Supporting Information. Reversible ph-responsive Behavior of. Ruthenium(II) Arene Complexes with. Tethered Carboxylate

Transcription

1 Supporting Information Reversible ph-responsive Behavior of Ruthenium(II) Arene Complexes with Tethered Carboxylate Francisco Martínez-Peña, Sonia Infante-Tadeo, Abraha Habtemariam and Ana M. Pizarro* IMDEA Nanociencia, Faraday 9, Ciudad Universitaria de Cantoblanco, Madrid 28049, Spain * 1

2 CONTENTS Preparation of Ruthenium(II) Arene Complexes... Supporting Figures... Supporting Tables... 2

3 Preparation of Ruthenium(II) Arene Complexes Complexes 1 4 were synthesised as described below for the individual reactions. Complex 5C was synthesized and isolated directly in its closed form. Closed tethered complexes 1C 4C were obtained and characterized in aqueous solution (vide infra), yet they were not isolated. [Ru(η 6 -C 6 H 5 CH 2 COOH)(µ-Cl)Cl] 2. 2,5-Dihydrophenylacetic acid (400 mg, 2.9 mmol) and RuCl 3 3H 2 O (473 mg, 1.81 mmol) were suspended in 10 ml of 1:4 (v/v) water/acetone in a closed pressure tube. The reaction mixture was heated at 100 ºC for 3 h. The red precipitate was filtered off, washed with cold ethanol and diethyl ether, and dried in vacuum. Yield: 445 mg, 80%. Elemental analysis: Cald. for C 16 H 16 Cl 4 O 4 Ru 2 (616.24): C, 31.19; H, Found: C, 31.66; H, H NMR (400 MHz, DMSO-d 6, δ): (br s, OH, 1H), 6.01 (t, J = 5.9 Hz, Ar H, 2H), 5.91 (d, J = 6.1 Hz, Ar H, 2H), 5.83 (t, J = 5.6 Hz, Ar H, 1H), 3.49 (s, CH 2, 2H). Red crystals suitable for X-ray diffraction were collected by filtration from the reaction mixture. [Ru(η 6 -C 6 H 5 CH 2 COOH)(en)Cl]Cl (1). [Ru(η 6 -C 6 H 5 CH 2 COOH)Cl 2 ] 2 (100 mg, mmol) was suspended in anhydrous ethanol (5 ml). Ethylenediamine (22 µl, mmol) was added, and the mixture was stirred for 2 h under reflux. The resultant yellow solution was filtered through a 0.45 µm syringe filter. The solvent was reduced to ca. 5% of its original volume, and diethyl ether (4 ml) was added. The sticky solid was sonicated to give a yellow precipitate, centrifuged, washed with diethyl ether and dried in vacuum. Yield: 96 mg (80%). Elemental analysis: Cald. for C 10 H 16 Cl 2 N 2 O 2 Ru (368.22): C, 32.62; H, 4.38; N, Found: C, 32.95; H, 4.74; N, H NMR (400 3

4 MHz, MeOD-d 4, δ): 6.43 (br s, NH 2, 2H), 5.75 (t, J = 5.7 Hz, Ar H, 2H), 5.67 (d, J = 5.7 Hz, Ar H, 2H), 5.64 (t, J = 5.5 Hz, Ar H, 1H), 4.04 (br s, NH 2, 2H), 3.57 (s, CH 2, 2H), (m, 2H), (m, 2H). ESI-MS (m/z): [M Cl H] + calcd. for C 10 H 15 N 2 O 2 Ru, 297.0; found, X-ray diffraction-quality crystals were grown from a methanol solution at ambient temperature over a period of 2 days. [Ru(η 6 :κ 1 -C 6 H 5 CH 2 COO)(en)] + (1C). During the aquation experiments carried out on complex 1 in the presence of AgOTf, intramolecular rearrangement afforded cation 1C, which was characterised in solution. 1 H NMR (400 MHz, D 2 O, δ): 6.08 (t, J = 5.9 Hz, Ar H, 2H), 5.63 (d, J = 6.1 Hz, Ar H, 2H), 5.12 (t, J = 5.5 Hz, Ar H, 1H), 3.34 (s, CH 2, 2H), (m, 4H). [Ru(η 6 -C 6 H 5 CH 2 COOH)(o-pda)Cl]Cl (2). [Ru(η 6 -C 6 H 5 CH 2 COOH)Cl 2 ] 2 (60 mg, mmol) was suspended in 5 ml of 1:1 water/ethanol. o-phenylenediamine ( 22 mg, mmol) was added, and the mixture was stirred for 2 h at ambient temperature. The solvent was reduced to dryness and the remaining solid was redissolved in 2 ml of ethanol. The resultant yellow solution was filtered through a 0.20 µm syringe filter. The solvent was reduced to ca. 5% of its original volume, and diethyl ether (4 ml) was added. The sticky precipitate was sonicated to give a yellow solid, which was separated by centrifugation, washed with diethyl ether and dried in vacuum. Yield: 49 mg (61%). Elemental analysis: Cald. for C 14 H 16 Cl 2 N 2 O 2 Ru (416.26): C, 40.39; H, 3.87; N, Found: C, 40.70; H, 3.83; N, H NMR (400 MHz, MeOD-d 4, δ): (m, 2H), (m, 2H), 5.84 (t, J = 5.7 Hz, Ar H, 2H), 5.79 (d, J = 5.7 Hz, Ar H, 2H), 5.74 (t, J = 5.5 Hz, Ar H, 1H), 3.64 (s, CH 2, 2H). ESI-MS (m/z): [M Cl H] + calcd. for C 14 H 15 N 2 O 2 Ru, 345.0; found,

5 [Ru(η 6 :κ 1 -C 6 H 5 CH 2 COO)(o-pda)] + (2C). During the aquation experiments carried out on complex 2 in the presence of AgOTf, intramolecular rearrangement afforded cation 2C, which was characterised in solution. 1 H NMR (400 MHz, D 2 O, δ): (m, Ar H, 4H), 6.23 (t, J = 6.0 Hz, Ar H, 2H), 5.75 (d, J = 6.0 Hz, Ar H, 2H), 5.22 (t, J = 5.6 Hz, Ar H, 1H), 3.77 (s, CH 2, 2H). [Ru(η 6 -C 6 H 5 CH 2 COOH)(phen)Cl]Cl (3). [Ru(η 6 -C 6 H 5 CH 2 COOH)Cl 2 ] 2 (60 mg, mmol) was suspended in ethanol (5 ml). 1,10-Phenanthroline (35 mg, mmol) was added, and the mixture was stirred for 2 h at ambient temperature. The solvent was reduced to dryness and redissolved in 2 ml of ethanol. The resultant yellow solution was filtered through a 0.20 µm syringe filter. The solvent was reduced to ca. 5% of its original volume, and diethyl ether (4 ml) was added. The sticky precipitate was sonicated to give a pale yellow solid, which was separated by centrifugation, washed with diethyl ether and dried in vacuum. Yield: 86 mg (91%). Elemental analysis: Cald. for C 20 H 16 Cl 2 N 2 O 2 Ru (488.33): C, 49.19; H, 3.30; N, Found: C, 49.37; H, 3.28; N, H NMR (400 MHz, MeOD-d 4, δ): 9.86 (dd, J = 5.3, 1.2 Hz, Ar H, 2H), 8.83 (dd, J = 8.2, 1.2 Hz, Ar H, 2H), 8.20 (s, Ar H, 2H), 8.09 (dd, J = 8.2, 5.3 Hz, Ar H, 2H), 6.33 (t, J = 6.1 Hz, Ar H, 2H), 6.25 (d, J = 6.1 Hz, Ar H, 2H), 5.94 (t, J = 5.7 Hz, Ar H, 1H), 3.71 (s, CH 2, 2H). ESI-MS (m/z): [M Cl H] + calcd. for C 20 H 15 N 2 O 2 Ru, 417.0; found, Crystals suitable for X-ray diffraction were obtained by slow evaporation from a methanol/diethyl ether solution of 3 at ambient temperature. [Ru(η 6 :κ 1 -C 6 H 5 CH 2 COO)(phen)] + (3C). During the aquation experiments carried out on complex 3 in the presence of AgOTf, intramolecular rearrangement afforded cation 5

6 3C, which was characterised in solution. 1 H NMR (400 MHz, D 2 O, δ): 9.76 (d, J = 5.0 Hz, Ar H, 2H), 8.73 (d, J = 8.1 Hz, Ar H, 2H), 8.08 (s, Ar H, 2H), 8.01 (m, Ar H, 2H), 6.55 (t, J = 6.0 Hz, Ar H, 2H), 6.13 (d, J = 6.5 Hz, Ar H, 2H), 5.23 (t, J = 5.5 Hz, Ar H, 1H), 3.75 (s, CH 2, 2H). [Ru(η 6 -C 6 H 5 CH 2 COOH)(ox)Cl]Na (4). [Ru(η 6 -C 6 H 5 CH 2 COOH)Cl 2 ] 2 (60 mg, mmol) was suspended in ethanol (5 ml). Sodium oxalate (26 mg, mmol) was added, and the mixture was stirred for 2 h at ambient temperature. The solvent was reduced to dryness and redissolved in 2 ml of ethanol. The resultant yellow solution was filtered through a 0.20 µm syringe filter. The solvent was reduced to ca. 5% of its original volume, and diethyl ether (4 ml) was added. The sticky precipitate was sonicated to give an orange solid, which was separated by centrifugation, washed with diethyl ether and dried in vacuum. Yield: 44 mg (57%). Elemental analysis: Cald. for C 10 H 8 ClNaO 6 Ru 2H 2 O (419.71): C, 28.62; H, Found: C, 28.56; H, H NMR (400 MHz, MeOD-d 4, δ): 5.83 (t, J = 5.8 Hz, Ar H, 2H), 5.68 (t, 5.6 Hz, Ar H, 1H), 5.61 (d, J = 6.1 Hz, Ar H, 2H), 3.60 (s, CH 2, 2H). ESI-MS (m/z): [M Cl H] + calcd. for C 10 H 9 O 6 Ru, 326.9; found, Yellow crystals grown from a warm methanol solution were suitable for X-ray diffraction studies. [Ru(η 6 :κ 1 -C 6 H 5 CH 2 COO)(ox)] - (4C). During the aquation experiments carried out on complex 4 in the presence of AgOTf, intramolecular rearrangement afforded anion 4, which was characterised in the solution. 1 H NMR (400 MHz, D 2 O, δ): 6.01 (t, J = 5.6 Hz, Ar H, 2H), 5.53 (d, J = 5.7 Hz, Ar H, 2H), 5.39 (t, J = 5.5 Hz, Ar H, 1H), 3.87 (s, CH 2, 2H). 6

7 [Ru(η 6 : 1 -C 6 H 5 CH 2 COO)(tmen)]Cl (5C). [Ru(η 6 -C 6 H 5 CH 2 COOH)Cl 2 ] 2 (60 mg, mmol) was suspended in 5 ml of 1:1 (v/v) water/ethanol. N,N,N,N - Tetramethylethylenediamine (29 µl, mmol) was added, and the mixture was stirred for 1 h at ambient temperature. The solvent was reduced to dryness and redissolved in 2 ml of ethanol. The resultant orange solution was filtered through a 0.20 µm syringe filter. The solvent was reduced to ca. 5% of its original volume, and diethyl ether (4 ml) was added. The sticky precipitate was sonicated to give an orange solid, which was separated by centrifugation, washed with diethyl ether and dried in vacuum. Yield: 70 mg (85%). Elemental analysis: Cald for C 14 H 23 ClN 2 O 2 Ru 2H 2 O (424.07): C, 39.67; H, 6.42; N, Found: C, 39.40; H, 5.98; N, H NMR (400 MHz, MeOD-d 4, δ): 6.31 (t, J = 6.0 Hz, Ar H, 2H), 5.62 (d, J = 6.4 Hz, Ar H, 2H), 5.46 (t, J = 5.7 Hz, Ar H, 1H), 3.73 (s, CH 2, 2H), 3.41 (s, 2CH 3, 6H), 2.71 (s, 2CH 3, 6H), (m, 2H), (m, 2H). ESI-MS (m/z): [M] + calcd. for C 14 H 23 N 2 O 2 Ru, 353.1; found, Complex 5C PF 6 with PF 6 as counterion was obtained by mixing complex 5C with an excess of NH 4 PF 6 in water. Precipitation of a yellow solid afforded the desired product. Its 1 H NMR spectrum was indistinguishable from that of the starting complex 5C, confirming that the cationic complex remained unaltered. Yellow crystals grown from an aqueous solution at room temperature were suitable for X-ray diffraction studies. 7

8 SUPPORTING FIGURES Figure S1. Figure S1. 1 H NMR spectra of complexes 1 and 5C in MeOD-d 4 at 298 K. The selected spectral region shows the signals corresponding to the η 6 -bound arene protons (, ortho-;, meta-; and, para-). (A) 1 H NMR spectrum of open-tether chlorido complex 1 showing the typical short span between the meta- and para- proton peaks of the η 6 -bound arene. (B) Closed-tether complex 5C shows a wider span in the signals corresponding to the η 6 -bound arene protons. This feature provides a useful tool to distinguish between open- and closed-tether analogous complexes. 8

9 Figure S2. Figure S2. Diagram showing π-stacking between the central ring of the phenanthroline ligand of adjacent molecules in the X-ray crystal structure of 3. The centroids are separated by Å. The counter ions and hydrogen atoms (except hydrogens of the carboxylic tether group) have been omitted for clarity. 9

10 Figure S3. Figure S3. (A) Asymmetric unit of the dimer formed by [Ru(η 6 - C 6 H 5 CH 2 COOH)(ox)Cl]Na (4) in the X-ray crystal, showing interactions of sodium cations with the oxalate ligands and solvent water. (B) Hydrogen-bond interactions observed between C H(arene) and O(ox) of adjacent molecules. 10

11 Figure S4. Figure S4. 1 H NMR spectra showing the 6 -bound arene region of the different Ruarene species obtained after dissolving complex 3 in a non-buffered aqueous solution (final ph = 2.7); (A) immediately after dissolving (ca. 10 min), (B) at equilibrium after 24 h, (C) upon addition of NaCl to the equilibrated solution. After 10 min the predominant species is the chlorido complex 3 ( ), and the closed tether complex 3C has also appeared ( ); at 24 h there is an equilibrium showing also the Ru-aqua adduct 3A ( ); upon addition of excess NaCl (100 mm) the three species revert to the original chlorido complex 3. 11

12 Figure S5 Figure S5. ph-dependent species distribution of complex 3A/B/D (, in red) and 3C (, in blue) on the basis of the 1 H NMR titration data. 12

13 Figure S6 Figure S6. Different percentage of species (closed-, chlorido-, and aqua-) observed by 1 H NMR after 24 h (at equilibrium) when complexes 1 4 and 5C were dissolved in: (A) buffered D 2 O solution at ph 7.3 and 100 mm NaCl; and (B) D 2 O and upon addition of AgOTf (the ph of the solutions ranges between for 1 4 and is 6.9 for the solution of 5C) and subsequent removal of AgCl. This graph shows that complexes 2 and 3 bearing -acceptor XY ligands favour the closed tether species, attributable to acidification of the metal centre. 13

14 Figure S7. Figure S7. 1 H NMR spectra showing the conversion of pyruvate to lactate catalysed by complex 1 in the presence of HCOONa (mol ratio 1:2:200, Ru/pyruvate/formate) in D 2 O at 310 K. 14

15 Figure S8. Figure S8. Plot showing the conversion of NAD + to NADH versus time for the transfer hydrogenation of NAD + (23.3 mm) using complexes 1 and 5C in presence of HCOONa (2.3 M) in D 2 O at 310 K (ph ca. 7.1). 15

16 Figure S9. Figure S9. (A) Conversion versus time plot for the transfer hydrogenation of NAD + to NADH using complex 1 with different HCOONa concentrations in D 2 O at ph ca. 7 at 310 K. (B) Representation of the different percentages of the reduced species 1,4- NADH and 1,6-NADH as dependent on the formate concentration over 24 h at 310 K. 16

17 Figure S10 Figure S10. Cell viability - as dose response curves - of complex 1 when co-incubated with different concentrations ( M) of sodium formate. 17

18 SUPPORTING TABLES Table S1. Crystallographic data of dimer [Ru(η 6 -C 6 H 5 CH 2 COOH)(µ-Cl)Cl] 2, and monomers [Ru(η 6 -C 6 H 5 CH 2 COOH)(en)Cl]Cl (1), [Ru(η 6 - C 6 H 5 CH 2 COOH)(phen)Cl]Cl (3), [Ru(η 6 -C 6 H 5 CH 2 COOH)(ox)Cl]Na (4) and [Ru(η 6 : 1 -C 6 H 5 CH 2 COO)(tmen)]PF 6 (5C PF 6 ). Complex dimer C PF 6 Formula C 16 H 16 Cl 4 O 4 Ru 2 C 10 H 16 Cl 2 N 2 O 2 Ru C 21 H 20 Cl 2 N 2 O 3 Ru C 10 H 8 ClNaO 7.75 Ru C 14 H 23 F 6 N 2 O 2 PRu MW Crystal description orange plate yellow prismatic orange prismatic yellow plate yellow prismatic Crystal size (nm) x x x x x x x x x x λ (Å) T (K) 296(2) 296(2) 296(2) 296(2) 293(2) Crystal system triclinic monoclinic orthorhombic orthorhombic monoclinic Space group P -1 P 1 21/c 1 P b c a P n a 21 P 1 21/n 1 a (Å) (3) (10) (5) (7) (6) b (Å) (4) (3) (5) (15) (10) c (Å) (6) (3) (5) (3) (7) α (deg) (2) β (deg) (2) (10) (3) γ (deg) (2) Vol (Å 3 ) (7) (5) (2) (2) (2) Z R [F > 4α(F)] R w GOF Δρ max and min (e Å -3 ) and and and and and RMS (e Å -3 )

19 Table S2. Cell viability data for the Ru II complexes studied in this work in A2780 human ovarian cancer cells. Complex IC 50 ( M) >200 4 >200 5C >200 cisplatin