. This is, in turn, reflected in the types of application which have been investigated for metallacarborane complexes, ranging from catalysis [4], to medicine [5] and materials science [6] where often the performance of the metallacarborane is evaluated in comparison to analogous Cp-based complexes (see, for example, Grishin et al. in Pol. Sci. (2015) [7], and Louie et al. in J. Med. Chem. (2011) [8]).
Recently, we have focused on mixed-sandwich ruthenacarborane complexes of the type closo-[3-(η6-arene)-3,1,2-RuC2B9H11] (with arene = p-cymene, biphenyl, 1-Me-4-CO2Et-C6H4), and on half-sandwich molybdacarboranes of the type [3-{L-κ2N,N}-3-(CO)2-closo-3,1,2-MoC2B9H11] (with L = N,N-chelating ligand) for potential applications in medicine, specifically as anti-tumor agents [9,10]. In our previous investigations, we showed that the ruthenacarboranes are chemically exceptionally stable compounds under biologically relevant conditions and possess moderate anti-proliferative activities in vitro against human colorectal carcinoma and breast adenocarcinoma cell lines, and a 10× higher selectivity towards cancer cell lines than to healthy cells (primary fetal fibroblasts and macrophages). Moreover, spectrophotometric studies on aqueous solutions of closo-[3-(η6-biphenyl)-3,1,2-RuC2B9H11] strongly suggested a tendency to form aggregates, at low micromolar concentrations of the complex [9]. The dynamics of aggregation for the anionic metallacarboranes of type [commo-3,3’-Co(1,2-C2B9H11)2] (COSAN) are broadly studied in the literature [11,12,13], and these complexes are generally described as non-classical amphiphiles which spontaneously self-assemble into nano- or microstructures [14]. On the other hand, no studies are found on the aggregation properties of neutral closo-metallacarboranes. Moreover, for potential application in medicine, characterization of the aggregation behavior of a drug candidate is of primary importance, for ensuring validity and reproducibility of the biological tests, as already discussed for aggregate-based organic inhibitors [15]. Here, we report a small series of 3,1,2-ruthenadicarbadodecaborane(11) complexes, bearing either polar (R = CO2Me) or non-polar (R = Me) groups at the carbon atoms of the dicarbollide ligand. The complexes were fully characterized, and the formation of aggregates in aqueous solutions was investigated via UV-Vis spectroscopy, mass spectrometry, and nanoparticle tracking analysis (NTA).

2. Results and Discussion

2.1. Synthesis and Characterization of Complexes 24 and 7

Complex 2, which bears a p-cymene ligand, is a known compound and was synthesized according to the literature [16]. Complexes 3 and 4 (Figure 2) were synthesized in moderate yields (45% for 3, 32% for 4), in an analogous way as previously reported [9], from Tl[3-Tl-1,2-Me2-3,1,2-C2B9H9] (1) and the respective ruthenium(II)–arene dimer [{(η6-arene)RuCl(μ-Cl)}2] (arene = biphenyl or 1-Me-4-CO2Et-C6H4). The spectroscopic data for complexes 2 to 4 are in accordance with those reported for mixed-sandwich closo-ruthenacarboranes, which also incorporate an arene ligand [9,17,18,19].
Complex 7 was synthesized in three steps from 1,2-(CO2Me)2-closo-1,2-C2B10H10 (5) (Scheme 1). 5 was deboronated under mild conditions (MeCN/H2O (2:1) (v/v) at room temperature) [20], to avoid cleavage of the Ccluster–CO2Me exo-skeletal bonds. For the deprotonation of 6, thallium(I) ethanolate was used as base at low temperature (−30 °C), instead of the KOH/thallium(I) acetate couple at 0 °C, used by Safronov et al. for the deprotonation of unsubstituted [nido-7,8-C2B9H12] [21], to avoid base-promoted cleavage of the methoxy ester.
The weighted average (see definition in Appendix B) of the 11B NMR signals of 7 is +3.5 ppm, which is in accordance to previously reported values for pseudocloso-ruthenacarborane structures [16,22] that are formally derived from a closo structure via breaking of the Ccluster–Ccluster bond. In comparison, the weighted average of the 11B signals for 2, 3, and 4 is −13.6, −12.8, and −11.7 ppm, respectively, which indicates closo structures. X-ray diffraction analysis of single crystals of 4 and 7 confirmed the closo and pseudocloso structures (Figure 3), with C(1)⋯C(2) distances of 1.680(5) Å and 2.243(2) Å, respectively. It is not unexpected that complex 7 presents a pseudocloso structure, since closo-to-pseudocloso cluster deformation is a commonly encountered phenomenon in ruthenacarborane complexes, when carbon-bound substituents introduce additional electron density into the Ccluster–Ccluster bond, as in the case of phenyl substituents reported by Brain et al. and Bould et al. [16,22]. The structural distortions in 7 are generally in accordance with those reported by Welch and co-workers for pseudocloso-[3-(η6-arene)-1,2-Ph2-3,1,2-RuC2B9H9] [22]. For example, the Ru–B(6) distance in 7 is 2.979(2) Å, which is 0.5 Å shorter than in the corresponding undistorted closo-[3-(η6-p-cymene)-3,1,2-RuC2B9H11] (8) (Table 1) [9], and the B(6)–B(10) and the C(1)–B(4) bonds are 1.885(2) Å (vs. 1.759(1) Å in 8) and 1.636(2) Å (vs. 1.718(1) Å in 8), respectively. The B(4)–B(5) bond is, however, 0.04 Å longer in the pseudocloso structure 7, compared to the closo one (8), in contrast to what was observed by Welch for diphenyl-substituted pseudocloso-[3-(η6-arene)-1,2-Ph2-3,1,2-RuC2B9H9] complexes, with respect to the corresponding closo-1,2-Ph2-C2B10H10 [22].

2.2. 11B NMR Spectra of Complex 3

Complexes 24 and 7 show moderate to good solubility in chloroform and dichloromethane, and good solubility in dimethylsulfoxide (DMSO). No displacement of either the arene or the (substituted) dicarbollide ligands occurred in wet DMSO-d6, at room temperature for over a month, in all complexes, as evidenced by 1H and 11B NMR spectroscopic analysis (Figures S1 and S2 in Supplementary Materials). This is in analogy to what was previously observed for unsubstituted closo-[3-(η6-arene)-3,1,2-RuC2B9H11] complexes [9], supporting the use of ruthenacarboranes as stable organometallic scaffolds for applications in medicine.
The 11B NMR spectra of complex 3 deserve special attention. In addition to the four (in DMSO-d6) or five (in CD2Cl2) doublets for the nine boron atoms of the [η5-(7,8-Me2-nido-7,8-C2B9H9)]2‒ ligand, additional low-intensity 11B signals are present in the region 0 to −20 ppm (Figure 4), which are unlikely due to impurities from the sample, as confirmed by elemental analysis. These low-intensity signals are instead most likely due to solvent effects on the dicarbollide cluster, which are already described in the literature for decaborane in terms of solvent polarizability that can give rise to additional peaks or shoulders in the 11B NMR spectra [23]. Particularly noteworthy is the small broad signal at +19.8 ppm (Figure 4, bottom), which is present in DMSO-d6 solution, but not in CD2Cl2. The small peak is present already in freshly dissolved samples of 3 in wet DMSO-d6 and remains stable in shift and intensity over one month.
This cannot be attributed to the protonated uncoordinated nido-carborane(−1) ligand. Deore et al. and Crociani et al. showed that the chemical shift of the 11B NMR signals is sensitive to changes in coordination geometry at the boron atom (trigonal at 20 to 30 ppm vs. tetrahedral at 5 to 10 ppm), and that such shifts could be used to distinguish between nano-sized polymeric structures and monomeric forms in solution [24,25]. The signal at +19.8 ppm in the 11B NMR spectrum of 3 could, therefore, be due to the presence of self-assembled nano-structures of 3 in solution, which rapidly interchange with monomers of 3, which are, under the conditions of the NMR experiment, still the dominant species in solution.
The interpretation of the 11B NMR data of potentially aggregating carborane-containing compounds is, however, not trivial and remains somewhat confusing and elusive in the literature. Just to give an example, Bonechi et al. investigated the solution behavior of sugar-substituted closo-ortho-carboranes via 1H and 11B NMR spectroscopy in parallel under aggregating (D2O) and “non-aggregating” conditions (C2D5OD) [26]. In the 11B{1H} NMR spectra in both D2O and C2D5OD, the presence of down-field shifted small peaks (ca. +20 ppm), analogous to that for complex 3 in DMSO-d6, is evident, but no rational behind this was proposed. It was simply concluded by the authors that there is no difference in the NMR spectra between aggregating and “non-aggregating” conditions, although it is not clear why an ethanolic solution should represent “non-aggregating” conditions, since closo-carborane derivatives are also known to form nano-structures in ethanol [27].

2.3. UV-Vis Spectroscopy, Mass Spectrometry and Nanoparticle Tracking Analysis (NTA)

The behavior of 2, 7 and the parent unsubstituted [3-(η6-p-cymene)-3,1,2-RuC2B9H11] (8) in aqueous solution was investigated, via UV-Vis spectroscopy, mass spectrometry and nanoparticle tracking analysis (NTA). The three ruthenacarborane complexes bear the same arene ligand (p-cymene) and differ only in the type of substituents at the cluster carbon atoms (methyl (2), CO2Me (7), and H (8)). UV-Vis spectra of 3, which bears a biphenyl ligand, were also measured, to support the 11B NMR data.
UV-Vis spectroscopy is a useful technique for studying both absorption and scattering phenomena, since the UV-Vis spectrum (ελ) is the result of two components, namely absorption and scattering [28]. The two phenomena can be distinguished, and sometimes separated, based on their different dependency on the wavelength (λ), ε λ for absorption, and ε λ 4 for Rayleigh scattering, respectively. The UV-Vis spectra of 2, 7, and 8 in phosphate-buffered saline (PBS)/DMSO mixtures do not show a clear absorption maximum in the range of 250 to 550 nm, whereas complex 3 has an absorption maximum at 290 nm (Figure 5).
The absorbance shows, however, for all four complexes, an exponential increase towards the blue region of the spectrum, which approximates the case limit of pure Rayleigh scattering. Increasing the concentration of the ruthenacarboranes up to 50 μM only increased the intensity of the exponential decay of the spectrum, and no absorption maxima were visible. Scattering is thus the major component of the absorbance spectra of 2, 3, 7, and 8, although the scattering intensity of 7 and 8 is much lower than for 2 and 3. This suggests the presence of self-assemblies of the ruthenacarborane complexes in PBS/DMSO mixtures, albeit, possibly, in different concentrations. Complex 3 shows the highest scattering intensity of the series, i.e., the highest concentration of aggregates in solution, which is likely the reason why aggregation could also be observed in its 11B NMR spectrum in DMSO-d6 (see above), but not in the spectra of 2 and 7, nor in the previously reported 11B NMR spectra of 8 [9].
ESI mass spectra of 2, 7, and 8 in MeCN/H2O (98:2, v/v) mixtures show a rather complicated fragmentation, with many, partially overlapping, isotopic patterns of carborane-containing species (Figure 6 (2) and Figure S3 (7,8) in Supplementary Materials). In the case of 2, for example, both the monomer ([M + Na]+), the dimer ([2M + Na]+), and the trimer ([3M + NH4]+) were found in the ESI(+) mass spectrum, together with many other peaks, which could not be unequivocally assigned (see the peaks marked with * in Figure 6). Moreover, reproducibility of the MS fragmentation patterns was very poor for all three complexes under the same experimental conditions, which suggests a random and uncontrolled spontaneous self-assembly in solution. From the analysis of the mass spectra alone, one might thus infer that the compound is not pure. Fortunately, the other analytical techniques used to characterize compounds 2, 7, and 8, i.e., NMR and IR spectroscopy, X-ray diffraction, and elemental analysis, clearly indicate that the complexes are analytically pure and void of any kind of impurities.
Samples of 2, 7, and 8 in PBS/DMSO mixtures were also measured via nanoparticle tracking analysis (NTA) to estimate the relative concentration, size, and size distribution of self-assemblies in solution observed by ESI mass spectrometry and UV-Vis spectroscopy. Nanoparticle tracking analysis (NTA) is a fairly new technique for the measurement of colloidal and nano-sized suspensions, which was first commercialized in 2006 by NanoSight Ltd, Salisbury, UK [29]. It has been used for the study of different kinds of samples, ranging from atmospheric [30], to food [31] and to biological samples [32]. The analysis principles and instrument set-up have been extensively discussed in the literature [33]. NTA is a light-scattering technique, in which particle tracking is based on the Brownian motion description of suspended particles in a fluid, captured simultaneously but individually by a charge-coupled device (CCD) camera. The software calculates size (hydrodynamic radius), size distribution, and concentration of the particles. NTA has the advantage over dynamic light scattering (DLS) methods in that it does not suffer from the known bias in size and size distribution of the latter. However, the applicability of NTA is limited to a narrow range of concentrations (106–109 particles mL−1), and the calculated values of size and concentration are highly sensitive to capture and processing parameters, as discussed recently [34]. Samples of 2, 7, and 8 were therefore measured using the same capture and processing parameters, for direct comparison.
All three metallacarboranes form self-assemblies of nanometer size in PBS/DMSO mixtures at 25 °C, albeit in different concentrations, namely 108 for 7 and 8, vs. 109 particles mL−1 for 2 (Figure 7 and Table S2 in Supplementary Materials). 2 shows a bimodal distribution of particle sizes, centered at 115 and 155 nm, respectively, but also presents a smaller fraction of particles with sizes up to 400 nm. Samples of 7 and 8 show broad size distributions of the particles, in the range of 95 to 300 nm (7) or 145 to 400 nm (8). Thus, all three complexes form fairly polydisperse self-assemblies in PBS/DMSO mixtures at room temperature, that is, under conditions, which approximate those of biological tests in vitro.
As already mentioned before, aqueous self-assembly of neutral (metalla)carboranes has been so far poorly investigated, and is limited to a few examples of C-substituted closo-carboranes [26,27]. No studies on the effect of spontaneous aggregation on the biological activity profile or stability in the biological medium are found in the literature. Therefore, comprehensive multi-spectroscopic bioanalytical investigations are now underway.

3. Materials and Methods

3.1. General Procedures and Instrumentation

Chemicals were used as purchased. Phosphate-buffered saline (PBS) was purchased from Sigma Aldrich (Taufkirchen, Germany). Tl[3-Tl-1,2-Me2-3,1,2-C2B9H9] (1) [35,36,37], closo-[3-(η6-p-cymene)-1,2-Me2-3,1,2-RuC2B9H9] (2) [16] and closo-[3-(η6-p-cymene)-3,1,2-RuC2B9H11] (8) [9] were synthesized as previously reported. Synthesis and characterization of 5 and 6 (precursor compounds) are given in the Supplementary Materials. All manipulations were carried out in a dry and oxygen-free nitrogen atmosphere using standard Schlenk techniques, unless otherwise stated. Thallium(I) ethanolate (Alfa Aesar©, Kandel, Germany) was stored under argon at −20 °C, protected from light. All manipulations involving thallium(I) compounds were performed wearing personal protective equipment as prescribed in the material safety data sheet (MSDS), and thallium(I)-containing waste was disposed of according to official regulations. Dried and degassed dichloromethane (CH2Cl2) and n-hexane were obtained from an MBRAUN solvent purification system (MB SPS-800, M. Braun Inertgas-Systeme GmbH, Garching, Germany) and stored under a nitrogen atmosphere over molecular sieves (4 Å). Tetrahydrofuran (THF) was dried over Na/benzophenone, freshly distilled prior to use and stored under nitrogen atmosphere over molecular sieves (4 Å). Acetonitrile (MeCN) was degassed, freshly distilled prior to use and stored under nitrogen. DMSO was dried over CaH2, freshly distilled prior to use and stored under nitrogen over molecular sieves (4 Å).
Thin-layer chromatography (TLC) was carried out on precoated glass plates (Merck Silica Gel 60 F254). Visualization of the compounds on TLC plates was achieved by means of an iodine chamber, or by treatment with a solution of PdCl2 (1 wt % in MeOH). Column chromatography was carried out with silica gel (0.035–0.070 mm, 60 Å). NMR spectra were acquired at room temperature with a Bruker AVANCE III HD 400 MHz spectrometer (Bremen, Germany). 1H (400.13 MHz) and 13C{1H} (100.16 MHz) NMR spectra were referenced to tetramethylsilane (TMS) as internal standard. 11B (128.38 MHz) NMR spectra were referenced to the unified Ξ scale [38]. Mass spectrometry measurements were carried out with an ESI-MS Bruker ESQUIRE 3000 (Benchtop LC Iontrap, Bremen, Germany) spectrometer. FT-IR spectra were obtained with a PerkinElmer system 2000 FTIR spectrometer (Baesweiler, Germany), scanning between 400 and 4000 cm−1. Elemental analyses were performed with a Heraeus VARIO EL oven (Lagenselbold, Germany). X-ray data were collected with a GEMINI CCD diffractometer (Rigaku Inc., Neu-Isenburg, Germany), using Mo-Kα radiation (λ = 0.71073 Å), T = 130(2) K and ω-scan rotation. Data collection and refinement data are given in Table S1 (Supplementary Materials). Absorption corrections were performed with SCALE3 ABSPACK [39]. The structures were solved by direct methods with SHELXS [40]. Structure refinement was done with SHELXL-2016 [41] by using full-matrix least-square routines against F2. All non-hydrogen atoms were refined with anisotropic thermal parameters, and the HFIX command was used to locate all hydrogen atoms for non-disordered regions of the structure. Crystals of 4 and 7 contain no solvent molecules. The C2 unit of the carborane cluster was located with bond length analysis. The pictures were generated with the program Diamond (version 3.2) [42]. CCDC 1915985 (4) and 1915986 (7) contain the supplementary crystallographic data for this paper. UV-Vis absorption spectra were measured with a PerkinElmer UV/VIS/NIR Lambda 900 spectrometer (Baesweiler, Germany), equipped with a xenon arc lamp, using quartz cuvettes (V = 3 cm3). Spectra were recorded at 25 °C, in the range of 250 to 550 nm at 1.0 nm resolution. All measurements were corrected by subtracting the blank (PBS + 1 vol % DMSO). Nanoparticle tracking analysis (NTA) measurements were performed using the NanoSight LM10 instrument from Malvern Instruments Ltd. (Worcestershire, UK), containing a sample chamber of about 0.25 mL, and equipped with a 532 nm laser, a microscope LM14B, and a camera sCMOS. All measurements were performed at 25 ± 0.1 °C. Each sample was measured in five independent captures. The time of each capture was set to 60 s. The NTA 3.0 analytical software (NanoSight Ltd., Salisbury, UK) was used for both capture and processing.

3.2. Syntheses

3.2.1. closo-[3-(η6-Biphenyl)-1,2-Me2-3,1,2-RuC2B9H9] (3)

Following Bould et al. [16], [{(η6-biphenyl)RuCl(μ-Cl)}2] (0.20 g, 0.31 mmol, 1.0 eq.) was dissolved in dry THF (15 mL) and cooled to 0 °C. 1 (0.52 g, 0.92 mmol, 3.0 eq.) was added in one portion, and the mixture was stirred at room temperature for 17 h. Silica (0.5 g) was then added to the brown-orange mixture and the solvent was evaporated in vacuo. The residue was purified via filtration through a short pad of silica gel (length = 5 cm, diameter = 2.5 cm) using CH2Cl2 as eluent, which yielded a single yellow band (Rf = 0.88 in CH2Cl2). The latter was collected and evaporated to dryness, yielding pure 3 as pale yellow, air-stable solid. 3 is soluble in CH2Cl2 and DMSO, and moderately soluble in CHCl3. Yield: 35.0 mg (45%). 1H NMR (CD2Cl2): δ (ppm) = 0.55–3.88 (br, B–H), 2.05 (6H, s, Ccage–CH3), 6.08–6.21 (3H, m, H1, H2 and H2′), 6.46 (2H, d, 3JHH = 5.7 Hz, H3 and H3′), 7.51 (3H, m, H7, H7′, and H8), 7.74 (2H, dd, 3JHH = 8.3, 1.6 Hz, H6 and H6′). 11B NMR (CD2Cl2): δ (ppm) = 2.4 (1B, d, 1JBH = 129 Hz), 0.5 (1B, d, 1JBH = 126 Hz), −2.9 (2B, d, 1JBH = 147 Hz), −9.4 (2B, d, 1JBH = 140 Hz), ‒14.1 (3B, d, 1JBH = 158 Hz). 13C{1H} NMR (CD2Cl2): δ (ppm) = 32.2 (s, CcageCH3), 75.9 (s, Ccage), 88.9 (s, C3 and C3′), 90.7 (s, C1), 91.1 (s, C2 and C2′), 106.0 (s, C4), 128.1 (s, C6 and C6′), 129.2 (s, C7 and C7′), 129.8 (s, C8), 133.5 (s, C5). IR (KBr; selected vibrations): ν ˜ (cm−1) = 3079 (m, νCHarom), 2929 (m, νCHcage), 2561 (s, νBH), 2515 (s, νBH), 1455 (s, νC=C), 1405 (m, νC=C), 1387 (m), 1015 (s, νCC), 835 (m) 764 (s, νBB), 694 (s, νBB). ESI-MS(−): m/z = 865.2356 (100%, [2M + Cl]). Anal. calcd for C16H25B9Ru (415.74): C, 46.23; H, 6.06. Found C, 46.70; H, 6.20.

3.2.2. closo-[3-(η6-(1-Me-4-COOEt-C6H4))-1,2-Me2-3,1,2-RuC2B9H9] (4)

4 was synthesized in an analogous manner as described for 3, from [{(η6-(1-Me-4-COOEt-C6H4))RuCl(μ-Cl)}2] (0.20 g, 0.30 mmol, 1.0 eq.) and 1 (0.51 g, 0.90 mmol, 3.0 eq.). The crude product was recrystallized from CH2Cl2/acetone (10:1, v/v) at room temperature to yield yellow plates of pure 4, suitable for single crystal X-ray diffraction analysis. 4 is an air-stable pale yellow solid, soluble in CH2Cl2, CHCl3, and DMSO. Yield: 25.3 mg (32%). 1H NMR (CD2Cl2): δ (ppm) = 0.56–3.96 (br, B–H), 1.39 (3H, t, 3JHH = 7.1 Hz, H8), 2.12 (6H, s, Ccluster–CH3), 2.42 (3H, s, H5), 4.41 (2H, q, 3JHH = 7.1 Hz, H7), 6.02 (2H, d, 3JHH = 6.4 Hz, H3 and H3′), 6.55 (2H, d, 3JHH = 6.4 Hz, H2 and H2′). 11B NMR (CD2Cl2): δ (ppm) = 2.7 (1B, br s), 1.6 (1B, br s) (the two doublets centered at 2.7 and 1.6 ppm in the 11B NMR spectrum are very broad, and it is therefore not possible to give accurate values of 1JBH coupling constants), −2.3 (2B, d, 1JBH = 147 Hz), −8.9 (2B, d, 1JBH = 140 Hz), −13.5 (3B, d, 1JBH = 160 Hz). 13C{1H} NMR (CD2Cl2): δ (ppm) = 14.0 (s, C8), 19.0 (s, C5), 31.7 (s, CclusterCH3), 62.7 (s, C7), 76.2 (s, Ccluster), 91.0 (s, C2 and C2′), 91.9 (s, C3 and C3′), 93.1 (s, C1), 105.0 (s, C4), 164.9 (s, C6). IR (KBr; selected vibrations): ν ˜ (cm−1) = 3067 (w, νCHarom), 2982 (w, νCHcluster), 2931 (w, νCHcluster), 2563 (s, νBH), 2520 (s, νBH), 1720 (s, νC=O), 1379 (s, νCO), 1369 (m, νCO), 1294 (s, νCO), 1015 (s, νCC), 881 (m), 776 (m, νBB). ESI-MS (−): m/z = 483.1953 (100%, [M + CO2Me]). Anal. calcd for C14H27B9O2Ru (425.73): C, 39.50; H, 6.39. Found C, 39.67; H, 6.50.

3.2.3. pseudocloso-[3-(η6-p-Cymene)-1,2-(CO2Me)2-3,1,2-RuC2B9H9] (7)

Deprotonation of the nido-carborane(−1) precursor. 6 (0.106 g, 0.39 mmol, 1.0 eq.) was dissolved in dry THF (6 mL) and cooled to −30 °C, protected from light. Thallium(I) ethanolate (0.243 g, 0.07 mL, 0.97 mmol, 2.5 eq.) was then added in one portion, causing immediate formation of a yellow precipitate. The mixture was allowed to warm to room temperature over one hour. Stirring was stopped and the mixture was left standing overnight. The supernatant solution was carefully removed via filtration, and the precipitate was washed with n-hexane (6 mL), THF (8 mL), and ethanol (3 mL). The yellow residue (Tl[Tl6]) was further dried in vacuo (10−3 mbar) (the thallium salt Tl[Tl6] was dried in vacuo without heating, because heating of a carborane dithallium salt promotes reprotonation to the nido-carborane(−1) species, as reported [43]) and used directly, without further purification.
Complexation reaction. [{(η6-p-cymene)RuCl(μ-Cl)}2] (86 mg, 0.14 mmol, 1.0 eq.) and Tl[Tl6] were placed in a Schlenk flask, thoroughly mixed and cooled to −65 °C. Degassed CH2Cl2 (10 mL) was then added, and the reaction mixture was left stirring for 1.5 h at −65 °C, then slowly warmed to room temperature, over one hour. The dark red-brown mixture was filtered, and the solution concentrated in vacuo to a 2 mL volume. Degassed silica was then added, and all volatiles were removed in vacuo. The residue was then purified via filtration through a silica gel pad (length = 10 cm, diameter 2.5 cm), under nitrogen atmosphere, using CH2Cl2 as eluent, which yielded a single orange band. The latter was collected and evaporated to dryness. The crude product was recrystallized from CH2Cl2/n-hexane (1.5:1, v/v) at −20 °C, to yield orange prisms of pure 7, suitable for single crystal X-ray diffraction analysis. 7 is air-stable, soluble in CHCl3, CH2Cl2, acetone, and DMSO. Yield: 54.0 mg (39%). 1H NMR (CDCl3): δ (ppm) = 0.53–3.38 (br, B–H), 1.33 (3H, d, 3JHH = 6.9 Hz, H7 and H7′), 2.32 (3H, s, H5), 2.89 (1H, hept, 3JHH = 6.9 Hz, H6), 3.78 (6H, s, OCH3), 5.83 (2H, d, 3JHH = 6.3 Hz, H2/2′ or H3/3′), 5.88 (2H, d, 3JHH = 6.3 Hz, H2/2′ or H3/3′). 11B NMR (CDCl3): δ (ppm) = 27.7 (1B, d, 1JBH = 122 Hz), 11.1 (1B, d, 1JBH = 149 Hz), 8.7 (1B, d, 1JBH = 115 Hz), 0.11 (2B, d) (the 1JBH coupling constant could not be determined, due to overlap with the peak at ‒1.6 ppm), −1.6 (3B, d, 1JBH = 142 Hz), ‒21.8 (1B, d, 1JBH = 172 Hz). IR (KBr; selected vibrations): ν ˜ (cm−1) = 3076 (w, νCHarom), 2950 (w, νCHcluster), 2548 (s, νBH), 1716 (s, νC=O), 1482 (w, νC=C), 1458 (w, νC=C), 1431 (m, νC=C), 1261 (s, νCO), 1110 (m, νCC), 1020 (m, νCC), 860 (w), 765 (w, νBB). ESI-MS(+): m/z = 483.1948 (100%, [M + H]+), 519.1705 (6%, [M + K]+). Anal. calcd for C16H29B9O4Ru (483.76): C, 39.73; H, 6.04. Found C, 39.78; H, 5.92.

3.3. Preparation of 2, 7, and 8 for UV-Vis Spectroscopy, Mass Spectrometry, and NTA Measurements

Stock solutions of 2, 3, 7, and 8 in DMSO (1.0 mM) were freshly prepared before measurements. An aliquot of the DMSO stock solution of 2, 3, 7 or 8 was added to a PBS solution (3 mL) so that the final concentration of metallacarborane was 20 μM. DMSO content was 1 vol % in all samples. The samples were measured via UV-Vis spectroscopy and nano tracking analysis (NTA) 30 min to one hour after preparation. Samples of 3 were only measured by UV-Vis spectroscopy. Capture and processing parameters for the NTA measurements were the same for all samples for direct comparison. Samples were measured undiluted.
Compounds 2, 7, and 8 (ca. 1.0 mg) were dissolved in a minimum amount of MeCN (a few μL) and brought to a final volume of 500 μL with MeCN/H2O (98:2, v/v). The final concentration of ruthenacarborane was ca. 100 μM. Samples were measured via ESI mass spectrometry (positive and negative mode) within 5 h from preparation.

4. Conclusions

A small series of neutral 3,1,2-ruthenadicarbaborane(11) complexes bearing either non-polar (methyl, 24) or polar (CO2Me, 7) groups at the cluster carbon atoms were synthesized and fully characterized. The complexes possess a closo (24) or pseudocloso (7) structure in analogy to other C-substituted ruthenacarboranes in the literature. 11B NMR spectra of 3 in DMSO-d6 suggested the presence of aggregates of the complex in solution, confirmed by spectrophotometric analysis of 3 in PBS/DMSO mixtures at 20 μM. Moreover, spontaneous self-assembly in aqueous solutions was observed for all tested complexes in PBS/DMSO and MeCN/H2O mixtures, regardless of the specific type of substitution at the Ccluster vertices. They form particles with diameters on the nanometer scale, with high polydispersity and concentrations ranging from 108 (7 and 8) to 109 (2) particles mL−1.
This study thus suggests that for perspective applications in medicine there is a strong need for further characterization of the spontaneous self-assembly in aqueous solutions of this class of ruthenacarboranes, as well as other neutral metallacarboranes, with the ultimate scope of finding the optimal conditions for modulating the aqueous behavior of the complexes. These studies are currently underway.

Supplementary Materials

The following are available online at https://0-www-mdpi-com.brum.beds.ac.uk/2304-6740/7/7/91/s1, Synthesis and characterization of compounds 5 and 6; Table S1: Crystal data for 4 and 7; Figure S1: 1H NMR spectra (400.13 MHz) of complexes 24 in wet DMSO-d6 in air at room temperature, after one month; Figure S2: 11B NMR spectra (128.83 MHz) of complexes 24 and 7 in wet DMSO-d6 in air at room temperature, after one month; Figure S3: ESI(+) mass spectra of 7 (top) and 8 (bottom) measured in MeCN/H2O (98:2, v/v); Table S2: Mean size and concentration of particles for PBS/DMSO solutions of 2, 7 and 8.

Author Contributions

M.G. designed the studies, performed the syntheses, analyzed data and wrote the paper; M.G. and B.S. performed the UV-Vis and the NTA experiments and analyzed the data; P.C. performed the single-crystal XRD measurements and solved the structures; E.H.-H. designed the studies and wrote the paper.

Funding

This work was supported by the Saxon State Ministry for Sciences and Arts (SMWK, doctoral grant for M.G.) [grant No. LAU-R-N-11-2-0615], the German chemical industry association (VCI, doctoral grant for B.S.) [grant No. 197021], the Studienstiftung des deutschen Volkes (doctoral grant for P.C.) and the Graduate School “Leipzig School of Natural Sciences—Building with Molecules and Nano-objects” (BuildMoNa).

Acknowledgments

We thank C. Zilberfain and I. Estrela-Lopis (Institute of Medicinal Physics and Biophysics, Leipzig University) for access to the NTA equipment and fruitful discussions on the NTA data and D. Maksimović-Ivanić and S. Mihatović (Institute for Biological Research “Siniša Stanković”, University of Belgrade) for fruitful discussion on aggregating compounds for application in medicine.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Nomenclature adopted for carborane clusters (according to IUPAC convention): closo = 12-vertex icosahedral cluster, with (n − 1) skeletal electron pairs (n = total number of vertices); nido = 11-vertex open-face cluster, with (n − 2) skeletal electron pairs (n = total number of vertices); ortho-, meta-, para- = 1,2-, 1,7-, 1,12-dicarba-closo-dodecaborane(12), respectively. For numbering of the carborane clusters refer to the IUPAC project 2012-045-1-800 by Beckett et al., Nomenclature for boranes and related species, Chemistry International 2018, 40, 33.

Appendix B

The weighted average was calculated multiplying the chemical shift value of each 11B signal by its relative intensity, and then dividing by the total number of 11B signals of the spectrum.

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Figure 1. General structure of 1,2-dicarba-closo-dodecaborane(12) (left) and 3,1,2-closo-metallacarboranes(11) (right). Only one isomer per each structure is shown. For cluster nomenclature see Appendix A.
Figure 1. General structure of 1,2-dicarba-closo-dodecaborane(12) (left) and 3,1,2-closo-metallacarboranes(11) (right). Only one isomer per each structure is shown. For cluster nomenclature see Appendix A.
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Figure 2. Structure of complexes 2 to 4.
Figure 2. Structure of complexes 2 to 4.
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Scheme 1. Synthesis of 7 from 1,2-(CO2Me)2-closo-1,2-C2B10H10 (5).
Scheme 1. Synthesis of 7 from 1,2-(CO2Me)2-closo-1,2-C2B10H10 (5).
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Figure 3. Molecular structures of 4 (left) and 7 (right). Thermal ellipsoids are shown at the 50% probability level. Hydrogen atoms are omitted for clarity. Numbering of selected boron and carbon positions is given.
Figure 3. Molecular structures of 4 (left) and 7 (right). Thermal ellipsoids are shown at the 50% probability level. Hydrogen atoms are omitted for clarity. Numbering of selected boron and carbon positions is given.
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Figure 4. 11B NMR spectra (at 128.83 MHz) of 3 freshly dissolved in CD2Cl2 (top) and wet DMSO-d6 (bottom). Signals for monomeric 3 and the signal for self-assemblies of 3 are observed in DMSO-d6, as suggested by Deore et al. and Crociani et al. [24,25]. * marks the low-intensity additional 11B signals, probably due to solvent effects.
Figure 4. 11B NMR spectra (at 128.83 MHz) of 3 freshly dissolved in CD2Cl2 (top) and wet DMSO-d6 (bottom). Signals for monomeric 3 and the signal for self-assemblies of 3 are observed in DMSO-d6, as suggested by Deore et al. and Crociani et al. [24,25]. * marks the low-intensity additional 11B signals, probably due to solvent effects.
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Figure 5. UV-Vis spectra of 2, 3, 7, and 8 in PBS/DMSO mixtures. Content of DMSO is 1 vol % for all samples. [ruthenacarborane] = 20 μM. Spectra are corrected via subtraction of the blank (PBS + 1 vol % DMSO).
Figure 5. UV-Vis spectra of 2, 3, 7, and 8 in PBS/DMSO mixtures. Content of DMSO is 1 vol % for all samples. [ruthenacarborane] = 20 μM. Spectra are corrected via subtraction of the blank (PBS + 1 vol % DMSO).
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Figure 6. ESI(+) mass spectrum of 2 (M = 397.22), measured in MeCN/H2O (98:2, v/v). The peaks which could not be unequivocally assigned are indicated by *. The inset shows a section of the region m/z = 950 to 1400.
Figure 6. ESI(+) mass spectrum of 2 (M = 397.22), measured in MeCN/H2O (98:2, v/v). The peaks which could not be unequivocally assigned are indicated by *. The inset shows a section of the region m/z = 950 to 1400.
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Figure 7. Size distribution of 2, 7, and 8 in PBS/DMSO mixtures, from nanoparticle tracking analysis (NTA). [2] = [7] = [8] = 20 μM. The dilution factor is the same for all samples. Content of DMSO was 1 vol % in all samples. Average data from five independent captures are shown. T = 25 °C. Particle concentrations and size values, with relative standard deviations, are given in Table S2 (Supplementary Materials).
Figure 7. Size distribution of 2, 7, and 8 in PBS/DMSO mixtures, from nanoparticle tracking analysis (NTA). [2] = [7] = [8] = 20 μM. The dilution factor is the same for all samples. Content of DMSO was 1 vol % in all samples. Average data from five independent captures are shown. T = 25 °C. Particle concentrations and size values, with relative standard deviations, are given in Table S2 (Supplementary Materials).
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Table 1. Selected bond lengths, distances (Å) and angles (°) in 4 and 7, and the respective unsubstituted ruthenacarboranes 8 and 9.
Table 1. Selected bond lengths, distances (Å) and angles (°) in 4 and 7, and the respective unsubstituted ruthenacarboranes 8 and 9.
[3-(η6-p-cymene)-3,1,2-RuC2B9H11] (8) a7[3-{η6-(4-Me-1-COOEt-C6H4)}-3,1,2-RuC2B9H11] (9) a4
Ru–Ctd1 b1.714(4)1.768(1)1.708(2)1.738(1)
Ru–Ctd2 b1.619(4)1.485(1)1.623(2)1.598(1)
Ru–B(C2B3 face) c2.203(3)2.216(2)2.205(8)2.195(5)
Ru–C(C2B3 face) c2.171(2)2.127(2)2.166(5)2.171(3)
Ru–C(arene) c2.224(3)2.265(2)2.217(7)2.237(3)
C–C(cluster)1.627(4)2.243(2)1.623(3)1.680(5)
B–B d1.774(7)1.799(3)1.778(7)1.772(7)
B–C(cluster) c1.720(5)1.662(3)1.719(3)1.722(6)
C(cluster)–C(exo) c1.497(1)1.517(5)
Ru–B(6)3.494(1)2.979(2)
B(6)–B(10)1.759(1)1.885(2)
B(4)–B(5)1.797(1)1.838(3)
C(1)–B(4)1.718(1)1.636(2)
C(1)–B(5)1.696(1)1.614(2)
Deviation from coplanarity e5.11(9)2.5(1)2.3(5)6.3(1)
Ru–C(1)–B(6)126.79(3)100.12(9)
C(1)–B(6)–C(2)55.99(2)88.7(1)
B(6)–C(2)–Ru126.49(5)100.14(9)
C(2)–Ru–C(1)44.02(4)69.75(6)
a From [9]. b Ctd1 = centroid of the C6 ring of the arene ligand. Ctd2 = centroid of the C2B3 face of the dicarbollide ligand. c Average value. d Average B–B value. For 7, the B(6)–B(10) bond length is not included. e Deviation from coplanarity of the arene and dicarbollide ligands was measured between the least-squares plane formed by the C6H4 ring of the arene ligand, and the least-squares plane formed by the lower boron belt (B5H5) of the cluster, as reported previously [9].

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Gozzi, M.; Schwarze, B.; Coburger, P.; Hey-Hawkins, E. On the Aqueous Solution Behavior of C-Substituted 3,1,2-Ruthenadicarbadodecaboranes. Inorganics 2019, 7, 91. https://0-doi-org.brum.beds.ac.uk/10.3390/inorganics7070091

AMA Style

Gozzi M, Schwarze B, Coburger P, Hey-Hawkins E. On the Aqueous Solution Behavior of C-Substituted 3,1,2-Ruthenadicarbadodecaboranes. Inorganics. 2019; 7(7):91. https://0-doi-org.brum.beds.ac.uk/10.3390/inorganics7070091

Chicago/Turabian Style

Gozzi, Marta, Benedikt Schwarze, Peter Coburger, and Evamarie Hey-Hawkins. 2019. "On the Aqueous Solution Behavior of C-Substituted 3,1,2-Ruthenadicarbadodecaboranes" Inorganics 7, no. 7: 91. https://0-doi-org.brum.beds.ac.uk/10.3390/inorganics7070091

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