Synthesis, characterization and behavior in water/DMSO solution of Ru(II) arene complexes with bioactive carboxylates

ACCEPTED MANUSCRIPT

Synthesis, Characterization and Behavior in Water/DMSO Solution of

Ru(II) Arene Complexes with Bioactive Carboxylates

a,b

b,c

a,b,*

Lorenzo Biancalana, Guido Pampaloni, Stefano Zacchini and Fabio Marchetti

a

Università di Pisa, Dipartimento di Chimica e Chimica Industriale, Via Moruzzi 13, I-56124 Pisa.

b

CIRCC, via Celso Ulpiani 27, I-70126 Bari, Italy.

c

Università di Bologna, Dipartimento di Chimica Industriale “Toso Montanari”, Viale

Risorgimento 4, I-40136 Bologna, Italy.

*

To whom correspondence should be addressed. E-mail: fabio.marchetti1974@unipi.it

Keywords: bioorganometallic chemistry; ruthenium arene complexes; carboxylato ligand.

Abstract.

6

The reactions of [RuCl(µ-Cl)(η -p-cymene)] with sodium carboxylates, in methanol or acetonitrile

2

6

solution, afforded the complexes [RuCl(κ O-RCO )(η -p-cymene)] (RCO = valproate, 1;

2

6

aspirinate, 2; diclofenate, 3), in 79-96% yields. Analogously, [RuCl(κ O-dfCO )(η -benzene)], 4,

2

6

was obtained in admixture with minor by-products from [RuCl(µ-Cl)(η -benzene)] and

2

6

sodium/silver diclofenate. The sequential reaction of [RuCl(µ-Cl)(η -p-cymene)] with sodium

2

6

salicylate and PPh gave [Ru(κ O,O’-salCO )(PPh )(η -p-cymene)], 5, in 70% yield. The hydride

3

2

3

6

complex [Ru Cl (µ-Cl)(µ-H)(η -p-cymene) ], 6, was produced in 36% yield from [RuCl(µ-Cl)(η -p-

2

cymene)] and sodium formate. An optimization of the experimental work-up allowed to isolate

2

6

[

RuCl(µ-Cl)(η -p-cymene)] with an improved yield respect to the literature (98% vs. 65%). The

2

bidentate coordination mode of the carboxylato ligands in 1-5 was unambiguously ascertained by

1

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IR and NMR spectroscopy, moreover the solid state structure of 1 was elucidated by single crystal

X-ray diffraction. Complexes 1-3 experience rapid and quantitative dissociation of the carboxylato

6

anion in DMSO/water/NaCl mixtures, mainly converting into [RuCl (DMSO)(η -p-cymene)], 7.

2

Introduction

6

The dimeric compounds [RuCl(µ-Cl)(η -arene)] are easily available from ruthenium trichloride [1]

2

and represent the starting materials to access mononuclear Ru(II)-arene complexes by addition of

suitable ligands able to cleave the Ru-Cl bridges. A wide variety of such derivatives have aroused

huge interest due to their medicinal [2] and catalytic [3] properties. Carboxylates are among the

ligands that can be engaged in this chemistry, thus a number of simple complexes with generic

2

6

2

1

6

formulas [RuCl(κ O-RCO )(η -arene)] and [Ru(κ O-RCO )(κ O-RCO )(η -arene)] (R = alkyl or

2

aryl group) have been described [4]. In general, the introduction of the carboxylato function is

6

achieved by treatment of the [RuCl(µ-Cl)(η -arene)] precursor with either sodium/silver

2

carboxylates or the carboxylic acid in the presence of a base, however also transmetalation from

Pb(MeCO ) has been reported [5]. Ru-bound carboxylato ligands may exhibit an interesting

2

4

1

reactivity favoring the activation of various organic substrates [6]. For instance, [Ru(κ O-

6

CF CO ) (H O)(η -p-cymene)], obtained in an attempt to prepare the related bis-carboxylate

3

2 2

2

complex, promotes the conversion of α-diazo-acetamides into γ-lactams in chlorinated solvent [4b].

Moreover, according to the beneﬁcial effect provided by the use of carboxylic acids or carboxylates

6

as additives in ruthenium-mediated C-H activation reactions [4c, 7], [Ru(RCO ) (η -p-cymene)] (R

2

t

=

2,4,6-C H , Bu) were proposed as well defined catalytic precursors for the arylation of arenes

6 3

t

6

[

4c, 4d], with [Ru( BuCO ) (η -p-cymene)] working in water solution [4d].

2 2

A range of carboxylic acids with documented biological/pharmacological functions have been

tethered through esterification reactions to the arene [8] or to N- and P-ligands [9], providing

enhanced cytotoxicity to the resulting Ru(II) arene complexes. In principle, the direct coordination

of the carboxylate moiety to the ruthenium center represents an alternative approach, but the

2

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possible fast release in aqueous medium, that is sometimes observed with bidentate oxygen ligands

[10], may represent an important drawback in view of application in physiological environment. As

a matter of fact, Ru(II) arene acetates manifest some lability of the acetato ligand in polar solvents

[

4a], and this feature has been exploited to perform ligand exchange reactions [11], even by

2

complex carboxylato units [12]. Sadler and co-workers studied the behavior of [RuCl(κ O-

6

MeCO )(η -p-cymene)] in water, and found that this compound converted into the hydroxo-bridged

2

6

+

dimer [{Ru(η -p-cymene)} (µ-OH) ] [13]. The only examples of biologically investigated Ru(II)

2

3

arene complexes with targeted carboxylato ligands have appeared in the literature very recently

14]; notwithstanding, the reported synthetic procedures and characterizations raise serious doubts

[

in some cases [14a-c, 15].

In the framework of our research pointing to the preparation of anticancer Ru(II) arene complexes

[

9c,e, 16], herein we describe a systematic study aimed to tether, directly to the ruthenium center, a

series of carboxylic acids which have been previously found to exert a known biological activity

and/or a synergic effect when associated to anticancer metal drugs, i.e. valproic acid [9c, 17],

acetylsalicylic acid (aspirin) [9c, 18], diclofenac [9c, 19], salicylic acid [20], gallic acid [21] and

dichloroacetic acid [16, 22] (Chart 1). Propiolic acid and formic acid were also included in this

study.

The synthesis and the characterization of Ru products will be described, together with the

assessment of their stability in water/DMSO medium roughly relevant to cytotoxic assays.

3

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Chart 1. Carboxylic acids cited in this work.

Results and discussion

The sodium salts of valproic acid, aspirin, gallic acid, dichloroacetic acid, propiolic acid and the

silver salts of aspirin and diclofenac were obtained optimizing the respective literature procedures

(see Supporting Information for details). The synthesis of sodium aspirinate required the use of

NaHCO , while stronger Brønsted bases (Na CO , NaOH) gave complications due to hydrolysis of

3

2

3

the acetyl ester group. Solid Na[aspCO ] is moisture-sensitive and was stored under dry N .

2

6

[

RuCl(µ-Cl)(η -p-cymene)] was obtained through the classical synthetic procedure reported by

2

Bennett [1], however optimized work-up allowed to isolate the product with increased yield (98%

6

vs. 65%). Then, the reactions of [RuCl(µ-Cl)(η -p-cymene)] with the sodium salts of valproic acid,

2

aspirin and diclofenac, in methanol or acetonitrile solution, afforded complexes [RuCl(κ O-

6

RCO )(η -p-cymene)], 1-3, in 79-96% yields (Scheme 1). In general, the use of sodium

2

carboxylates resulted suitable to the synthesis of the complexes; otherwise, the use of silver salts

was attempted as an alternative approach in the case of 2 and 3, resulting in less clean reactions.

6

The reactions of [RuCl(µ-Cl)(η -p-cymene)] with sodium gallate, dichloroacetate and propiolate

2

proceeded with low conversion of the starting ruthenium material, and unidentified mixtures of

products were obtained (see Experimental).

4

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Scheme 1. Synthesis of ruthenium p-cymene complexes with bioactive carboxylato ligands.

Compound 1 is unprecedented, while 3 was recently published and also 2 was claimed to be

prepared by the same authors [14a, 15]. A correct synthetic procedure to cleanly access 2 and

accurate IR and NMR assignments for 2 and 3 are supplied herein. The IR spectra of 1-3 (in the

solid state) contain two bands ascribable to the asymmetric and symmetric stretching vibration of

−1

the carboxylato group, falling at ca. 1510 and 1430 cm , respectively. The two bands are closer in

wavenumber value if compared to the situation in the respective sodium salts (∆ν₍_C_O₂₎in Table 1);

this is as expected for a bidentate coordination mode [23], and the values resemble those reported

−1

for analogous acetate/trifluoroacetate systems [4a]. In 2, an additional absorption at 1768 cm

accounts for the ketonic unit, confirming that this is not involved in the coordination. In the NMR

spectra of 1-3 (CDCl solution), the carboxylato carbon resonates in the range 182.2-196.4 ppm, i.e.

3

1

downfield shifted compared to the corresponding sodium salt reactant. The H NMR spectra contain

a single set of resonances, including those related to the p-cymene group showing two-fold (C_S)

symmetry: this feature agrees with the absence of chirality at the ruthenium, due to the presence of

the bidentate, symmetric carboxylate.

Crystals of 1 suitable for X-ray analysis were obtained from a hexane solution. A view of the

molecular structure is shown in Figure 1, with main bonding parameters given in the caption.

5

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Compound 1 adopts a typical three-leg piano-stool geometry, and the bond distances and angles

2

6

around the ruthenium center resemble those reported for analogous [RuCl(κ O-RCO )(η -p-

2

cymene)] complexes [6, 13, 14]. This is the first example of a X-ray characterized ruthenium

complex with a valproate ligand.

Figure 1. View of the molecular structure of 1. Displacement ellipsoids are at the 30% probability level. H-

atoms have been omitted for clarity. Key bond lengths (Å) and angles (°): Ru(1)-O(1) 2.152(7), Ru(1)-Cl(1)

6

2

.391(4), Ru(1)-(η -p-cymene)_a_v_e_r_a_g_e2.16(3), O(1)-Ru(1)-O(1)#1 60.3(4), Cl(1)-Ru(1)-O(1) 85.7(2). Symmetry

transformation used to generate equivalent atoms: #1 x, -y+1/2, z.

Under the conditions employed for the synthesis of 1-3, the reactions of M[dfCO ] (M = Na, Ag)

2

6

2

6

with [RuCl(µ-Cl)(η -benzene)] in MeOH led to the formation of [RuCl(κ O-dfCO )(η -benzene)],

2

4

(Scheme 2), in admixture with minor by-products. The latter could not be removed due to

unexpected instability of 4 (including benzene release) during work-up.

Scheme 2. Formation of ruthenium benzene diclofenate complex.

6

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We extended the series of investigated carboxylic acids to salicylic acid, containing a side hydroxyl

6

function which, in principle, may be involved in coordination. When [RuCl(µ-Cl)(η -p-cymene)]₂

was treated with sodium salicylate in methanol, the formation of two major ruthenium-salicylato

products was recognized by NMR. Subsequent addition of AgNO (1 equivalent) led to a small

3

variation of their ratio, while NaOH addition determined a shift of the NMR resonances for one of

the two compounds, without favoring the formation of a unique species. Only one Ru(p-cymene)-

salicylato species was detected by mass spectrometry, corresponding to the formula

[

Ru(salCO )(H O)(p-cymene)] [24]. We propose that the two complexes differ in the coordination

2 2

mode of the salicylato ligand (Scheme 3a).

6

The treatment of the [RuCl(µ-Cl)(η -p-cymene)] / Na[salCO ] / NaOH mixture with PPh resulted

2

3

2

6

in the clean formation of [Ru(κ O,O’-salCO )(PPh )(η -p-cymene)], 5, which was finally isolated in

2

3

7

2

0% yield (Scheme 3b). Triphenylphosphine is a typical ligand for Ru(II) arene scaffolds [1, 16,

5], and was previously reported to confer some stability to the coordination of bidentate O,O-

ligands [10b].

Ru

O

(

a)

X

Ru

O

H

O

X

X = Cl, solvent

O

OH

O

Na[salCO₂]

NaOH

Cl

Ru

1

_

2

PPh3

Cl

(

b)

Ru

Ph P

3

O

MeOH

reflux T

NaCl

CHCl3

reflux T

O

Cl

O

5

Scheme 3. Different coordination modes of the salicylato ligand in a Ru-p-cymene complex (a) and

synthesis of complex 5 (b).

In the IR spectrum of 5, the absorptions due to the stretching vibrations of the carboxylato unit have

−1

13

been recognized at 1581 and 1331 cm . The C resonance of the carboxylato carbon experiences a

7

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small upfield shift on going from Na[salCO ] to 5 (∆δ = −4.1 ppm), while a more significant

2

downfield variation (∆δ = +9.0 ppm) concerns the hydroxyl-bound carbon. This latter feature

indicates the involvement of the hydroxyl group in the coordination of the salicylate as a bidentate

1

ligand. The H NMR spectrum of 5 displays two sets of signals for the aromatic and the methyl

protons belonging to the p-cymene moiety, in agreement with the ruthenium center to be

3

1

stereogenic. The P spectrum of 5 consists of a single resonance at 26.7 ppm.

13

Table 1. Comparison of selected IR and C NMR data for Ru complexes 1-5 and related ligands.

−1 a

13

b

IR: ν/cm

C NMR: δ/ppm

Compound

c

ν_a_s_y_m(CO₂)

ν_s_y_m(CO₂)

∆ν(CO₂)

Other bands

RCO₂

Other signals

1

1503s

1550s

1432s

1403s

71

-

196.4

-

d

Na[vpCO₂]

147

186.6

C=O_e_s_t_e_r

73.4

:

2

1507s

1422s

1394s

85

C=O_e_s_t_e_r: 1768s

182.2

1

C=O_e_s_t_e_r

:

C=O_e_s_t_e_r

169.9

Na[aspCO₂]

1608s-sh

214

173.6

190.2

1

769m, 1748m

3

1515s-sh

1510m-sh

1573s

1437s

1434s-sh

1397s

78

76

NH: 3330m

-

e

4

NH: 3301w-br

190.3

179.7

171.7

f

Na[dfCO₂]

5

176

250

206

NH: 3387w

-

1581s

1331s

C−O: 170.9

g

Na[salCO₂]

1580s

1374s

-

175.8

C−O: 161.9

a

b

c

Solid-state IR data. NMR data in CDCl although otherwise specified. Wavenumber difference between

anti-symmetric and symmetric stretching of the carboxylate moiety. NMR data in D O taken from ref [26].

NMR data in (CD ) CO. NMR data in phosphate buffer aqueous solution taken from ref [27]. NMR data in

3

d

e

2

f

g

3

2

CD OD taken from ref [28].

3

6

In order to further extend our systematic study, we carried out the reaction of [RuCl(µ-Cl)(η -p-

cymene)] with sodium formate in methanol solution. This reaction led to the isolation of the µ-

2

6

hydride complex [Ru Cl (µ-Cl)(µ-H)(η -p-cymene) ], 6, in a moderate yield (Scheme 4).

2

Compound 6 was identified by IR and NMR spectroscopy, and it was formerly reported as

6

produced by treatment of [RuCl(µ-Cl)(η -p-cymene)] with H in the presence of Et N [11a] or

2

3

1

Et SiH [29]. The salient spectroscopic feature of 6 is given by the H NMR resonance at −10.18

3

-1

ppm, accounting for the Ru-H moiety; a weak band at 1885 cm in the IR spectrum of 6 (solid

state) is probably ascribable to the stretching of the Ru-H-Ru group [11a].

8

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The formation of 6 points out that the formate anion does preferentially act as a hydride donor

towards the Ru centre, rather than as a O,O-ligand. This result is in alignment with the capability of

Ru(II) arene chloride species of behaving as catalytic precursors in transfer hydrogenation reactions

of organic substrates using formate as the hydrogen source [30].

Scheme 4. Nucleophilic chloride/hydride substitution by reaction of Ru(II) chloride p-cymene dimer with

Na[HCO₂].

In order to perform a preliminary evaluation of the suitability of 1-3 and 5 to biological studies, we

assessed by NMR spectroscopy the behavior of these complexes in DMSO-d /D O 9:1 solutions

6

2

containing 0.1 M sodium chloride at 37 °C, as a function of time. This chloride concentration is

similar to that present in blood, while the use of DMSO/water mixtures is required since the

compounds have limited solubility in water, and stock solutions in DMSO are usually employed for

in vitro assays in similar situations [31]. Other authors suggested that 2 and 3 resisted in DMSO

solution up to 12 h, and dissociation of the carboxylate followed [14a]. The results of our

experiments are summarized in Table 2.

Table 2. % NMR detected species in DMSO-d /D O/NaCl solutions of 1-3 and 5 at 37 °C.

6

2

1

2

3

5

(

R = vp)

(R = asp)

(R = df)

(R = sal)

a

Time / h

0

72

0

72

0

72

0

72

9

Starting complex

(DMSO)(p-cymene)], 7

0

17

-

0

42

-

44

-

[

RuCl

2

50

-

48

-

39

-

50

-

[

RuCl

2

(PPh

Na[RCO

p-cymene

3

)(p-cymene)], 8

28

-

19

-

b

2

]

50

0

60

23

-

40

0

22

7

50

0

51

7

-

24

48

-

b

Na[salCO

2

]

b

-

7

16

-

28

-

CH

3

CO

2

H

-

7

-

a

b

Shortly after dissolution (t < 10 min). Including the respective conjugate acid/base in rapid equilibrium.

9

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NMR data clearly indicate that 1-3 undergo very rapid and quantitative release of the carboxylato

moiety under the conditions mentioned above, and also minor dissociation of the p-cymene group

was detected (see Scheme 5 and Figures S20-S22 for details). The prevalent ruthenium species

6

formed in solution is the complex [RuCl (κS-DMSO)(η -p-cymene)], 7, which was identified by

2

comparison with literature data [31]. Complex 5 is more resistant in the DMSO/D O/NaCl solution,

2

6

and [RuCl (κP-PPh )(η -p-cymene)], 8 [16], was identified as its main degradation product;

2

3

however, only < 10% of the starting material was found unaltered in solution after 72 h. The higher

inertness displayed by 5, compared to 1-3, appears to be the consequence of the peculiar

coordination fashion of the salicylate, involving the hydroxyl group and thus allowing the formation

of a relatively more stable six-membered metallacycle.

Scheme 5. Release of the carboxylate ligands from 1-3 (a) and 5 (b) in the DMSO/D O/NaCl solution.

2

Analogous experiments on 2 and 3, but in the absence of NaCl, revealed the immediate conversion

of the starting compounds into 7 (intramolecular Cl-migration) and a complicated mixture of

products (Table 3). Significant release of the p-cymene ligand was observed afterwards.

Table 3. % NMR detected species in DMSO-d /D O solutions of 2-3 at 37 °C.

6

2

3

1

0

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(

R = asp)

(R = df)

a

Time / h

0

14

0

72

0

14

0

72

0

Starting complex

0

[

RuCl

2

(DMSO)(p-cymene)], 7

22

0

19

0

4

29

32

-

22

26

-

9

Na[RCO

2

]

0

26

-

Na[salCO

2

]

0

1

p-cymene

Other Ru species

Other {RCO } species

Shortly after dissolution (t < 10 min).

0

34

3

49

0

16

4

23

2

27

51

12

27

2

43

46

32

40

a

Conclusions

There is currently a huge interest in the development of ruthenium arene complexes suitable to

medicinal and catalytic applications. If on the one hand the introduction of O,O-coordinated

carboxylato ligands is a feature that has been explored in catalysis, only few reports on the

potentiality of Ru-arene carboxylates as drugs have been published in the literature. Herein, we

have described the convenient synthesis and the accurate characterization of a series of Ru-p-

cymene carboxylates, showing that the p-cymene/benzene replacement may be detrimental to the

stability. The isolated compounds, which are indefinitely stable in the solid state, release very

2

quickly the κ O-coordinated carboxylate anion under conditions roughly relevant to in vitro

biological assays. This finding is consistent with what was previously reported by Sadler and co-

workers on a prototypal acetate system, and is independent on the nature of the carboxylate, unless

the structural variability of the latter allows the involvement in the coordination of an additional

function. The essential lability of the carboxylato moiety is reflected in the sluggishness exhibited

6

by the [RuCl(µ-Cl)(η -arene)] system when allowed to react with some carboxylate salts. As a

2

general conclusion, Ru(II) arene complexes designed with a targeted ligand, which binds the

ruthenium center as a classical bidentate carboxylate, appear hardly adequate to medicinal

applications, losing their identity very quickly in relevant medium.

4. Experimental section

4.1. General experimental details.

1

ACCEPTED MANUSCRIPT

RuCl ·xH O (%Ru = 41.87) was purchased from Chimet S.p.A., while valproic acid (2-

3

2

propylpentanoic acid, vpCO H), aspirin (acetylsalicylic acid, aspCO H), sodium diclofenate

2

(

sodium 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate, Na[dfCO ]), sodium salicylate (sodium 2-

2

hydroxybenzoic acid, Na[salCO ]), gallic acid (3,4,5-trihydroxybenzoic acid, glCO H),

2

dichloroacetic acid (Cl CHCO H), propiolic acid (HC≡CCO H) and other reactants and solvents

2

were obtained from Alfa Aesar, Sigma Aldrich or TCI Europe, and were of the highest purity

available. 1.00 M NaOH solution in H O was prepared from Normex solution (Carlo Erba) and

2

6

standardized by potassium hydrogen phthalate titration before use. Compound [RuCl(µ-Cl)(η -

6

benzene)] was synthesized according to the literature [1]. The syntheses of [RuCl(µ-Cl)(η -p-

2

6

cymene)]₂,

Na[glCO₂]

and

[RuCl(µ-Cl)(η -p-cymene)] /Na[glCO ],

[RuCl(µ-Cl)(η -

2

benzene)] /Na[dfCO ] reactions were carried out under a N atmosphere using standard Schlenk

2

6

techniques and deaerated solvents. The synthesis of 2 and [RuCl(µ-Cl)(η -p-cymene)] /Ag[RCO ]

2

(

R = asp, df) reactions were carried out under a N atmosphere using standard Schlenk techniques

2

and solvents distilled over appropriate drying agents. All the other operations were carried out in air

with common laboratory glassware. Once isolated, Na[RCO ] (R = vp, gl, asp) and 2 were stored

2

under N , all the other compounds being air- and moisture-stable in the solid state. Light sensitive

2

compounds Ag[RCO ] (R = asp, df) and Na[HC≡CCO ] were stored in the dark. Silica gel (Merck,

2

70-230 mesh) was used for column chromatography. NMR spectra were recorded at 25 °C on a

Bruker Avance II DRX400 instrument equipped with a BBFO broadband probe. Chemical shifts

1

13

(

expressed in parts per million) are referenced to the residual solvent peaks ( H, C) [32] or to

3

1

31

external standards ( P to 85% H PO ). Spectra were assigned with the assistance of H{ P},

3

4

1

13

DEPT-135, H- H (COSY) and H- C (gs-HSQC and gs-HMBC) correlation experiments [33].

CDCl stabilized either with Ag foil (Carlo Erba) or Na CO was used for NMR analysis; indeed 1-

3

2

3

revealed to be highly sensitive to the impurities formed in aged CDCl solutions [34]. Infrared

3

spectra were recorded on a Perkin Elmer Spectrum One FT-IR spectrometer, equipped with a

UATR sampling accessory; IR spectra were processed with Spectragryph software [35]. IR

1

2

ACCEPTED MANUSCRIPT

assignments of carboxylate stretching bands were based on the literature [36]. Carbon, hydrogen

and nitrogen analyses were performed on a Vario MICRO cube instrument (Elementar). Mass

spectrometry measurements in positive ion scan mode were performed with an API 4000 instrument

(SCIEX) equipped with an Ionspray/APCI source.

4

.2. Synthesis and characterization of Ru complexes.

6

.2.1. [RuCl(µ-Cl)(η -p-cymene)] , (Chart 2).

2

The preparation of the title compound was adapted from the literature [1]. In a 500 mL round-

bottom Schlenk flask, α-phellandrene (22 mL, 136 mmol) was added to a dark brown solution of

RuCl ·xH O (%Ru = 41.87%, 4.000 g, 16.57 mmol) in deaerated EtOH (200 mL). The reaction

3

2

mixture was refluxed for 17 hours then cooled to room temperature. Volatiles were then removed

under vacuum (50 °C), affording an orange liquid and a red precipitate. Following addition of

petroleum ether (100 mL), the resulting suspension was stirred at room temperature for 1 hour then

filtered on a celite pad. The red-brown solid was thoroughly washed with petroleum ether then a red

solution was eluted with CH Cl . The title compound was obtained as a brick-red solid upon

2

─1

volatiles removal under vacuum (50 °C). Yield: 4.970 g, 98% (lit. 65%). IR (solid state): ῦ/cm =

3

1

9

2

055m, 3032m, 2961m, 2924m, 2869m, 1531w, 1496m, 1471m, 1447m, 1409w, 1389m, 1379m,

362m, 1326w, 1281w, 1201w, 1161w, 1114m, 1094m, 1056m, 1034m, 1005m, 960w, 945w,

1

3

28w, 905w, 877s, 804w, 734w, 689w, 670w. H NMR (CDCl ): δ/ppm = 5.46 (d, J = 5.3 Hz,

3

HH

3

H, C4-H), 5.32 (d, J = 5.3 Hz, 2H, C3-H), 2.90 (hept, J = 6.6 Hz, 1H, C6-H), 2.14 (s, 3H,

HH

3

13

1

C1-H), 1.26 (d, J = 6.7 Hz, 6H, C7-H). C{ H} NMR (CDCl ): δ/ppm = 101.3 (C5), 96.8 (C2),

HH

3

81.4 (C4), 80.6 (C3), 30.7 (C6), 22.2 (C7), 19.0 (C1).

1

3

ACCEPTED MANUSCRIPT

6

Chart 2. Structure of [RuCl(µ-Cl)(η -p-cymene)] (numbering refers to carbon atoms).

2

6

4

.2.2. [RuCl(κ O-vpCO )(η -p-cymene)], 1 (Chart 3).

2

6

A solution of Na[vpCO ] (161 mg, 0.969 mmol) in MeOH (5 mL) was treated with [RuCl(µ-Cl)(η -

2

p-cymene)] (260 mg, 0.425 mmol) and stirred at room temperature for 2 hours, affording a red-

2

1

orange solution. The progress of reaction was checked by H NMR (CDCl ) then volatiles were

3

removed under vacuum. The residue was suspended in Et O then filtered through celite. Volatiles

2

were removed under vacuum from the filtrate solution (50 °C), affording an orange solid. Yield:

3

38 mg, 96%. Compound 1 is soluble in MeOH, acetone, CH Cl , CHCl and Et O, poorly soluble

2 2 3 2

in DMSO and insoluble in H O. Solubility in hydrocarbons (heptane, hexane, pentane) is strongly

2

temperature-dependent. Orange needle-like X-ray quality crystals of 1 were obtained by allowing a

boiling hexane solution to cool down slowly to room temperature. Anal Calcd. For C H ClO Ru:

1

8

29

2

─1

C, 52.22; H, 7.06. Found: C, 52.07; H, 7.18. IR (solid state): ῦ/cm = 3072w, 2957s, 2930m,

2870m, 2854w-sh, 1530w, 1503s (ν_a_s_,_C_O₂), 1465s, 1453s-sh, 1432s (ν_s_,_C_O₂), 1388m-sh, 1377m,

1

361m-sh, 1324m, 1293m, 1275m, 1221w, 1203w, 1160w, 1140w, 1112m, 1089w, 1060w, 1033w,

1

003w, 979w, 960w, 932w, 904m, 891w, 871s, 811w, 777w, 753s, 691w, 664w, 658w. H NMR

3

(

CDCl ): δ/ppm = 5.57 (d, J = 6.0 Hz, 2H, C4-H), 5.37 (d, J = 6.1 Hz, 2H, C3-H), 2.95 (hept,

3 HH HH

3

J_H_H= 6.9 Hz, 1H, C6-H), 2.31 (s, 3H, C1-H), 1.98–1.89 (m, 1H, C9-H), 1.53–1.42 (m, 2H, C10-

3

H), 1.37 (d, J = 6.9 Hz, 6H, C7-H), 1.35–1.20 (m, 6H, C10-H’ + C11-H), 0.84 (t, J = 7.1 Hz,

HH

1

3

1

6

H, C12-H). C{ H} NMR (CDCl ): δ/ppm = 196.4 (C8), 100.6 (C5), 94.1 (C2), 78.2 (C3/C4) 78.1

3

(C3/C4), 47.9 (C9), 33.8 (C10), 31.6 (C6), 22.5 (C7), 20.6 (C11), 18.9 (C1), 14.1 (C12).

When the reaction was carried out with excess Na[vpCO ] (1.3 eq.), the formation of a second Ru

2

6

species was observed, presumably the bis-carboxylate [Ru(κO-vpCO )(κ O-vpCO )(η -p-cymene)].

2

1

3

H NMR (CDCl ): δ/ppm = 5.70 (d-br, 2H, C4-H), 5.51 (d-br, 2H, C3-H), 2.86 (hept, J = 7.0 Hz,

3

HH

3

1

H, C6-H), 2.23 (s, 3H, C1-H), 2.14 (m-br, 2H, C9-H), {1.54–1.43 (m)}, 1.33 (d, J = 6.9 Hz,

HH

C7-H), {1.31–1.21 (m)}.

1

4

ACCEPTED MANUSCRIPT

2

6

Chart 3. Structure of [RuCl(κ O-vpCO )(η -p-cymene)], 1 (numbering refers to carbon atoms).

2

6

4

.2.3. [RuCl(κ O-aspCO )(η -p-cymene)], 2 (Chart 4).

2

6

In a 25-mL Schlenk tube, a suspension of [RuCl(µ-Cl)(η -p-cymene)] (90 mg, 0.145 mmol) and

2

Na[aspCO ] (64 mg, 0.32 mmol) in MeOH (10 mL) was stirred at room temperature for 2.5 hours,

2

1

affording an orange-red solution. The progress of reaction was checked by H NMR (CDCl ) then

3

volatiles were removed under vacuum. The residue was suspended in CH Cl then filtered over

2

celite. The filtrate solution was concentrated to a few mL under reduced pressure, then transferred

in a test tube, layered with hexane (15 mL) and settled aside at −20 °C for 2 days. A brown oily

residue and an orange-red solution were thus obtained. The solution was separated; the residue was

suspended in CH Cl :Et O 1:1 v/v then filtered over celite. The two solutions were combined and

2

taken to dryness under vacuum. The resulting orange residue was triturated with Et O then hexane

2

(1:1 v/v ratio) was added under stirring. The suspension was filtered; the resulting orange solid was

washed with hexane, dried under vacuum (RT, over P O ) and stored under N . Yield: 104 mg,

2

5

2

6

7

9%. On the other hand, the reaction of [RuCl(µ-Cl)(η -p-cymene)] and Ag[aspCO ] in dry THF

2 2

under N at room temperature led to the formation of 2 and other byproducts. Compound 2 is

2

soluble in MeOH, acetone, CH Cl , CHCl and Et O, insoluble in H O and hexane. Anal Calcd. For

2

3

2

─1

C H ClO Ru: C, 50.72; H 4.70. Found: C, 50.58; H, 4.61. IR (solid state): ῦ/cm = 3067w,

19

21

4

3

037w, 2968w, 2931w, 2876w, 1768s (ν_C₁₅₌_O), 1605m, 1586m, 1507s (ν_a_s_,_C_O₂), 1488m, 1464m,

422s (ν_s_,_C_O₂), 1411s-sh, 1389m, 1371m, 1322w, 1298w, 1281w, 1253w, 1216m-sh, 1192s, 1163s,

1

8

149m-sh, 1144m-sh, 1121w, 1097m, 1091m-sh, 1059w, 1033m, 1007m, 962w, 919m, 897w,

1

84m, 866s, 821m, 806m, 765s, 759m-sh, 706m, 680m, 651w. H NMR (CDCl ): δ/ppm = 7.90 (d,

3

1

5

ACCEPTED MANUSCRIPT

3

J_H_H= 7.6 Hz, 1H, C10-H), 7.45 (t, J = 7.2 Hz, 1H, C12-H), 7.20 (t, J = 7.6 Hz, 1H, C11-H),

HH

3

6

.98 (d, J = 8.1 Hz, 1H, C13-H), 5.68 (d, J = 5.7 Hz, 2H, C4-H), 5.46 (d, J = 5.8 Hz, 2H,

HH HH HH

3

C3-H), 2.95 (hept, J = 6.9 Hz, 1H, C6-H), 2.35, 2.34 (s, 6H, C1-H + C16-H); 1.40 (d, J = 6.9

HH

1

3

1

Hz, 6H, C7-H). C{ H} NMR (CDCl ): δ/ppm = 182.2 (C8), 169.9 (C15), 150.2 (C14), 133.8

3

(

C12), 131.5 (C10), 125.8 (C11), 124.7 (C9), 123.3 (C13), 99.9 (C5), 94.3 (C2), 79.3 (C4), 78.3

C3), 31.7 (C6), 22.6 (C7), 21.6 (C16), 19.0 (C1).

(

2

6

Chart 4. Structure of [RuCl(κ O-aspCO )(η -p-cymene)], 2 (numbering refers to carbon atoms).

2

6

4

.2.4. [RuCl(κ O-dfCO )(η -p-cymene)], 3 (Chart 5).

2

6

A solution of [RuCl(µ-Cl)(η -p-cymene)] (64 mg, 0.105 mmol) in MeCN (10 mL) was treated with

2

Na[dfCO ] (66 mg, 0.21 mmol) then stirred at room temperature for 7.5 hours, affording a yellow-

2

1

orange solution and colorless precipitate (NaCl). The progress of reaction was checked by H NMR

6

(

CDCl ; [RuCl(µ-Cl)(η -p-cymene)] conversion = 90%) then volatiles were removed under

3

2

vacuum. The residue was suspended in CH Cl and filtered over celite. Volatiles were removed

2

under vacuum from the filtrate solution and the orange residue was treated with Et O (2 mL).

2

Addition of hexane (2 mL) and subsequent trituration gave a yellow powder. Therefore the

suspension was filtered, the solid was washed with Et O (1-2 mL), hexane and dried under vacuum

2

(40 °C). Yield: 101 mg, 85%. Analogous reaction in MeOH as solvent gave 84% yield. On the other

6

hand, the reaction of [RuCl(µ-Cl)(η -p-cymene)] and Ag[dfCO ] in dry THF under N at room

2

temperature led to the formation of 3 and other byproducts. Compound 3 is soluble in EtOH,

acetone, CH Cl , CHCl , less soluble in MeOH, poorly soluble in Et O, insoluble in hexane and

2

3

2

H O. X-ray quality crystals of 3 were obtained from a CH Cl solution layered with pentane or

2

1

6

ACCEPTED MANUSCRIPT

hexane and settled aside at -20 °C. Structural parameters match those previously reported [14a].

Anal Calcd. For C H Cl NO Ru: C, 50.93; H, 4.27; N, 2.47. Found: C, 51.10; H, 4.36; N, 2.58. IR

2

4

24

3

2

─1

(

solid state): ῦ/cm = 3300m (ν ), 3044w, 2963w, 2929w, 2875w, 1603w, 1588m, 1576w,

NH

1564m, 1515s-sh (ν_a_s_,_C_O₂), 1505s, 1497s, 1468s, 1451s, 1437s (ν_s_,_C_O₂), 1409s, 1389m-sh, 1377m-sh,

1362m-sh, 1318m, 1302m, 1284m, 1278m, 1250m, 1188m, 1174m, 1158w, 1145w, 1104w, 1089m,

1057m, 1003w, 958w, 944m, 868m, 845w-sh, 835w, 805w, 773s, 763s, 750s, 720s, 710s, 662m.

The IR spectrum of crystalline 3 match that of the bulk yellow powder obtained by the procedure

1

3

above described. H NMR (CDCl ): δ/ppm = 7.32 (d, J = 8.0 Hz, 2H, C18-H), 7.16 (d, J =

HH

3

HH

3

7

.0 Hz, 1H, C11-H), 7.09 (t, J = 7.8 Hz, 1H, C13-H), 6.99–6.94 (m, 2H, C19-H + NH), 6.91 (t,

HH

3

J_H_H= 7.5 Hz, 1H, C12-H), 6.50 (d, J = 7.7 Hz, 1H, C14-H), 5.60 (d, J = 5.8 Hz, 2H, C4-H),

HH

3

5

.38 (d, J = 5.8 Hz, 2H, C3-H), 3.53 (s, 2H, C9-H), 2.86 (hept, J_H_H= 7.0 Hz, 1H, C6-H), 2.27

HH

3

1

(

s, 3H, C1-H), 1.29 (d, J_H_H= 6.9 Hz, 6H, C7-H). No change in the H spectrum was observed after

1

3

1

7

days at room temperature. C{ H} NMR (CDCl ): δ/ppm = 190.2 (C8), 143.1 (C15), 138.3

3

(

C16), 131.0 (C11), 130.0 (C17), 128.9 (C18), 127.9 (C13), 124.3 (C10), 124.0 (C19), 121.9 (C12),

18.2 (C14), 99.9 (C5), 94.0 (C2), 79.0 (C4), 78.0 (C3), 41.9 (C9), 31.6 (C6), 22.4 (C7), 18.9 (C1).

When the reaction was carried out with excess Na[dfCO ] (1.3 eq.), the formation of a second Ru

1

2

6

species was observed, presumably the bis-carboxylate [Ru(κO-dfCO )(κ O-dfCO )(η -p-cymene)]

2

1

3

[

4]. H NMR (CDCl ): δ/ppm = 7.24–7.15, 6.99–6.91, 6.89–6.82, 6.78–6.70 (m, Ar); 6.40 (d, J

=

3

HH

7

3

.7 Hz, 2H, C14-H), 5.61 (d-br, 2H, C4-H), 5.54 (d-br, 2H, C3-H); 3.77 (s) + 3.74 (s-br, 3H, C9-H);

.08–3.00 (m, C6-H), 2.25 (s, 3H, C1-H), 1.29 (d, C7-H).

2

6

Chart 5. Structure of [RuCl(κ O-dfCO )(η -p-cymene)], 3 (numbering refers to carbon atoms).

2

1

7

ACCEPTED MANUSCRIPT

2

6

4

.2.5. [RuCl(κ O-dfCO )(η -benzene)], 4 (Chart 6).

2

6

Via silver carboxylate. A suspension of [RuCl(µ-Cl)(η -benzene)] (33 mg, 0.066 mmol) and

2

Ag[dfCO ] (53 mg, 0.132 mmol) in MeOH (6 mL) was stirred at room temperature overnight. The

2

resulting mixture (yellow solution + colorless solid) was filtered over celite. Volatiles were

removed under vacuum from the filtrate solution, affording a yellow-orange solid (yield: 30 mg).

1

NMR analysis ( H, CDCl ) revealed the presence of the desired compound (δ/ppm = 5.77, 73%

3

mol. ratio) and other byproducts (δ/ppm = 5.80, 14%; 5.69, 6%; 5.60, 7%) (Ru-benzene signals).

6

Via sodium carboxylate. In a 25-mL Schlenk tube under N , a suspension of [RuCl(µ-Cl)(η -

2

benzene)] (39 mg, 0.078 mmol) and Na[dfCO ] (50 mg, 0.157 mmol) in deaerated MeOH (10 mL)

2

was stirred at reflux temperature for 5 hours, affording a yellow-orange solution. Volatiles were

then removed under vacuum and the residue was suspended in acetone. The suspension was filtered

over celite and the filtrate was taken to dryness under vacuum (40 °C), affording a yellow-orange

1

solid (yield: 24 mg). NMR analysis ( H, acetone-d ) revealed the presence of the desired compound

6

(δ/ppm = 5.88, 90% mol. ratio) and other byproducts (δ/ppm = 5.74, 8%; 5.62, 1%; 5.60, 1%) (Ru-

benzene signals).

All attempts to purify the title compound by re-precipitation/re-crystallization were frustrated by its

concomitant degradation. Compound 4 is soluble in MeOH, CH Cl , CHCl , less soluble in acetone

2

3

─1

and insoluble in Et O, hexane. IR (solid state): ῦ/cm = 3301w-br (ν ), 3066w, 2975w, 2921w,

2

NH

1

8

708w, 1619m, 1606m, 1577m, 1555m, 1510m-sh (ν_a_s_,_C_O₂), 1502s, 1498s, 1449s, 1434s-sh (ν_s_,_C_O₂),

387m, 1351m, 1303m, 1277m, 1251m, 1195m, 1148m, 1092w, 1046w, 1008w, 981w, 951w,

1

3

90w, 839m, 770m-sh, 745s, 718m. H NMR (CDCl ): δ/ppm = 7.33 (d, J = 8.1 Hz, 2H, C12-

3

HH

3

H), 7.14 (d, J = 7.4 Hz, 1H, C5-H), 7.10 (t, J = 8.0 Hz, 1H, C13-H, C7-H), 6.97 (t, J = 8.2

HH

3

Hz, 1H, C6-H), 6.92 (t, J = 7.5 Hz, 1H, C13-H), 6.75 (s, 1H, OH), 6.50 (d, J = 8.2 Hz, 1H,

HH

1

3

C8-H), 5.77 (s, 6H, C1-H), 3.56 (s, 2H, C2-H). H NMR (Acetone-d ): δ/ppm = 7.44 (d, J = 8.0

6

HH

3

Hz, 1H, C12-H), 7.17–7.04, 7.02–6.96 (m, 3H, C5-H + C7-H + C13-H), 6.89 (t, J = 7.4 Hz, 1H,

HH

3

C6-H), 6.41 (d, J = 8.3 Hz, 1H, C8-H), 5.98 (s, 1H, OH), 5.88 (s, 6H, C1-H), 3.46 (s, 2H, C3-H).

HH

1

8

ACCEPTED MANUSCRIPT

1

3

1

C{ H} NMR (Acetone-d ): δ/ppm = 190.3 (br, C2), 144.1 (C9), 139.0 (C10), 131.7 (C5), 130.5

6

(C11), 129.7 (C12), 128.3 (C7), 125.4 (C13), 122.4 (C6), 118.6 (C8), 80.5 (C1), 66.0 (C2). Release

of benzene (δ/ppm = 7.35, 25% mol. ratio) was observed after 4 days at room temperature in the

acetone-d solution of 4.

6

2

6

Chart 6. Structure of [RuCl(κ O-dfCO )(η -benzene)], 4 (numbering refers to carbon atoms).

2

6

4

.2.6. [Ru(κ O,O’-salCO )(PPh )(η -p-cymene)], 5 (Chart 7).

2 3

6

1

.0 M NaOH (0.35 mL, 0. 35 mmol) was added to a brick-red suspension of [RuCl(µ-Cl)(η -p-

cymene)] (105 mg, 0.171 mmol) and Na[salCO ] (55 mg, 0.344 mmol) in MeOH (10 mL) and the

2

mixture was stirred at reflux temperature for 3 hours. The resulting orange solution was allowed to

cool to room temperature then volatiles were removed under vacuum. The residue was suspended in

CHCl and insoluble NaCl was filtered over celite. The filtrate solution was treated with PPh (91

3

mg, 0.347 mmol) and stirred at reflux temperature for 3.5 hours. The progress of reaction was

3

1

checked by P NMR then the orange solution was allowed to cool to room temperature and filtered

over celite. The filtrate was taken to dryness under vacuum and the residue was suspended in Et O

2

(

2-3 mL). The suspension was filtered and the resulting orange-brown solid was washed with Et O

2

(2 mL) then dried under vacuum (40 °C). Yield: 152 mg, 70%. Compound 5 is soluble in DMSO,

CH Cl , CHCl , less soluble in MeOH, poorly soluble in Et O and insoluble in hexane, H O. Anal

2

3

2

─1

Calcd. For C H Cl Ru : C, 66.34; H, 5.25. Found: C, 66.18; H, 5.35. IR (solid state): ῦ/cm

=

2

0

29

3

2

3

1

904w, 3853w, 3837w, 3801w, 3748w, 3675w, 3649w, 3054w, 2967w, 2924w, 2868w, 1600s,

581s (ν_a_s_,_C_O₂), 1571s-sh, 1505w, 1482m, 1460s, 1445s, 1434s, 1379m, 1331s (ν_s_,_C_O₂), 1248m,

1186w, 1129m, 1117m-sh, 1094s, 1030m, 999w, 874m, 855m, 823w, 799w, 758s, 750s, 696s,

1

9

ACCEPTED MANUSCRIPT

1

3

6

67w-sh, 663w-sh. H NMR (CDCl ): δ/ppm = 7.86 (d, J = 7.6 Hz, 1H, C10-H), 7.67 (pseudo-t,

3

HH

3

J_H_H= J = 8.8 Hz, 6H, C16-H), 7.41–7.31 (m, 9H, C17-H + C18-H), 6.98 (t, J_H_H= 7.3 Hz, 1H,

HP

3

C12-H), 6.68 (d, J = 8.1 Hz, 1H, C13-H), 6.45 (t, J = 7.1 Hz, 1H, C11-H), 5.26 (d, J = 6.0

HH

3

Hz, 1H, C4-H), 5.17 (d, J = 5.8 Hz, 1H, C4’-H), 5.05 (d, J = 5.7 Hz, 1H, C3-H), 4.70 (d, J

HH

3

=

5.7 Hz, 1H, C3’-H), 2.50 (hept, J_H_H= 6.6 Hz, 1H, C6-H), 1.87 (s, 3H, C1-H), 1.18 (d, J = 7.2

HH

3

1

Hz, 3H, C7-H), 1.14 (d, J = 6.9 Hz, 3H, C7’-H). No change in the H spectrum was observed

HH

after 24 hours at room temperature whereas degradations products were observed after 6 days.

1

3

1

2

C{ H} NMR (CDCl ): δ/ppm = 171.7 (C8), 170.9 (C14), 134.1 (d, J = 10 Hz, C16), 133.3

3

CP

1

4

3

(

C10), 132.2 (d, J_C_P= 44 Hz, C15), 131.0 (C12), 130.5 (d, J = 2 Hz, C18), 128.4 (d, J = 10

CP CP

2

Hz, C17), 122.5 (C9), 121.9 (C13), 114.4 (C11), 106.5 (C5), 98.0 (C2), 88.5 (d, J_C_P= 5 Hz, C4),

2

8

7.3 (d, J = 5 Hz, C3/C3’), 87.2 (d, J = 3 Hz, C3/C3’), 85.8 (d, J = 3 Hz, C4’), 30.7 (C6),

CP

3

1

31

1

2

3.0 (C7’), 21.9 (C7), 17.4 (C1). P{ H} NMR (CDCl ): δ/ppm = 26.7. P{ H} NMR (CH OD):

3

δ/ppm = 27.0.

2

6

Chart 7. Structure of [Ru(κ O,O’-salCO )(PPh )(η -p-cymene)], 5 (numbering refers to carbon atoms).

2

3

6

4

.2.7. [Ru Cl (µ-Cl)(µ-H)(η -p-cymene) ], 6 (Chart 8).

2 2 2

6

A suspension of [RuCl(µ-Cl)(η -p-cymene)] (89 mg, 0.145 mmol) and Na[HCO ] (20 mg, 0.29

2

mmol) in MeOH was stirred at room temperature for 2 hours, affording an orange-red solution. The

1

progress of reaction was checked by H NMR (CDCl ) and TLC then volatiles were removed under

3

vacuum. The mixture of Ru complexes was dissolved in CH Cl and loaded on top of a silica

2

column (h 8 cm, d 1 cm). A red-violet band was collected using CH Cl /THF 5:1 v/v as eluent, then

2

taken to dryness under vacuum. The resulting red-violet solid was washed with pentane and dried

2

0

ACCEPTED MANUSCRIPT

under vacuum (room T). Yield: 30 mg, 36%. Reaction with a stoichiometric amount of Na[HCO₂]

(1 eq.) in the same conditions led to incomplete conversion of the precursor (60%) and analogous

selectivity; reaction with increased Na[HCO ] amount (4 eq.) led to lower selectivity. Compound 6

2

is highly soluble in CH Cl , soluble in MeOH, acetone, poorly soluble in Et O, insoluble in hexane.

2

─1

Anal Calcd. For C H Cl Ru : C, 41.56; H, 5.06. Found: C, 41.62; H, 5.12. IR (solid state): ῦ/cm

2

0

29

3

2

=

3074w-sh, 3061w, 3044w-sh, 2966m, 2929w, 2871w, 1880-1886w (ν_R_u_-_H_-_R_u), 1530w, 1498w,

1

471s, 1447m-sh, 1386m-sh, 1373s, 1320w, 1277w, 1260w, 1222w, 1197w, 1156w-sh, 1146w,

1

113w, 1089w, 1058m, 1029m, 1001w, 964w, 931w, 889w, 855s, 804s, 693w, 660s. H NMR

3

(

CDCl ): δ/ppm = 5.65 (d, J = 5.7 Hz, 2H, C4-H), 5.55 (d, J = 5.3 Hz, 2H, C3’-H), 5.31 (d,

3 HH HH

3

J_H_H= 5.8 Hz, 2H, C4’-H), 4.85 (d, J = 5.7 Hz, 2H, C3-H), 2.99 (hept, J = 6.9 Hz, 2H, C6-

HH

3

H), 2.29 (s, 6H, C1-H), 1.45 (d, J = 6.9 Hz, 6H, C7-H), 1.41 (d, J = 7.0 Hz, 6H, C7’-H), -

HH

13

1

0.18 (s, 1H, Ru-H). C{ H} NMR (CDCl ): δ/ppm = 103.5 (C5), 98.2 (C2), 85.2 (C4’), 83.5

3

(C3’), 81.9 (C4), 81.2 (C3), 31.8 (C6), 23.7 (C7’), 22.8 (C7), 19.9 (C1).

6

Chart 8. Structure of [Ru Cl (µ-Cl)(µ-H)(η -p-cymene) ], 6 (numbering refers to carbon atoms).

2

6

4

.2.8. Other [RuCl(µ-Cl)(η -p-cymene)] /Na[RCO ] reactions.

2 2

6

Na[glCO ]. In a 25-mL Schlenk tube, [RuCl(µ-Cl)(η -p-cymene)] (44 mg, 0.072 mmol),

2

Na[glCO ] (26 mg, 0.14 mmol) and deaerated MeOH (5 mL) were introduced. The reaction mixture

2

was stirred at room temperature for 15 hours, affording an orange solution and a dark green

precipitate, which was separated by filtration. The orange solution was taken to dryness under

6

1

vacuum, and the resulting orange residue was identified as [RuCl(µ-Cl)(η -p-cymene)] ( H NMR,

2

1

CDCl ). The poorly soluble dark green solid was analyzed by H NMR (CD OD), revealing the

3

2

1

ACCEPTED MANUSCRIPT

presence of a mixture of compounds. No reaction occurred using deaerated MeCN as solvent under

6

otherwise analogous conditions: an orange solution containing [RuCl(µ-Cl)(η -p-cymene)] and

2

insoluble Na[glCO ] could be recovered at the end of the experiment.

2

6

Na[Cl CHCO ]. A suspension of [RuCl(µ-Cl)(η -p-cymene)] (48 mg, 0.078 mmol) and

2

Na[Cl CHCO ] (24 mg, 0.16 mmol) in THF (5 mL) was stirred at reflux temperature for 2.5 hours,

2

1

affording an orange-red solution and a colorless precipitate. H NMR analysis of the solution

6

(

CDCl ) revealed the formation of a mixture of products and unreacted precursor [RuCl(µ-Cl)(η -p-

3

cymene)] (ca. 30%). A similar outcome was observed using MeCN or MeOH as solvents at room

2

temperature.

6

Na[HC≡CCO ]. A suspension of [RuCl(µ-Cl)(η -p-cymene)] (49 mg, 0.080 mmol) and

2

Na[HC≡CCO ] (15 mg, 0.16 mmol) in MeOH (4 mL) was stirred at room temperature in the dark

2

1

for 2 days, affording an orange solution. H NMR analysis of the solution (CDCl ) revealed the

3

6

formation of several minor products and unreacted precursor [RuCl(µ-Cl)(η -p-cymene)] (ca.

2

50%). An identical result was obtained when performing the reaction in MeCN.

6

Na[salCO ]. A suspension of [RuCl(µ-Cl)(η -p-cymene)] (83 mg, 0.14 mmol) and Na[salyCO ]

2

(47 mg, 0.29 mmol) in MeOH (5 mL) was stirred at reflux temperature for 14 hours, affording an

1

orange-red solution. H NMR analysis (CDCl and CD OD) revealed the presence of unreacted

3

6

ruthenium precursor [RuCl(µ-Cl)(η -p-cymene)] (≈ 30%) and the formation of two Ru-salicylate

2

A

B

complexes (Ru :Ru ratio ca. 1:2). Therefore AgNO (27 mg, 0.16 mmol) was added and the

3

mixture was stirred at room temperature in the dark. After 2 hours, volatiles were removed under

vacuum and the residue was suspended in CH Cl . The suspension was filtered over celite and the

2

1

filtrate solution was taken to dryness under vacuum, affording a yellow solid. H NMR analysis:

A

B

1

two Ru-salCO complexes (Ru :Ru ratio ca. 1:1 in CD OD) and minor byproducts. H NMR

2

3

(

CDCl ): δ/ppm = 11.30, 10.08 (s, 1H, OH); 7.79–7.69 (m, 1H, C H ), 7.40–7.28 (m, 1H, C H ),

3 6 4 6 4

6

.97–6.71 (m, 2H, C H ), 5.89, 5.75, 5.68, 5.53 (s-br, 4H, Ru-CH); 3.04–2.86 (m, J = 6.9 Hz, 1H,

6 4

1

CHMe ), 2.34 (s, 3H, CCH ); 1.42 (d), 1.39 (s-br) (6H, CHMe ). H NMR (CD OD): δ/ppm = 7.85

2

3

2

3

2

ACCEPTED MANUSCRIPT

3

(

d, J = 7.6 Hz, 1H, C H ), 7.43 (t, J = 7.5 Hz, 1H, C H ), 6.93–6.84 (m, 2H, C H ); 5.69

HH

6

4

HH

6

4

6

4

A

B

A

B

(

Ru ), 5.55 (Ru ), 5.47 (Ru ), 5.28 (Ru ) (d, J ≈ 6.0 Hz, 4H, Ru-CH); 2.77 (hept, J = 6.9 Hz, 1H,

CHMe ); 2.19, 2.18 (s, 3H, CCH ); 1.35–1.30 (m, 6H, CHMe ). Minor signals: δ/ppm = 5.91, 5.87,

2

3

2

5.64, 5.41, 5.21 (d). ESI-MS(+), see Figure S23: Ru-containing molecular ion clusters at m/z 306-

+

−1

3

16 (pattern fits for [RuCl(H O)(p-cymene)+Na] , C H ClNaORu, M = 311.98 g mol ), 347-357

2

10 16

+

−1

and 384-393 (pattern fits for [Ru(salCO )(H O)(p-cymene)] , C H O Ru, M = 390.04 g mol ).

2

17 20

4

Na[salCO ] / NaOH. The above procedure was repeated with the initial addition of NaOH (1.0 M

2

1

solution in H O, 1.0 eq) to the reaction mixture. After the first step, H NMR analysis (CD OD) of

2

3

A’

B

the resulting orange solution revealed the formation of two Ru-salCO complexes (Ru :Ru ratio

2

A’

B

ca. 3:2). After treatment with AgNO , the Ru :Ru ratio changed to ca. 4:1 and formation of other

3

1

3

minor products was observed ( H NMR, CD OD). H NMR (CD OD): δ/ppm = 7.81 (d, J = 7.5

3

HH

3

B

A’

Hz, 1H, C H ), 7.25 (t, J = 7.6 Hz, 1H, C H ), 6.78–6.72 (m, 2H, C H ); 5.53 (Ru ), 5.39 (Ru ),

6

4

HH

6

4

6

4

B

A’

5

1

.26 (Ru ), 5.19 (Ru ) (d, J ≈ 6 Hz, 4H, Ru-CH); 2.76 (m, 1H, CHMe ); 2.17, 2.16 (s, 3H, CCH ),

2 3

.32–1.28 (m, 6H, CHMe ). Minor signals: δ/ppm = 5.61, 5.36, 5.06 (d). ESI-MS(+), see Figure

2

S24: Ru-containing molecular ion clusters at m/z 306-316 (pattern fits for [RuCl(H O)(p-

2

+

cymene)+Na] , C H ClNaORu, M = 311.98 g/mol), 347-357 and 384-393 (pattern fits for

1

0

16

+

[

Ru(salCO )(H O)(p-cymene)] , C H O Ru, M = 390.04 g/mol).

2 2 17 20 4

4.3. X-ray crystallography.

Crystal data and collection details for 1 are reported in Table 4. The diffraction experiment was

carried out on a Bruker APEX II diffractometer, equipped with a CMOS detector using Mo-Kα

radiation. Data were corrected for Lorentz polarization and absorption effects (empirical absorption

correction SADABS) [37]. The structure was solved by direct methods and refined by full-matrix

2

least-squares based on all data using F [38]. Hydrogen atoms were fixed at calculated positions and

refined by a riding model. All non-hydrogen atoms were refined with anisotropic displacement

2

3

ACCEPTED MANUSCRIPT

parameters. The asymmetric unit of the unit cell contains two halves of two molecules, both located

6

2

on a mirror plane. Some groups of the η -p-cymene and κ O-valproate ligands are disordered over

two equally populated positions related by a mirror plane. Details of the restraints applied during

refinement have been included in the CIF files.

Table 4. Crystal data and measurement details for 1.

Formula

18 2

C H29ClO Ru

FW

413.93

100(2)

T, K

λ

, Å

0.71073

Monoclinic

P2 /m

Crystal system

Space group

a, Å

1

10.228(4)

9.596(3)

b, Å

c, Å

19.562(7)

103.455(8)

β

, °

3

Cell Volume, Å

Z

1867.3(11)

4

-

3

D

c

, g·cm

1.472

0.987

−1

µ, mm

F(000)

856

Crystal size, mm

0.15×0.13×0.11

2.047–25.041

θ limits, °

Reflections collected

Independent reflections

Data / restraints /parameters

17948

3521 [Rint = 0.1017]

3521 / 306 / 293

1.231

2

Goodness of fit on F

R

1

(I > 2σ(I))

wR (all data)

Largest diff. peak and hole, e Å

0.1010

2

0.1996

-

3

2.357 / –2.696

4.4. Stability studies in DMSO/water/NaCl solution

2

4

ACCEPTED MANUSCRIPT

General procedure. DMSO-d /D O 9:1 v/v or DMSO-d /D O 9:1 v/v + NaCl (0.11 M) solutions

6

2

6

2

-3

were used for the stability experiments. Dimethyl sulfone (Me SO , 5.6·10 M) was added to each

2

1

solution as a reference for H NMR spectra (δ = 2.97 ppm in DMSO-d /D O 9:1) [39]. Complexes

6

2

-2

1

-3 and 5 were dissolved in the selected DMSO-d /D O mixture (0.6 mL; [Ru] = 1.5·10 M) and

6 2

1

31

1

the resulting orange solutions were analyzed by H/ P{ H} NMR shortly thereafter (t < 10 min).

The solutions were then maintained at 37 °C for 72 hours and periodically analysed by NMR upon

brief cooling to room temperature. Results are compiled in Tables 2 and 3; percent values of

1

compounds in solution are based on H NMR spectroscopy and refer to identified compounds only.

Reference data. NMR spectra of the following compounds were recorded in the DMSO-d /D O 9:1

6

2

1

v/v solution and used for comparison for NMR assignments. p-cymene. H NMR: δ/ppm = 7.12–

.03 (m, 4H), 2.80 (hept, J = 6.9 Hz, 1H), 2.23 (s, 3H), 1.15 (d, J = 6.9 Hz, 6H). [RuCl (κS-

7

2

6

1

DMSO)(η -p-cymene)], 7 [16, 31, 40]. H NMR: δ/ppm = 5.79 (d, J = 6.3 Hz, 2H), 5.74 (d, J = 6.3

6

Hz, 2H), 2.79 (hept, J = 6.9 Hz, 1H), 2.07 (s, 3H), 1.17 (d, J = 6.9 Hz, 6H). [RuCl (PPh )(η -p-

2

3

1

cymene)], 8 [16]. H NMR: δ/ppm = 7.77–7.66 (m, 6H), 7.46–7.35 (m, 9H), 5.27 (d, J = 5.9 Hz,

31

1

2

H), 5.21 (d, J = 5.6 Hz, 2H), 1.74 (s, 3H), 0.93 (d, J = 6.8 Hz, 6H). P{ H} NMR: δ/ppm = 24.2.

1

Na[vpCO ]. H NMR: δ/ppm = 1.97 (s, 1H), 1.40 (s-br, 2H), 1.18 (s-br, 6H), 0.80 (s-br, 6H).

2

1

Na[aspCO ]. H NMR: δ/ppm = 7.76 (d-br, 1H), 7.30 (t, J = 7.0 Hz, 1H), 7.16 (t-br, 1H), 6.93 (d, J

2

1

=

7.5 Hz, 1H), 2.17 (s, 3H). Na[dfCO ]. H NMR: δ/ppm = 7.44 (d, J = 8.0 Hz, 2H), 7.12–7.06 (m,

2

1

2

H), 6.94 (t, J = 7.7 Hz, 1H), 6.76 (t, J = 6.8 Hz, 1H), 6.23 (d, J = 7.8 Hz, 1H). Na[salCO ]. H

2

NMR: δ/ppm = 7.70 (d, J = 7.3 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.71–6.62 (m, 2H), 2.07 (s, 3H).

1

CH CO H. H NMR: δ/ppm = 1.90 (s, 3H).

3

2

Stability studies: compounds 1-3 in DMSO-d :D O 9:1 (Table 2, Scheme 5a). Quantitative

6

2

–

1

formation of 7 and [RCO ]. No signal due to the original species was present in the H spectrum.

2

1

Stability studies: compound 5 in DMSO-d :D O 9:1 (Table 2, Scheme 5b). 5. H NMR (DMSO-

6

2

d :D O 9:1): δ/ppm = 7.59–7.50 (m), 7.49–7.36 (m), 6.91 (t, J = 6.9 Hz, 1H), 6.56 (d, J = 8.0 Hz,

6

2

1H), 6.32 (t, J = 7.1 Hz, 1H), 5.32 (d, J = 5.9 Hz, 2H), 5.15 (d, J = 6.2 Hz, 1H), 4.94 (d, J = 5.8 Hz,

2

5

ACCEPTED MANUSCRIPT

3

1

H), 2.25 (hept, J = 6.9 Hz, 1H), 1.75 (s, 3H), 1.04–1.01 (m, 6H). P{ H} NMR (DMSO-d :D O

6 2

1

9

:1): δ/ppm = 27.7. Other species (72 h). H NMR (DMSO-d :D O 9:1): δ/ppm = 5.67 (d, J = 6.6

6

2

3

1

Hz), 5.45 (d, J = 5.9 Hz), 1.37 (s), 1.25–1.18 (m). P{ H} NMR (DMSO-d :D O 9:1): δ/ppm =

6

2

27.1, 24.4, -7.03 (PPh₃).

Stability studies: compounds 2 and 3 in DMSO-d :D O 9:1 + NaCl (0.11 M) (Table 3). Formation

6

2

of a complicated mixture of products, including 7. Calculations for mol. % values were based on

aromatic (“Other {RCO } species” in Tab. 3) and coordinated arene (“Other Ru species” in Tab. 3)

2

1

protons separately. Compound 2. Other species (0 h). H NMR: δ/ppm = 7.82 (m-br), 7.61 (d, J =

7.5 Hz), 7.58 (d, J = 7.2 Hz), 7.45 (t, J = 7.6 Hz), 7.39 (t, J = 7.6 Hz), 7.29–7.16 (m), 7.10–7.00 (m,

J = 10.5 Hz), 6.73 (d, J = 8.1 Hz), 6.44 (t, J = 7.4 Hz), 6.17 (m-br), 5.98 (m-br), 5.84 (s), 5.59 (d, J

1

=

6.5 Hz), 2.24 (s), 2.19 (d, J = 6.4 Hz), 2.10–2.04 (m). Compound 3. Other species (0 h). H

NMR: δ/ppm = 7.50 (d, J = 8.2 Hz), 7.18–7.10 (m), 7.03–6.98 (m), 6.86–6.78 (m), 6.02–5.90 (m),

.21 (d, J = 5.7 Hz), 5.10 (d, J = 6.4 Hz), 3.58 (s), 3.46 (s-br), 1.99 (s), 1.03 (d, J = 6.4 Hz).

5

Supporting Information. IR and NMR spectra for complexes 1-6. NMR spectra of 1-3 in

DMSO:D O mixtures. ESI-MS spectra. CCDC reference number 1829374 (1) contains the

2

supplementary crystallographic data for the X-ray study reported in this paper. These data can be

obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge

Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (internat.) +44-

1223/336-033; e-mail: deposit@ccdc.cam.ac.uk].

Acknowledgements.

The University of Pisa is gratefully acknowledged for financial support.

2

6

ACCEPTED MANUSCRIPT

References

[

1]

2]

M. A. Bennett, A. K. Smith, J. Chem. Soc., Dalton Trans. (1974) 233-241.

a) A. Kumar Singh, D. Shankar Pandey, Q. Xu, P. Braunstein, Coord. Chem. Rev. 270–271 (2014)

3

1–56. b) A. A. Nazarov, C. G. Hartinger, P. J. Dyson, J. Organomet. Chem. 751 (2014) 251-260. c)

S. M. Meier-Menches, C. Gerner, W. Berger, C. G. Hartinger, B. K. Keppler, Chem. Soc. Rev. 47

2018) 909-928. d) P. Zhang, P. J. Sadler, J. Organomet. Chem. 839 (2017) 5-14. e) A. M. Basri, R.

(

M. Lord, S. J. Allison, A. Rodriguez-Barzano, S. J. Lucas, F. D. Janeway, H. J. Shepherd, C. M. Pask,

R. M. Phillips, P. C. McGowan, Chem. Eur. J. 23 (2017) 6341-6356.

[

3]

a) B. Vilhanová, J. Vaclavík, P. Šot, J. Pecháček, J. Zápal, R. Pažout, J. Maixner, M. Kuzma, P.

Kačer, Chem. Commun. 52 (2016) 362-365. b) L. Delaude, A. Demonceau, Dalton Transactions

4

1 (2012) 9257-9268. c) J. M. Stubbs, R. J. Hazlehurst, P. D. Boyle, J. M. Blacquiere,

Organometallics 36 (2017) 1692−1698. d) M. Simonetti, G. J. P. Perry, X. C. Cambeiro, F. Juliá –

Hernàndez, J. N. Arokianathar, I. Larrosa, J. Am. Chem. Soc. 138 (2016) 3596−3606. e) D. Zell, S.

Warratz, D. Gelman, S. J. Garden, L. Ackermann, Chem. Eur. J. 22 (2016) 1248-1252.

[

4]

(a) D. A. Tocher, R. O. Gould, T. A. Stephenson, M. A. Bennett, J. P. Ennett, T. W. Matheson, L.

Sawyer, V. K. Shah, J. Chem. Soc. Dalton Trans. (1983) 1571-1581. (b) V. Kar-Yan Lo, Z. Guo, M.

Kwok-Wai Choi, W.-Y. Yu, J.-S. Huang, C.-M. Che, J. Am. Chem. Soc. 134 (2012) 7588-7591. (c)

L. Ackermann, R. Vicente, H. K. Potukuchi, V. Pirovano, Organic Letters 12 (2010) 5032-5035. (d)

P. B. Arockiam, C. Fischmeister, C. Bruneau, P. H. Dixneuf, Angew. Chem. Int. Ed. 49 (2010)

6

629-6632.

[

5]

6]

G. Albertin, S. Antoniutti, J. Castro, J. Organomet. Chem. 697 (2012) 6-14.

D. L. Davies, O. Al-Duaij, J. Fawcett, M. Giardiello, S. T. Hilton, D. R. Russell, Dalton Trans.

(

2003) 4132–4138.

[

7]

8]

M. Simonetti, G. J. P. Perry, X. C. Cambeiro, F. Juliá-Hernández, J. N. Arokianathar, I. Larrosa, J.

Am. Chem. Soc. 138 (2016) 3596–3606.

(a) A. A. Nazarov, S. M. Meier, O. Zava, Y. N. Nosova, E. R. Milaeva, C. G. Hartinger, P. J. Dyson,

Dalton Trans., 2015, 44, 3614-3623; (b) W. H. Ang, L. J. Parker, A. De Luca, L. Juillerat-Jeanneret,

C. J. Morton, M. Lo Bello, M. W. Parker, P. J. Dyson, Angew. Chem. Int. Ed., 2009, 48, 3854-3857.

Selected recent references: a) E. Păunescu, M. Soudani, P. Martin, R. Scopelliti, M. Lo Bello, P. J.

Dyson, Organometallics 2017, 36, 3313−3321. b) A. Ashraf, M. Hanif, M. Kubanik, T. Söhnel, S. M.

F. Jamieson, A. Bhattacharyya, C. G. Hartinger, J. Organomet. Chem. 2017, 839, 31-37. c) L.

Biancalana, L. K. Batchelor, A. De Palo, S. Zacchini, G. Pampaloni, P. J. Dyson, F. Marchetti, Dalton

Trans., 2017, 46, 12001–12004. d) M. V. Babak, D. Plazuk, S. M. Meier, H. J. Arabshahi, J.

Reynisson, B. Rychlik, A. Błauz, K. Szulc, M. Hanif, S. Strobl, A. Roller, B. K. Keppler, C. G.

Hartinger, Chem. Eur. J. 2015, 21, 5110-5117. e) L. Biancalana, A. Pratesi, F. Chiellini, S. Zacchini,

T. Funaioli, C. Gabbiani, F. Marchetti, New J. Chem., 2017, 41, 14574-14588.

[

9]

2

7

ACCEPTED MANUSCRIPT

[

10]

a) L. Biancalana, G. Pampaloni, S. Zacchini, F. Marchetti, J. Organomet. Chem. 848 (2017) 214-

2

21. b) S. Parveen, M. Hanif, S. Movassaghi, M. P. Sullivan, M. Kubanik, M. A. Shaheen, T.

Söhnel, S. M. F. Jamieson, C. G. Hartinger, Eur. J. Inorg. Chem. (2017) 1721–1727. c) A.

Habtemariam, M. Melchart, R. Fernàndez, S. Parsons, I. D. H. Oswald, A. Parkin, F. P. A. Fabbiani,

J. E. Davidson, A. Dawson, R. E. Aird, D. I. Jodrell, P. J. Sadler, J. Med. Chem. 49 (2006) 6858-

6

868.

[

11]

12]

13]

14]

a) M. A. Bennett, J. P. Ennett, Organometallics 3 (1984) 1365-1374. b) J. D. Fotheringham, T. A.

Stephenson, J. Organomet. Chem. 284 (1985) C12-Cl4.

S. Mirtschin, A. Slabon-Turski, R. Scopelliti, A. H. Velders, K. Severin, J. Am. Chem. Soc. 132

(

2010) 14004–14005.

M. Melchart, A. Habtemariam, S. Parsons, S. A. Moggach, P. J. Sadler, Inorg. Chim. Acta 359

2006) 3020–3028.

(

a) P. Mandal, B. Kumar Kundu, K. Vyas, V. Sabu, A. Helen, S. Singh Dhankhar, C. M. Nagaraja,

D. Bhattacherjee, K. Pada Bhabak, S. Mukhopadhyay, Dalton Trans. 47 (2018) 517-527. b) A.

Sulaiman Al-Ayed, Appl. Organometal. Chem. 31 (2017) e3605. c) A. Tadić, J. Poljarević, M.

Krstić, M. Kajzerberger, S. Aranđelović, S. Radulović, C. Kakoulidou, A. N. Papadopoulos, G.

Psomas, S. Grgurić-Šipka, New J. Chem. 42 (2018) 3001-3019. d) P. Štarha, Z. Trávníček, J. Vaňco,

Z. Dvŏrák, Molecules 23 (2018) 420-435.

[

15]

In [14]a: The preparation of potassium carboxylates (reactants) is not described: according to our

1

13

experiments, this feature is not trivial in the case of the aspirinate salt. Indeed, the H and C NMR

2

6

data of the claimed [RuCl(κ O-aspirinate)(η -p-cymene)] (named 4) are not consistent with those

1

reported herein (compound 2), and the H NMR spectrum shown in the Supporting Information

suggests the presence of a mixture. Yields of all Ru products are not given.

2

In [14]b: In compounds 2-5, the author claims a κ O coordination through the carboxylate group of

the ligand. As a matter of fact, the inequivalency of the methyl protons for the p-cymene ligand in

1

2

the H NMR spectrum is an evidence against such a coordination mode. A non-symmetric κ O,O’

coordination involving the α-ketoacid function seems more probable, as we recently determined for a

1

13

structurally similar ligand [10a]. Some H and C NMR assignments appear unlikely.

In [14]c: For all reported compounds, the authors propose a monodentate κO coordination of the

6

+

carboxylate ligand within a very unusual anionic complex, M[RuCl (κO-RCO )(η -arene)] (M = K ,

2

+

6

NH ), without providing clear evidence. In particular, K[RuCl (κO-RCO )(η -arene)] were obtained

4

2

6

under the same conditions as those usually leading to [RuCl(κ O-RCO )(η -arene)] complexes. The

2

1

6

H NMR resonances of the arene in the presumed (NH )[RuCl (κO-RCO )(η -p-cymene)] (R =

4

2

6

mefenamic acid, DMSO-d solution) match those of the arene in [RuCl (κS-DMSO)(η -p-cymene)]

6

2

(

compound 7 in the present work).

[

16]

L. Biancalana, S. Zacchini, N. Ferri, M. G. Lupo, G. Pampaloni, F. Marchetti, Dalton Trans. 46

2017) 16589-16604

(

2

8

ACCEPTED MANUSCRIPT

[

17]

M. Ravera, E. Gabano, I. Zanellato, A. Gallina, E. Perin, A. Arrais, S. Cantamessa, D. Osella, Dalton

Trans., 2017, 46, 1559–1566.

[

18]

19]

Q. Cheng, H. Shi, H. Wang, Y. Min, J. Wang, Y. Liu, Chem. Commun. 50 (2014) 7427-7430.

E. Păunescu, S. McArthur, M. Soudani, R. Scopelliti, P. J. Dyson, Inorg. Chem. 2016, 55,

1

788−1808.

[

20]

a) F. Lopez-Tapia, C. Brotherton-Pleiss, P. Yue, H. Murakami, A. C. Costa Araujo, B. Reis dos

Santos, E. Ichinotsubo, A. Rabkin, R. Shah, M. Lantz, S. Chen, M. A. Tius, J. Turkson, ACS Med.

Chem. Lett. 9 (2018) 250-255. b) C. N. Banti, C. Papatriantafyllopoulou, A. J. Tasiopoulos, S. K.

Hadjikakou, Eur. J. Med. Chem. 143 (2018) 1687-1701.

[

21]

a) A. P. Subramanian, A. A. John, M. V. Vellayappan, A. Balaji, S. K. Jaganathan, E. Supriyanto,

M. Yusof, RSC Adv., 2015, 5, 35608–35621. b) B. Badhani, N. Sharma, R. Kakkar, RSC Adv.,

2

015, 5, 27540–27557. c) R. Y. Kosuru, A. Roy, S. K. Das, S. Bera, Mol. Nutrition & Food Res. 62

2 (2018) 1700699.

6

[

22]

23]

24]

S. Dhar, S. J. Lippard, PNAS 106 (2009) 22199-22204.

G. B. Deacon, R. J. Phillips, Coord. Chem. Rev. 33 (1980) 227–250.

Other Ru-containing molecular ion clusters were found in the 306 < m/z < 357 region; M = 372.03 g

−1

mol for the fragment {Ru(salyCO )(p-cymene)}.

2

[

25]

26]

(a) L. Biancalana, G. Pampaloni, F. Marchetti, Chimia 71 (2017) 573-579. (b) P. Crochet, V.

Cadierno, Dalton Trans. 43 (2014) 12447–12462.

I. A. Alsarra, M. Al-Omar, F. Belal, Profiles Drug Subst. Excip. Relat. Methodol. 32 (2005) 209-

2

40.

[

27]

28]

Z.-S. Ji, C.-G. Li, X.-A. Mao, M.-L. Liu, J.-M. Hu, Chem. Pharm. Bull. 50 (2002) 1017—1021.

R. Jorge Dinis-Oliveira, P. Guedes de Pinho, A. C. Silva Ferreira, A. M. S. Silva, C. Afonso, M. de

Lourdes Bastos, F. Remiao, J. Alberto Duarte, F. Carvalho, Toxicology 249 (2008) 130–139.

B. Chatterjee, C. Gunanathan, Chem. Commun. 50 (2014) 888-890.

[

29]

30]

a) D. Wang, D. Astruc, Chem. Rev. 115 (2015) 6621-6686. b) S. V. Slungard, T.-A. Krakeli, T. H.

K. Thvedt, E. Fuglseth, E. Sundby, B. H. Hoff, Tetrahedron 67 (2011) 5642-5650. c) J. Canivet, G.

Labat, H. Stoeckli-Evans, G. Suss-Fink, Eur. J. Inorg. Chem. 22 (2005) 4493-4500.

M. Patra, T. Joshi, V. Pierroz, K. Ingram, M. Kaiser, S. Ferrari, B. Spingler, J. Keiser, G. Gasser,

Chem. Eur. J. 19 (2013) 14768–14772.

[

31]

[

32]

33]

34]

H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem. 62 (1997) 7512-7515.

W. Willker, D. Leibfritz, R. Kerssebaum, W. Bermel, Magn. Reson. Chem. 31 (1993) 287-292.

6

1

A significant amount of the precursor [RuCl(µ-Cl)(η -p-cymene)] was found in H NMR spectra of

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[

RuCl(κ O-RCO )(η -p-cymene)] complexes (1-3) dissolved in aged CDCl .

2 3

[

35]

F. Menges, "Spectragryph - optical spectroscopy software", Version 1.2.5, @ 2016-2017,

http://www.effemm2.de/spectragryph.

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Article Doi

Synthesis, characterization and behavior in water/DMSO solution of Ru(II) arene complexes with bioactive carboxylates

DOI: 10.1016/j.jorganchem.2018.05.020

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