Polyhedron 50 (2013) 512–523

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Polyhedron

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Structural features of palladium(II) complexes with a-hydroxycarboxylateand aromatic a,a0-diimine ligands

Susana Balboa a, Rosa Carballo b, Alfonso Castiñeiras a,⇑, Josefa María González-Pérez c,Juan Niclós-Gutiérrez c

a Departamento de Química Inorgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spainb Departamento de Química Inorgánica, Facultad de Química, Universidad de Vigo, E-36310 Vigo, Spainc Departamento de Química Inorgánica, Facultad de Farmacia, Universidad de Granada, E-18071 Granada, Spain

a r t i c l e i n f o

Article history:Received 15 October 2012Accepted 14 November 2012Available online 8 December 2012

Keywords:Palladium complexesa-HydroxycarboxylatesAromatic a,a0-diiminesCrystal structure analysisCytotoxic activity

0277-5387/$ - see front matter � 2012 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.poly.2012.11.048

⇑ Corresponding author. Tel.: +34 88181 4951; fax:E-mail address: alfonso.castineiras@usc.es (A. Cast

a b s t r a c t

The neutral a-hydroxycarboxylate complexes [Pd(bpy)(GLYO)]�3H2O (1), [Pd(bpy)(MANO)]�4H2O (2) and[Pd(GLYO)(phen)]�5H2O (3), together with the palladium(II) complexes [Pd(phen)2](NO3)2 (4) and[Pd(CH2COCH3)(bpy)(Cl)] (5) (where GLYO and MANO are the glycolate and mandelate dianions, respec-tively, and bpy and phen, 2,20-bipyridine and 1,10-phenantrholine, respectively), have been prepared byreaction of [Pd(bpy)Cl2] or [PdI2(phen)] with salts of a-hydroxycarboxylic acids in water. These com-pounds were characterized by elemental analysis, mass spectrometry, 1H and 13C NMR, UV–Vis, IR spec-troscopy, TG analysis and single crystal X-ray diffraction. The aforementioned studies confirmed theformation of a variety of square-planar mononuclear compounds (1–3) where the a,a0-diimine ligandsexhibit a rather simple bidentate chelating role and the a-hydroxycarboxylate ligands are dianionic. Avariety of ligand distortions, hydrogen-bonding and stacking interactions were found and these werethoroughly analyzed. In compounds 1 and 3, the complex molecules are stacked in such a way thatthe coordination planes are parallel to one another. The Pd� � �Pd distances between the nearest stackedneighbors are 3.8043(6) and 3.302(2)/3.475(1) Å, respectively. Compounds 1–3 have been testedin vitro for cytotoxicity on HeLa-299 human tumor cell lines.

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1. Introduction

Palladium(II) complexes are of great interest due to theirremarkable catalytic properties [1]. Moreover, palladium(II) com-pounds could be considered as potential anticancer agents due tothe close resemblance between PdII and PtII complexes [2]. Morerecently, some attention has been paid to related compounds thatcontain bulky planar ligands, which are believed to be kineticallyand thermodynamically more stable than simple analogs of cis-diaminedichloroplatinum(II) (cisplatin, cis-DDP), the most widelyrecognized anticancer agent [3]. Taking into account the informa-tion outlined above, the synthesis of novel palladium(II) complexeswith planar amines has led to particular interest in their potentialpharmaceutical applications.

a-Hydroxycarboxylic acids are involved in a variety of biochem-ical processes [4–7]. In addition, bidentate hydroxycarboxylic acidplatinum(II) complexes have shown antitumor activity [8] and, inparticular, cis-diamineglycolatoplatinum(II) (nedaplatin) [9] and1,2-diamino-methyl-cyclobutaneplatinum(II)-lactate [10] are sec-

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+34 88181 5090.iñeiras).

ond or third generation analogs of cisplatin and show a lowerednephrotoxicity [11]. Alternatively, aromatic a,a0-diimine ligandscan form stable mixed-ligand complexes in solution and theiraromatic rings open up the possibility of establishing stackinginteractions that may stabilize the crystals of such complexes. Fur-thermore, weak interactions, and in particular intermolecularstacking of planar aromatic a,a0-diimine units (N-N), such as 2,20-bipyridine (bpy) and 1,10-phenanthroline (phen) in square planarcoordination, are essential factors in the crystal packing in the me-tal complex [12,13]. For these reasons, we have investigated newaromatic a,a0-diimine palladium(II) complexes with a-hydroxy-carboxylate(2�) as co-ligands and have analyzed their crystal andmolecular structures together with the spectral properties.

2. Materials and techniques

H2GLYO, H2LACO, H2MANO, bpy, phen, and other chemicals(reagent grade) were purchased from Sigma–Aldrich and, unlessotherwise specified, were used as received. The solvents werepurified using conventional methods. [Pd(bpy)Cl2] [14] and [PdI2

(phen)] [15] were prepared as described in the literature.Elemental analyses were carried out on a Carlo Erba EA-1108

S. Balboa et al. / Polyhedron 50 (2013) 512–523 513

microanalyzer. Melting points were determined on a Büchi appara-tus. Mass spectra (FAB, 3-nitrobenzyl alcohol, Xe, 8 kV) were ob-tained on a Hewlett Packard HP5988A spectrometer. Electronimpact ionization (70 eV) was effected using the direct sampleinsertion system with the lowest feasible sample temperature.Infrared spectra in the 4000 to 400 cm�1 range were recorded usingKBr pellets on a Perkin-Elmer 597 spectrophotometer, and in the700 to 100 cm�1 range using polyethylene-sandwiched Nujol mullson a Bruker IFS-66v spectrophotometer. 1H and 13C NMR spectra inDMSO-d6 or CD3OD-d4 were run on Bruker AMX 300 and WM 300instruments, respectively, using TMS as internal reference. Theelectronic spectra of microcrystalline samples were obtained bythe diffuse reflectance method on Shimadzu UV-3101PC spectro-photometers over the range 900–250 nm. TGA studies (pyrolyticdecomposition) of compounds 1 and 2 (20–700 �C, 10 �C/min) werecarried out with a constant air flow (100 mL/min) using a ShimadzuThermobalance TGA-DTG-50H instrument, and between 21 and 24FT-IR spectra of evolved gases were recorded in a strategicallytime–spaced manner in each experiment using a coupled FT-IRNicolet Magna 550 spectrophotometer.

2.1. Synthesis of the complexes

2.1.1. Synthesis of [Pd(bpy)(GLYO)]�3H2O (1)[Pd(bpy)Cl2] (0.20 g, 0.60 mmol) was suspended in water

(25 mL). Silver nitrate (0.20 g, 1.19 mmol) in water (5 mL) was addedand the reaction mixture was stirred for 6 h at 60 �C and then at roomtemperature, always in absence of light. The resulting solution wascentrifuged and filtered to remove AgCl. A few drops of water,glycolic acid (0.05 g, 0.66 mmol) and 1 M NaOH (1.20 mL) wereadded to the filtrate. The resulting solution was stirred for 5 daysand concentrated at 60 �C to 5 mL on a rotary evaporator. The mix-ture was cooled to room temperature and the yellow powder was fil-tered off and dissolved from water and again concentrated to 5 mL.Yellow single crystals suitable for X-ray diffraction were obtainedfrom the resulting solution by slow evaporation at room tempera-ture. Yield: 41%, m.p.: 212 �C. Elemental Anal. Calc. for C12H16N2O6Pd(390.67): C, 36.9; H, 4.1; N, 7.2. Found: C, 36.7; H, 4.0; N, 7.1%.

MS (FAB+): m/z [assignment(relative intensity)]: 337(35) [M+],262(94), 157(100). IR (KBr, mmax/cm�1): 3376 m,br, 3207 m,br,m(OH); 1626 s, m(CC), masym(CO2); 1497 w, 1451 m, m(CC,CN); 1370m, msim(CO2); 415 m. Far-IR (Nujol, mmax/cm�1): 385 s, m(Pd–O);252 m, m(Pd–N). 1H NMR (CD3OD, d/ppm): 4.35 (s, 2H, b), 7.71 (m,2H, 5,50), 8.28 (m, 2H, 4,40), 8.39 (d, 2H, 3,30), 8.49 (d, 2H, 6,60). 13CNMR (CD3OD, d/ppm): 72.71 (1C, b), 124.93 (2C, 3,30), 128.64,129.04 (2C, 5,50), 142.44, 142.78 (2C, 4,40), 150.10, 151.44 (2C,6,60). UV–Vis (mmax/cm�1): 36101, 30120, 26525 (Reflectance).

2.1.2. [Pd(bpy)(MANO)]�4H2O (2)A synthetic procedure similar to that for compound 1 was fol-

lowed, using [Pd(bpy)Cl2] (0.13 g, 0.39 mmol), AgNO3 (0.13 g,7.65 mmol), mandelic acid (0.06 g, 0.39 mmol) and 1 M NaOH(0.80 mL). Yellow single crystals suitable for X-ray diffraction wereobtained from the final yellow solution by slow evaporation atroom temperature. Yield: 59%, m.p.: 142 �C. Elemental Anal. Calc.for C18H22N2O7Pd (484.78): C, 44.6; H, 4.6; N, 5.8. Found: C, 44.5;H, 4.5; N, 5.8%.

MS (FAB+): m/z [assignment(relative intensity)]: 413(35) [M+],262(49), 157(39). IR (KBr, mmax/cm�1): 3401 m,br and 3267 sh,m(OH); 1624 s, m(CC), masym(CO2); 1494 w, 1450 m, m(CC,CN);1359 m, msim(CO2); 417 m. Far-IR (Nujol, mmax/cm�1): 378 m,m(Pd–O); 248 m, m(Pd–N). 1H NMR (DMSO-d6, d/ppm): 4.85 (s,1H, b), 7.17 (t, 1H, d0), 7.27 (t, 2H, c0), 7.63 (d, 2H, b0), 7.74 (m,2H, 5,50), 8.29 (m, 2H, 4,40), 8.39, 8.48 (2d, 2H, 6,60), 8.53 (d, 2H,3,30). 13C NMR (DMSO-d6, d/ppm): 82.69 (1C, b), 123.54 (2C, 3,30),126.08, 126.29, 127.20, 127.48, 127.71 (5C, b0 c0 d0 and 5,50),

140.42, 140.83 (2C, 4,40), 145.72 (1C, a0), 147.65, 149.34 (2C, 6,60),154.32, 155.14 (2C, 2,20), 187.05 (1C, a). UV–Vis (mmax/cm�1):36496, 29586 (Reflectance).

2.1.3. [Pd(GLYO)(phen)]�5H2O (3)The complex was prepared following the synthetic procedure

described for complex 1 using [Pd(phen)I2] (0.20 g, 0.37 mmol),Ag2SO4 (0.11 g, 0.35 mmol), glycolic acid (0.03 g, 0.39 mmol) and1 M NaOH (0.74 mL). Some yellow crystals suitable for X-ray dif-fraction were obtained by slow evaporation at room temperaturefrom a solution in acetone. Yield: 5%, m.p.: 258 �C. Elemental Anal.Calc. for C14H20N2O8Pd (450.72): C, 37.3; H, 4.5; N, 6.2. Found: C,37.5; H, 4.3; N, 6.1%.

IR (KBr, mmax/cm�1): 3411 m,br, m(OH); 1650 sh, m(CC); 1622 s,masym(CO2); 1517 w, 1430 m, m(CC,CN); 1354 m, msim(CO2); 423 w.Far-IR (Nujol, mmax/cm�1): 385 s, m(Pd–O); 254 m, m(Pd–N). 1HNMR (DMSO-d6, d/ppm): 4.35 (s, 2H, b), 8.14 (m, 2H, 3,8), 8.29 (s,2H, 5,6), 8.96 (d, 2H, 4,7), 8.99 (d, 2H, 2,9).

2.1.4. [Pd(phen)2](NO3)2 (4)The procedure for the preparation of 1 was repeated using

[Pd(phen)I2] (0.32 g, 0.59 mmol), AgNO3 (0.20 g, 1.18 mmol), lacticacid (0.06 g, 0.57 mmol) and 1 M NaOH (0.6 mL), but slow evapora-tion in air at room temperature of the resulting aqueous solutionafforded just a few brown crystals of complex 4.

2.1.5. [Pd(CH2COCH3)(bpy)(Cl)] (5)[Pd(bpy)Cl2] (0.10 g, 0.30 mmol) was suspended in water

(4 mL). Lactic acid (0.03 g, 0.28 mmol) and 1 M NaOH (0.60 mL)were dissolved in water (10 mL) and then added to the mixture,which was heated under reflux at 150 �C with continuous stirringuntil a clear yellow solution was obtained. The solution was fil-tered and acetone (10 mL) was added to the solution. The reactionmixture was cooled to 4 �C for a long time (2 months), resultingyellow crystals of complex 5. Yield: 33%. m.p.: 250 �C. ElementalAnal. Calc. for C13H13ClN2OPd (355.10): C, 44.0; H, 3.7; N, 7.9.Found: C, 44.1; H, 3.6; N, 7.8%.

IR (KBr, mmax/cm�1): 1634 s, m(CO); 1621 s, m(CC); 1496 m, 1443s, m(CC,CN). Far-IR (Nujol, mmax/cm�1): 333 m, m(Pd–Cl); 285 m,m(Pd–C); 243 m, m(Pd–N). 1H NMR (CDCl3, d/ppm): 2.40 (s, 3H, c),3.01 (s, 2H, a), 7.61 (m, 2H, 5,50), 8.02 (m, 4H, 3,30 and 4,40), 9.31,9.51 (2d, 2H, 6,60).

2.2. X-ray data collection, structure solution and refinement

Diffraction data were obtained on a Bruker SMART CCD-1000Area detector diffractometer [16] at room temperature for crystalsof 1, 2 and 5 and at 120 K for crystals of 3 and 4 mounted on glassfibers. Data were corrected for Lorentz and polarization effects andfor absorption following the SADABS method [17]. The structureswere solved by direct methods [18], which revealed the positionsof all non-hydrogen atoms. These were refined on F2 by a full-ma-trix least-squares procedure using anisotropic displacementparameters [18]. In 4, the nitrogen atom and one oxygen atom ofan NO3 are on a twofold axis, the other NO3 appears to occur intwo positions related by a twofold axis with occupancy factorsfor the two orientations of 0.5. All hydrogen atoms were locatedin difference maps (crystals 1 and 2) or included in geometricallyidealized positions (crystals 3–5) and included as riding modelswith isotropic displacement parameters constrained to 1.2 Ueq oftheir carrier atoms. In 3, the hydrogen atoms of five water mole-cules, O(6) to O(10), were not located. Criteria for a satisfactorycomplete analysis were the ratios of rms shift to standard deviationof less than 0.001. Molecular graphics were generated with PLATON

[19] and DIAMOND [20]. The crystal data, experimental details andrefinement results are summarized in Table 1.

Table 1Crystal data and structure refinement for [Pd(bpy)(GLYO)] 3H2O (1), [Pd(bpy)(MANO)] 4H2O (2), [Pd(GLYO)(phen)] 5H2O (3), [Pd(phen)2](NO3)2 (4) and [Pd(acet) (bpy)Cl] (5).

Compound 1 2 3 4 5

Empirical formula C12H16N2O6Pd C18H22N2O7Pd C14H20N2O8Pd C24H16N6O6Pd C13H13ClN2OPdFormula weight 390.67 484.78 450.72 590.83 355.10Temperature (K) 293(2) 293(2) 120(2) 293(2) 120(2)Crystal system monoclinic monoclinic triclinic monoclinic triclinicSpace group P21/c P21/c P�1 C2/c P�1Unit cell dimensionsa (Å) 10.1842(19) 12.107(2) 12.0114(17) 15.019(3) 7.621(2)b (Å) 19.637(4) 18.083(3) 12.2227(17) 20.244(4) 9.175(3)c (Å) 7.1496(13) 9.1565(15) 13.6399(19) 7.1343(15) 9.267(3)a (�) 90 90 75.673(2) 90 87.756(3)b (�) 94.721(4) 104.334(3) 72.997(2) 102.985(3) 77.978(9)c (�) 90 90 62.466(2) 90 79.466(9)Volume (Å�3) 1425.0(5) 1942.2(6) 1683.1(4) 2113.7(8) 623.1(3)Z 4 4 4 4 2dcalc (Mg/m3) 1.821 1.658 1.779 1.857 1.893Absorption coefficient (mm�1) 1.331 0.998 1.149 0.938 1.691F(000) 784 984 912 1184 352Crystal size 0.55 � 0.13 � 0.11 0.99 � 0.09 � 0.08 0.32 � 0.07 � 0.06 0.37 � 0.31 � 0.26 0.30 � 0.05 � 0.04h Range (�) 2.01–26.38 1.74–26.42 1.58–26.41 1.72–26.39 2.25–26.38Limiting indices, h,k,l �12/12, 0/24, 0/8 �15/14, 0.22, 0/11 �14/15, �14/15, 0/17 �18/18, 0/25, 0/8 �9/9, �11/11, 0/11Reflections collected/unique 9046/2908 11869/3969 19142/6827 7794/2161 10407/2534Data/parameters 2908/190 3969/253 6827/451 2161/183 2534/163Goodness-of-fit (GOF) on F2 1.03 1.24 1.01 1.10 1.04Final R indices 0.023/0.059 0.051/0.112 0.065/0.139 0.025/0.068 0.054/0.137R indices (all data) 0.032/0.063 0.0683/0.1203 0.142/0.175 0.027/0.070 0.076/0.145Largest difference in peak/hole 0.34/�0.39 1.57/�0.61 2.46/�1.45 0.61/�0.53 1.88/�2.31

Table 2Selected bond lengths (Å) and angles (�) for [Pd(bpy)(GLYO)] 3H2O (1), [Pd(bpy)(-MANO)] 4H2O (2), [Pd(GLYO)(phen)] 5H2O (3).

Compound 1 2 3

I II

DistancesPd(1)–O(11) 1.9897(18) 1.977(4) 1.982(7) 2.012(6)Pd(1)–O(13) 1.9720(17) 1.985(4) 1.975(7) 1.972(7)Pd(1)–N(1) 1.989(2) 2.000(5) 2.012(8) 1.993(9)Pd(1)–N(2) 2.0016(18) 2.002(4) 2.028(9) 2.015(8)Pd(1)–Pd(1)a 3.8043(6) 3.302(2)

514 S. Balboa et al. / Polyhedron 50 (2013) 512–523

2.3. Cytotoxicity studies

The new palladium(II) complexes and cisplatin (cis-DDP) werescreened for their cytotoxic effects against HeLa-229 (human cer-vix carcinoma) cell lines, using the method described previously[21] (see Supplementary material). For comparison purposes, thecytotoxicities of cisplatin, [Pd(bpy)Cl2], [Pd(phen)I2] and complex5 were evaluated under the same experimental conditions. Allcompounds were tested in two independent studies with triplicatepoints. The in vitro studies were performed at the Screening Unit ofthe Institute for Industrial Pharmacy of the USC (Spain).

Pd(1)–Pd(1)b 3.8043(6)Pd(1)–Pd(2) 5.2898(12)Pd(2)–Pd(2)c 3.475(1)

AnglesO(11)–Pd(1)–O(13) 84.40(8) 84.03(16) 83.9(3) 84.7(3)O(11)–Pd(1)–N(1) 97.34(8) 96.08(18) 179.3(3) 178.6(3)O(11)–Pd(1)–N(2) 177.51(7) 176.64(17) 98.6(3) 97.3(3)O(13)–Pd(1)–N(1) 178.22(7) 178.7(2) 95.6(3) 96.7(3)O(13)–Pd(1)–N(2) 97.74(8) 99.19(17) 177.5(3) 177.9(3)N(1)–Pd(1)–N(2) 80.51(8) 80.71(19) 82.0(4) 81.3(3)

Symmetry transformations used to generate equivalent atoms: (1), a: x, �y + 1/2,z + 1/2; b: x, �y + 1/2, z � 1/2; (3), a: �x, �y + 1, �z + 1; c: �x + 1, �y + 1, �z.

3. Results and discussion

3.1. General comments on synthesis

Reactions of [Pd(bpy)Cl2] or [Pd(phen)I2] with the a-hydroxy-carboxylic acids, i.e. glycolic [H2GLYO] or mandelic [H2MANO]acids, in basic aqueous media afforded crystalline yellow solidsof formulae [Pd(bpy)(GLYO)]�3H2O (1), [Pd(bpy)(MANO)]�4H2O(2) and [Pd(GLYO)(phen)]�5H2O (3). However, the final productsof the reactions between [Pd(phen)I2] or [Pd(bpy)Cl2] and lacticacid [H2LACO] were not as expected ([Pd(LACO)(phen)] and[Pd(bpy)(LACO)]) but the slow evaporation of the mother liquors,in air at room temperature, yielded crystals of [Pd(phen)2](NO3)2](4) and [Pd(CH2COCH3)(Cl)(bpy)] (5), respectively. The formationof these complexes was established by chemical analysis and thepresence of appropriate peaks in the positive FAB-MS at m/z 337,413 and 361, which correspond to the molecular ion [M+] for 1–3, respectively. The structure of 5 at 243 K was first reported byAnanias et al. [22]. Our structural results using data collected atlow-temperature (120 K) confirm those already published.

3.2. Molecular structures (1–3)

The crystal structures of 1–3 consist of neutral palladium(II)complex molecules and a number of water molecules of crystalli-zation. The asymmetric unit of 3 has two non-equivalent complex

molecules (I and II) and five molecules of water. Relevant bond dis-tances and angles are given in Table 2. Plots of the complex mole-cules in 1 to 3 are shown in Figs. 1–3, respectively. The palladiumatom lies in a cis-square-planar coordination geometry formed bytwo nitrogen atoms of one a,a0-diimine ligand and two oxygenatoms belonging to a bidentate a-hydroxycarboxylate(2–) ligand.Hence, the Pd(II) atom participates in the formation of a five-mem-bered chelate ring with each chelating ligand. In the square-planarenvironment (mean deviation of 0.0083 Å for 1, 0.0202 Å for 2 and0.0010/0.0020 Å for 3), the palladium atom lies in the least-squaresplane defined by the four nitrogen or oxygen atoms [0.015(1) Å,0.003(2) Å and 0.010(4)/0.008(3) Å for 1–3, respectively]. The Pd–N distances are longer than the Pd–O distances and are similar tothe Pd–N distances in other square-planar palladium complexeswith aromatic diimines [23]. The difference in these bond distances

Fig. 1. Structure of the complex molecule in the crystal of 1, showing the atom-numbering scheme. Displacement ellipsoids at the 50% probability level. Uncoor-dinated water molecules are omitted for clarity.

S. Balboa et al. / Polyhedron 50 (2013) 512–523 515

(Pd–N > Pd–O) is in contrast to the soft acid character of Pd(II) andthe borderline (N) or hard (O) behavior of the donor atoms and canbe attributed to the divalent anionic forms of the a-hydroxycarb-oxylate ligands versus the neutral aromatic character of a,a0-dii-mine co-ligands. In addition, the coordination geometry and thechelating character lead to Pd–O distances that are shorter thanPd–O distances in other palladium alkylcarboxylate complexes(Table 2).

3.3. Coordination plane and bpy distortions

Out-of-plane distortions in square-planar complexes can bedescribed in terms of tetrahedrality. Any tetra-coordinate complexcan be characterized by the h4 dihedral angle subtended by twoplanes, each encompassing the metal center and two adjacentdonor atoms [24]. For strictly square-planar complexes the

Fig. 2. Structure of the complex molecule in the crystal of 2, showing the atom-numberinmolecules are omitted for clarity.

tetrahedrality is 0�, whereas for true tetrahedral complexes h4 is90�. From the Cambridge Structural Database [25], we examinedthe tetrahedrality of relevant square-planar palladium(II) com-plexes that contain bpy and an O,O0-bidentate dianionic co-ligandand give rise to planar five-membered chelate rings or to planar/non-planar six-membered chelate rings, respectively. We also con-sidered compounds [PdX2(bpy)] and 5 (Table 3) for comparativepurposes. The h4 angle ranges from 0.28 to 4.26� although, ingeneral, higher values correspond to complexes containing anon-planar six-membered chelate ring. A pseudo tetrahedralgeometry, as in complex 4 (vide infra), is responsible for the valueof 22.46� for the angle h4 in this complex (Table 3). Complexes of 1and 2 show intermediate h4 values similar to those observed in[PdI2(bpy)] and much lower than in 5.

Inspired by the Addison parameter s5 for five-coordinated metalcomplexes [39], Houser et al. [40] proposed an index s4 for thegeometry of four-coordinated complexes. This index is defined asthe sum of a and b angles (the two largest angles in the four-coordinated species) subtracted from 360� and divided by 141�:

s4 ¼360

�� ðaþ bÞ141

�

The values of s4 will range from 1.00, for a perfect tetrahedralgeometry, to zero, for a perfect square-planar geometry. Intermedi-ate geometries, including trigonal pyramidal and see-saw, fallwithin the range 0 to 1.00. The s4 index is also useful to measurethe degree of out-of-plane distortion from the square-planargeometry in coordination complexes. A number of s4 values forrepresentative examples of palladium(II) complexes are given inTable 3. Complexes 1 and 2, previously described as square-planar,have s4 values of 0.030 and 0.033, respectively, and these are con-sistent with a slight see-saw description, i.e. much less pronouncedthan in most of the complexes considered here (with values in therange 0.032 to 0.102).

The distortions from planarity in complexes 1 and 2 (step con-formation) can also be observed using the dihedral angle (hS) be-tween the coordination plane (defined by least-squares plane ofthe four donor atoms surrounding the palladium(II) atom) andthe coordination plane of the bpy ligand (defined by NCC0N0 atoms)[41]. The hS data show that bpy moieties are out of the palladiumcoordination plane by 3.60� and 2.35� for 1 and 2, respectively.For all the other palladium complexes listed in Table 3, the hS

values are smaller (ranging from 0� to 2.30�) except for 5 and [PdCl2(bpy)] [26], Pd(bzdo)(bpy)] [31] and [Pd(oxoldo)(bpy)] [32].

g scheme. Displacement ellipsoids at the 50% probability level. Uncoordinated water

Fig. 3. Non-equivalent complex molecules of the asymmetric unit in the crystal of 3, showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50%probability level. Dashed line represents the ring–metal interactions. Uncoordinated water molecules are omitted for clarity.

Table 3Coordination geometry deformation and bpy or phen deformation in palladium(II) complexesa.

Compoundb Coordination out-plane deformation bpy/phen deformation Reference

h4 s4 hS hdl hP

[Pd(bpy)Cl2] 3.45 0.065 3.19 3.12 9.34 [26][Pd(bpy)Br2] 0.28 0.066 0.03 3.19 8.44 [27][Pd I2(bpy)] 1.83 0.059 1.68 2.91 6.62 [28]

1.17 0.032 1.99 2.43 12.32 [29][Pd(bpy)(naphdo)] 1.82 0.035 0.91 2.09 10.57 [30][Pd(bpy)(bzdo)] 2.58 0.044 3.54 0.76 11.72 [31][Pd(bpy)(oxoldo)] 1.82 0.036 3.10 2.72 10.91 [32][Pd(bpy)(onca)] 0.66 0.101 0.76 0.62 10.73 [33]

1.57 0.102 1.07 2.88 10.40[Pd(bpy)(F6acac)](F6acac) 0.73 0.072 0.49 2.54 11.10 [34][Pd2(bacac)(bpy)2](PF6)2 3.27 0.089 2.27 1.12 10.31 [35]

2.55 0.082 2.16 3.50 11.62[Pd(bpy)(cbdca)] 1.95 0.080 0.82 4.69 13.04 [36][Pd(bpy)(bzmal)] 4.26 0.089 2.14 1.85 11.82 [37][Pd(bpy)(phmal)] 3.69 0.072 2.06 0.31 10.43 [38]

2.55 0.084 1.80 4.73 11.29[Pd(bpy)(phemal)] 3.88 0.088 2.29 3.61 11.26 [38][Pd(bpy)(phpmal)] 3.08 0.089 1.87 3.77 12.49 [38]1 1.28 0.030 3.60 2.20 10.90 this work2 1.74 0.033 2.35 3.37 10.70 this work3 0.76 0.023 3.29 2.93 5.24 this work

0.58 0.025 1.43 1.48 6.834 22.46 0.210 11.40 2.43 7.75 this work5 4.27 0.071 3.39 5.00 7.40 this work

aFor definitions see text.bAbbreviations: naphdo = 2,3-naphthalenediolate dianion, bzdo = benzene-1,2-diolate dianion, oxoldo = meso-oxolane-3,4-diolate dianion, onca = 3-oxidonaphthalene-2-carboxylate dianion, F6acac = (hexafluoroacetylacetonate, bacac = bisacetylacetonate dianion, cbdca = 1,1-cyclobutanedicarboxylate,phmal = phenylmalonate, bzmal = benzylmalonate, phemal = phenethylmalonate, phpmal = phenylpropylmalonate.

516 S. Balboa et al. / Polyhedron 50 (2013) 512–523

The exception is again the pseudo tetrahedral complex 4 (vide in-fra), with a hS value of 11.40� (Table 3).

As far as the distortion of the bpy is concerned, we consideredthe values of the dihedral angle hdl between the least-squaresplanes of the two pyridyl rings [41], and the values of the anglehP between the two lines through the pyridine rings in the xy pro-jection, with x parallel to the long dimension of the bpy, and z per-pendicular to the best plane through the ligand [42]. The calculatedout-of-plane distortions of the bpy ligand, represented by hdl, for

the series of dioxobipyridine and dihalobipyridine palladium(II)complexes studied in Table 3 range from 0.31� to 4.73�. In contrast,the values for complexes studied herein are 2.20� for 1 and 3.37�for 2. Thus, the shorter distortions in these complexes are appar-ently less important for bpy.

In-plane bending distortions are quantified by the value of thedihedral angle hP. In 1 and 2 the hP values are very similar andwithin the range (hP = 10.3–13.0�) found for dioxobipyridine palla-dium(II) complexes (Table 3). Likewise, these values lie in the

S. Balboa et al. / Polyhedron 50 (2013) 512–523 517

range 2.9–12.5�, with a mean value of 7.8�, as reported by Hazell[42] for systems in the Cambridge Structural Database [25] relatedto metal-complexes containing N,N0-coordinated bipyridyl ligands.

3.4. Hydrogen-bond networks and crystal packing

Interestingly, the supramolecular structures of the three com-plexes are different. The molecular compounds are associated byhydrogen bonds in the crystal lattices and the number of suchbonds per molecule depends on the molecular topology and thepresence of hydrogen-bonding centers. Therefore, an analysis ofthe topology of the hydrogen-bond network was carried out usingthe graph set notation terminology introduced by Etter [43] and re-vised by Bernstein [44].

Compound 1, with three solvate water molecules, presents anextensive hydrogen-bonding network involving all oxygen atomsof the crystal structure except for O(11) (Table 4). The water mol-ecules act as donors through all their hydrogen atoms, while O(12)and O(13) and O-water atoms act as acceptors. The solvate watermolecules are involved simultaneously as hydrogen-bond donorsand acceptors to form a cyclic R6 water cluster [45] (Fig. 4a). Con-sidering the interactions with glycolate ligands, R6

6 (12) and R44 (12)

ring motifs are formed. These two rings alternate in a chain alongthe c axis (Fig. 5a). Additionally, two water molecules form

Table 4Hydrogen bond parameters (Å, �) for [Pd(bpy)(GLYO)] 3H2O (1), [Pd(bpy)(MANO)]4H2O (2), [Pd(GLYO)(phen)] 5H2O (3).

Compound D–H� � �A D–H H� � �A D� � �A \DHA

1O(1)–H(1A)� � �O(3) 0.80 2.20 2.998(3) 171.8O(1)–H(1B)� � �O(13) 0.81 1.91 2.699(3) 165.1O(2)–H(2A)� � �O(13) 0.84 1.92 2.726(3) 162.9O(2)–H(2B)� � �O(1)a 0.82 1.90 2.717(3) 176.3O(3)–H(3A)� � �O(2)b 0.82 1.93 2.729(3) 165.6O(3)–H3B)� � �O(12)c 0.85 1.97 2.821(3) 173.9

2O(1)–H(1A)� � �O(12) 0.85 2.03 2.841(69 159.2O(1)_H(1A)� � �O(11) 0.85 2.74 2.485(6) 148.0O(1)–H(1B)� � �O(12)a 0.85 2.01 2.847(7) 165.6O(3)–H(3A)� � �O)(2) 0.85 2.03 2.762(8) 144.2O(3)–H(3B)� � �O(4) 0.86 1.94 2.760(8) 160.6O(4)–H4A)� � �O(4)c 0.84 2.18 2.757(9) 126.0O(4)–H(4B)� � �O(13)d 0.85 1.98 2.779(6) 157.9

3O(1)–H(1A)� � �O(4) 0.85 1.87 2.713(10) 169.5O(1)–H1B)� � �O(9)c 0.84 2.29 2.840(11) 123.3O(2)–H(2A)� � �O(13)a 0.85 1.85 2.693(10) 176.1O(2)–H(2B)� � �O(1)c 0.85 1.95 2.789(10) 167.5O(3)–H(3A)� � �O(8)d 0.85 1.97 2.781(11) 159.7O(3)–H(3B)� � �O(6)c 0.84 2.08 2.800(10) 142.9O(4)–H(4A)� � �O(7) 0.84 1.96 2.788(11) 168.9O(4)–H(4B)� � �O(12)e 0.83 2.02 2.803(11) 156.9O(5)–H(5A)� � �O(10)f 0.84 1.99 2.798(12) 161.8O(5)–H(5B)� � �O(2) 0.84 1.97 2.794(10) 167.4O(6)� � �O(3)a 2.800(10)O(6)� � �O(7) 2.712(11)O(7)� � �O(23) 2.704(11)O(7)� � �O(8)d 2.749(12)O(9)� � �O(11) 2.822(11)O(9)� � �O(1)a 2.840(11)O(10)� � �O(21) 2.823(11)

Symmetry transformations used to generate equivalent atoms:Compound 1, a: �x + 1, �y, �z + 1; b: x, y, z � 1; c: x, �y + 1/2, z � 1/2.Compound 2, a: �x + 1, �y, �z + 2; b: x � 1, y, z; c: �x, �y, �z + 1; d: �x + 1, �y,�z + 1.Compound 3, a: �x, �y + 1, �z + 1; b: �x + 1, �y + 1, �z; c: �x + 1, �y, �z + 1; d: x, y,z + 1; e: x + 1, y, z; f: �x + 1, �y + 1, �z + 1.

Fig. 4. View of the water clusters in (a) compound 1, (b) compound 2 and (c)compound 3.

hydrogen bonds through their O(2)–H(2A) and O(3)–H(3B) withO(13) and O(12)d (d: x, y, �1 + z) acceptors, respectively, resultingin fused ring motifs R6

6 (18) that are interleaved with the aforemen-tioned chains along the b axis. In conclusion, a hydrogen-bondedwater-a-hydroxycarboxylate 2D framework parallel to the bcplane is formed between water molecules and glycolate ligands(Fig. 5a).

In compound 2 the water molecules are hydrogen-bonded toform infinite 1D chains C5 {45] (Fig. 4b). Taking into account thehydrogen bonds between the water molecules and the mandelateligand, a ring motif R2

4 (8) is formed and this links the O(12) ofmandelate ligands and O(12)a (a: 1 � x, �y, 2 � z) of neighboringmolecules through a water molecule O(1) and its centro-symmet-rical O(1)a, thus creating dimeric units (Fig. 6). The other threewater molecules of crystallization are joined together and are alsolinked to dimeric molecules by O(4)–H(4B). . .O(13)d (d: �x + 1, �y,�z + 1) hydrogen bonds (Table 4).

The hydrogen-bonding pattern of 3 is more complicated due tothe presence of ten crystallization water molecules for every twomolecules of complex. The water molecules are hydrogen-bondedinto a 2D network (Fig. 4c) with an L5(5)6(8)8(8)10(8) motif [45].The interactions of water molecules with three glycolate ligandsgive infinite two-dimensional networks parallel to the bc plane(Fig. 5b). The water molecules O(3), O(4), O(6) and O(7) are involvedmutually as donors and acceptors of hydrogen bonds to form thering motif R6

8 (16), while water molecules O(1), O(5) and O(8) withO(11) and O(12) from a glycolate ligand form the ring motif R8

8 (20).In addition, the water molecules O(1), O(2) and O(8) are involved inhydrogen-bonding interactions with O(11) and O(13) from a

Fig. 5. The 2D water-a-hydroxycarboxylate association in (a) complex 1 and (b) complex 3. For symmetry codes see Table 4.

518 S. Balboa et al. / Polyhedron 50 (2013) 512–523

glycolate ligand to produce a ring motif R68 (22). These rings are

fused alternately with rings R88 (20) to give chains along the b axis.

At same time, the rings are linked with the rings R68 (16) through

O(5)–H(5A)� � �O(6) hydrogen bonds (Fig. 5b).Square-planar complexes of palladium(II) often form dimers

with intermolecular Pd� � �Pd contacts within the range 2.7Å < d < 3.5 Å. In compound 1, the Pd� � �Pd length is 3.804(1) Åand this value lies considerably outside the usual range. In com-pound 3, Pd� � �Pd distances between neighboring metal atoms are3.302(2) Å and 3.475(1) Å, which suggest a weak intermetallic con-tact [46].

The structure of 1 has stacked columns of complexes (Fig. 7a)and adjacent columns are parallel to the c axis. Hence, nearby

molecules comprising these adjacent columns lie in the same abplane and the molecules are rotated by 180� (Fig. 7a). Analysis ofthe columnar arrays and the relationships between neighboringmolecules in stacks shows that slippage of the molecular planesis significant (21.9�) and a zigzag array of adjacent Pd� � �Pd� � �Pdis present with an angle of 140.0�, resulting a Pd� � �Pd separationof 3.80 Å. This length is significantly longer than the sum of thevan der Waals radii (3.26 Å) [47], which suggests that there is nointeraction between the adjacent metal centers in the stackedcolumns (see Supporting material SM1). Along each column, pairsof adjacent molecules related by twofold axes in the direction ofthe a axis are rotated by 7.53�. Intermolecular interactionsbetween molecules along the columns and between adjacent

Fig. 6. Representation of complex 2 pairing with ring motif R24 (8).

Fig. 7. Partial view of the columnar stack of (a) complex 1, (b) complex 2 and (c) complex 3, showing the zigzag array of adjacent Pd� � �Pd� � �Pd.

S. Balboa et al. / Polyhedron 50 (2013) 512–523 519

columns are reinforced by the hydrogen-bonding interactions de-scribed above (see Supporting material SM2).

Compound 2 also features columns aligned along the c axis(Fig. 7b), with alternating molecules related by a twofold axisand rotated by 146.7�. As observed in 1, the columns are paralleland neighboring molecules belong to the same plane, which is par-allel to the ab plane of the crystal (see Supporting material SM3and SM4). However, the planes of the molecules are slipped withrespect to the column axis by 14.0� and the Pd� � �Pd� � �Pd anglesare narrower (106.9�), relative to compound 1, giving an increasedPd� � �Pd separation of 5.70 Å. The interplanar molecular separationalong the columns remains at 3.50 Å. In the crystal lattice, the col-umns are linked by hydrogen bonds (vide supra).

Complex 3 also has a columnar array (Fig. 7c) where pairs ofcentro-symmetrically related molecules, I and II, alternate alongthe columns in a sequence � � �I–I–II–II–I–I–II–II� � �. Consequently,the complex features two different relative intermoleculararrangements between alternating molecules comprising thecolumnar stacks. Thus, the Pd� � �Pd separations differ significantly:5.290(1) Å for Pd1–Pd2, 3.302(1) Å for Pd1–Pd1a and 3.475(1) Å for

Pd2–Pd2a (a: 1 � x, 1 � y, �z), while the interplanar molecularseparation along the columns remains approximately constant at3.38, 3.50 and 3.64 Å for the pairs I–I, II–II and I–II, respectively.The slippage of these latter molecular planes is significant (12.2�)(see Supporting material SM5). Along the column, the zigzag arrayof adjacent Pd� � �Pd� � �Pd varies and this influences the Pd� � �Pddistances, with values of 138.45� for Pd1� � �Pd1� � �Pd2 and 113.93�for Pd1� � �Pd2� � �Pd2.

Furthermore, in complexes 1–3 other intermolecular interac-tions are present such as ring–metal interactions, with centroid–metal distances below 4 Å (see Supporting material SM6), andthese have different molecular patterns to associate themselvesand build the crystal packing.

3.5. Crystal structure analysis of 4

Crystals of 4 are built up of discrete NO3� anions and

[Pd(phen)2]2+ cations. In the cations (Fig. 8a) the palladium atomis in a special position lying on a twofold crystallographic axis.The Pd–N bond lengths (Table 5) are close to those reported for

Fig. 8. Structure of 4 with displacement ellipsoids drawn at the 50% probability level. View of the cation of 4, emphasizing the twist distortion of phen ligand: (a, top) top view,(b and c, bottom) side view (Symmetry code for unlabelled atoms, a: �x, y, �z + 3/2).

520 S. Balboa et al. / Polyhedron 50 (2013) 512–523

[Pd(N-N)2]2+ cations [41,48]. As in [Pd(bpy)2](NO3)2�H2O [49] or[Pd(phen)2](ClO4)2 [50], the coordination geometry around the pal-ladium atom is tetrahedrally distorted from square planarity witha dihedral angle between phen planes of 28.46(2)�. Consequently,the planar ligands (rms deviation 0.026 Å) alleviate their stericinteractions through a twist conformation, as shown in Fig. 8band c. This situation is in contrast to other [Pd(N-N)2]X2 complexessuch as [Pd(bpy)2](PF6)2 or [Pd(phen)2](PF6)2 [41], in which astrictly planar geometry is imposed on the Pd atom by the crystal-

lographic symmetry. As a result, the crowding between the two li-gands in the cations in the latter complexes is relieved partly bythe cation assuming a step conformation and partly by a bowingof each of the two chelating ligands.

In the crystal packing the cations are stacked in such way thatone phen ligand of each cation is facing a phen ligand of a neighbor-ing cation (see Supporting material SM7), with ring centroiddistances between 3.630(2) and 3.732(2) Å and dihedral anglesbetween planes of 0–2.1(1)�. There are also intramolecular

Table 5Selected bond lengths (Å) and angles (�) for [Pd(phen)2](-NO3)2 (4).

DistancesPd(1)–N(11) 2.044(2)Pd(1)–N(12) 2.043(2)Pd(1)–N(11)a 2.044(2)Pd(1)–N(12)a 2.043(2)

AnglesN(11)–Pd(1)–N(12) 80.93(9)N(11)–Pd(1)–N(11)a 100.62(11)N(11)–Pd(1)–N(12)a 165.48(8)N(12)–Pd(1)–N(11)a 165.48(8)N(12)–Pd(1)–N(12)a 101.23(12)N(11)a–Pd(1)–N(12)a 80.93(9)

Symmetry transformations used to generate equivalentatoms: a: �x, y, �z + 3/2.

S. Balboa et al. / Polyhedron 50 (2013) 512–523 521

interactions between the palladium(II)-phen chelate ring and thebenzene central ring of the phen ligand, with a centroid–centroiddistance of 3.620(2) Å and an angle between planes of 1.7(1)� [51].

3.6. Thermogravimetric analysis

Thermogravimetric studies were carried out in order to examinethe thermal stability of compounds 1 and 2. The results are given inTable 6. Compound 1 loses a proportion of its crystallization waterin a flow of dry air and [Pd(GLYO)(bpy)]�2H2O remains. In the range25–140 �C the loss of two H2O is observed (found 9.16%, calc. for2H2O 9.24%) (see Supporting material SM8). The complex starts todecompose at ca. 200 �C and a rapid pyrolytic decomposition be-gins. This process represents the loss of about 60% of the sampleand produces CO2, H2O, CO and N2O. The residue obtained is as-sumed to be PdO on the basis of residual mass. Compound 2 loses1.5 molecules of H2O per mole of complex in a stream of dry air,indicating the presence of [Pd(MANO)(bpy)]�2.5H2O. In the firststep (30–135 �C) only water was lost (found 9.22%, calc. for 2.5H2O 9.29%), as evidenced by the corresponding FT-IR spectra (seeSupporting material SM9). The complex starts to decompose at ca.135 �C and the second step (135–350 �C) corresponds to the pyroly-sis of MANO2– and decomposition of bpy in an overlapping process.These processes are accompanied by a significant evolution ofnitrogen oxides (N2O and NO) along with CO2, H2O and CO. The finalresidue (at 400 �C) is believed to be PdO based on residual mass(found 26.78%, found 25.25%).

In summary, the thermograms clearly indicate loss of watermolecules at temperatures below 140 �C, confirming that thesemolecules are not involved in coordination to metal. Above150 �C, pyrolysis of hydroxycarboxylate is the first process to occurand this is followed by the decomposition of bpy with the emissionof different nitrogen oxides. There is significant overlap in thedecomposition stages of both classes of ligands and this is more

Table 6Data for the thermogravimetric analysis of compounds 1 and 2.

Stage Temp. (�C) Weight loss

Exp. (%) Calc

Compound 1I 25–140 9.16 9.24II 140–325 59.28Residue 325 33.69 31.3

Compound 2I 30–135 9.22 9.29II 135–350 44.92III 350–400 19.13

Residue 400 26.78 25.2

evident in compound 1. This thermal decomposition is quite simi-lar to that experienced by other metal-hydroxycarboxylate com-plexes mixed with aromatic a,a0-diimines [13].

3.7. Spectral studies

The IR spectra of the Pd(II) complexes contain broad bands inthe range 3410–3365 cm�1 and these correspond to m(OH) fromcrystallization water molecules. Bands observed between 1500and 1450 cm�1 are due to ring stretching of diimines. In all com-plexes the mas(COO) and ms(COO) are assigned to the bands ataround 1620 and 1350 cm�1, respectively, which indicates aj2O,O’’ bidentate chelate coordination of the bideprotonatedhydroxycarboxylate ligand. In the far infrared region, the bandscorresponding to Pd–Ndiimine and Pd–O appear at around 250 and420 cm�1, respectively [52], suggesting the coordination of theseatoms to the metal center. The diamagnetic nature of palladiumcomplexes confirms their planar geometries, while their electronicspectra exhibit strong absorptions at around 26500 cm�1, whichare assigned to a metal–ligand charge transition from the palla-dium d-orbital to a p⁄-orbital of the diimine. The other transitionsat around 30000 and 36000 cm�1 are assigned to internal p–p⁄

transitions of diimines [53].In solution, the 1H NMR spectra of 1 (in CD3OD-d4), 2 and 3 (in

DMSO-d6) show a set of diimine signals consistent with theformulation [Pd(N-N0)(O-O0)] (N-N0 = a,a0-diimine, O-O0 = a-hydroxycarboxylate dianion). The chemical shifts of the protonsof a,a0-diimine ligands in the complexes were compared withthose in the parent [PdCl2(bpy)] and [Pd I2(phen)] complexes andthey experience upfield shifts, especially for the ortho-diimine pro-tons. This observation can be explained in terms of the strongerbonding of a-hydroxycarboxylate dianions to palladium(II) andmore backbonding from the palladium dp orbitals to the p⁄ orbitalof the a,a0-diimine [54,55]. The 1H NMR spectra of the glycolatecomplexes show a singlet at 4.35 ppm for the two methylene pro-tons and the mandelate complex, a signal at 4.85 ppm for themethane proton, and three signals at 7.17, 7.27 and 7.63 ppm,which correspond to phenyl protons. In complexes 1–3, signalsdue to protons of the carboxylic and hydroxylic groups of the a-hydroxycarboxylic acids were not observed, confirming the dian-ionic nature of these ligands in solution. The chemical shifts ofthe protons of a,a0-diimine ligands in the mixed-ligand complexeswere compared with those in the related [Pd(N-N)Cl2] complexes[54,56] and they invariably experience an upfield shift in themixed-ligand complexes. In the 13C spectra, the single signal at72.7 ppm (in 1) and 82.7 ppm (in 2), assigned to the methyleneor methine carbon atoms of hydroxycarboxylate ligands, hasundergone a downfield shift after coordination and formation ofPd–O–C bond. The 13C NMR signal of the carbonyl group of 1 wasnot observed, but in the case of 2 this signal was observed at187.0 ppm as a singlet. This chemical shift is close to the values

Identified gases Observations

. (%)

H2O �2H2OCO2, H2O, CO, N2O GLYO2�, bpy

4 PdO

H2O �2.5H2OCO2, H2O, CO, N2O, NO MANO2�, bpyCO2, H2O, CO, NO bpy

5 PdO

Table 7IC50 ± SD (lM) and Emax (%inhibition) values obtained at20 lM concentration for compounds 1–3 with respect tocis-DDP in the human cervix carcinoma cell-lines (HeLa-229).

Emax IC50

[Pd(bpy)Cl2] 3 ± 2 –[PdI2(phen)] 74 ± 2 3.8 ± 31 2 ± 2 –2 3 ± 3 –3 80 ± 4 3.2 ± 45 17 ± 4 –cis-DDP 83 ± 4 0.81 ± 6

522 S. Balboa et al. / Polyhedron 50 (2013) 512–523

found for carbonyl carbons reported for other carboxylate com-plexes [57,58]. This observation confirms the five-membered ringstructure for the bidentate a-hydroxycarboxylate ligands insolution.

3.8. Cytotoxicity assays

The in vitro growth inhibitory effect of the new complexes 1–3and cis-DDP was evaluated on HeLa cells. The Emax and IC50 valuesof the three complexes are listed in Table 7. For comparison pur-poses, the cytotoxicity of [PdCl2(bpy)], [PdI2(phen)] and complex5 are included.

The primary antitumor screening of the compounds at 20 lMconcentration shows that only [PdI2(phen)] and 3 exhibit activityin the low-micromolar range (growth inhibition > 50%). Thesecompounds were further tested by measuring IC50 values (drugconcentration that reduces the number living cells by 50%). Analy-sis of the data (Table 7) shows that the IC50 values for compound 3are higher than for cis-DDP. It can be seen from the results that thecytotoxicity of the complexes has an apparent dependence on thediimine ligand, which could mainly be due to the greater aromaticregion of phen compared to bpy. This difference gives rise to ahighly conjugated planar structure that may interact more stronglywith DNA inside the cells by a probable intercalation mechanism.

4. Conclusions

New palladium complexes with glycolate or mandelate and bpyor phen as secondary ligands were synthesized and characterized,and their molecular and crystal structures were analyzed. In com-plexes 1–3, the water molecules are interconnected by hydrogenbonds to produce different water associations and build ordered2D arrangements of oxygen rings. The crystal packings are charac-terized by a columnar stacking that is influenced by the presence ofweak Pd� � �Pd interactions. The biological activities of the com-plexes against the HeLa cancer cell line were tested. Complex 3exhibits good cytotoxic activity and this correlates well with theirplanar structure.

Acknowledgments

Financial support from the Ministry of Science and Innovation andFEDER-EC (MAT2010-15594), Xunta de Galicia (INCITE08P-XIB203128PR and 10TMT314002PR) and the University of Granada(Domestic Grant P18-2009) is gratefully acknowledged. We alsothank Dr. A. Domínguez-Martín for critical reading of the manuscript.

Appendix A. Supplementary material

CCDC 888935–888939 contains the supplementary crystallo-graphic data for compounds 1–5, respectively. These data can be

obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Cen-tre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk. Supplementary data asso-ciated with this article can be found, in the online version, athttp://dx.doi.org/10.1016/j.poly.2012.11.048.

References

[1] A.P. Neves, G.B. da Silva, M.D. Vargas, C.B. Pinheiro, L.C. Visentin, J.D.B.M. Filho,A.J. Araújo, L.V. Costa-Lotufo, C. Pessoa, M.O. de Moraes, Dalton Trans. 39(2010) 10203.

[2] A. Garoufis, S.K. Hadjikakou, N. Hadjiliadis, Coord. Chem. Rev. 253 (2009) 1384.[3] E. Budzisz, M. Malecka, B.K. Keppler, V.B. Arion, G. Andrijewski, U. Krajewska,

M. Rozalski, Eur. J. Inorg. Chem. (2007) 3728.[4] M. Biagioli, L. Strinna-Erre, G. Micela, A. Panzanelli, M. Zema, Inorg. Chim. Acta

310 (2000) 1.[5] P. Kiprof, W. Scherer, L. Pajdla, E. Herdtweck, W.A. Herrmann, Chem. Ber. 125

(1992) 43.[6] G.G. Bombi, B. Corain, A.A. Sheikh-Osman, G.C. Valle, Inorg. Chim. Acta 171

(1990) 79.[7] Z. Guo, P.J. Sadler, Angew. Chem., Int. Ed. Engl. 38 (1999) 1512.[8] T. Totani, K. Aono, Y. Adachi, M. Komura, O. Shiratori, K. Sato, Bidentate

hydroxycarboxylic acid platinum(II) complexes with antitumor activity, in: N.Marino (Ed.), Platinum and Other Metal Coordination Compounds in CancerChemotherapy, Martinus Nijhoff, Boston, 1988, p. 744.

[9] D. Lebwohl, R. Canetta, Eur. J. Cancer 34 (1998) 1522.[10] (a) J.A. Gietema, E.G.E. de Vries, D.Th. Sleijfer, P.H.B. Willemse, H.-J. Guchelaar,

D.R.A. Uges, P. Aulenbacher, R. Voegeli, N.H. Mulder, Br. J. Cancer 67 (1993)396;(b) Q. Wu, S. Qin, F.-M. Teng, Ch.-J. Chen, R. Wang, J. Hematol. Oncol. 4 (2010)1.

[11] (a) M.A. Jakupoc, M. Galaski, B.K. Keppler, Rev. Physiol. Biochem. Pharmacol.196 (2003) 1;(b) D. Wang, S.J. Lippard, Nat. Rev. Drug Discov. 4 (2005) 307.

[12] R. Carballo, B. Covelo, S. Balboa, A. Castiñeiras, J. Niclós, Z. Anorg. Allg. Chem.627 (2001) 948.

[13] S. Balboa, J. Borrás, P. Brandi, R. Carballo, A. Castiñeiras, A.B. Lago, J. Niclós-Gutiérrez, J.A. Real, Cryst. Growth Des. 11 (2011) 4344.

[14] B.J. McCormick, E.N. Jaynes Jr., R.I. Kaplan, Inorg. Synth. 13 (1971) 217.[15] S.C. Dhara, Indian J. Chem. 8 (1970) 193.[16] Bruker, SMART and SAINT. Area Detector Control Integration Software, Bruker

Analytical X-ray Instruments, Inc., Madison, Wisconsin, USA, 1999.[17] G.M. Sheldrick, SADABS, Program for Empirical Absorption Correction of Area

Detector Data, University of Göttingen, Germany, 1997.[18] G.M. Sheldrick, Acta Crystallogr., Sect. A 64 (2008) 112.[19] A.L. Spek, J. Appl. Crystallogr. 36 (2003) 7.[20] K. Brandenburg, H. Putz, DIAMOND, ver. 3.2, Crystal Impact GbR, Bonn, Germany,

2009.[21] A. Castiñeiras, N. Fernández-Hermida, I. García-Santos, L. Gómez-Rodriguez,

Dalton Trans. 41 (2012) 13486–13495.[22] S.R. Ananias, A.E. Mauro, K. Iatin, C.M.C. Picchi, R.H.A. Santos, Transition Met.

Chem. 29 (2004) 284.[23] H.-B. Bürgi, J.D. Dunitz (Eds.), Structure Correlations, VCH, Weinheim,

Germany, 1994. p. 809.[24] L. Gutiérrez, G. Alzuet, J. Borrás, M. Liu-González, F. Sanz, A. Castiñeiras,

Polyhedron 20 (2001) 703.[25] F.H. Allen, Acta Crystallogr., Sect. B 58 (2002) 380.[26] A.J. Canty, B.W. Skelton, P.R. Traill, A.H. White, Aust. J. Chem. 45 (1992) 417.[27] W.J.J. Smeets, A.L. Spek, J.L. Hoare, A.J. Canty, N. Hovestad, G. van Koten, Acta

Crystallogr., Sect. C C53 (1997) 1045.[28] A.J. Canty, M.G. Gardiner, R.C. Jones, M. Sharma, Aust. J. Chem. 64 (2011) 1355.[29] P. Ghosh, A. Begum, D. Herebian, E. Bothe, K. Hildenbrand, K. Wieghardt,

Angew. Chem., Int. Ed. 42 (2003) 563.[30] N. Okabe, K. Hagihara, M. Odoko, Y. Muranishi, Acta Crystallogr., Sect. C C60

(2004) m150.[31] N. Okabe, T. Aziyama, M. Odoko, Acta Crystallogr., Sect. E E61 (2005) m1943.[32] M. Achternbosch, P. Klufers, Acta Crystallogr., Sect. C C50 (1994) 175.[33] Y. Wang, N. Okabe, Acta Crystallogr., Sect. E E61 (2005) m3.[34] A.R. Siedle, R.A. Newmark, A.A. Kruger, L.H. Pignolet, Inorg. Chem. 20 (1981)

3399.[35] G.-Q. Mei, K.-L. Huang, H.-P. Huang, Y.-Z. Li, Acta Crystallogr., Sect. E E62

(2006) m2368.[36] Y. Muranishi, N. Okabe, Acta Crystallogr., Sect. C C60 (2004) m47.[37] E. Gao, Y. Sun, Q. Liu, L. Duan, J. Coord. Chem. 59 (2006) 1295.[38] E. Gao, M. Zhu, L. Liu, L. Wang, Ch. Shi, Y. Sun, Inorg. Chem. 49 (2010) 3261.[39] A.W. Addison, T.N. Rao, J. Reedijk, J. van Rijn, G.C. Verschoor, J. Chem. Soc.,

Dalton Trans. (1994) 1349.[40] L. Yang, D.R. Powell, R.H. Houser, Dalton Trans. (2007) 955.[41] S. Geremia, L. Randaccio, G. Mestroni, B. Milani, J. Chem. Soc., Dalton Trans.

(1992) 2117.[42] A. Hazell, Polyhedron 23 (2004) 2081.[43] M.C. Etter, J.C. MacDonald, J. Bernstein, Acta Crystallogr., Sect. B 46 (1990) 256.

S. Balboa et al. / Polyhedron 50 (2013) 512–523 523

[44] J. Bernstein, R.E. Davis, L. Shimoni, N.-L. Chang, Angew. Chem., Int. Ed. Engl. 34(1995) 1555.

[45] L. Infantes, S. Motherwell, CrystEngComm 4 (2002) 454.[46] G. Aullón, P. Alemany, S. Álvarez, Inorg. Chem. 35 (1996) 5061.[47] A. Bondi, J. Phys. Chem. 68 (1964) 441.[48] B. Milani, A. Anzilutti, L. Vicentini, A. Sessanta o Santi, E. Zangrando, S.

Geremia, G. Mestroni, Organometallics 1 (6) (1997) 5064.[49] A.J. Carty, P.C. Chieh, Chem. Commun. (1972) 158.[50] J.R. Rund, A.C. Hazell, Acta Crystallogr., Sect. B 36 (1980) 3103.[51] Ch. Janiak, J. Chem. Soc., Dalton Trans. (2000) 3885.[52] K. Nakamoto, Infrared and Raman Spectra of Inorganic and Coordination

Compounds, fourth ed., Wiley-Interscience, New York, 1986. p. 231.

[53] A.P.B. Lever, Inorganic Electronic Spectroscopy, second ed., Elsevier,Amsterdam, 1984. pp. 203–376.

[54] S.S. Kamath, V. Uma, T.S. Srivastava, Inorg. Chim. Acta 161 (1989) 49.[55] V.X. Jin, J.D. Ranford, Inorg. Chim. Acta 304 (2000) 38.[56] L. Kumar, N.R. Kandasamy, T.S. Srivastava, A.J. Amonkar, M.K. Adwankar, M.P.

Chitnis, J. Inorg. Biochem. 23 (1985) 1.[57] T. Totani, K. Aono, M. Komura, Y. Adachi, Chem. Lett. (1986) 429.[58] T.K. Miyamoto, J. Okude, K. Maeda, H. Ichida, Y. Sasaki, T. Tashiro, Bull. Chem.

Soc. Jpn. 62 (1989) 3239.