Synthetic Route of Trithiolato-Bridged Dinuclear Arene ...

doi.org/10.26434/chemrxiv.11590350.v2

Synthetic Route of Trithiolato-Bridged Dinuclear Arene Ruthenium(II)Complexes [(η6-P-MeC6H4Pri)2Ru2(μ2-SR)3]+Hedvika Primasova, Silviya Ninova, Ulrich Aschauer, julien Furrer, Mario de Capitani, Jana daepp

Submitted date: 22/04/2020 • Posted date: 23/04/2020Licence: CC BY-NC-ND 4.0Citation information: Primasova, Hedvika; Ninova, Silviya; Aschauer, Ulrich; Furrer, julien; Capitani, Mario de;daepp, Jana (2020): Synthetic Route of Trithiolato-Bridged Dinuclear Arene Ruthenium(II) Complexes[(η6-P-MeC6H4Pri)2Ru2(μ2-SR)3]+. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.11590350.v2

Several dinuclear thiophenolato-bridged arene ruthenium complexes[(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-R)3]+ could so far onlybe obtained with moderate yields using the synthetic route established in the early 2000s. With much lessreactive aliphaticthiols or with bulky thiols, the reactions become even less efficient and the desired complexes are obtainedwith low yieldsor not at all. We employed density functional theory (DFT) calculations to gain a fundamental understanding ofthe reactionmechanisms leading to the formation of dithiolato and trithiolato complexes starting from thedichloro(pcymene)ruthenium(II) dimer [(η6-p-MeC6H4Pri)Ru(μ2-Cl)Cl]2. The results of the DFT study enabled us to rationaliseexperimental results and allowed us, via a modified synthetic route, to synthesise previously unreported andhithertoconsidered as unrealistic complexes. Our study opens possibilities for the synthesis of so far inaccessiblethiolato-bridgeddinuclear arene ruthenium(II) complexes but more generally also the synthesis of other thiolato-bridgeddinuclear group 8and 9 metal complexes could be reexamined.

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Dinuclear thiolato-bridged arene ruthenium complexes: from

reaction conditions and mechanism to synthesis of new

complexes

Hedvika Primasová a#, Silviya Ninova a,b#, Mario De Capitani a, Jana Daepp a, Ulrich Aschauer a* and Julien Furrer a*

Several dinuclear thiophenolato-bridged arene ruthenium complexes [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-R)3]+ could so far only

be obtained with moderate yields using the synthetic route established in the early 2000s. With much less reactive aliphatic

thiols or with bulky thiols, the reactions become even less efficient and the desired complexes are obtained with low yields

or not at all. We employed density functional theory (DFT) calculations to gain a fundamental understanding of the reaction

mechanisms leading to the formation of dithiolato and trithiolato complexes starting from the dichloro(p-

cymene)ruthenium(II) dimer [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2. The results of the DFT study enabled us to rationalise

experimental results and allowed us, via a modified synthetic route, to synthesise previously unreported and hitherto

considered as unrealistic complexes. Our study opens possibilities for the synthesis of so far inaccessible thiolato-bridged

dinuclear arene ruthenium(II) complexes but more generally also the synthesis of other thiolato-bridged dinuclear group 8

and 9 metal complexes could be reexamined.

1. Introduction

Dinuclear tris(thiolato)-bridged arene complexes are typically

obtained from the reaction of the precursor [(arene)MCl(µ2-

Cl)2M(arene)Cl] M = Fe, Ru, Rh, Os, Ir with thiolate compounds

and represent an interesting class of organometallic

compounds. Iron complexes serve as carbon-halogen bond

activation reagents, and carbon-halogen bond-cleavage

agents,1–4 while osmium5, iridium, rhodium 6–12 and especially

ruthenium complexes13,14,23–25,15–22 have in vitro

antiproliferative activity against cancer cell lines and several

protozoan parasites. Tris(thiolato)-bridged dimolybdenum

complexes are also readily available but are synthesised using

other strategies such as the direct oxidation of low-valence

carbonyl precursors or reductive process from higher-valence

derivatives,26–28 which will not be discussed here.

It is interesting to note that arene ruthenium(II) complexes

were first obtained fortuitously about fifty years ago by

Winkhaus and Singer and subsequently Zelonka and Baird.29–32

Only years later, these dimeric arene–ruthenium dichloride

complexes [(η6-arene)Ru(µ2-Cl)Cl]2 were found to react with

thiols to give cationic trithiolato complexes of the type [(η6-

arene)2Ru2(µ2-SR)3]+, the first examples being

the hexamethylbenzene derivative [(η6-C6Me6)2Ru2(µ2-SPh)3]+

reported by Rakowski DuBois and coworkers33 and the p-

cymene derivative [(η6-p-MeC6H4Pri)2Ru2(µ2-SPh)3]+ reported by

Nakamura and coworkers, both of which contain three

thiophenolato bridges.34 Over the last fifteen years, the series

of dinuclear trithiolato bridged arene ruthenium complexes was

extended, including complexes of the general formula [(η6-p-

MeC6H4Pri)2Ru2(µ2-SC6H4-R)3]+ and so-called mixed complexes

of the general formula [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-R1)2(µ2-

SC6H4-R2)]+, bearing two types of thiol ligands.13,14,36–39,15,18–20,22–

24,35 Like many organometallic compounds, these dinuclear

thiolato-bridged arene ruthenium complexes have originally

been designed as catalysts, for instance for the carbonylation of

methanol.40 While they did not attract much attention for this

application, a revival started in 2008, when water-soluble arene

ruthenium complexes were discovered to be cytotoxic.14,40–44

Remarkably, almost all tested trithiolato compounds are highly

cytotoxic with IC50 values being in the submicromolar range,

the most potent ones with IC50 values of 30 nM against A2780

cells and cisplatin-resistant A2780cisR cells.13,19,21,22 Recent

in vivo studies have demonstrated that these complexes indeed

have potential as anticancer drugs, since for instance

the compound [(η6-p-MeC6H4Pri)2Ru2(µ2-S-p-C6H4But)3]Cl

(termed diruthenium-1) significantly prolongs the survival of

tumour-bearing mice25 and substantially influences metabolism

of A2780cisR cells involving changes related to redox

homeostasis, Warburg effect and lipid metabolism.45 Other

derivatives appear less promising.44,46 Dinuclear thiolato-

bridged arene ruthenium complexes are also promising as

antiprotozoal agents, with IC50 values of up to 1.2 nM against

T. gondii, N. Caninum and T. Brucei and IC50 values against

human foreskin fibroblasts > 800 µM, leading to selectivity

indexes > 20’000.16,17,47

The current synthesis route for obtaining dinuclear cationic

trithiolato bridged arene ruthenium complexes of the general

formula [(η6-p-MeC6H4Pri)2Ru2(µ2-S-R)3]+ with good yields dates

back to the early 2000s and involves the reaction of the dimer

[(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 with an excess of

the corresponding thiol (see Scheme 1) usually in refluxing

ethanol (EtOH).37 For thiophenolato complexes, depending on

the thiophenol used, it is possible to adjust the conditions to

direct the synthesis exclusively to the cationic trithiophenolato

complex [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-R)3]+,15 the neutral

dithiophenolato complex [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-

R)2Cl2],48 or even the neutral monothiophenolato complex [(η6-

p-MeC6H4Pri)2Ru2Cl2(µ-Cl)(µ2-SC6H4-R)].49 The reactivity of

the thiol undoubtedly plays an important role and decides to a

great extent the outcome of the reaction. For instance,

the trithiophenolato complexes [(η6-p-MeC6H4Pri)2Ru2(µ2-

SC6H4-R)3]+ with the electron attracting substituents R = NO2 or

R = F could so far be only obtained with moderate yields (48 and



45%, respectively) using the standard strategy described in

Scheme 1.19 Similarly, when much less reactive aliphatic thiols

are used, the reaction becomes more demanding and

the desired trithiolato complexes are either obtained with

modest yields or the reactions only give the neutral dithiolato

complex. For instance, the trithiolato complex [(η6-p-

MeC6H4Pri)2Ru2(µ2-SC8H17)3]+ was only obtained with a yield of

28%, despite a long 7 day reaction in EtOH under inert

atmosphere and reflux conditions,50 and the trithiolato complex

[(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H11)3]+ could not be obtained from

the neutral dithiolato complex [(η6-p-MeC6H4Pri)2Ru2(µ2-

SC6H11)2Cl2], presumably due to steric reasons.48

Scheme 1. Synthesis of dinuclear cationic trithiolato-bridged arene ruthenium

complexes.37

These experimental facts raise the question as to whether

the formation of dinuclear trithiolato-bridged arene ruthenium

complexes with different thiols is thermodynamically or

kinetically hindered, which would give indications as to how

conditions should be altered to enable reactions or to improve

yields.

In the present work we aim at a fundamental understanding of

the reaction mechanisms leading to the formation of trithiolato

complexes starting from the dichloro(p-cymene)ruthenium(II)

dimer [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and to modify, where

necessary, the existing synthetic route to (i) increase the yields,

(ii) reduce the overall reaction time (currently reflux in EtOH,

18 h), and to (iii) synthesise novel thiolato bridged complexes.

To this end, we employ density functional theory (DFT)

calculations of the possible synthetic routes for trithiolato

complexes [(η6-p-MeC6H4Pri)2Ru2(µ2-SR)3]+. The DFT results

agree with new experimental results obtained for

the trithiophenolato complexes [(η6-p-MeC6H4Pri)2Ru2(µ2-

SC6H4-R)3]+ with R = H (1), R = p-OMe (2), and R = p-NO2 (3), and

the previously unreported trithiolato complexes [(η6-p-

MeC6H4Pri)2Ru2(µ2-SC6H11)3]+ (4) and (5). Applying this approach

further, we improved yield for (6) and were also able to

synthesise two new dithiophenolato complexes (7) and (8)

(Figure 1), previously considered inaccessible, since only

dithiobenzylato complexes could be obtained so far.18,46,48

2. Computational methods

All calculations were carried out with the CP2K package51 within

the mixed Gaussian and Plane-Wave DFT formalism.52,53

The core-region of wave functions was smoothed out with

norm-conserving dual-space Goedecker-Teter-Hutter

pseudopotentials54,55, whereas the valence pseudo-wave

functions were expanded in molecularly optimised double-zeta

valence polarised (DZVP) Gaussian basis sets for all elements.56

The auxiliary plane-wave basis set, used to calculate the Hartree

potential, had a cut-off of 750 Ry. The BLYP functional was

used57,58 with Grimme’s D3 dispersion correction59 and Becke-

Johnson (BJ) for the DFT-D3 damping function, which was

reported to reduce the error for reaction barriers in BLYP

calculations.60 Hybrid functionals, such as B3LYP, B3PW91 and

PBE0, have been previously used to computationally investigate

Ru-complexes.61–64 Due to the small geometry, energy and

occupied electronic-structure differences between PBE0, B3LYP

and BLYP, reported in the SI (see Table S7) and combined with

the higher computational cost of hybrid-functional calculations

in particular for barriers, we opt to carry out all calculations with

BLYP. The wave function optimization was carried out with

the orbital transformation method,65 while the geometry of

complexes was relaxed until forces converged below 0.02 eV/Å

and the energy difference between subsequent self-consistent

steps was less than 10-6 Ha. Calculations were carried out in

periodic simulation boxes of dimensions 30×30×30 Å that limit

spurious interactions due to a distance of about 15 Å between

periodic images of the complexes. The Ru(II) ion is considered

to be non-magnetic as a geometry optimised ferromagnetic

complex with spin multiplicity 9 lies 1.6 eV higher in energy.

With this computational protocol, the average geometry

deviation was determined to be about 0.81% with respect to

experiment (see Table S7 in SI).

All reaction mechanisms and their corresponding barriers were

determined with the climbing image variant of the Nudged

Elastic Band method.66 Each path was minimised until the

energy difference converged below 0.002 eV.

The self-consistent continuum solvation model, SCCS,67 was

used to implicitly account for the presence of a solvent. The

cavity was defined as regions in the simulation cells with an

electron density higher than 10-4 e/Bohr3, while the continuum

region is defined for densities smaller than 10-5 e/Bohr3.

The dielectric constants for dichloromethane and ethanol were

set to 8.93 and 24.55, respectively. No further geometry

relaxation was performed for structures in implicit solvent.68

3. Experimental section

The dichloro(p-cymene)ruthenium(II) dimer [(η6-p-

MeC6H4Pri)Ru(µ2-Cl)Cl]2, p-nitrothiophenol (technical grade),

cyclohexylthiol, thiophenol and N,N-Diisopropylethylamine

(DIPEA) were purchased from Sigma Aldrich. p-

methoxythiophenol was bought from Alfa Aesar. CDCl3 and

MeOD were obtained from Cambridge Isotope Laboratories,

CD2Cl2 was obtained from Eurisotop. All reactions were

performed under inert atmosphere using standard Schlenk

technique. NMR spectra were recorded on Bruker

spectrometers: AVANCE III HD 300 MHz equipped with a 5 mm

ATM BBFO probehead, AVANCE III HD 400 MHz equipped with

a 5 mm ATM BBFO SmartProbe probehead, AVANCE II 400 MHz


equipped with a 5 mm ATM Dual probehead and AVANCE II 500

MHz equipped with a 1.7 mm TXI 1H probehead, respectively.

Unless specified otherwise NMR spectra were recorded at room

temperature (25 °C) and processed using Topspin software

(Bruker Biospin). MS and elemental analysis were performed, a

LTQ Orbitrap XL with nano ESI (Thermo). All syntheses and

purifications employing column chromatography are described

in more detail in the SI.

3.1 Synthesis of 1

[(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H5)3]Cl (1) was obtained from the

reaction of the dichloro(p-cymene)ruthenium(II) dimer [(η6-p-

MeC6H4Pri)Ru(µ2-Cl)Cl]2 with thiophenol.34 Four different

reaction conditions were evaluated: (i) in DCM, 1 was obtained

with 62% yield in 7 h, (ii) in DCM with addition of DIPEA, with

79% yield in 3 h, (iii) in EtOH with 69% yield in 23 h and (iv) in

EtOH with addition of DIPEA with 80% yield in 3 h. Reactions in

EtOH were performed under reflux at 78-83 °C while reactions

in DCM were performed at 40-45°C. The analytical data are

provided in the SI (Figures S9-11) and are in agreement with

the literature.34

3.2 Synthesis of 2

[(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-OMe)3]Cl (2) was obtained in

73% yield from the reaction of [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2

with p-methoxythiophenol in DCM under reflux at 38-45 °C

under N2 atmosphere in 9 h. The analytical data are provided in

the SI (Figures S12-14) and are in agreement with

the literature.19

3.3 Synthesis of 3

[(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-NO2)3]Cl (3) was obtained in

73% yield from the reaction of [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2

with p-nitrothiophenol in DCM under reflux at 40-45 °C under

N2 atmosphere in 2 h. The analytical data are provided in SI

(Figures S15-17) and are in agreement with the literature.19

3.4 Synthesis of 4

[(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H11)3]Cl (4) was obtained from an 7

day reaction of [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 with

cyclohexanethiol in DCM with addition of DIPEA under reflux at

40-45 °C under Ar atmosphere taking. Despite of our efforts,

the desired complex 4 could not be obtained in pure form,

because an inseparable mixture trithiolato/dithiolato was

obtained. Analytical data (Figures S18-21): 1H NMR (400.1 MHz,

CDCl3): δH = 5.48 (m, 4H; H-Ar p-cymene), 5.35 (m, 2H; H-Ar p-

cymene), 5.29 (d, JH,H = 5.0 Hz, 2H; H-Ar p-cymene), 2.57 (sept,

JH,H = 6.7 Hz, 2H; CH(CH3)2), 2.37 (m, 6H; H1 thiol), 2.21 (s, 6H;

CH3), 1.73 (m, 6H; thiol), 1.51 (m, 6H; thiol), 1.39 (m, 6H; thiol),

1.31 (d, JH,H = 6.7 Hz, 6H; CH(CH3)2), 1.26 (d, JH,H = 6.7 Hz, 6H;

CH(CH3)2), 0.96 ppm (m, 9H; thiol); 13C NMR (100 MHz; CDCl3):

δC = 106.5 (C1 p-cymene), 101.4 (C4 p-cymene), 83.7 (Ar CH p-

cymene), 83.2 (Ar CH p-cymene), 83.1 (Ar CH p-cymene), 82.9

(Ar CH p-cymene), 39.0 (thiol), 32.8 (thiol), 31.6 (CH(CH3)2 +

thiol), 28.9 (thiol), 24.0 (CH(CH3)2), 22.6 (thiol), 22.4 (CH(CH3)2),

18.3 (CH3), 14.1 ppm (thiol); ESI-MS (positive mode, MeOH):

m/z = 817.2; Mw = 851.67 g/mol.

3.5 Synthesis of 5

[(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H13)3]Cl (5) was obtained from the

reaction [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and 1-hexanethiol in

DCM under reflux at 40-45 °C with addition of DIPEA and Ar

atmosphere in 68 h. An analogous reaction was performed in

ethanol for comparison. The reaction in DCM gave the product

in 62% yield, in EtOH in 42% yield. Analytical data (Figures S22-

24): 1H NMR (300.1 MHz, CDCl3): δH = 5.47 (m, 4H; H-Ar p-

cymene), 5.34 (d, JH,H = 5.7 Hz, 2H; H-Ar p-cymene), 5.28 (d, JH,H

= 5.7 Hz, 2H; H-Ar p-cymene), 2.56 (sept, JH,H = 7.0 Hz, 2H;

CH(CH3)2), 2.36 (m, 6H; SCH2), 2.19 (s, 6H; CH3 p-cymene), 1.73

(m, 6H; CH2), 1.50 (p, JH,H = 7.5 Hz, 6H; CH2), 1.37 (m, 12H, CH2),

1.29 (d, JH,H = 7.0 Hz, 6H; CH(CH3)2), 1.17 (d, JH,H = 7.0 Hz, 6H;

CH(CH3)2), 0.95 ppm (t, JH,H = 6.8 Hz, 9H; CH3 thiol); 13C NMR

(100 MHz, CDCl3): δC = 106.5 (Cq p-cymene), 101.4 (Cq p-

cymene), 83.7 (Ar CH p-cymene), 83.2 (Ar CH p-cymene), 83.1

(Ar CH p-cymene), 82.9 (Ar CH p-cymene), 39.1 (SCH2), 32.9

(CH2), 31.7 and 31.6 (CH(CH3)2 and CH2), 29.7, 28.9 (CH2), 24.0

(CH(CH3)2), 22.6 (CH(CH3)2), 22.5 (CH2), 18.3 (CH3 p-cymene),

14.1 (CH3 thiol). ESI-MS (positive mode, EtOH): m/z = 823.2;

elemental analysis calcd (%) for C38H67Ru2S3Cl·½H2O: C 52.66, H

7.91; Found: C 52.57, H 7.95; Mw = 866.73 g/mol.

3.6 Synthesis of 6

[(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-F)3]Cl (6) was obtained in 80%

yield from the reaction of [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and p-

fluorothiophenol in DCM under Ar atmosphere and reflux at 40-

45 °C with addition of DIPEA in 3.5 h. The analytical data are

described in SI (Figures S25-27) and are in agreement with

the literature.19

3.7 Synthesis of 7

[(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-p-But)2Cl2] (7) was obtained in

quantitative yield from the reaction of [(η6-p-MeC6H4Pri)Ru(µ2-

Cl)Cl]2 and p-t-butylthiophenol in DCM cooled to 0 °C in 3.5 h.

Analytical data (Figures S28-30): 1H NMR (300.1 MHz, CDCl3):

δH = 7.89 and 7.54 (br, 4H; H-Ar thiol), 7.34 (d, JH,H = 7.7 Hz, 4H;

H-Ar thiol), 5.28, 5.18 and 5.04 (br, 8H; H-Ar p-cymene), 2.21

(br, 2H; CH(CH3)2), 1.90 and 1.74 (br, 6H, CH3 p-cymene), 1.30

(br, 18H; C(CH3)3), 0.99 and 0.91 ppm (br, 12H; CH(CH3)2); 13C

NMR (100 MHz, CDCl3): δC = 152.3 (C(CH3)3), 136.7 (Ar Cq thiol),

131.8 (CH thiol), 126.4 (CH thiol), 83.6 - 83.3 (Ar CH p-cymene),

34.9, 31.2 (C(CH3)3), 30.6 (CH(CH3)2), 22.1 (CH(CH3)2), 17.9 (p-

cymene CH3); ESI-MS (positive mode, EtOH): m/z 837.1;

elemental analysis calcd (%) for C40H54S2Ru2Cl2·½CH2Cl2:

C 53.19, H 6.06; found: C 53.24, H 6.05; Mw = 914.50 g/mol.



Figure 1. Structures of the six dinuclear trithiolato-bridged (1-6) and the two dinuclear dithiolato-bridged arene ruthenium complexes (7-8) investigated and

synthesised.

3.8 Synthesis of 8

[(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-p-But)2Cl2] (8) was

obtained from the reaction of [(η6-p-MeC6H4Pri)Ru(µ2-

Cl)Cl]2 and p-methoxythiophenol in DCM stirred at room

temperature for 4 h, but not in high purity. Analytical data

(Figure S31-33): 1H NMR (400.1 MHz, CDCl3): δH = 7.93 and

7.56 (br, 4H; H-Ar thiol), 6.87 (d, JH,H = 8.4 Hz, 4H; H-Ar thiol),

5.18 and 5.00 (br, 8H; H-Ar p-cymene), 3.82 (s, 6H, OCH3),

2.31 (m, 2H; CH(CH3)2), 1.89 and 1.73 (br, 6H, CH3 p-

cymene), 1.02 ppm (br, 12H; CH(CH3)2); 13C NMR (100 MHz,

CDCl3): δC = 160.4 (CO), 133.8 and 133.3 (CH thiol), 129.0

(CH thiol), 114.9 (CH thiol), 84.6-82.2 (Ar CH p-cymene),

55.7 (OCH3), 30.8 (CH(CH3)2), 22.3 (CH(CH3)2), 17.9 ppm (p-

cymene CH3); ESI-MS (positive mode, EtOH): m/z 784.04;

Mw = 819.86 g/mol

3.9 Reaction kinetics of 1-4 followed by 1H NMR

The kinetic of formation of complexes 1-4 was followed by

NMR at 0 °C or 25 °C. For each reaction, [(η6-p-

MeC6H4Pri)Ru(µ2-Cl)Cl]2 was first dissolved in 500 µL CD2Cl2,

and the NMR tube was sealed with a septum and flushed

with stream of N2. Next, 4 eq of the corresponding

thiophenol dissolved in 300 µL CD2Cl2 was injected into the

tube (Table S9). Once prepared, each tube was immediately

inserted into the spectrometer and NMR measurements

were started at a spinning rate of 10 Hz. For measurements

at 0 °C, the spectrometer was pre-cooled and ice-cold

CD2Cl2 was used for sample preparation. Processed 1H NMR

spectra were transferred to Dynamic Center where

normalised integrals of signals were



plotted and fitted with built-in functions to find an optimal fit in

order to obtain k.69–71 The reaction in DCM at 45 °C could not be

performed directly in the tube. Instead, aliquots of each

reaction mixture were collected at different time points,

the original solvent immediately removed in vacuo, the residue

dissolved in a suitable deuterated solvent and transferred into

a new tube for NMR measurements. As such, only a low number

of time points could be recorded, and k values could not be

calculated, but an estimation of the kinetic of the reaction was

still possible at this temperature (Figures S34-39).

4. Results and discussion

4.1 DFT calculations

4.1.2 Formation mechanism The formation of dinuclear

trithiolato-bridged arene ruthenium complexes is assumed to

follow a three-step substitution mechanism (see Figure 2). In

each of the first two steps, one of the bridging chlorine atoms is

substituted by a thiolate ligand. The last step consists in

accommodating the third bridging thiol, while releasing at

the same time the remaining non-bridging chlorine atoms. Each

of these steps is accompanied by the formation of one

equivalent HCl while, additionally, in the last step, the complex

acquires a singly positive charge with one chlorine ion providing

counter charge. Each of the three individual steps consists of

the release of the chlorine, the deprotonation of the thiol group

and the insertion of the sulphur atom, the exact sequence of

these sub steps as well as their respective contribution to

the overall reaction barrier being unknown. Such detailed

information on the formation mechanism would however be

crucially required for a knowledge-based optimization of

the synthesis conditions and the yield of such complexes. We

hence determine the mechanism of each individual step by

means of density functional theory (DFT) calculations on

Complex 1.

We tested two pathways for the insertion of the first thiol.

The first pathway proceeds by initially forming a Ru-S bond with

the subsequent release of HCl and the second one by reversing

these steps with initial HCl formation followed by insertion of

the thiolate. We find both pathway initializations to converge to

the same final mechanism with two transition states (see Figure

S1a). The first lower-energy transition state corresponds to

the Ru-S bond formation (12.8 kcal/mol), whereas the second

higher-energy transition state is the thiol deprotonation (19.9

kcal/mol). In protic solvents thiols could exist as deprotonated

anions and we would expect a reduced barrier for the second

step. This is indeed confirmed by our calculations, where

the barrier of insertion of the thiolate is reduced by 8.8 kcal/mol

(see Figure S2). As these deprotonated systems are not charge

neutral and computationally more challenging in our periodic

setup, we will in the following consider only reaction

mechanism for the neutral molecule but assume that protic

solvents should systematically reduce reaction barriers.

The insertion of the second thiophenol follows the same

mechanism as for the first one. However, the accommodation

of the thiol in the Ru-complex core is hindered, which is

reflected in the first transition state having a much higher

activation barrier (24.0 kcal/mol, see Figure S1b).

The deprotonation step on the other hand requires less energy

(10.9 kcal/mol) than for the first insertion. The final step in the

formation of the trithiolato Ru-complex is kinetically most

demanding. While the barrier for the Ru-S bond formation is

similar to the two preceding steps (17.5 kcal/mol),

the deprotonation is accompanied by rearrangement of

the two other thiol ligands, so as to accommodate the third one,

which results in a barrier of 31.4 kcal/mol (see Figure S1c).

The overall pathway for thiol ligands is shown as the black curve

in Figure 3. It can be seen that the formation of all thiolato

complexes is thermodynamically favourable. Nevertheless,

the kinetic barriers continuously increase from formation of

the monothiolato to the formation of the trithiolato complex, in

correlation with lower experimental yield for the trithiolato

complexes compared to mono- and dithiolato ones.

Figure 2. Stepwise formation of dinuclear trithiolato-bridged arene ruthenium

complexes. We adopted the following abbreviations for the complexes – starting dimer

[(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 : 0S, neutral monothiolato complex [(η6-p-

MeC6H4Pri)2Ru2Cl2(µ-Cl)(µ2-SR)] : 1S, neutral dithiolato complex [(η6-p-

MeC6H4Pri)2Ru2(µ2-SR)2Cl2] : 2S and cationic trithiolato complex [(η6-p-

MeC6H4Pri)2Ru2(µ2-SR)3]+ : 3S.



Figure 3. Energy evolution and transition states along the formation pathway form the

starting dimer dichloride (0S) to the trithiolato (3S) Ru complex via the mono- (1S) and

dithiolato complexes. The black line represents thiophenol, while the red, blue and green

lines are for thiophenols with -OCH3 and -NO2 substituents in para position and

cyclohexanethiol respectively. The values for the kinetic barriers are summarised in Table

S1 (SI).

Electron withdrawing/donating substituents The reactivity of

arene ligands can be tuned by the presence of different

substituents on the benzene ring. For thiophenol, the presence

of a strong electron withdrawing -NO2 group is expected to

facilitate deprotonation. Indeed, we compute a deprotonation

barrier that is 2.9 kcal/mol lower with the -NO2 group in para

position (3) than without it (see Figure 3 and Figure S4). This

kinetic enhancement is however not observed for the formation

of the di- and trithiolato complex, where we predict almost no

change in barrier and an increase by 10.4 kcal/mol, respectively.

In addition, the formation of the trithiolato complex is

thermodynamically no longer favourable in presence of the -

NO2 group. The opposite effect in terms of deprotonation is

expected for electron donating substituents, such as a methoxy

group and indeed we systematically predict a slight increase in

deprotonation activation energies with respect to the non-

substituted ligands. Also, for the -OCH3 substituent (2)

the formation of the trithiolato complex is kinetically strongly

hindered and thermodynamically no longer favourable. In both

cases the destabilization of the di- and trithiolato complexes as

well as the increase in barriers leading to their formation can be

ascribed on one hand to the increased steric bulkiness of

the ligands, which negatively affects the overall cluster

geometry. On the other hand, the destabilization can be

attributed to the significant dipole moment each thiolato-ligand

carries and introduces into the complex. In fact, both -OCH3 and

-NO2 have non-negligible Hammett substituent constants p, -

0.27 and 0.7872 respectively, which reflect the strong electron

asymmetry within such thiols. The fact that 3S is destabilised

disagrees with the experimental data, since the trithiolato -NO2

complex can be obtained in good yields (when performing

the reaction in DCM as described in Experimental Section).

Aliphatic thiol We investigated the formation of the trithiolato

complex in the case of the bulky aliphatic cyclohexanethiol (4),

which was found difficult to obtain experimentally.48 Our

simulations predict that the insertion of the ligand and

the formation of the Ru-S bond is the only transition state for

the first two steps (see Figure 3 and Figure S5), which points at

steric hinderance. The energy necessary to insert the first

cyclohexanethiol is similar to the other ligands, whereas

the barrier of the second step is significantly higher, which

could kinetically hinder the formation of the di- and trithiolato

complexes. The final step, however, also has a transition state

corresponding to the deprotonation step, in agreement with all

other trithiolato-complexes. The kinetic barriers of this 2S→3S

step are still comparable to those for the substituted aromatic

thiols.

Effect of the halogen in the starting dimer [(η6-p-

MeC6H4Pri)Ru(µ2-Cl)Cl]2 Next, we investigate what effect the

halogen has on the reaction by substituting chlorine with iodine

in the starting dimer [(η6-p-MeC6H4Pri)Ru(µ2-I)I]2. In Figure 4 we

compare the energy evolution of the three reaction steps and

see that iodine increases (by 9.9 kcal/mol) the barrier of the first

step, changing it to the Ru-S bond formation instead of

the deprotonation. The barriers for the subsequent steps

remain roughly the same as for chlorine (see Table S2 for

numerical values). We observe however a reduced

thermodynamic stability in presence of iodine, the mono-, di-

and trithiolato complexes being significantly less stable than

their chlorine counterparts and the formation of the trithiolato

complex even being uphill in energy. As the structure of

the trithiolato complex itself is the same for both halogens, this

can be attributed to the weaker H-I bond compared to H-Cl.

While the kinetics are thus only mildly affected by iodine, we

expect significantly less driving force for the formation of the

thiolato complexes. Experimental results have indeed shown

that trithiolato complexes [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-R)3]+

starting from [(η6-p-MeC6H4Pri)Ru(µ2-I)I]2 could not be obtained

in pure form.73

Figure 4. Energy evolution of the trithiolato complex 1 formation in presence of chlorine

and iodine. The transition-state barriers are presented numerically in Table S2 (SI) and

the NEB pathways can be found in Figure S6 (SI).

Temperature and solvent effects Based on the computed

barriers, we estimate the reaction rates at 0 °C, 25 °C, 45 °C and

80 °C, where the last two temperatures correspond to the usual

experimental conditions in dichloromethane (DCM) and ethanol


respectively (see Section 2, Experimental results), using Eyring’s

equation74 within transition state theory the reaction rate is

� � ��

ℎ�

�

#

��

where kB is Boltzmann’s constant, T the temperature, h Plank’s

constant, and E# is the computed barrier, listed in Table S1.

From the data shown in Figure 5 and Table S4, we can see that

while steps 1 and 2 have reasonable reaction rates at room

temperature, step 3 has very slow kinetics, which is further

hindered by the substituents on the thiophenol. Only elevated

temperatures lead to reaction rates that enable the complex

formation on experimental timescales. These are in agreement

with the experimental findings, that the 3rd step needs

significant thermal energy to proceed.

Experimentally, the three-step reaction takes place in a polar

solvent, ethanol or DCM (in the present work). We simulate

the polarizability of the solvent with an implicit solvation model,

which correctly describes the electrostatic effect of medium.

Accounting for any reaction with the solvent, however, such as

H-bonding or proton transfer would require computationally

expensive molecular dynamics calculations, where the solute is

simulated with explicit solvent molecules. A compromise could

be the addition of a few solvent molecules in combination with

implicit solvent. Considering though the great number of

possible solvent orientations and interactions with structurally

flexible solutes as shown by test calculations, in particular for

the transition states, there is a considerable risk of missing

important information and thus of compromising the validity of

the results. We therefore consider that the implicit model,

despite its limitations, yields more reliable trends for solvated

complexes than a mixed explicit/implicit scheme. We perform

calculations with dielectric constants 8.93 and 24.55,

corresponding to DCM and ethanol respectively and show the

energy evolution in Figure 6 and compare it with

Figure 5. Change in the rate constants with temperature for the Complexes 1-4 for the

three steps. The numerical values are summarised in Table S4 (SI).

Figure 6. Effect of implicit DCM and ethanol solvents on the energy evolution. The

numerical values are in Table S3 (SI).

the one in vacuum. The higher dielectric constant makes

the thiolato complexes thermodynamically more favourable

but has a distinct destabilizing effect on the transition states

corresponding to the insertion of the thiol group into

the complex’ core. This increase of the barriers is less marked

for the lower dielectric constant that however also does not

stabilise the complexes as much. This suggests that strongly

polar solvents are kinetically unfavourable for the formation of

the di- and especially the trithiophenolato complexes.

The effect of the temperature on the reaction kinetics and

the individual insertion of the thiol has already been

experimentally demonstrated. For a given thiol, it was shown

that the synthesis exclusively leads to the cationic

trithiophenolato complex [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-R)3]+.

At 0 °C and for thiols with decreased reactivity, typically

benzylthiols, but also for some thiophenols, the neutral

dithiophenolato complex [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-

R)2Cl2], or even the neutral monothiophenolato complex [(η6-p-

MeC6H4Pri)2Ru2Cl2(µ-Cl)(µ2-SC6H4-R)] can be obtained in pure

forms.49

4.2 Experimental results

Synthesis of complexes 1-3 The reaction pathway shown in

Figure 6 suggests that a solvent with lower dielectric constant

than the usual EtOH could kinetically favour the formation of

the di- and especially trithiolato complexes. Trithiolato

complexes should therefore be easier to obtain when

the reaction is performed in DCM.

Complex 1 was obtained with a yield of 62% after a 7 h reaction

performed at 45 °C in DCM as compared to a 69% yield obtained

from the same reaction but performed in EtOH at 80 °C for 23 h.

In literature, 44% yield was reached for the reaction performed

in MeOH.34 More interestingly, irrespective of the solvent used,

EtOH or DCM, the addition of DIPEA 1 h after beginning of the

reaction allowed obtaining 1 in 80% or 79% yield, respectively,

in only 3 h. The reaction leading to 1 was followed by NMR

spectroscopy (Figures 7-8; S34-35). It can be seen that at

elevated temperatures, the dithiolato complex is readily

formed followed by formation of the trithiolato complex.



Interestingly, it seems that in DCM at 45 °C the trithiolato

complex is formed slightly faster compared to the reaction

performed in EtOH at 80 °C. The reaction was also performed in

CD2Cl2 at 25 °C and 0 °C respectively, and followed by 1H NMR,

in order to determine experimental rate constants k.69–71 From

the reactions performed at 0 °C and 25 °C, we were only able to

estimate the rate constant for the dithiolato complex formation

applying the Bodenstein approximation.75 The formation of

the monothiolato complex is very fast and no reliable NMR data

could be extracted. It turns out that the rate constant obtained

from the kinetic data (see Table 1 and Figures S40, 41) was of

the same order of magnitude as the one calculated for

the reaction performed at 25 °C. Surprisingly and unlike

theoretically predicted, the rate constant k at 0 °C is of

similar order of magnitude.

Figure 7. Synthesis of 1 followed by 1H NMR. The spectra show the reaction monitoring

(Thiol- (5-5.5 ppm) and p-cymene aromatic resonances (7-8 ppm) are shown)

after ~5 min, 0.5 h, 1 h, 5 h, and 9 h) in EtOH (black line) at 80 °C and in DCM (red line)

at 45 °C. Aliquots of reaction mixture samples at individual time points were dried and

transferred to CDCl3 prior to measurement.

Figure 8. Synthesis of 1 followed by 1H NMR. The spectra show the reaction monitoring

(the p-cymene methyl resonances are shown) after ~5 min, 0.5 h, 1 h, 5 h, and 9 h) in

EtOH (black line) at 80 °C and in DCM (red line) at 45 °C. Aliquots of reaction mixture

samples at individual time points were dried and transferred to CDCl3 prior to

measurement.

Complex 2 Complex 2 was obtained in 73% yield from

the reaction performed at 45°C in DCM after 9 h as compared

to 93% yield obtained from 18 h reaction performed in EtOH at

80 °C 76. The rate constant k of the corresponding dithiolato

complex 8 obtained from the reaction in CD2Cl2 followed by 1H

NMR was close to the calculated k (see Table 1 and Figure 9,

S42, 43). Surprisingly and in contrast to calculations, k obtained

for the reaction performed at 25 °C was lower than at 0 °C. This

could be ascribed to the different dependence of the forward

and backward reaction rates with temperature (see Tables S4

and S5) if we assume the process to be in equilibrium. Indeed,

the equilibrium constant K at 0 °C is higher than the one at 25 °C

(see Table S6), so the forward reaction is favoured at lower

temperatures. Interestingly, such a rate dependence was not

observed for 1, even though, based on the calculations, we

would expect even higher differences in K. This leads us to

conclude that further processes and factors not captured by

the calculations, i.e. solvents and entropy,77 are likely to play

a role.

Table 1. Rate constants k for the first two steps calculated from the constants of the

individual steps (see Table S4) or determined experimentally from NMR kinetic data,

respectively.

R

ksteps 1 + 2 (min-1)

Calculated Experimental

0 °C 25 °C 0 °C 25 °C

-C6H5 (1) 8.6·10-7 9.2·10-2 7.5·10-4 2.9·10-3

-C6H4OMe (2) 1.1·10-6 1.1·10-3 6.5·10-3 2.2·10-3

-C6H4NO2 (3) 2.4·10-3 1.32 9.2·10-3 1.2·10-3

Figure 9. Formation of 2. Reaction between the dimer [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and

p-methoxythiophenol in CD2Cl2 at 25°C followed by 1H NMR. The data points represent

normalised integrals. Black: resonance at 6.86 ppm (p-methoxythiophenol, 2) blue:

resonance at 5.34 ppm (p-cymene ring, starting dimer).


Complex 3 Complex 3 was obtained with a yield of 73% of when

the reaction was performed in DCM at 45 °C compared to 48%

reported in literature for the reaction performed in EtOH under

reflux for 18 h.19 The reaction in CD2Cl2 was followed at 0 °C and

25 °C. The rate constant obtained for the corresponding

dithiolato complex was of the same order of magnitude as

the one calculated for the reaction performed at 0 °C (Table 1;

Figure S15-16). Similarly to 2, the reaction appears to be faster

at 0 °C as opposed to 25 °C. At 45 °C, the results suggest that p-

nitrothiophenol reacts immediately with the dimer [(η6-p-

MeC6H4Pri)Ru(µ2-Cl)Cl]2 (Figure S44, 45).

Synthesis of the new trithiolato complexes 4 and 5

The synthesis of 4 was attempted several years ago by Süss-Fink

and coworkers, but they could only obtain the neutral dithiolato

complex [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H11)2Cl2], which did not

react further in ethanol heated at reflux, presumably due to

steric reasons.48 Indeed, computational results predict high

barriers already for the mono- and dithiolato intermediates.

The difficulty to obtain 4 is in this context not surprising.

Nevertheless, by significantly extending the reaction time,

performing the reaction in DCM and using activating DIPEA, we

were able to obtain 4, however not in a pure form, as

inseparable mixtures containing the dithiolato complex [(η6-p-

MeC6H4Pri)2Ru2(µ2-SC6H11)2Cl2] (and possibly other impurities)

were always obtained. Determining k by 1H NMR for

the reaction of cyclohexylthiol with the starting dimer in CD2Cl2

was not successful in this case. The results however show that

the reaction proceeds rather slowly (Figure S46, 47).

The new complex 5 with aliphatic thiol ligands has been

obtained in 62% yield from the reaction in DCM with addition of

DIPEA. An analogous reaction in ethanol with addition of DIPEA

lead to 42% yield. Attempts to obtain 5 by performing

the reaction in DCM without DIPEA were unsuccessful, only

the neutral dithiolato complex [(η6-p-MeC6H4Pri)2Ru2(µ2-

SC6H13)2Cl2] was observed, which can be ascribed to the low

reactivity of 1-hexanethiol. Of note, a similar trithiolato complex

[(6-p-MeC6H4Pri)2Ru2(µ2-SC8H17)3]+ was obtained by Stibal et al.

in 2016, who reported an analogous reaction with octanethiol

under reflux in EtOH for 168 h and obtained 28% yield.50

Synthesis of the trithiolato complex 6 In the literature, 6 was

obtained in 45% yield from the reaction between the starting

dimer and p-fluorothiophenol in refluxing ethanol for 18 h.76 By

performing the reaction in DCM and adding DIPEA after 2 h , we

were able to obtain 6 in 80% yield in only 3.5 h.

Synthesis of the new dithiophenolato complexes 7 and 8 So

far, only dithiobenzylato complexes were reported, but no

dithiophenolato. Thiophenols were considered to be too

reactive, and the reactions with the starting dimer always led to

inseparable mixtures of trithiolato and dithiolato complexes.47

By using optimised conditions, we were able to obtain the two

new dithiophenolato complexes 7 and 8 from the reaction in

DCM at 0 °C. Notably, 7 was obtained in quantitative yield and

good purity. While 8 could not be purified to a satisfactory

degree, we can confirm that 8 was indeed formed. A further

reaction using these two new intermediates with another thiol

could thus lead to new mixed trithiolato complexes of the form

[(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-p-But)2(µ2-R)]+ and [(η6-p-

MeC6H4Pri)2Ru2(µ2-SC6H4-p-OMe)2(µ2-R)]+, which could have

interesting anticancer and antiparasitic properties.

5. Conclusions

In summary, we have conducted a DFT study aiming at a

fundamental understanding of the reaction mechanisms

leading to the formation of dinuclear thiolato-bridged arene

ruthenium complexes [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-R)3]+

starting from the dichloro(p-cymene)ruthenium(II) dimer [(η6-

p-MeC6H4Pri)Ru(µ2-Cl)Cl]2. Further, we studied variations in

reaction conditions experimentally and followed the kinetics

with NMR.

The presence of electron-withdrawing or donating substituents

on the thiol significantly influences the formation of

the trithiolato complex, which is thermodynamically no longer

favourable in presence of the former. In addition, the calculated

reaction pathways suggest using a solvent with a lower

dielectric constant could decrease the kinetic barriers for

the formation of the di- and trithiolato complexes.

Experimentally, changing the reaction solvent from EtOH to

DCM indeed leads mostly to similar or better yields, but at lower

temperature as compared to EtOH. Use of a base such as DIPEA

allows to further increase the yield in a shorter reaction time.

By this tuning of the reaction conditions, we were able to

synthesise two new trithiolato complexes with aliphatic thiol

ligands, improve the yields for two trithiolato complexes with

aromatic thiol ligands and further synthesise two new

dithiophenolato complexes, impossible to obtain so far. As

such, our results and suggested adapted synthetic route open

new possibilities for the synthesis of so far inaccessible

dinuclear dithiophenolato- and especially trithiolato-bridged

arene ruthenium(II) complexes that are known to possess very

interesting anticancer and antiparasitic properties. More

generally, the synthesis of other challenging thiolato-bridged

dinuclear group 8 and 9 metal complexes could be reexamined.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This research was funded by the SNF Professorship Grant

PP00P2_157615. Calculations were performed on UBELIX

(http://www.id.unibe.ch/hpc), the HPC cluster at the University

of Bern

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SUPPORTING INFORMATION

Dinuclear thiolato-bridged arene ruthenium complexes:

from reaction conditions and mechanism to synthesis of new

complexes

Hedvika Primasováa#, Silviya Ninovaa,b#, Mario De Capitani a, Jana Daeppa, Ulrich Aschauera*, Julien

Furrera*

a Departement für Chemie und Biochemie, Universität Bern, Freiestrasse 3, CH-3012 Bern, Switzerland b Department of Chemistry and Physics of Materials, Paris-Lodron Universität Salzburg, Jakob-Haringer-Strasse 2a, A-5020

Salzburg, Austria

Table of Contents

1. Computational part ................................................................................................................................... 4

1.1 Density functional theory calculations ................................................................................................................ 4 Energy barriers and pathways ................................................................................................................................................... 4

1.2 Reaction rates ...................................................................................................................................................... 10

1.3 Ru-dimer Geometry and Functional dependence ............................................................................................ 11

2. Experimental part ................................................................................................................................... 13

2.1 Synthesis .............................................................................................................................................................. 13

2.2 Characterisation ................................................................................................................................................. 16

2.3 Kinetics ................................................................................................................................................................ 28

References ....................................................................................................................................................... 38

List of Tables

Table S1. Activation barriers (in kcal/mol) for each of the three thiolphenolato-substitutions.

Table S2. Activation barriers (in kcal/mol) for the Complex 1 with Chlorine and Iodine.

Table S3: Activation barriers (in kcal/mol) for the Complex 1 in implicit solvents.

Table S4. Forward reaction rates (min-1) for each substitution step.

Table S5. Backward reaction rates (min-1) for each substitution step.

Table S6. Equilibrium constants.

Table S7. Theoretical Geometry Parameters for Complex 1.

Table S8. Energy differences (kcal/mol) and functional dependence for the first reaction step.

Table S9. Starting materials for kinetics experiments.

List of Figures

Figure S1. NEB reaction pathways for each substitution step of the trithiolato bridged ruthenium complex

formation using thiophenol (1).

Figure S2. NEB reaction pathway for 1,

Figure S3. NEB reaction pathways for each substitutional step of the trithiolato bridged ruthenium complex

formation using 4-methoxythiophenol (2).


formation using 4-nitrothiophenol (3).


formation using cyclohexylthiol (4).


formation, where the halogen element is Iodine.

Figure S7. The geometry of the initial ruthenium dimer without any thiolate ligands

Figure S8. Projected Density of States for the initial Ru complex (0S)

Figure S9. 400 MHz 1H NMR of 1 in CDCl3.

Figure S10. 100 MHz 13C NMR of 1 in CDCl3.

Figure S11. ESI-MS of 1 dissolved in MeOH and recorded in positive mode.

Figure S12. 400.1 MHz 1H NMR of 2 in CD2Cl2.

Figure S13. 100 MHz 13C NMR of 2 in CD2Cl2.


Figure S15. 400.1 MHz 1H NMR of 3 in MeOD.

Figure S16. 100 MHz 13C NMR of 3 in MeOD.


Figure S18. 500.1 MHz 1H NMR of 4 in CDCl3.

Figure S19. 100 MHz 13C NMR of crude 4 in CDCl3.

Figure S20. 500.1 MHz 13C HSQC of 4 in CDCl3.

Figure S21. ESI-MS of 4 dissolved in acetonitrile and recorded in positive mode.

Figure S22. ESI-MS of 5 dissolved in EtOH and recorded in positive mode

Figure S23. 400.1 MHz 1H NMR of complex 5 in CDCl3, 128 scans.

Figure S24. 100 MHz 13C NMR of complex 5 in CDCl3, 12288 scans.

Figure S25. ESI-MS of 6 dissolved in acetonitrile and recorded in positive mode

Figure S26. 500.1 MHz 1H NMR of complex 6 in MeOD, 16 scans.

Figure S27. 100 MHz 1H NMR of complex 6 in MeOD, 8192 scans.



Figure S30. 100 MHz 1H NMR of complex 7 in CDCl3, 8192 scans.




Figure S34. Synthesis of 1 in EtOH under reflux. 1H NMR in CDCl3 recorded at t =: 0 h, 30 min, 1 h, 2 h,

3 h, 4 h, 5 h, 7.5 h, 9 h. Aromatic region.

Figure S35. Synthesis of 1 in EtOH under reflux. 1H NMR in CDCl3 recorded at t =: 0 h, 30 min, 1 h, 2 h,

3 h, 4 h, 5 h, 7.5 h, 9 h. Aliphatic region.

Figure S36. Kinetics of formation of 2 and intermediates at 45 °C. Aliquots of reaction mixture in DCM

transferred to CDCl3. 500.1 MHz 1H NMR recorded at t =: 0 h, 0.5 h, 1 h, 2 h, 3 h, 5 h, 7 h, 9 h. Aromatic

region.

Figure S37. Kinetics of formation of 2 and intermediates at 45 °C. Aliquots of reaction mixture in DCM

transferred to CDCl3. 500.1 MHz 1H NMR recorded at t =: 0 h, 0.5 h, 1 h, 2 h, 3 h, 5 h, 7 h, 9 h. Aliphatic

region.

Figure S38. Kinetics of formation of 3 at 45 °C in DCM. 500.1 MHz 1H NMR in CDCl3 recorded at t =: 0 h,

0.25 h, 0.5 h, 1 h, 2 h. Aromatic region.

Figure S39. Kinetics of formation of 3 at 45 °C in DCM. 500.1 MHz 1H NMR in CDCl3 recorded at t =: 0 h,

0.25 h, 0.5 h, 1 h, 2 h. Aliphatic region.

Figure S40. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and thiophenol towards 1 in CD2Cl2 at 0 °C

followed by 1H NMR.

Figure S41. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and thiophenol towards 1 in CD2Cl2 at

25 °C followed by 1H NMR.

Figure S42. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and p-methoxythiophenol towards 2 in

CD2Cl2 at 0 °C followed by 1H NMR.

Figure S43. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and p-methoxythiophenol towards 2 in

CD2Cl2 at 25 °C followed by 1H NMR.

Figure S44. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and p-nitrothiophenol towards 3 in CD2Cl2

at 0 °C followed by 1H NMR.

Figure S45. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and p-nitrothiophenol towards 3 in CD2Cl2

at 25 °C followed by 1H NMR.

Figure S46. Kinetics of formation of 4 and intermediates. 400.1 MHz 1H NMR in CD2Cl2 recorded at t =:

0 h, 2 h, 5 h, 11 h, 15 h, 30 h, 35 h, 50 h, 70 h, 409 h. Aromatic region.

Figure S47. Kinetics of formation of 4 and intermediates. 400.1 MHz 1H NMR in CD2Cl2 recorded at t =:

0 h, 2 h, 5 h, 11 h, 15 h, 30 h, 35 h, 50 h, 70 h, 409 h. Aliphatic region.

1. Computational part

1.1 Density functional theory calculations

Energy barriers and pathways

The theoretically derived reaction barriers are schematically presented in Figures 3 and 4 in the main text. The

corresponding values for the two transition states at each substitution step are presented in Table S1 and Table S2.

The NEB pathways for each substitutional step are summarised in Figure S1 for 1 (R-C6H5), Figure S3 for 2 (R-C6H4-

OMe), Figure S4 for 3 (R-C6H4-NO2), Figure S5 for 4 (R-C6H11), Figure S6 for 1 with Iodine; where (a) is the 1st step,

(b) the 2nd step and (c) the 3rd step, respectively.

Table S1. Activation barriers (in kcal/mol) for each of the three thiophenolato-substitutions. Each substitution step has two

transition states (TS), while the third number is the energy of the products with respect to the reactants in each step.

1st step 2nd step 3rd step

1 TS 2 TS 1S 1 TS 2 TS 2S 1 TS 2 TS 3S

1 R-C6H5 12.8 19.9 -18.4 24.0 10.9 -16.7 17.5 31.4 -4.1

2 R-C6H4-OMe 19.8 22.0 -13.9 21.8 9.5 -16.7 24.7 41.0 2.4

3 R-C6H4-NO2 15.7 16.1 -17.7 23.5 21.2 -13.7 27.9 43.9 7.6

4 R-C6H11 21.1 - -11.6 42.0 - -10.4 25.2 40.3 5.2

Table S2. Activation barriers (in kcal/mol) for the trithiolato bridged ruthenium complex reaction pathway, where different

halogen atoms are used. Each substitution step has two transition states (TS), while the third number is the energy of the products

with respect to the reactants in each step.

Halogen 1st step 2nd step 3rd step


Chlorine 12.8 19.9 -18.4 24.0 10.9 -16.7 17.5 31.4 -4.1

Iodine 22.7 19.6 -6.5 22.6 11.4 -4.2 17.9 34.0 3.0

Table S3: Activation barriers (in kcal/mol) for the Complex 1 reaction pathway calculated in vacuum and in DCM or Ethanol as

implicit solvents without further optimization of the geometries. Each substitution step has two transition states (TS), while

the third number is the energy of the products with respect to the reactants in each step.



Vacuum 12.8 19.9 -18.4 24.0 10.9 -16.7 17.5 31.4 -4.1

DCM 11.8 19.0 -18.3 37.4 10.6 -16.0 59.5 30.8 -7.8

Ethanol 5.6 12.8 -24.4 74.7 10.5 -16.0 177.2 36.9 -8.5

Figure S1. NEB reaction pathways for each substitution step of the trithiolato bridged ruthenium complex formation using

thiophenol (1).

Figure S2. NEB reaction pathway for 1, where a deprotonated thiophenol was used for the reaction. The first transition state

corresponds to the insertion of the thiophenol anion, the second transition state would normally correspond to the deprotonation

and formation of H-Cl bond; in this case and together with the third transition state it corresponds to the adjustments of

the structure when the Cl anion leaves.

Figure S3. NEB reaction pathways for each substitutional step of the trithiolato bridged ruthenium complex formation using 4-

methoxythiophenol (2).

Figure S4. NEB reaction pathways for each substitutional step of the trithiolato bridged ruthenium complex formation using 4-

nitrothiophenol (3).

Figure S5. NEB reaction pathways for each substitutional step of the trithiolato bridged ruthenium complex formation using

cyclohexylthiol (4).

Figure S6. NEB reaction pathways for each substitutional step of the trithiolato bridged ruthenium complex formation, where the

halogen element is Iodine.

1.2 Reaction rates

Table S4. Forward reaction rates (min-1) for each substitution step where only the highest barrier per step is considered (see Table

S1) at four temperatures.


k (min-1) at 0°C

1 R-C6H5 4.1·10-2 2.1·10-5 2.6·10-11

2 R-C6H4-OMe 8.9·10-4 1.2·10-3 5.9·10-19

3 R-C6H4-NO2 4.6·101 5.3·10-5 2.8·10-21

4 R-C6H11 4.8·10-3 8.7·10-20 2.1·10-18

k (min-1) at 25°C

1 R-C6H5 9.7·10-1 9.5·10-4 3.6·10-9

2 R-C6H4-OMe 2.9·10-2 3.7·10-2 3.6·10-16

3 R-C6H4-NO2 6.0·102 2.2·10-3 2.6·10-18

4 R-C6H11 1.4·10-1 6.2·10-17 1.2·10-15

k (min-1) at 45°C

1 R-C6H5 8.5·100 1.3·10-2 1.1·10-7

2 R-C6H4-OMe 3.2·10-1 4.0·10-1 3.0·10-14

3 R-C6H4-NO2 3.5·103 2.8·10-2 3.0·10-16

4 R-C6H11 1.4·100 5.7·10-15 8.9·10-14

k (min-1) at 80°C

1 R-C6H5 2.1·102 6.2·10-1 1.6·10-5

2 R-C6H4-OMe 1.1·101 1.4·101 2.0·10-11

3 R-C6H4-NO2 4.9·104 1.2·100 3.2·10-13

4 R-C6H11 4.1·101 4.6·10-12 5.5·10-11

Table S5. Backward reaction rates (min-1) for each substitution step where only the highest barrier per step is considered (see

Table S1) at two temperatures.


k (min-1) at 0°C

1 R-C6H5 7.8·10-17 9.3·10-19 1.4·10-14

2 R-C6H4-OMe 6.3·10-15 5.1·10-17 4.5·10-17

3 R-C6H4-NO2 3.3·10-13 5.7·10-16 3.1·10-15

4 R-C6H11 2.7·10-12 4.4·10-28 2.9·10-14

k (min-1) at 25°C

1 R-C6H5 3.1·10-14 5.5·10-16 3.6·10-12

2 R-C6H4-OMe 1.8·10-12 2.1·10-14 1.9·10-14

3 R-C6H4-NO2 6.7·10-11 1.9·10-13 9.2·10-13

4 R-C6H11 4.6·10-10 1.6·10-24 7.1·10-12

Table S6. Equilibrium constant calculated as the ratio between the forward (see Table S4) and backward (see Table S5) reactions

for each step at two temperatures.


K at 0°C

1 R-C6H5 5.3·1014 2.3·1013 1.9·103

2 R-C6H4-OMe 1.4·1011 2.3·1013 1.3·10-2

3 R-C6H4-NO2 1.4·1014 9.3·1010 8.9·10-7

4 R-C6H11 1.8·109 2.0·108 7.4·10-5

K at 25°C

1 R-C6H5 3.1·1013 1.7·1012 1.0·103

2 R-C6H4-OMe 1.6·1010 1.7·1012 1.9·10-2

3 R-C6H4-NO2 9.0·1012 1.1·1010 2.9·10-6

4 R-C6H11 3.0·108 4.0·107 1.7·10-4

K(0°C) / K (25°C)

1 R-C6H5 17.2 13.2 1.9

2 R-C6H4-OMe 8.6 13.2 0.7

3 R-C6H4-NO2 15.3 8.3 0.3

4 R-C6H11 6.0 5.0 0.5

1.3 Geometry and Functional dependence of the ruthenium dimer

The starting ruthenium dimer consists of a core with two Ruthenium atoms coordinated with three Chlorine atoms each

and a p-cymene. Our gas phase calculation with BLYP agrees well with the experimental structure (see Error!

Reference source not found.). In comparison, other GGA (PBE) or hybrid (B3LYP, PBE0) functionals deviate more

from the experimental geometry. We note that the experimental structure is crystallised, so even bigger deviations could

be expected with respect to the calculated gas phase geometry.

Figure S7. The geometry of the initial ruthenium dimer without any thiolate ligands is presented with the labels on the

atoms in the core of the complex, to be related to the structural parameters in Table S7.

Table S7. Change in the bond lengths and angles with respect to the experimental values as obtained after a geometry relaxation

of 0S using different exchange-correlation functionals.

Bonds (Å)/Angles (°) Experiment1 0S

BLYP B3LYP PBE PBE0

Ru1-Ru2 3.693 3.708 3.658 3.681 3.615

Ru1-Cl1 2.435 2.411 2.399 2.384 2.374

Ru1-Cl3(S) 2.488 2.484 2.461 2.453 2.430

Ru1-Cl4 2.461 2.479 2.459 2.449 2.427

Ru2-Cl2 2.420 2.416 2.403 2.387 2.377

Ru2-Cl3(S) 2.450 2.482 2.461 2.451 2.428

Ru2-Cl4 2.437 2.476 2.455 2.446 2.425

Ru1-Cl3(S)-Ru2 96.8 96.6 96.0 97.3 96.2

Ru1-Cl4-Ru2 97.9 96.9 96.2 97.5 96.3

Cl1-Ru1-Cl3(S) 88.4 87.4 87.7 87.0 87.2

Cl2-Ru2-Cl3(S) 87.2 87.5 87.7 86.9 87.3

Cl1-Ru1-Cl4 87.1 87.0 87.2 86.8 86.8

Cl2-Ru2-Cl4 85.2 87.2 87.4 86.9 86.9

Average error (%) 0.81 0.92 0.87 1.34

Figure S8. Projected Density of States for the initial ruthenium dimer (0S) (a) and the thiophenolato-substituted one (1S) (b)

calculated with BLYP (above) and B3LYP (below). A Gaussian broadening of 0.1 eV was used.

In terms of electronic structure, there are no pronounced differences when the GGA (BLYP) or the two hybrid (B3LYP,

PBE0) exchange-correlation functionals are used (see Figure S8) neither for the initial ruthenium dimer (0S) nor for

the monosubstituted one (1S). Indeed, the characters of HOMO/LUMO states are similar with all three functionals,

giving us the reason to assume that our results with BLYP would be qualitatively confirmed by the other two functionals.

Moreover, the energetics of the first reaction step - the monothiolato complex (1S) formation – agrees well with the

BLYP results. Quantitatively, the hybrid functionals predict a higher barrier for the transition states. The PBE

approximation stabilises to a great extent the product, as opposed to the BLYP/B3LYP.

Table S8: Energy differences (kcal/mol) for the first reaction step as calculated with different functionals on the BLYP geometry.

BLYP B3LYP PBE PBE0

0S 0.0 0.0 0.0 0.0

1 TS 12.8 15.5 11.9 15.7

2 TS 19.5 22.8 16.5 21.3

1S -18.4 -19.5 -25.3 -25.1

2. Experimental part

2.1 Synthesis

Synthesis of 1

Synthesis in EtOH [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (101.6 mg, 0.166 mmol) was dissolved in EtOH abs.

(45 mL) under reflux. Thiophenol (75.6 mg, 0.686 mmol, 4.1 eq) in EtOH abs. (5 mL) was slowly dropped into

the refluxing solution and the mixture was left to react for 23 h. After purification on silica column 1 was

obtained as an orange solid (105.7 mg, 0.114 mmol, 69%).

Synthesis in DCM [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (106.3 mg, 0.174 mmol) was dissolved in dry

DCM (45 mL) and thereafter left to reflux. Thiophenol (80.2 mg, 0.728 mmol, 4.2 eq) in dry DCM

(5 mL) was added dropwise into the refluxing solution and left to react for 7 h. After purification 1 was

obtained as an orange solid (127.4 mg, 0.138 mmol, 62%).

Synthesis in DCM with DIPEA [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (106.6 mg, 0.174 mmol) was

dissolved in dry DCM (45 mL) and left to reflux thereafter. Thiophenol (81.4 mg, 0.739 mmol, 4.2 eq)

in dry DCM (5 mL) was added dropwise and the reaction mixture was left to react for 1 h. Next, the

reaction mixture was cooled down in ice/water bath. DIPEA (69.6 mg, 0.539 mmol, 3.1 eq) in dry DCM

(1 mL) was added dropwise into cooled and stirred reaction mixture dropwise during 10 min.

Afterwards, the reaction mixture was heated again and left to react for further 1 h and 50 min under

reflux. Purification allowed 1 to be obtained as an orange solid (127.4 mg, 0.138 mmol, 79%).

Synthesis in EtOH with DIPEA [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (101.4 mg, 0.166 mmol) was

dissolved in EtOH abs. (45 mL) under reflux. Thiophenol (76.2 mg, 0.692 mmol, 4.2 eq) in EtOH abs.

(5 mL) was added dropwise into refluxing solution and the reaction was left stirred. After 1 h, DIPEA

(66.6 mg, 0.515 mmol, 3.1 eq) in EtOH abs. (1 mL) was added slowly dropwise into refluxing mixture

during 10 min. The reaction was left to react for 1 h and 50 min. Purification allowed to obtain 1 as

an orange solid (123.0 mg, 0.132 mmol, 80%).

For purification of 1 column chromatography with DCM/EtOH 10:1 was used. As needed in case of reaction

performed in EtOH employing DIPEA, the product was further loaded on silica column with hexane/chloroform

100:1 and washed with gradient of hexane/chloroform, pure chloroform and finally released with DCM/EtOH

5:1.

Analytical data (Figures S9-11): 1H NMR (400.1 MHz, CDCl3): δH = 7.89 (d, JH,H = 6.0 Hz, 6H; Ar H2, H6),

7.39 (m, 9H; Ar H3, H4, H5), 5.41 (d, JH,H = 5.6 Hz, 2H; H-Ar p-cymene), 5.24 (d, JH,H = 5.6 Hz, 2H; H-Ar p-

cymene), 5.12 (m, 4H; H-Ar p-cymene), 1.92 (sept, JH,H = 6.8 Hz, 2H; CH(CH3)2), 1.62 (s, 6H; CH3), 0.89 (d,

JH,H = 6.8 Hz, 6H; CH(CH3)2), 0.77 ppm (d, JH,H = 6.8 Hz, 6H; CH(CH3)2); 13C NMR (100 MHz, CDCl3): δC =

137.8 (thiol C1), 132.6 (thiol C2/C6), 129.2 (thiol C3/C4/C5), 128.5 (thiol C3/C4/C5), 107.4 (C1 p-cymene),

100.0 (C4 p-cymene), 85.4 (Ar CH p-cymene), 85.0 (Ar CH p-cymene), 84.7 (Ar CH p-cymene), 83.6 (Ar CH

p-cymene), 30.6 (CH(CH3)2), 22.5 (CH(CH3)2), 22.0 (CH(CH3)2), 17.7 ppm (CH3); ESI-MS (positive mode,

MeOH) m/z = 799.1; elemental analysis calcd (%) for C38H43S3Ru2Cl·2CH3CH2OH: C 54.50, H 5.99; found:

C 54.22, H 6.26; Mw = 925.67 g/mol.

Synthesis of 2

[(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (100.6 mg, 0.164 mmol) was dissolved in dry DCM (45 mL) under N2

atmosphere and heated to reflux at 38-45 °C. p-methoxythiophenol (92.4 mg, 0.659 mmol, 4.0 eq) in dry DCM

(5 mL) was added dropwise into refluxing solution and it was left to react for 9 h. Purification on silica column

employing DCM/EtOH 5:1 as mobile phase allowed to obtain 2 as an orange solid (115.7 mg, 0.121 mmol,

73%).

Analytical data (Figures S12-14): 1H NMR (400.1 MHz, CD2Cl2): δH = 7.79 (d, JH,H = 8.8 Hz, 6H; H-Ar thiol),

6.91 (d, JH,H = 8.8 Hz, 6H; H-Ar thiol), 5.31 (d, JH,H = 5.8 Hz, 2H; H-Ar p-cymene), 5.18 (d, JH,H = 5.8 Hz, 2H;

H-Ar p-cymene), 5.08 (m, 4H; H-Ar p-cymene), 3.86 (s, 9H; OCH3), 1.96 (sept, JH,H = 6.9 Hz, 2H; CH(CH3)2),

1.61 (s, 6H; CH3 p-cymene), 0.91 (d, JH,H = 6.9 Hz, 6H; CH(CH3)2), 0.81 ppm (d, JH,H = 6.9 Hz, 6H; CH(CH3)2); 13C NMR (100 MHz, CD2Cl2): δC = 160.1 (COCH3), 133.7, 128.6, 114.5, 107.3, 99.5, 85.3, 84.7, 84.4, 83.5,

55.5, 30.6, 22.2, 21.8, 17.5 (CH3); ESI-MS (positive mode, MeOH): m/z 889.1; elemental analysis calcd (%) for

C41H49O3Ru2S3Cl·2H2O: C 51.32, H 5.57; found: C 51.58, H 5.70; Mw = 959.64 g/mol; Figure S24-26.

Synthesis of 3

[(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (101.6 mg, 0.166 mmol) was dissolved in dry DCM (40 mL) under N2 atmosphere and heated to reflux at 40-45 °C. 80% technical grade p-nitrothiophenol (128.7 mg, 0.664 mmol, 4.0 eq) in dry DCM (10 mL) was added dropwise into the refluxing solution. After 30-60 min after addition of the thiol the mixture turned slowly dark red. The reaction was left to react for 2 h in total. Purification on silica column using DCM/EtOH 5:1 as an eluent allowed 3 to be isolated as a red solid (125.8mg, 0.121 mmol, 73%).

An alternative approach employing an organic base was tested: [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (99.1 mg,

0.161 mmol) was dissolved in dry DCM (40 mL) under N2 and heated to reflux. p-nitrothiophenol (150.1 mg,

0.967 mmol, 6.0 eq) was added dropwise into refluxing solution. After 1 h, heating was stopped and DIPEA

(69.1 mg, 0.535 mmol, 3.3 eq) has been added dropwise into temperature-regulated stirred reaction mixture.

Afterwards, the mixture was left to react for further 1 h under reflux, but progressively turned black indicating

starting material decomposition. This approach has been abandoned.

Analytical data (Figures S15-17): 1H NMR (400.1 MHz, MeOD): δH = 8.25 (ABq, JH,H = 8.9 Hz, 12H; H-Ar

thiol), 5.76 (d, JH,H = 5.7 Hz, 2H; H-Ar p-cymene), 5.63 (d, JH,H = 5.7 Hz, 2H; H-Ar p-cymene), 5.43 (m, 4H;

H-Ar p-cymene), 1.99 (sept, JH,H = 6.9 Hz, 2H; CH(CH3)2), 1.67 (s, 6H; CH3 p-cymene), 0.92 (d, JH,H = 6.9 Hz,

6H; CH(CH3)2), 0.80 ppm (d, JH,H = 6.9 Hz, 6H; CH(CH3)2); 13C NMR (100 MHz, MeOD): δC = 147.8 (thiol

C1/C4), 146.8 (thiol C1/C4), 133.7 (thiol CH), 123.6 (thiol CH), 108.3 (C1 p-cymene), 101.1 (C4 p-cymene),

85.8 (Ar CH p-cymene), 85.8 (Ar CH p-cymene), 85.5 (Ar CH p-cymene), 85.0 (Ar CH p-cymene), 30.9

(CH(CH3)2), 21.4 (CH(CH3)2), 20.7 (CH(CH3)2), 16.5 ppm (CH3); ESI-MS (positive mode, MeOH): m/z 934.0;

elemental analysis calcd (%) for C38H40N3O6S3Ru2Cl·6/7 DCM: C 44.82, H 4.04; found: C 45.03, H 3.74;

Mw = 1041.32 g/mol.

Synthesis of 4

[(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (100 mg, 0.163 mmol) was dissolved in dry DCM (40 mL) under Ar and heated to reflux at 40-45 °C. Cyclohexanethiol (166.5 mg, 1.433 mmol, 8.8 eq) in dry DCM (10 mL) was added dropwise into refluxing solution and the reaction mixture was left to react for 18 h. As a next step, DIPEA (86.0 mg, 0.665 mmol, 4.1 eq) in dry DCM (5 mL) was added slowly into the solution during 5-10 min. The mixture was left to react for further 6 days. Three-step purification on silica column was applied. First, the product was pre-purified on silica column using DCM/EtOH 5:1 as a mobile phase. The orange fraction has been concentrated and further purified on silica column using CHCl3/acetone 3:2 as an eluent. Finally, a concentrate of fractions containing the product was purified on silica column using gradient elution system of acetone with increasing amount of 10% acetic acid up to 1:1 ratio to obtain 4 as viscous orange brown matter (30 mg). The product contained impurities. Due to the nature and amount of the product no thermal analysis could be done.

Synthesis of 5

[(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (101.3 mg, 0.165 mmol) was dissolved in DCM (40 mL) under Ar atmosphere, heated to reflux at 40-45 °C and 1-hexanethiol (77.9 mg, 0.659 mmol, 4.0 eq) was slowly dropped into refluxing solution. It was left to react for 1 h. Next, DIPEA (62 mg, 0.480 mmol, 2.9 eq) was added dropwise into solution and this was then left to react for further 67 h. The crude product was concentrated under reduced pressure and subsequently purified on silica column using aceton/DCM 9:1 to yield orange-brown solid giving a yield of 62% (88.3 mg, 0.103 mmol). For comparison, performing the reaction in EtOH under reflux with use of DIPEA analogously, 5 was obtained in 42% yield (59.3 mg, 0.068 mmol).

Synthesis of 6

[(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (100.0 mg, 0.163 mmol) was dissolved in DCM (40 mL) under Ar atmosphere and heated to reflux at 40-45 °C. p-fluorothiophenol (122.5 mg, 0.956 mmol, 5.9 eq) was added slowly and the reaction mixture was left stirred for 2 h. Next, DIPEA (69.3 mg, 0.536 mmol, 3.3 eq) was added dropwise and the mixture was left stirred for further 1.5 h. Afterwards the crude product was concentrated under reduced pressure and purified on silica column using DCM/EtOH 5:1 as an eluent. 6 was obtained as an orange solid in 80% yield (121.1 mg, 0.131 mmol). Analytical data (Figures S25-27): 1H NMR (500.1 MHz, MeOD): δH = 7.97 (m, 6H; H-Ar thiol), 7.17 (m, 6H; H-Ar thiol), 5.56 (d, JH,H = 5.6 Hz, 2H; H-Ar p-cymene), 5.45 (d, JH,H = 5.6 Hz, 2H; H-Ar p-

cymene), 5.30 (m, 4H; H-Ar p-cymene), 1.96 (sept, JH,H = 5.6 Hz, 2H; CH(CH3)2), 1.64 (s, 6H; CH3), 0.93 (d, JH,H = 6.8 Hz, 6H; CH(CH3)2), 0.83 ppm (d, JH,H = 6.8 Hz, 6H; CH(CH3)2). 13C NMR (100.1 MHz, MeOD): δC = 164.3 (CF), 161.8 (CF), 134.5 and 134.4 (CH thiol), 133.23 and 133.21 (Ar C thiol), 115.8 and 115.5 (Ar C thiol), 107.3 (Ar C thiol), 100.2 (Ar C thiol), 85.4 (Ar CH p-cymene), 85.2 (Ar CH p-cymene), 84.8 (Ar CH p-cymene), 83.9 (Ar CH p-cymene), 30.7 (CH(CH3)2), 21.3 and 20.9 (CH(CH3)2), 16.4 ppm (CH3); ESI-MS (positive mode, acetonitrile): m/z 853.0; Mw = 926.88 g/mol.

Synthesis of 7

p-t-butylthiophenol (53.6 mg, 0.322 mmol, 2.0 eq) was dropwise added into stirred and cooled solution of [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (99.0 mg, 0.162 mmol) in DCM and the mixture was left to react for 4 h at 0 °C. Subsequently, the crude product was concentrated and purified on silica column using DCM/EtOH 6:1 to give orange solid 7 in quantitative yield (144.4 mg, 0.158 mmol).

Synthesis of 8

[(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 (105.5 mg, 0.172 mmol) was dissolved in DCM (50 mL) and p-methoxythiophenol (50.8 mg, 0.362 mmol, 2.1 eq) was added dropwise into stirred solution. The mixture was left to react stirred at room temperature for 4 h. Subsequently, it was concentrated and purified on silica column using DCM/EtOH 5:1 as an eluent. The product was obtained as dark orange solid (119.7 mg) but contained impurities.

2.2 Characterisation

Figure S9. 400 MHz 1H NMR of 1 in CDCl3.

Figure S10. 100 MHz 13C NMR of 1 in CDCl3.


Figure S12. 400.1 MHz 1H NMR of 2 in CD2Cl2.

Figure S13. 100 MHz 13C NMR of 2 in CD2Cl2.


Figure S15. 400.1 MHz 1H NMR of 3 in MeOD.

Figure S16. 100 MHz 13C NMR of 3 in MeOD.


Figure S18. 500.1 MHz 1H NMR of 4 in CDCl3.

Figure S19. 100 MHz 13C NMR of crude 4 in CDCl3.

Figure S90. 500.1 MHz 13C HSQC of 4 in CDCl3.

Figure S21. ESI-MS of 4 dissolved in ACN and recorded in positive mode.

Figure S22. ESI-MS of 5 dissolved in EtOH and recorded in positive mode.


Figure S24. 100 MHz 13C NMR of complex 5 in CDCl3, 12288 scans.

Figure S25. ESI-MS of 6 dissolved in acetonitrile and recorded in positive mode.

Figure S26. 500.1 MHz 1H NMR of complex 6 in MeOD, 16 scans.

Figure S27. 100 MHz 1H NMR of complex 6 in MeOD, 8192 scans.



2.3 Kinetics

Table S9. Starting materials for kinetics experiments.

R Ru dimer Thiol

mg µmol mg µmol

C6H5 (0°C) 2.1 3.4 1.5 13.6 C6H5 (25°C) 2.0 3.3 1.5 13.6

C6H4NO2 (0°C) 2.0 3.3 2.6 13.4 C6H4NO2 (25°C) 2.1 3.4 2.7 13.9

C6H4OMe 2.0 3.3 1.9 13.6 C6H11 2.0 3.3 1.6 13.8

Figure S34. Synthesis of 1 in EtOH under reflux at 78-83 °C. 1H NMR in CDCl3 recorded at t =: (from bottom to top): 0h, 30min,

1h, 2h, 3h, 4h, 5h, 7.5h, 9h. Aromatic region.

Figure S35. Synthesis of 1 in EtOH under reflux at 78-83 °C. 1H NMR in CDCl3 recorded at t =: (from bottom to top): 0h, 30min,

1h, 2h, 3h, 4h, 5h, 7.5h, 9h. Aliphatic region.

Figure S36. Kinetics of formation of 2 and intermediates at 45°C. Aliquots of reaction mixture in DCM transferred to CDCl3.

500.1 MHz 1H NMR recorded at t =: (from bottom to top): 0h, 0.5h, 1h, 2h, 3h, 5h, 7h, 9h. Aromatic region.

Figure S37. Kinetics of formation of 2 and intermediates at 45°C. Aliquots of reaction mixture in DCM transferred to CDCl3.

500.1 MHz 1H NMR recorded at t =: (from bottom to top): 0h, 0.5h, 1h, 2h, 3h, 5h, 7h, 9h. Aliphatic region.

Figure S38. Kinetics of formation of 3 at 45°C in DCM. 500.1 MHz 1H NMR in CDCl3 recorded at t =: (from bottom to top): 0h,

0.25h, 0.5h, 1h, 2h. Aromatic region.

Figure S39. Kinetics of formation of 3 at 45°C in DCM. 500.1 MHz 1H NMR in CDCl3 recorded at t =: (from bottom to top): 0h,

0.25h, 0.5h, 1h, 2h. Aliphatic region.

Figure S40. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and thiophenol towards 1 in CD2Cl2 at 0 °C followed by 1H NMR. (a) resonance at 4.92 ppm; (b) 2.28 ppm; (c) 1.84 ppm; (d) 1.68 ppm; (e) 0.94 ppm.

Figure S41. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and thiophenol towards 1 in CD2Cl2 at 25 °C followed by 1H NMR. (a) resonance at 7.97 ppm; (b) 7.61 ppm; (c) 5.15 ppm; (d) 2.28 ppm; (e) 0.97 ppm.

Figure S42. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and p-nitrothiophenol towards 2 in CD2Cl2 at 0 °C followed by 1H NMR. (a) resonance at 7.89 ppm; (b) 7.51 ppm; (c) 3.81 ppm; (d) 2.29 ppm; (e) 1.83 ppm; (f) 1.68 ppm.

Figure S43. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and p-methoxythiophenol towards 2 in CD2Cl2 at 25 °C followed

by 1H NMR. (a) resonance at 7.89 ppm; (b) 7.52 ppm; (c) 6.86 ppm; (d) 5.13 ppm; (e) 3.79 ppm; (f) 1.01 ppm.

Figure S44. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and p-nitrothiophenol towards 3 in CD2Cl2 at 0 °C followed by 1H NMR. (a) resonance at 8.23 ppm; (b) 7.85 ppm; (c) 5.37 ppm; (d) 1.88 ppm; (e) 1.71 ppm; (f) 0.98 ppm.

Figure S45. Reaction between [(η6-p-MeC6H4Pri)Ru(µ2-Cl)Cl]2 and p-nitrothiophenol towards 3 in CD2Cl2 at 25 °C followed by 1H NMR. (a) resonance at 8.22 ppm; (b) 8.18 ppm; (c) 7.88 ppm; (d) 5.29 ppm; (e) 1.01 ppm.

Figure S46. Kinetics of formation of 4 and intermediates. 400.1 MHz 1H NMR in CD2Cl2 recorded at t =: (from bottom to top):

0h, 2h, 5h, 11h, 15h, 30h, 35h, 50h, 70h, 409h. Aromatic region.

Figure S47. Kinetics of formation of 4 and intermediates. 400.1 MHz 1H NMR in CD2Cl2 recorded at t =: (from bottom to top):

0h, 2h, 5h, 11h, 15h, 30h, 35h, 50h, 70h, 409h. Aliphatic region.

References (1) Claire S Allardyce, Paul J Dyson, David J Ellis, Paul A Salter, Rosario Scopelliti, Synthesis and characterisation of some

water soluble ruthenium(II)–arene complexes and an investigation of their antibiotic and antiviral properties, Journal of

Organometallic Chemistry, 2003, 668, 35-42

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