Ruthenium-Catalyzed Thiocarbonyl-Directed Ferrocene C–H Arylation

evaluated with a number of commonly employed functionals. Hence, single point calculations were performed using the PBE0 hybrid GGA functional^[134] and the PW6B95 hybrid-meta-GGA functional^[145] (Figure 34). Energies obtained with Truhlar’s PW6B95 functional were overall in good agreement with the B3LYP results, which is in line with a comparable performance of these functionals in various benchmark studies.^{[136, 146]} In contrast, calculations at the PBE0 level resulted in comparatively more stable intermediates 6.D-6.G and transition states TS6.3 and TS6.4, whereas only relatively minor changes in the relative Gibbs free energies for the C–H ruthenation step were observed.

Figure 34: Relative Gibbs free energy profile at the B3LYP (black line), PW6B95 (red), and PBE0 (blue) level of theory.

3.7 Ruthenium-Catalyzed Thiocarbonyl-Directed Ferrocene C–H Arylation

Substituted ferrocenes constitute an important class of compounds with numerous applications in organocatalysis and transition metal catalysis.^[112] Additionally, bioactivity studies revealed promising antimalarial and anticancer properties of functionalized ferrocenes (Scheme 77).^[113]

6.A

3 Results and Discussion

Scheme 77: Selected ferrocene-containing ligands and drugs.

Despite the undisputable advances in catalyzed C–H activation towards the development of environmentally-benign synthetic methods, these reactions are usually conducted in environmentally problematic, non-recyclable organic solvents, thus compromising the overall sustainability of the C–H activation methodology.^[147] While water would at first glance offer an alternative as a non-toxic and non-flammable ubiquitous reaction medium, the limited solubility of commonly employed catalysts and organic compounds usually leads to an impaired reaction outcome.

With this aspect in mind, Dr. S. R. Yetra in the Ackermann group observed that the use of micelle-forming surfactant TPGS-750M allowed for the ruthenium-catalyzed C–H arylation of ferrocenes 156 to occur with high efficacy in water (Scheme 78).^[148] Ruthenium(II)-biscarboxylate catalysts facilitated the thiocarbonyl-directed direct C–H arylation, delivering the desired mono-functionalized products 158 in good to excellent yields. Interestingly, replacement of the thiocarbonyl directing group with simple ketones resulted in a complete shutdown of the reaction under otherwise identical conditions.

Scheme 78: Optimized reaction conditions for ruthenium-catalyzed C–H arylations of ferrocenes 156.

3.7 Ruthenium-Catalyzed Thiocarbonyl-Directed Ferrocene C–H Arylation Intrigued by the vastly different behavior of thiocarbonyls and ketones, the key C–H activation step was studied computationally by means of DFT calculations. Geometry optimization and vibrational frequency calculations were performed at the TPSS-D3(BJ)/def2-TZVP meta-GGA level of theory.[125, 126, 127] In the single point calculations, Truhlar’s PW6B95 hybrid-meta-GGA functional^[145] was employed in combination with D3(BJ) dispersion correction and def2-TZVP basis set, while solvent effects were accounted for through the use of the COSMO solvation model^[142]

with a dielectric constant corresponding to toluene (for full details see Section 6.5). The use of toluene as reaction medium led to comparable results and, therefore, toluene was chosen as the solvent in the calculations for the sake of simplicity. Furthermore, the adamantyl carboxylate ligands were replaced by acetate, due to a similar performance in the reaction.

Starting from adduct complex 7.A, which is formed by coordination of 156a to ruthenium and dissociation of one acetate ligand, C–H activation proceeds via formation of agostic complex 7.B with an energy barrier of 10.9 kcal mol^–1 (Figure 35). Afterwards, concerted C–H cleavage/Ru–C formation in TS7.2 generates cyclometalated intermediate 7.C with an overall barrier of 14.8 kcal mol^–1, which is in good agreement with studies on comparable ruthenium-catalyzed reactions (vide supra). In all calculated structures, the Cp-rings of the ferrocene-moiety adopt an eclipsed rather than a staggered configuration,^[149] and the Cp-rings are noticeable tilted towards each other in cyclometalated intermediate 7.C (Figure 36). In stark contrast, replacing sulfur in complex 7.A with oxygen led to a significant destabilization by 8.6 kcal mol^–1. Consequently, the relative Gibbs free energies of the later intermediates and transition states increased by 10.7–

13.0 kcal mol^–1 compared to the respective sulfur analogues along with higher energy barriers of 13.0 and 19.2 kcal mol^–1. Calculations of the corresponding selenium analogues revealed these structures to be slightly more stable than the initial sulfur complexes with energy differences of 0.2–3.1 kcal mol^–1. Nevertheless, the energy barriers for the formation of agostic intermediate 7.B and cyclometalated complex 7.C are 12.6 and 15.8 kcal mol^–1, respectively, which represents a small increase compared to thiocarbonyl as the directing group.

3 Results and Discussion

Figure 35: Relative Gibbs free energy profile for the C–H activation of ferrocene 156a with thioketone (black line), ketone (red), and selenoketone (blue) directing group.

Figure 36: Structure of cyclometalated complex 7.C (X = S). Non-participating hydrogen atoms are omitted for clarity.

7.A 0.0

TS7.1

10.9 7.B

8.9

TS7.2 14.8

7.C 5.6

−3.1

9.5 8.7

12.7

4.3 8.6

21.6 19.9

27.8

17.5

3.7 Ruthenium-Catalyzed Thiocarbonyl-Directed Ferrocene C–H Arylation Although the increasing size of the chalcogen atoms (van-der-Waals radii: 1.52 Å for oxygen, 1.80 Å for sulfur, and 1.90 Å for selenium^[150]) and the consequently greater X–Ru and X–C bond lengths should reduce the steric repulsion within the complex and also the ring-strain in cyclometalated intermediate 7.C (for selected bond lengths see Section 6.5.3), this effect does not rationalize the already considerable energy differences in intermediate 7.A. To this end, a distortion-interaction analysis^[151] was performed for transition state TS7.1 to quantify differences in the complex geometries (Figure 37). The structures were separated into a substrate and a [Ru(OAc)(p-cymene)]⁺ fragment and the energies of the fragments were compared to the freely optimized structures. Notably, the distortion energy is almost identical for all structures with differences of less than 1.0 kcal mol^–1, thereby substantiating the suspected marginal geometric influences on the observed energy differences. In contrast, the interaction energies showed more pronounced differences with larger stabilizations for the higher chalcogens. With respect to the corresponding intermediates 7.A, the interaction energy decreased by 3.1 kcal mol^–1 and 1.3 kcal mol^–1, when the ketone was compared to the thioketone and selenoketone, respectively.

Figure 37: Distortion-interaction analysis for transition state TS7.1 with distortion energies for the substrate (red column) and the metal fragment (orange), interaction energies (blue), and

22.4 22.8 22.9

Gibbs free energy contribution / kcal mol−1

Substrate fragment Metal fragment Interaction Total

3 Results and Discussion

Along with an increase in size the polarizability drastically increases for higher chalcogens (in a.u.:

5.3 for oxygen, 19.4 for sulfur, and 28.9 for selenium^[152]), which might result in stronger attractive London dispersion interactions within the complexes. A comparison of energies calculated with and without Grimme’s D3 correction revealed a largely neglectable influence with differences of less than 2.0 kcal mol^–1 for all structures (Figure 38). As expected, the largest influence was observed for structures containing highly polarizable selenoketone as the directing group.

Figure 38: Relative Gibbs free energy profile for C–H ruthenation with thioketone (black line), ketone (red), and selenoketone (blue) directing group with (solid lines) and without dispersion

correction (dashed lines).