Neutral and cationic half-sandwich arene ruthenium, Cp*Rh and Cp*Ir oximato and oxime complexes: Synthesis, structural, DFT and biological studies

University of Huddersfield Repository Adhikari, S., Palepu, N.R., Sutradhar, D., Shepherd, S.L., Phillips, R.M., Kaminsky, W, Chandra, A.K. and Kollipara, M.R. Neutral and cationic half-sandwich arene ruthenium, Cp*Rh and Cp*Ir oximato and oxime complexes: Synthesis, structural, DFT and biological studies Original Citation Adhikari, S., Palepu, N.R., Sutradhar, D., Shepherd, S.L., Phillips, R.M., Kaminsky, W, Chandra, A.K. and Kollipara, M.R. (2016) Neutral and cationic half-sandwich arene ruthenium, Cp*Rh and Cp*Ir oximato and oxime complexes: Synthesis, structural, DFT and biological studies. Journal of Organometallic Chemistry, 820. pp. 70-81. ISSN 0022-328X This version is available at http://eprints.hud.ac.uk/id/eprint/29196/ The University Repository is a digital collection of the research output of the University, available on Open Access. Copyright and Moral Rights for the items on this site are retained by the individual author and/or other copyright owners. 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Chandra, Mohan Rao Kollipara PII: S0022-328X(16)30325-4 DOI: 10.1016/j.jorganchem.2016.08.004 Reference: JOM 19583 To appear in: Journal of Organometallic Chemistry Received Date: 19 June 2016 Revised Date: 21 July 2016 Accepted Date: 2 August 2016 Please cite this article as: S. Adhikari, N.R. Palepu, D. Sutradhar, S.L. Shepherd, R.M. Phillips, W. Kaminsky, A.K. Chandra, M.R. Kollipara, Neutral and cationic half-sandwich arene ruthenium, Cp*Rh and Cp*Ir oximato and oxime complexes: Synthesis, structural, DFT and biological studies, Journal of Organometallic Chemistry (2016), doi: 10.1016/j.jorganchem.2016.08.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Neutral and cationic half-sandwich arene ruthenium, Cp*Rh and Cp*Ir 2 oximato and oxime complexes: Synthesis, structural, DFT and biological 3 studies. 4 5 RI PT 1 Sanjay Adhikaria, Narasinga Rao Palepua, Dipankar Sutradhara, Samantha L 7 Shepherdb, Roger M Phillipsb, Werner Kaminskyc, Asit K. Chandraa, Mohan Rao M AN U SC 6 Kolliparaa* 8 9 10 a 11 India. E-mail: mohanrao59@gmail.com 12 Telephone Number: +91 364 2722620 13 Fax Number: +91 364 2550076 14 b 15 HD1 3DH, UK 16 c TE D Centre for Advanced Studies in Chemistry, North-Eastern Hill University, Shillong 793022, EP Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield AC C Department of Chemistry, University of Washington, Seattle, WA 98195, USA 1 ACCEPTED MANUSCRIPT Graphical Abstract 18 Reaction of strongly electron withdrawing cyano substituted pyridyl oxime with metal precursor 19 afforded the neutral oximato metal complexes due to the deprotonation of the oxime hydrogen 20 whereas reaction of weakly electron donating substituted phenyl and methyl oximes yielded 21 cationic oxime complexes. The iridium complexes were found to be more active against 22 MIAPaCa-2 cancer cell line. EP AC C 23 TE D M AN U SC RI PT 17 2 ACCEPTED MANUSCRIPT Abstract 25 The reaction of [(p-cymene)RuCl2]2 and [Cp*MCl2]2 (M = Rh/Ir) with chelating ligand 2-pyridyl 26 cyanoxime {pyC(CN)NOH} leads to the formation of neutral oximato complexes having the 27 general formula [(arene)M{pyC(CN)NO}Cl] {arene = p-cymene, M = Ru, (1); Cp*, M = Rh (2); 28 Cp*, M = Ir (3)}. Whereas the reaction of 2-pyridyl phenyloxime {pyC(Ph)NOH} and 2- 29 thiazolyl methyloxime {tzC(Me)NOH} with precursor compounds afforded the cationic oxime 30 complexes bearing formula [(arene)M{pyC(ph)NOH}Cl]+ and [(arene)M{tzC(Me)NOH}Cl]+ 31 {arene = p-cymene M = Ru, (4), (7); Cp*, M = Rh (5), (8); Cp*, M = Ir (6), (9)}. The cationic 32 complexes were isolated as their hexafluorophosphate salts. All these complexes were fully 33 characterized by analytical, spectroscopic and X-ray diffraction studies. The molecular structures 34 of the complexes revealed typical piano stool geometry around the metal center within which the 35 ligand acts as a NNʹ donor chelating ligand. The Chemo-sensitivity activities of the complexes 36 evaluated against HT-29 (human colorectal cancer), and MIAPaCa-2 (human pancreatic cancer) 37 cell line showed that the iridium-based complexes are much more potent than the ruthenium and 38 rhodium analogues. Theoretical studies were carried out to have a deeper understanding about 39 the charge distribution pattern and the various electronic transitions occurring in the complexes. 40 Keywords: Ruthenium, rhodium, iridium, oximes, cytotoxicity AC C EP TE D M AN U SC RI PT 24 3 ACCEPTED MANUSCRIPT 41 1. Introduction The study of half-sandwich arene ruthenium (arene = p-cymene and its derivatives) 43 Cp*Rh and Cp*Ir complexes represents one of the most versatile subject in the field of 44 organometallic chemistry because of their potential applications in various areas [1-6]. These 45 complexes bearing the general formula [(arene)(M)(L)X]+ (M = Ru, Rh and Ir, L is a chelating 46 ligand and X is a halide) have been extensively studied as potential metal-based anticancer drugs 47 [7-11]. The coordination sphere of the metal center in these half-sandwich complexes is 48 stabilized by the arene moiety which protects the metal’s oxidation state occupying three 49 coordinating sites, the chelating ligand L which controls the reactivity through various 50 interactions and the M-Cl bond which easily gets dissociated and produces the active site for the 51 metal ion to target biomolecules [12, 13]. It is seen that the leaving group, the chelating ligand 52 and the arene substituent strongly influence the biological and structure activity relationship of 53 these complexes [14]. Sadler et. al carried out number of experiments with chelating N,N-, N,O- 54 and O,O- ligands to study the SAR activity of cytotoxic ruthenium(II) complexes by increasing 55 the size of the arene ring [15]. Also it has been proposed by various research groups that the 56 cytotoxicity of half-sandwich metal complexes increases with increase in size of the arene 57 substituent [16-18]. These complexes have also displayed their remarkable activity as catalyst in 58 various organic transformation reactions such as hydrogenation, water oxidation and C-H 59 activation [19-21]. In recent years many half-sandwich complexes with NNʹ chelating nitrogen 60 donor ligands have been accomplished in our laboratory [22]. SC M AN U TE D EP AC C 61 RI PT 42 Oxime ligands in particular have developed a keen interest in the field of coordination 62 chemistry [23]. The oxime ligand can act as an ambidentate ligand and can coordinate with metal 63 ions either through nitrogen or oxygen atoms [24]. Cyanoximes having the general formula 4 ACCEPTED MANUSCRIPT {HO-N=C(CN)-R}, where R is an electron withdrawing group represents an important class of 65 biologically active compounds and transition metal complexes of cyanoximes have shown 66 pronounced cytotoxicity and antimicrobial activity [25, 26]. The presence of the cyano group as 67 a substituent close to the oxime fragment increases the acidity of the oxime several thousand 68 times greater than that of common oximes [27]. The anions of 2-pyridyl oximes serve as a 69 versatile ligand for preparation of complexes with unusual topologies exhibiting interesting 70 magnetic properties [28]. Oximes have the capability to remain intact in the co-ordination sphere 71 of the metal by undergoing O-H bond cleavage to afford oximate derivatives [29]. Despite 72 having a rich diversified chemistry of metal oxime and oximato complexes, it is noteworthy that 73 only a few half-sandwich platinum group metal oxime complexes have been reported to date [30, 74 31]. M AN U SC RI PT 64 In our present work we report the synthesis of ruthenium, rhodium and iridium half- 76 sandwich oximato and oxime complexes, their biological activity and theoretical studies. 77 Ligands used in the present study are shown in Chart-1. 78 2 Experimental 79 2.1. Materials and methods EP TE D 75 All reagents were purchased from commercial sources and used as received without 81 further purification. RuCl3.nH2O, RhCl3.nH2O, IrCl3.nH2O was purchased from Arora Matthey 82 limited. 83 pyridylacetonitrile was obtained from Alfa Aesar and hydroxylamine hydrochloride was 84 obtained from himedia. The solvents were purified and dried according to standard procedures 85 [32]. The starting precursor metal complexes [(p-cymene)RuCl2]2 and [Cp*MCl2]2 (M = Rh/Ir) 86 were prepared according to the literature methods [33, 34]. The oxime ligands 2-pyridyl AC C 80 2-acetylthiazole and 2-benzoylpyridine 5 were obtained from Aldrich, 2- ACCEPTED MANUSCRIPT cyanoxime, 2-pyridyl phenyloxime and 2-thiazolyl methyloxime were synthesized according to 88 published procedures [29, 35 and 36]. Infrared spectra were recorded on a Perkin-Elmer 983 89 spectrophotometer by using KBr pellets in the range of 400-4000 cm-1. 1H NMR spectra were 90 recorded on a Bruker Avance II 400 MHz spectrometer using DMSO-d6 as solvents. Absorption 91 spectra were recorded on a Perkin-Elmer Lambda 25 UV/Vis spectrophotometer in the range of 92 200-800 nm at room temperature in acetonitrile. Mass spectra were recorded using Q-Tof APCI- 93 MS instrument (model HAB 273). Elemental analyses of the complexes were performed on a 94 Perkin-Elmer 2400 CHN/S analyzer. 95 2.2. M AN U Structure determination by X-ray crystallography SC RI PT 87 Suitable single crystals of complexes (1), (2) and (3), were obtained by slow diffusion of 97 hexane into acetone solution and crystals of complexes (4), (5), (7) and (8) were obtained by 98 diffusing hexane into DCM solution. Single crystal X-ray diffraction data for the complexes 99 were collected on an Oxford Diffraction Xcalibur Eos Gemini diffractometer at 293 K using 100 graphite monochromated Mo-Kα radiation (λ = 0.71073 Å). The strategy for the data collection 101 was evaluated using the CrysAlisPro CCD software. Crystal data were collected by standard 102 ‘‘phi–omega scan’’ techniques and were scaled and reduced using CrysAlisPro RED software. 103 The structures were solved by direct methods using SHELXS-97 and refined by full-matrix least 104 squares with SHELXL-97 refining on F2 [37, 38]. The positions of all the atoms were obtained 105 by direct methods. Metal atoms in the complex were located from the E-maps and non-hydrogen 106 atoms were refined anisotropically. The hydrogen atoms bound to the carbon were placed in 107 geometrically constrained positions and refined with isotropic temperature factors, generally 1.2 108 Ueq of their parent atoms. Crystallographic and structure refinement parameters for the 109 complexes are summarized in Table 1, and selected bond lengths and bond angles are presented AC C EP TE D 96 6 ACCEPTED MANUSCRIPT 110 in Table 2. Figures 1-3 were drawn with ORTEP3 program whereas Figures S2-S6 was drawn by 111 using MERCURY 3.6 program [39]. The crystal structure of complex (5) contains disordered hexane molecule, which has 113 been removed by SQUEEZE method [40]. Crystal structure of complex (6) contains fourfold 114 disordered solvent molecule, which has been refined and removed by SQUEEZE method. 115 Crystal structure of complex (8) contains solvent molecule in their solved structure. 116 2.3. RI PT 112 SC Biological studies The complexes (1-9) were dissolved in DMSO at 100 mM and stored at -20 °C until 118 required. The cytotoxicity of the complexes was studied against HT-29 (human colorectal 119 cancer) and MIAPaCa-2 (human pancreatic cancer) cell line. Cells were seeded into 96 well 120 plates at 1 x 103 cells per well and incubated at 37 °C in a CO2 enriched (5%), humidified 121 atmosphere overnight to adhere. The cells were exposed to a range of drug concentrations in the 122 range of 0-100 µM for four days before cell survival was determined using the MTT assay [41]. 123 To each well MTT (0.5 mg/ml) in phosphate buffered saline was added and was further 124 incubated at 37 °C for 4 hours. The MTT was then removed from each well and the formazan 125 crystals formed were dissolved in 150 µM DMSO and the absorbance of the resulting solution 126 was recorded at 550 nm using an ELISA spectrophotometer. The percentage of cell inhibition 127 was calculated by dividing the absorbance of treated cell by the control value absorbance 128 (exposed to 0.1 % DMSO). The IC50 values were determined from plots of % survival against 129 drug concentration. Each experiment was repeated three times and a mean value obtained and 130 stated as IC50 (µM) ± SD. AC C EP TE D M AN U 117 7 ACCEPTED MANUSCRIPT 131 2.4. Computational Methodology The geometry optimization of all the complexes were done in the gas phase using the 133 Density Functional Theory (DFT) based B3LYP method in conjugation with 6-31G** basis set 134 for lighter atoms (H, C, N, O, Cl, S, P and F) and LANL2DZ [42, 43] basis set for heavier atoms 135 (Ru, Rh and Ir). LANL2DZ is a widely used Effective Core Potential (ECP) basis set which 136 considers the core electrons as chemically inactive and performs only on the valence electrons 137 and thus reduces the computational cost. Harmonic frequency calculations were carried out at the 138 same level to ensure that the geometries are minima at the potential energy surface (PES). 139 Natural Bond Orbital (NBO) [44] analysis was carried out to get charges on individual atoms 140 present in the complexes. Time dependent-Density Functional Theory (TD-DFT) [45] has been 141 employed to evaluate the absorption spectra and the electronic transitions of the metal 142 complexes. In order to incorporate the effect of the solvent around the molecule, the Polarizable 143 Continuum Model (PCM) [46] was used in TD-DFT calculations. The composition of the 144 molecular orbital analysis was carried out using the Chemissian software package [47]. All the 145 electronic energy calculations were carried out using Gaussian 09 suite of program [48]. 146 2.5. TE D M AN U SC RI PT 132 EP General procedure for synthesis of neutral complexes (1-3) A mixture of starting metal precursor (0.1 mmol) and ligand 2-pyridyl cyanoxime, 148 {pyC(CN)NOH} (0.2 mmol) were dissolved in dry methanol (10 ml) and stirred at room 149 temperature for 8 hours (Scheme-1). A yellow colored compound precipitated out from the 150 reaction mixture. The precipitate was filtered, washed with cold methanol (2 x 5 ml) and diethyl 151 ether (3 x 10 ml) and dried in vacuum. 152 2.5.1. [(p-cymene)Ru{pyC(CN)NO}Cl] (1) AC C 147 8 ACCEPTED MANUSCRIPT Yield: 62 mg (74%); IR (KBr, cm-1): 2959(m), 2203(m), 1603(m), 1482(m), 1443(m), 1396(s), 154 1368(m), 871(m), 788(m); 1H NMR (400 MHz, DMSO-d6): δ = 9.20 (d, 1H, J = 8.0 Hz , CH(py)), 155 7.94 (t, 1H, CH(py)), 7.38 (t, 1H, CH(py)), 7.30 (d, 1H, J = 8.0 Hz, CH(py)), 1.01 (dd. 6H, J = 8 and 156 8 Hz, CH(p-cym)), 2.07 (s, 3H, CH(p-cym)), 2.62 (sept, 1H, CH(p-cym)), 5.60 (d, 1H, J = 8.0 Hz, CH(p- 157 cym)), 5.68 (d, 1H, J = 4.0, CH(p-cym)), 5.80 (d, 1H, J = 8.0, CH(p-cym)), 5.87 (d, 1H, J = 8.0 Hz, 158 CH(p-cym)); HRMS-APCI (m/z): 417.0302 (M+H)+; UV-Vis { Acetonitrile, λmax nm (ε/10-4 M-1 159 cm-1)}: 237 (1.83), 302 (1.18), 370 (0.61); Anal. Calc for C17H18ClN3ORu (416.86); C, 48.98; H, 160 4.35; N, 10.08. Found: C, 49.14; H, 4.42; N, 10.23 %. 161 2.5.2. [Cp*Rh{pyC(CN)NO}Cl] (2) 162 Yield: 66 mg (78%); IR (KBr. cm-1): 2918(m), 2212(m), 1602(m), 1481(m), 1444(m), 1398(s), 163 1372(s), 1155(m), 766(m); 1H NMR (400 MHz, DMSO- d6): δ = 8.54 (d, 1H, J = 4.0 Hz, CH(py)), 164 7.88 (t, 1H, CH(py)), 7.40 (t, 1H, CH(py)), 7.31 (d, 1H, J = 8.0 Hz, CH(py)), 1.59 (s, 15H, CH(Cp*)); 165 HRMS-APCI (m/z): 420.0451 (M+H)+; UV-Vis { Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}: 236 166 (1.78), 255 (1.35), 289 (1.08), 374 (0.71); Anal. Calc for C17H19ClN3ORh (419.71); C, 48.65; H, 167 4.56; N, 10.01. Found: C, 48.68; H, 4.62; N, 10.18 %. 168 2.5.3. [Cp*Ir{pyC(CN)NO}Cl] (3) 169 Yield: 80 mg (78%); IR (KBr. cm-1): 2922(m), 2204(m), 1605(w), 1483(m), 1394(s), 1368(s), 170 765(m); 1H NMR (400 MHz, DMSO-d6): δ = 8.54 (d, 1H, J = 4.0 Hz, CH(py)), 7.80 (t, 1H, 171 CH(py)), 7.52 (d, 1H, J = 4 Hz, CH(py)), 7.23 (t, 1H, CH(py)), 1.62 (s, 15H, CH(Cp*)); HRMS-APCI 172 (m/z): 510.0824 (M+H)+; UV-Vis { Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}: 233 (1.46), 288 173 (0.96), 378 (0.53); Anal. Calc for C17H19ClN3OIr (509.02); C, 40.11; H, 3.76; N, 8.26. Found: C, 174 40.28; H, 3.88; N, 8.38 %. 175 2.6. AC C EP TE D M AN U SC RI PT 153 General procedure for synthesis of cationic complex (4-9) 9 ACCEPTED MANUSCRIPT A mixture of starting metal precursor (0.1 mmol) and ligand 2-pyridyl phenyloxime 177 {pyC(Ph)NOH} or 2-thiazolyl methyloxime {tzC(Me)NOH} (0.2 mmol) and 2.5 equivalents of 178 NH4PF6 were dissolved in dry methanol (10 ml) and stirred at room temperature for 8 hours 179 (Scheme-2 and 3). The solvent was evaporated the residue was dissolved in dichloromethane and 180 filtered through celite, the filtrate was concentrated to 1 ml and excess hexane was added to 181 precipitate the compound. The precipitate was collected and dried in vacuum. 182 2.6.1. [(p-cymene)Ru{pyC(Ph)NOH}Cl](PF6) (4) 183 Yield: 96 mg (78%); IR ((KBr. cm-1): 3314(b), 3090(s), 2967(w), 1598(s), 1472(s), 1366(m), 184 1192(s), 1031(s) 838(s); 1H NMR (400 MHz, DMSO-d6): 9.45 (d, 1H, J = 8.0 Hz, CH(py)), 8.04 185 (t, 1H, CH(py)), 7.66 (t, 1H, CH(py)), 7.54-7.59 (m, 3H, CH(py), (Ar)), 7.29-7.32 (m, 3H, CH(Ar)), 186 1.06 (d 3H, J = 8.0 Hz, CH(p-cym)), 1.13 (d, 3H, J = 8.0 Hz, CH(p-cym)), 2.26 (s, 3H, CH(p-cym)), 187 2.70 (sept, 1H, CH(p-cym)), 5.72 (d, 1H, J = 8.0 Hz, CH(p-cym)), 6.02 (d, 1H, J = 8.0 Hz, CH(p-cym)), 188 6.12 (d, 1H, J = 8.0 Hz, CH(p-cym)), 6.19 (d, 1H, J = 8.0 Hz, CH(p-cym)), OH not observed; HRMS- 189 APCI (m/z): 469.0652 (M-PF6)+; UV-Vis {Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}: 233 (2.28), 190 272 (0.95), 376 (0.29); Anal. Calc for C22H24ClF6N2OPRu (613.93); C, 43.04; H, 3.94; N, 4.56. 191 Found: C, 43.21; H, 4.06; N, 4.63 %. 192 2.6.2. [Cp*Rh{pyC(Ph)NOH}Cl](PF6) (5) 193 Yield: 108 mg (87%); IR (KBr. cm-1): 3314(b), 3112(m), 2922(m), 1595(s), 1470(w), 1378(w), 194 1189(s), 1027(s), 841(s); 1H NMR (400 MHz, DMSO-d6): δ = 8.77 (d, 1H, J = 4.0 Hz, CH(py)), 195 8.06 (t, 1H, CH(py)), 7.77 (t, 1H, CH(py)), 7.59-7.63 (m, 3H, CH(py), (Ar)), 7.40-7.45 (m, 3H, 196 CH(Ar)), 1.77 (s, 15 H, CH(Cp*)), OH not observed; HRMS-APCI (m/z): 471.0721 (M-PF6)+; UV- 197 Vis {Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}: 266 (0.75), 357 (0.30); Anal. Calc for 198 C22H25ClF6N2OPRh (616.77); C, 42.84; H, 4.09; N, 4.54. Found: C, 42.91; H, 3.96; N, 4.67 %. AC C EP TE D M AN U SC RI PT 176 10 ACCEPTED MANUSCRIPT 2.6.3. [Cp*Ir{pyC(Ph)NOH}Cl](PF6) (6) 200 Yield: 110 mg (78%); IR (KBr. cm-1): 3438(b), 3137(m), 2975(m), 1624(s), 1457(w), 1378(w), 201 1142(s), 1033(s), 843(s); 1H NMR (400 MHz, DMSO-d6): δ = 8.78 (d, 1H, J = 4.0 Hz, CH(py)), 202 7.92 (t, 1H, CH(py)), 7.79 (t, 1H, CH(py)), 7.48-7.53 (m, 3H, CH(py), (Ar)), 7.43-7.47 (m, 3H, 203 CH(Ar)), 1.77 (s, 15 H, CH(Cp*)), OH not observed; HRMS-APCI (m/z): 561.1283 (M-PF6)+; UV- 204 Vis {Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}: 296 (0.78), 360 (0.59); Anal. Calc for 205 C22H25ClF6N2OPIr (706.08); C, 37.42; H, 3.57; N, 3.97. Found: C, 37.58; H, 3.65; N, 4.11 %. 206 2.6.4. [(p-cymene)Ru{tz(CH3)NOH}Cl](PF6) (7) 207 Yield: 88 mg (79%); IR (KBr. cm-1): 3594(s), 3429(b), 3109(m), 2970(m), 1631(s), 1505(m), 208 1471(w), 1381(s), 1140(s), 1040(m), 846(s); 1H NMR (400 MHz, DMSO-d6): δ = 11.3 (s, 1H, 209 OH), 8.50 (d, 1H, J = 4.0 Hz, CH(tz)) 7.89 (d, 1H, J = 8.0 Hz, CH(tz)), 2.52 (s, 3H, CH3), 1.10 (d, 210 3H, J = 8 Hz, CH(p-cym)), 1.18 (d, 1H, J = 8 Hz, CH(p-cym)), 2.29 (s, 3H, CH(p-cym)), 2.75 (sept, 1H), 211 6.06 (d, 1H, J = 4 Hz, CH(p-cym)), 5.89 (d, 2H, J = 8 Hz, CH(p-cym)), 5.64 (d, 1H, J = 4 Hz, CH(p- 212 + -4 -1 -1 cym)); HRMS-APCI (m/z): 413.0118 (M-PF6) ; UV-Vis {Acetonitrile, λmax nm (ε/10 M cm )}: 213 297 (0.48), 350 (0.32); Anal. Calc for C15H20ClF6N2OPRuS (557.88); C, 32.29; H, 3.61; N, 5.02. 214 Found: C, 32.41; H, 3.69; N, 5.13 %. 215 2.6.5. [Cp*Rh{tzC(CH3)NOH}Cl](PF6) (8) 216 Yield: 84 mg (75%); IR (KBr. cm-1): 3618(s), 3433(b), 3138(m), 2824(w), 1598(s), 1470(w), 217 1382(w), 1139(m), 1027(w), 842(s); 1H NMR (400 MHz, DMSO-d6): δ = 11.81 (s, 1H, OH), 218 8.14 (d, 1H, J = 4 Hz, CH(tz)), 8.08 (d, 1H, J = 4 Hz, CH(tz)), 2.56 (s, 3H, CH3), 1.78 (s, 15 H, 219 CH(Cp*)); HRMS-APCI (m/z): 415.0131 (M-PF6)+; UV-Vis { Acetonitrile, λmax nm (ε/10-4 M-1 220 cm-1)}: 230 (0.53), 287 (0.35), 351 (0.32); Anal. Calc for C15H21ClF6N2OPRhS (560.73); C, 221 32.13; H, 3.77; N, 5.00. Found: C, 32.19; H, 3.85; N, 5.12 %. AC C EP TE D M AN U SC RI PT 199 11 ACCEPTED MANUSCRIPT 2.6.6. [Cp*Ir{tzC(CH3)NOH}Cl](PF6) (9) 223 Yield: 100 mg (77%); IR (KBr. cm-1): 3619(s), 3339(b), 3136(m), 2926(m), 1599(m), 1458(m), 224 1387(m), 1144(w), 1036(m), 844(s); 1H NMR (400 MHz, DMSO-d6): δ = 11.81 (s, 1H, OH), 225 8.25 (d, 1H, J = 4 Hz, CH(tz)), 8.23 (d, 1H, J = 4 Hz, CH(tz)), 2.58 (s, 3H, CH3), 1.77 (s, 15 H, 226 CH(Cp*)); HRMS-APCI (m/z): 505.0761 (M-PF6)+; UV-Vis {Acetonitrile, λmax nm (ε/10-4 M-1 cm- 227 1 228 4.31. Found: C, 27.90; H, 3.32; N, 4.41 %. 229 3. Results and discussion 230 3.1. Synthesis of the complexes RI PT 222 M AN U SC )}: 290 (0.76), 360 (0.346); Anal. Calc for C15H21ClF6N2OPIrS (650.04); C, 27.72; H, 3.26; N, The neutral metal oximato complexes (1-3) were isolated by the reaction of metal 232 precursors with 2-pyridyl cyanoxime. The neutral metal complexes were formed as a result of 233 deprotonation of the oxime hydrogen as confirmed by spectroscopic and X-ray diffraction 234 studies. It is assumed that the presence of the cyano group as a substituent in 2-pyridyl 235 cyanoxime increases its acidity leading to its deprotonation and resulting in elimination of HCl. 236 Furthermore deprotonation of oxime hydrogen generates an anionic charge on oxime-O which 237 was found to be delocalized over the 2-pyridyl cyanoxime moiety as reflected from the bond 238 lengths values (Table 2). The cationic metal oxime complexes (4-9) were prepared by the 239 reaction of metal precursors with 2-pyridyl phenyloxime and 2-thiazolyl methyloxime. 240 Deprotonation of oxime hydrogen was not observed in this case with phenyl and methyl as 241 substituent. The cationic complexes were isolated with PF6 counter ion. All these complexes 242 were isolated as yellow solids except complexes (6 and 9) which were isolated as orange solids. 243 These complexes are non-hygroscopic, stable in air as well as in solid state. They are soluble in 244 common organic solvents like acetone, acetonitrile, dichloromethane and DMSO but insoluble in AC C EP TE D 231 12 ACCEPTED MANUSCRIPT 245 hexane and diethyl ether. All these complexes were fully characterized by spectroscopic 246 techniques. 247 3.2. Spectral studies of the complexes The IR spectra of all the complexes shows characteristic stretching frequencies for C=N 249 and C=C around 1450-1620 cm-1 and these values are shifted to higher frequencies as compared 250 to the free ligand following coordination of the ligand to the metal atom. The C≡N stretching 251 frequencies for the neutral complexes (1-3) appeared in the lower frequency region around 2204- 252 2212 cm-1 as compared to the free ligand at 2229 cm-1 which may be due to delocalization of the 253 anionic charge on oxime-O. The disappearance of the OH stretching frequency around 3100- 254 3400 cm-1 in the neutral complexes (1-3) indicates the deprotonation of the oxime hydrogen, 255 which is also confirmed from the crystal structures. The presence of the OH stretching frequency 256 around 3100-3450 cm-1 in cationic complexes (4-9) suggests that the binding occurs through the 257 nitrogen atom. In addition, the cationic metal complexes (4-9) displayed a strong intense band 258 around 838-849 cm-1 corresponding to the P-F stretching frequency of the counter ion [49]. TE D M AN U SC RI PT 248 In the 1H NMR spectra of the complexes the signals for the aromatic protons of the ligand 260 was observed in the downfield region around 7.32-9.50 ppm. The shift of the ligand resonance 261 signals clearly indicates the coordination of the ligand to the metal ion. The disappearance of the 262 OH proton signal in the neutral complexes (1-3) as compared to the free ligand at 13.02 ppm 263 indicates the deprotonation of the hydroxyl proton. The OH proton resonance for complexes (7- 264 9) was observed as singlet around 11.3-11.9 ppm respectively. Besides these resonance signals 265 for the aromatic part of the ligand complexes (1, 4 and 7) displayed an unusual pattern of signal 266 for the p-cymene moiety. The aromatic proton signal for the p-cymene ligand showed four 267 doublets for complexes (1) and (4) at around 5.60-6.19 ppm and three doublets for complex (7) AC C EP 259 13 ACCEPTED MANUSCRIPT around 5.64-6.06 ppm instead of two doublets in the starting metal precursor. And also methyl 269 protons of isopropyl group displayed two doublets for complex (4) and (7) and one doublet of 270 doublet for complex (1) around 1.01-1.18 ppm instead of one doublet in the metal precursor. 271 This surprising pattern of signals is due to desymmetrization of the p-cymene ligand upon 272 coordination of the oxime ligand and these results are in good agreement with similar reported 273 complexes [50]. Complexes (1, 4 and 7) displayed septet and singlet around 2.07-2.75 ppm 274 corresponding to the methine protons of the isopropyl group and methyl group of the p-cymene 275 ligand. The methyl proton resonance for complexes (8) and (9) was observed as a singlet at 2.56 276 and 2.58 ppm. In addition, to all these signals a strong peak for the Cp*Rh complexes (2, 5 and 277 8) and the Cp*Ir complexes (3, 6 and 9) was observed between 1.59-1.78 ppm for the methyl 278 protons of the pentamethylcyclopentadienyl ligand. M AN U SC RI PT 268 In the mass spectra of the neutral complexes (1-3), the molecular ion peak was observed 280 as (M+H)+ ion peak at m/z: 417.0302, m/z: 420.0451 and m/z: 510.0824 respectively. Whereas 281 the mass spectra of the cationic complexes (4-9) displayed their molecular ion peaks at m/z: 282 469.0652, m/z: 471.0721, m/z: 561.1283, m/z: 413.0118, m/z: 415.0131 and m/z: 505.0761 283 which corresponds to the [M-PF6]+ ion. The mass spectra values of the complexes strongly 284 support the formation of the complexes. EP The absorption spectra of the complexes were recorded in acetonitrile at 10-4 M AC C 285 TE D 279 286 concentration at room temperature and the plot is shown in (Figure S1). The electronic spectra of 287 the complexes display absorption band in the higher energy region around 230-305 nm which 288 can be assigned as ligand centered π-π* and n-π*transition [51]. The low spin Ru(II), Rh(III) and 289 Ir(III) complexes provides filled dπ (t2g) orbitals of proper symmetry which can interact with low 290 lying π* orbitals of the ligand. Therefore a metal to ligand charge transfer (MLCT) band is 14 ACCEPTED MANUSCRIPT 291 expected in their absorption spectra. The bands in the lower energy region around 350-380 nm 292 can be assigned as metal to ligand charge transfer (MLCT) dπ(M) to π*(L) transition [52]. 293 3.3. Molecular structures of complexes The molecular structures of some of the respective complexes were established by single 295 crystal X-ray analysis. Suitable single crystals were attached to a glass fiber and transferred into 296 the Oxford Diffraction Xcalibur Eos Gemini diffractometer. The crystallographic details and 297 structure refinement details are summarized in Table 1. The geometrical parameters around the 298 metal atom involving ring centroid are listed in Table 2. Complex (1) crystallized in 299 orthorhombic system with space group Pca21. Complexes (2, 3 and 8) crystallized in monoclinic 300 crystal system with space group P21/c whereas complexes (4) and (7) crystallized with P21/n and 301 P21/m space group in monoclinic crystal system. Complex (5) crystallized in triclinic system 302 with space group P ͞1. M AN U SC RI PT 294 The molecular structures of the complexes revealed a typical three legged “piano stool” 304 geometry about the metal center with the metal atom coordinated by the arene/Cp* ring in a η6/ 305 η5 manner, two nitrogen donor atoms from chelating ligand in a bidentate κ2 NNʹ fashion and one 306 chloride atom. The metal atom in these complexes is situated in a pseudo-octahedral arrangement 307 with the ligand coordinating through the pyridine and oxime nitrogen atom forming a five 308 membered metallocyclic ring. The bite angle values N(1)-Ru(1)-N(2) in ruthenium complexes 309 are 77.81(13) (1), 75.66(7) (4) and 78.0(10) (7). The average Ru-C distances in complexes (1) 310 and (4) are almost equal 2.203 and 2.205 Å, while in complex (7) the Ru-C distance is 2.179 Å. 311 The Ru-centroid of the arene ring distances in complexes (1) and (4) are equal 1.696 Å while in 312 complex (7) it is slightly longer 1.728 Å. The bite angle values N(1)-M(1)-N(2) in rhodium and 313 iridium complexes are 78.06(16) (2), 78.0(3) (3), 74.92(11) (5) and 75.16(15) (8). The average AC C EP TE D 303 15 ACCEPTED MANUSCRIPT M-C distances (where M = Rh/Ir) are {2.165 (2), 2.170 (3), 2.157 (5) and 2.149 (8) Å} while the 315 distance between the metal to centroid of the Cp* ring is found to be in the range of 1.775-1.803 316 Å respectively. The M-N and M-Cl bond distances (where M = Ru, Rh and Ir) in all these 317 complexes are found to be in close agreement with previously reported values for ruthenium, 318 rhodium and iridium complexes with NNʹ donor ligands [53]. Surprisingly, the molecular 319 structures of complexes (1, 2 and 3) revealed the deprotonation of the oxime hydrogen 320 generating an anionic charge on oxime-O. This anomalous behavior of deprotonation of the 321 oxime hydrogen is not surprising as the presence of electron withdrawing cyano group increases 322 the acidity of the oxime fragment. It was further observed that the anionic charge on the oxime-O 323 was delocalized over the 2-pyridyl cyanoxime moiety. This is supported by the oximate C(6)- 324 N(2) {1.330(5) (1), 1.334(7) (2) and 1.360(11) (3) Å} and N(2)-O(1) {1.271(4) (1), 1.262(5) (2) 325 and 1.254(9) (3) Å} bond lengths which is slightly larger and smaller than the corresponding C- 326 N {1.287(2) Å} and N-O {1.367(2) Å} bond in the free ligand indicating their partial double 327 bond character and delocalization of the anionic charge (Scheme-1) [54]. These results are 328 further supported by the theoretical calculations as well (Table S1). A similar pattern of 329 delocalization of charge was reported for the cyclometalated iridium complex [Ir(ppy)2(pyald)] 330 (ppy = 2-phenylpyridine, pyald = 2-pyridinealdoxime) where the anionic charge was delocalized 331 over the pyridine aldoxime moiety [55]. The positive charge of the ruthenium atom in complex 332 (1) is balanced by one negative charge from chloride ion and one negative charge from the 333 oxime-O. Similarly in complexes (2) and (3), the positive charge of the metal atom is balanced 334 by one anionic charge from Cp* ligand, one chloride ion and anionic oxime-O. AC C EP TE D M AN U SC RI PT 314 335 Further the crystal structure of complex (1) displayed three different types of 336 intermolecular hydrogen bonding; the first between the anionic oxime-O and hydrogen atom 16 ACCEPTED MANUSCRIPT from pyridine (2.393 Å), the second between the oxime-O and methine hydrogen (2.383 Å) and 338 third from the aromatic hydrogen of p-cymene ligand (2.531 Å). Also C-H····Cl (2.848 Å) 339 interaction between the chloride atom and H-atom of pyridine ring (Figure S2) has been 340 observed. Crystal structure of complex (2) exhibits two different types of C-H·····Cl (2.813 and 341 2.902 Å) interactions between the chloride atom attached to metal and H-atom of Cp* group and 342 pyridine and also C-H·····π (2.904 Å) interaction was observed between the methyl-H atom and 343 Cp* group (Figure S3). The crystal structure of complex (3) is stabilized by C-H·····π (2.756 Å) 344 interaction between the methyl-H atom and Cp* group and C-H·····Cl (2.917 Å) interaction 345 between chloride atom and methyl H atom of Cp*. It also exhibits two types of intermolecular 346 hydrogen bonding C-H·····O (2.713 Å) between the anionic oxime-O and methyl-H of Cp* and 347 C-H·····N (2.689 Å) interaction between nitrogen atom of cyano group and pyridine-H atom 348 (Figure S4). The crystal packing of complex (4) and (5) forms a dimeric unit via weak 349 intermolecular C-H·····O (2.700 and 2.848 Å) and O-H·····Cl (2.228 and 2.245 Å) interactions 350 between the methyl-H atom of Cp* and oxime-O and oxime-H atom and chloride atom attached 351 to metal ion (Figure S5). Further the crystal structure of complex (8) crystallized with one water 352 molecule which forms four different types of intermolecular hydrogen bonding the first between 353 the hydrogen atom of water molecule and chloride atom O-H·····Cl (2.807 Å), the second 354 between the fluorine atom of counter ion PF6 and H-atom of water molecule O-H·····F (2.319 Å), 355 the third between the O-atom and H-atom of Cp* group C-H·····O (2.507 Å) and the last between 356 the O-atom and H-atom of oxime moiety O-H·····O (1.829 Å) (Figure S6). These weak 357 interactions play an important role in the formation of supramolecular motifs. 358 3.4. AC C EP TE D M AN U SC RI PT 337 Chemosensitivity studies 17 ACCEPTED MANUSCRIPT The oximato and oxime metal complexes (1-9) were tested for their in vitro activity 360 against two cancer cell lines HT-29 (human colorectal cancer) and MIAPaCa-2 (human 361 pancreatic cancer) using the MTT assay. The response of the cell line HT-29 and MIAPaCa-2 to 362 the test complexes (1-9) and cisplatin is presented in graphical form in Figure 4 and in tabular 363 form in Table 3. Complexes (1) and (8) were found to be inactive against both the cell line with 364 IC50 values > 100 µM. Complexes (4) and (5) were found to be less active against HT-29 cell 365 line whereas complex (4) was found to be more active against MIAPaCa-2 cell line. In contrast 366 complexes (2) and (7) displayed moderate activity against both cell lines with IC50 value in the 367 range of 8.28 to 23.74 µM. However, among all the ruthenium, rhodium and iridium complexes, 368 the iridium complexes (3), (6) and (9) with cyano, phenyl and methyl substituted oximes 369 displayed high cytotoxicity. The iridium complexes were found to be highly active against HT- 370 29 cancer cell line with IC50 values in the range of 5.82 to 10.54 µM. Also, the iridium 371 complexes exhibits high potency against MIAPaCa-2 cell line with IC50 values ranging from 372 2.89 to 9.65 µM. However among all the iridium complexes, the iridium oximato compound (3) 373 with cyano substituent was found to be the most potent towards MIAPaCa-2 cell line (IC50 = 374 2.87 ± 0.26 µM) with IC50 value comparable to that of cisplatin (IC50 = 2.84 ± 2.05 µM). This 375 high remarkable activity of the iridium based complexes suggests that the presence of the 376 substituent in the chelating ligand plays a crucial role and affects the cytotoxicity [8]. This study 377 demonstrates that the cytotoxicity of the complexes can be finely tuned by changing the nature 378 and position of the substituent in the chelating ligand without changing the arene systems. 379 3.5. AC C EP TE D M AN U SC RI PT 359 Optimized structural geometry 380 The comparison of the geometric parameters (selected bond lengths and bond angles) of 381 the optimized structures and the crystal structures of the complexes (1-9) are listed in Table S1. 18 ACCEPTED MANUSCRIPT The calculated bond lengths and the bond angles of the complexes are in good agreement with 383 the experimental data indicating the reliability of the theoretical method (B3LYP/6- 384 31G**/LanL2DZ) used in the present study. It should be noted that a slight discrepancy from the 385 experimental value in N(2)-Ru(1)-Cl(1), N(1)-Ru(1)-Cl(1) and N(2)-Rh(1)-Cl(1) bond angle for 386 complexes (1), (4) and (8) has been observed (Table S1). 387 3.6. RI PT 382 Molecular electrostatic potential (MESP) MESP is an important quantity to understand sites for electrophilic attack and 389 nucleophilic attack as well as hydrogen bond interactions [56, 57]. The MESP diagram for all the 390 complexes are shown in Figure 5. The red region represents the negative electrostatic potential, 391 which is related to the nucleophilic reactivity whereas the blue regions represents the positive 392 electrostatic potential and is related to the electrophilic reactivity. The red regions in complexes 393 containing 2-pyridyl cyanoxime and 2-pyridyl phenyloxime does not change much drastically, 394 but in complexes containing 2-thiazolyl methyloxime, the intensity of red color decreases 395 slightly in complexes (8) and (9) as compared to complex (7). 396 3.7. TE D M AN U SC 388 Charge Distribution The charges on the selected atoms as obtained from NBO analysis are listed in Table S2. 398 The charge on the metal (Ru, Rh and Ir) for complexes (1-9) ranges between -0.028 e (complex 399 7) and 0.0248 e (complex 3), which are less than their formal charges of +2 (Ru) and +3 (Rh/Ir). 400 Moreover, as indicated in Table S2, the negative charge on the N1 decreases in all the complexes 401 as compared to their charge in isolated ligands. These results confirm that the ligands transfer 402 their negative charges to the metal on complex formation. The charge on the chloride atom for 403 all the complexes ranges between -0.342 e and -0.406 e. It should be noted that the negative 404 charges on chloride for ruthenium complexes are comparatively lower whereas it is higher for 405 rhodium and iridium complexes. These lowering of charges in ruthenium complexes are the AC C EP 397 19 ACCEPTED MANUSCRIPT reflection of the negative charges on ruthenium complex (1) and (7) and very small positive 407 charge of 0.002 e on Ru in complex (4). As observed from the experimental results, that in the 408 neutral complexes (1, 2 and 3) the anionic charge on oxime-O was delocalized over the 2-pyridyl 409 cyanoxime moiety, therefore we further tried to justify these results with theoretical data as well. 410 In isolated ligand, 2-pyridyl cyanoxime, the charges on the O1, N2 and C6 are found to be - 411 0.545, -0.037 and 0.062 e. On complex formation, the negative charges on the O1 and N2 412 decreases and attains a value of -0.381, -0.387, -0.403 e and 0.159, 0.126, 0.107 e respectively, 413 whereas C6 attains negative charges of -0.050, -0.036 and -0.036 e (Table S2). These results 414 confirm that the anionic charge on the oxime-O is delocalized on complex formation. Moreover, 415 as seen from the bond lengths values (Table 2), on complex formation, the N2-O1 bond is 416 shortened and attains a partial double bond character whereas the N2-C6 bond is elongated as 417 compared to the bonds in isolated ligand. 418 3.8. M AN U SC RI PT 406 TE D Frontier Molecular Orbital and Absorption spectra It is well known that the frontier molecular orbitals (HOMO and LUMO) help in 420 characterizing the electron donating and electron accepting ability of a molecule. Moreover, the 421 HOMO-LUMO energy gap has been utilized as an important parameter to understand the 422 reactivity of a molecule. A lower HOMO-LUMO gap means lesser stability and higher reactivity 423 whereas for higher HOMO-LUMO gap, it is the reverse case. The details of the frontier 424 molecular orbitals are shown in Figure 6 where the red and the green regions represent the 425 positive and the negative phase respectively. The energy gap is least for complex (6) whereas it 426 is highest for complex (8). It should be noted that the energy gap is less for the complexes 427 containing 2-pyridyl phenyloxime indicating its less stability and greater reactivity as compared 428 to the complexes containing ligand 2-pyridyl cyanoxime and 2-thiazolyl methyloxime. The % 429 composition of molecular orbital analysis as shown in Table S3, predicts that for the complexes AC C EP 419 20 ACCEPTED MANUSCRIPT containing 2-pyridyl cyanoxime (complexes 1, 2 and 3), the maximum percentage of HOMO i.e. 431 42%, 35% and 39% is located on the ligand itself. The same case can be encountered for 432 complexes (7) and (8) as well whereas for complexes (4), (6) and (9) most percentage of HOMO 433 is located on the metal (Table S3). On the other hand, the LUMO is located mainly on the ligand 434 for almost all the complexes except for complex (2), where it is located on the Rh metal (about 435 37%). RI PT 430 The electronic absorption spectra were calculated using the TD-DFT method in 437 acetonitrile solvent employing PCM model. The calculated and the experimental absorption data, 438 HOMO-LUMO energy gaps, and the character of electronic transitions are listed in Table 4. The 439 H→L transitions for complexes (1), (3), (7) and (8) occurring at 492, 468, 450 and 485 nm 440 corresponds to ILCT character, for complexes (4), (6) and (9) at 453, 464 and 463 nm 441 corresponds to MLCT character whereas for complexes (2) and (5) at 512.44 and 477 nm 442 corresponds to LMCT and LLCT character. These MLCT character can be assigned as 443 dπ(M)→π∗(L) transitions, ILCT character are for π→π∗ transitions and LLCT for Pπ(Cl)→π*(L) 444 transitions. In agreement with the experimental results, few MLCT transitions has also been 445 observed at 357 nm (4), 359, 335 nm (7), 336 nm (8) and 350 nm (9). Further, few ILCT and 446 LLCT transitions have been observed between 230-304 nm which are in well agreement with the 447 experimental data. 448 4. M AN U TE D EP AC C 449 SC 436 Conclusion In summary, we have successfully synthesized ruthenium, rhodium and iridium half- 450 sandwich oximato and oxime complexes. These complexes were full characterized by various 451 spectroscopic studies and X-ray analysis. The ligands under study preferably bind to the metal in 452 a bidentate κ2 NNʹ fashion using pyridine and oxime nitrogen atom. X-ray structure of 21 ACCEPTED MANUSCRIPT complexes (1-3) reveals the deprotonation of the oxime hydrogen atom leading to the formation 454 of neutral complexes. Chemosensitivity activity of the complexes carried out against HT-29 and 455 MIAPaCa-2 cancer cell lines displayed that some of the complexes are cytotoxic however 456 iridium-based complexes displayed more potency than ruthenium and rhodium complexes. In 457 particularly the neutral iridium oximato compounds possessed the highest activity among other 458 cationic iridium oxime complexes. Further, TD-DFT calculated absorption spectral data are in 459 well agreement with experimental results. 460 Acknowledgements 461 Sanjay Adhikari and Dipankar Sutradhar thanks UGC, New Delhi, India for providing financial 462 assistance in the form of university fellowship (UGC-Non-Net). We thank DST-PURSE 463 SCXRD, NEHU-SAIF, Shillong, India for providing Single crystal X-ray analysis and other 464 spectral studies. AKC thanks Computer center, NEHU, for computational facilities. 465 Appendix A. Supplementary data TE D M AN U SC RI PT 453 466 CCDC 1486252 (1), 1486253 (2), 1486254 (3), 1486255 (4), 1486256 (5), 1486257 (7) 467 and 1486258 (8) contains the supplementary crystallographic data for this paper. 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Chem. 808 (2016) 87. 548 [51] N. Mohan, S. Muthumari, R. Ramesh, J. Organomet. Chem. 807 (2016) 45. 549 [52] G. Gupta, S. Park, S. S. Lee, J. Kim, Z. Anorg. Allg. Chem. 637, 2011, 1516. 550 [53] (a) K.T. Prasad, B. Therrien, K.M. Rao, J. Organomet. Chem. 693 (2008) 3049; (b) G. RI PT 547 Gupta, S. Gloria, B. Das, K.M. Rao, J. Mol. Struc. 979 (2010) 205; (c) J.M. Gichumbi, 552 H.B. Friedrich, B. Omondi, J. Mol. Catal. A: Chemical 416 (2016) 29; (d) L.C. 553 Matsinha, S.F. Mapolie, G.S. Smith, Polyhedron 53 (2013) 56. [54] M AN U 554 SC 551 A.A. Mokhir, K.V. Domasevich, N.K. Dalley, X. Kou, N.N. Gerasimchuk, O.A. Gerasimchuk, Inorg. Chim. Acta. 284 (1999) 85. 555 [55] S. Pal, B.C. Singh, Acta Crystallogr. E69 (2013) m159. 557 [56] L. Xiao-Hong, C. Hong-Ling, Z. Rui-Zhou, Z. Xian-Zhou, Spectrochim. Acta A: Mol. Biomol. Spectrosc. 137 (2015) 321. 560 Y. Wang, Q. Liu, T. Wang, H. Yuan, J. Lin and S. Luo, 150 (2015), 902. AC C 561 [57] EP 558 559 TE D 556 562 563 564 565 Chart-1 26 Scheme-1 Preparation of neutral complexes (1-3) Scheme-2 Preparation of cationic complexes (4-6) AC C EP 569 570 TE D M AN U 566 567 568 SC RI PT ACCEPTED MANUSCRIPT 571 572 Scheme-3 Preparation of cationic complexes (7-9) 27 M AN U SC RI PT ACCEPTED MANUSCRIPT 573 Figure 1 (a) Ortep diagram of complex (1), (b) Ortep diagram of complex (2) and (c) Ortep diagram of complex (3) with 50% 575 probability thermal ellipsoids. Hydrogen atoms are omitted for clarity. AC C EP TE D 574 28 SC RI PT ACCEPTED MANUSCRIPT 576 Figure 2 (a) Ortep diagram of complex (4) and (b) Ortep diagram of complex (5) with 50% 578 probability thermal ellipsoids. Counter ions and hydrogen atoms (except on O1) are omitted for 579 clarity. M AN U 577 581 AC C EP TE D 580 582 Figure 3 (a) Ortep diagram of complex (7) and (b) Ortep diagram of complex (8) with 50% 583 probability thermal ellipsoids. Counter ions and hydrogen atoms (except on O1) are omitted for 584 clarity. 29 M AN U SC RI PT ACCEPTED MANUSCRIPT 585 Figure 4 Response of HT-29 (human colorectal cancer) and MIAPaCa-2 (human pancreatic 587 cancer) to compounds and cisplatin. Cell was exposed to compounds (1-9) for 96 hours. Each 588 value represents the mean ± standard deviation from three independent experiments. AC C EP TE D 586 30 589 590 AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT Figure 5 Molecular electrostatic potential diagrams for complexes (1-9). 31 Figure 6 HOMO, LUMO energies and their energy gaps of complexes (1-9). EP 592 AC C 591 TE D M AN U SC RI PT ACCEPTED MANUSCRIPT 32 ACCEPTED MANUSCRIPT Table 1 Crystal data and structure refinement parameters of complexes. [2] C17H19ClN3ORh 419.71 291(2) 0.71073 Monoclinic P21/c 8.3023(9)/90 27.612(2)/112.173(12) c (Å)/γ (°) 14.6872(4)/90 1721.07(9) Volume (Å3) Z Density (calc) (Mg/m-3) Absorption coefficient (µ) (mm-1) [5]PF6 C22H25ClF6N2OPRh 616.77 296(2) 0.71073 Triclinic P ͞1 9.0597(5)/67.455(5) 12.7557(7)/82.956(5) [7]PF6 C15H20ClF6N2OPRuS 557.88 291(2) 0.71073 Monoclinic P21/m 10.5576(7)/90 9.3658(7)/104.388(7) [8]PF6·H2O C15H23ClF6N2O2PRhS 578.74 295(2) 0.71073 Monoclinic P21/c 12.6553(5)/90 10.8936(4)/98.858(4) 19.6319(9)/90 2486.38(19) 13.2635(8)/87.886(5) 1404.86(14) 13.2319(10)/90 1267.34(16) 16.3323(6)/90 2224.75(15) 4 1.640 2 1.458 2 1.462 4 1.728 0.815 0.919 1.117 [4]PF6 C22H24ClF6N2OPRu 613.92 292(2) 0.71073 Monoclinic P21/n 9.0701(4)/90 14.1127(6)/98.340(4) 8.1421(8)/90 1728.5(3) [3] C17H19ClN3OIr 509.00 295(2) 0.71073 Monoclinic P21/c 8.3165(6)/90 27.5547(13)/112.388( 7) 8.2007(5)/90 1737.61(18) 4 1.609 4 1.613 4 1.946 1.073 1.149 7.844 RI PT [1] C17H18ClN3ORu 416.86 292(2) 0.71073 Orthorhombic Pca21 14.9960(5)/90 7.8142(2)/90 SC Compounds Empirical formula Formula weight Temperature (K) Wavelength (Å) Crystal system Space group a (Å)/α (°) b (Å)/β (°) M AN U 593 0.865 840 848 976 1232 620 556 1160 Crystal size (mm3) 0.24 x 0.19 x 0.09 0.24 x 0.19 x 0.08 0.29 x 0.25 x 0.02 0.29 x 0.24 x 0.12 0.21 x 0.19 x 0.15 0.36 x 0.25 x 0.23 0.25 x 0.21 x 0.19 Theta range for data collection Index ranges Reflections collected Independent reflections 3.05 to 28.74° -20<=h<=16, 10<=k<=9, 17<=l<=18 6209 3438 [R(int) = 0.0311] 3.08 to 28.74° -6<=h<=11, 36<=k<=36 10<=l<=10 8785 3956 [R(int) = 0.0602] 3.03 to 28.73° -11<=h<11, 30<=k<=36, 10<=l<=5 9093 3978 [R(int) = 0.0494] 3.07 to 29.07° -10<=h<=12, 18<=k<=10, 26<=l<17 9847 5682 [R(int) = 0.0186] 3.22 to 29.12° -11<=h<=11, 16<=k<=11, 17<=l<17 9798 6373 [R(int) = 0.0329] 3.58 to 28.93° -12<=h<=14, 11<=k<=12, 10<=l<17 4790 3037 [R(int) = 0.0230] 3.14 to 29.01° -13<=h<=15, 12<=k<=13, 22<=l<20 8932 5071 [R(int) = 0.0261] Completeness to theta = 25.00° 99.7 % 99.5 % Absorption correction Semi-empirical from equivalents 0.9096 and 0.7828 Semi-empirical from equivalents 0.9137 and 0.7700 Refinement method Full-matrix least- Data/restraints/parameters squares on F2 3438/1/211 Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Largest diff. peak and hole ( e.Å-3) CCDC No. 594 1.00 R1 = 0.0322, wR2 = 0.0498 R1 = 0.0425, wR2 = 0.0526 0.583 and -0.461 1486252 99.6 % 99.5 % 98.3 % 99.5 % Semi-empirical from equivalents 0.9033 and 0.7875 Semi-empirical from equivalents 0.8875 and 0.8474 Semi-empirical from equivalents 0.8164 and 0.7331 Semi-empirical from equivalents 0.8159 and 0.7677 Full-matrix leastsquares on F2 Full-matrix leastsquares on F2 Full-matrix leastsquares on F2 Full-matrix leastsquares on F2 Full-matrix leastsquares on F2 Full-matrix leastsquares on F2 3956/0/213 5071/3/275 EP 99.6 % Semi-empirical from equivalents 0.8589 and 0.2094 3978/30/213 5682/0/311 6373/136/412 3037/172/229 1.057 1.085 1.090 1.059 1.005 1.049 R1 = 0.0566, wR2 = 0.0966 R1 = 0.1081, wR2 = 0.1077 0.790 and -0.865 R1 = 0.0526, wR2 = 0.1118 R1 = 0.0713, wR2 = 0.1217 2.329 and -1.955 R1 = 0.0331, wR2 = 0.0728 R1 = 0.0426, wR2 = 0.0777 0.377 and -0.519 R1 = 0.0473, wR2 = 0.1153 R1 = 0.0649, wR2 = 0.1241 0.449 and -0.350 R1 = 0.0524, wR2 = 0.1426 R1 = 0.0640, wR2 = 0.1540 0.871 and -0.857 R1 = 0.0475, wR2 = 0.1064 R1 = 0.0706, wR2 = 0.1211 0.734 and -0.393 AC C Max. And min. transmission 1486253 2 TE D F(000) 2 1486254 2 2 1486255 2 2 1/2 Structures were refined on F0 : wR2 = [Σ[w(F0 - Fc ) ] / Σw(F0 ) ] , where w 33 -1 1486256 1486257 1486258 2 2 2 = [Σ(F0 )+(aP) +bP] and P = [max(F0 , 0)+2Fc2]/3 ACCEPTED MANUSCRIPT Table 2 Selected bond lengths (Å) and bond angles (°) of complexes. 1 2 3 4 5 7 8 M(1)-CNT 1.696 1.799 1.803 1.696 1.788 1.728 1.775 M(1)-N(1) 2.073(3) 2.093(4) 2.084(7) 2.0587(18) 2.103(3) 2.09(2) 2.108(3) M(1)-N(2) 2.028(3) 2.065(4) 2.039(7) 2.0854(19) 2.102(3) 2.08(3) 2.131(4) M(1)-Cl(1) 2.3897(11) 2.3870(16) 2.391(2) 2.4191(7) 2.4225(10) 2.415(2) 2.3991(12) M(1)-Cave 2.203 2.165 2.170 2.205 2.157 2.179 2.149 N(2)-O(1) 1.271(4) 1.262(5) 1.254(9) ----- ---- ---- ---- N(2)-C(6) 1.330(5) 1.334(7) 1.360(11) ---- ---- ---- ---- N(1)-M(1)-N(2) 77.81(13) 78.06(16) 78.0(3) 75.66(7) 74.92(11) 78.0(10) 75.16(15) N(1)-M(1)-Cl(1) 85.22(9) 87.07(13) 84.8(2) 85.10(6) 87.58(9) 88.4(5) 88.51(10) N(2)-M(1)-Cl(1) 84.87(9) 86.72(14) 85.6(2) 84.20(5) 89.30(9) 81.1(6) 89.14(11) N(1)-M(1)-CNT 132.9 132.5 133.8 132.0 129.6 132.3 128.6 N(2)-M(1)-CNT 130.6 130.4 131.2 131.5 130.5 133.0 132.4 Cl(1)-M(1)-CNT 127.3 125.5 125.7 129.2 127.7 127.8 126.3 SC RI PT Complex M AN U 595 CNT represents the centroid of the arene/Cp* ring; Cave represents the average bond distance of 597 the arene/Cp* ring carbon and metal atom. 598 Table 3 Response of HT-29 (human colorectal cancer) and MIAPaCa-2 (human pancreatic 599 cancer) to complexes (1-9) and cisplatin. Each value represents the mean ± standard deviation 600 from three independent experiments. IC50 (µM) HT-29 MIAPaCa-2 >100 >100 1 23.74 ± 4.25 9.16 ± 2.89 2 5.82 ± 2.41 2.87 ± 0.26 3 68.83 ± 27.0 26.42 ± 0.67 4 42.32 ± 10.69 67.18 ± 3.16 5 7.92 ± 1.00 8.35 ± 0.29 6 12.56 ± 4.45 8.28 ± 0.42 7 >100 >100 8 10.54 ± 4.73 9.65 ± 1.68 9 Cisplatin 0.25 ± 0.11 2.84 ± 2.05 IC50 = concentration of the drug required to inhibit the growth of 50% of the cancer cells (µM). AC C EP Complexes TE D 596 601 34 ACCEPTED MANUSCRIPT 602 Table 4 Energy gap, theoretical and experimental absorption bands, electronic transitions and 603 dominant excitation character for various singlet states of the complexes (1-9) calculated with 604 TD-DFT method. 492.28 371.17 362.01 304.45 301.08 238.25 235.61 3.67 4.50 3.93 4.61 4.89 5.91 5.92 H→L H-2→L+2 H→L+3 H-6→L+1 512.44 364.41 293.93 253.61 3.65 4.59 4.65 5.77 H→L H-2→L H-3→L+1 H-1→L+2 H-6→L+2 467.55 376.61 290.41 283.58 232.24 3.70 4.26 5.24 4.68 6.20 H→L H-2→L H-1→L+2 H-4→L+1 H-4→L+3 452.56 379.18 357.48 271.57 231.48 3.42 4.09 4.46 4.86 5.51 H→L H-1→L+2 H-2→L H-6→L+1 476.51 357.91 345.27 267.72 3.48 4.27 3.95 5.28 H→L 464.21 3.32 H-1→L+1 H-7→L H-3→L+1 352.62 294.49 290.68 4.52 5.07 5.13 H→L 450.26 3.39 Complex 1 0.0021 0.0025 0.0488 0.1337 0.0161 0.0034 0.0485 Complex 2 0.0046 0.0306 0.0438 0.1544 Complex 3 0.0036 0.0523 0.0192 0.0903 0.0153 Complex 4 0.0024 0.0245 0.0106 0.0021 0.0180 Complex 5 0.0093 0.1024 0.0105 0.0341 Complex 6 0.0223 AC C EP TE D H→L H-3→L H-1→L H→L+3 H→L+4 H-2→L+6 H-5→L+2 Oscillator strength (f) Dominant excitation Character 0.0372 0.0102 0.0026 Complex 7 0.0038 35 Experimental λ (nm) RI PT Energy gap E (eV) L1→L1(ILCT) L1→L1(ILCT) L1→L1(ILCT) L1→L1(ILCT) L1→Cp*(LLCT) Cl→L1(LLCT) Ru→L1(MLCT) SC Calculated λ (nm) M AN U The most important orbital excitations L1→Rh(LMCT) Cl→Rh(LMCT) L1→L1(ILCT) Rh→L1(MLCT) L1→L1(ILCT) Cl→L1(LLCT) L1→Ir(LMCT) L1→L1(ILCT) Ir→L1(MLCT) Ru→L2(MLCT) L2→L2(ILCT) Ru→L2(MLCT) L2→Ru(LMCT) L2→L2(ILCT) Cl→L2(LLCT) Cl→Ru(LMCT) Cl→L2(LLCT) L2→Rh(LMCT) 370 302 237 374 289 255 378 288 233 376 272 233 357 266 Ir+Cl→L2(MLCT/ LLCT) Cl→L2(LLCT) 360 Ir→L2(MLCT) 296 L2→L2(ILCT) L3→L3(ILCT) ACCEPTED MANUSCRIPT 4.01 5.01 5.59 5.30 H→L H-1→L+2 H-3→L H-3→L+2 H-8→L+1 484.85 345.81 335.78 285.07 229.87 3.87 4.52 4.40 4.73 5.27 H→L H-1→L+1 H-2→L 463.13 350.0 288.36 3.72 4.81 4.37 0.0091 0.0036 0.0598 0.0328 Complex 8 0.0028 0.0506 0.0238 0.0296 0.0127 Complex 9 0.0010 0.0182 0.0250 L3→L3(ILCT) L3→L3(ILCT) Rh→L3(MLCT) Rh→L3(MLCT) Rh→L3(MLCT) Ir→L3(MLCT) Ir→L3(MLCT) L3→L3(ILCT) AC C EP TE D M AN U 605 Ru→L3(MLCT) Ru→L3(MLCT) Ru→L3(MLCT) L3→Ru(LMCT) 36 347 297 349 RI PT 359.31 334.71 293.24 291.42 SC H-3→L H-3→L+1 H-4→L H→L+3 287 360 ACCEPTED MANUSCRIPT Highlights RI PT
Neutral oximato and cationic oxime complexes of ruthenium, rhodium and iridium were isolated with electron withdrawing and electron donating substituted pyridyl oximes. SC
DFT calculations demonstrate that the calculated values are in good agreement with the experimental data. M AN U
Iridium based oximato and oxime complexes exhibited better activity than AC C EP TE D ruthenium and rhodium complexes.