Synthesis, structural, DFT calculations and biological studies of rhodium and iridium complexes containing azine Schiff-base ligands

Article abstract of DOI:10.1016/j.poly.2016.06.001

The reaction of [Cp*MCl₂]₂(M?=?Rh/Ir) with N–N′ azine Schiff-base ligands (L1–L4) leads to the formation of mononuclear cationic half-sandwich complexes having the general formula [Cp*M(L)Cl]⁺(1–8), (M?=?Rh/Ir and L?=?(2-hydroxy-4-methoxybenzylidene)2-pyridylamidrazone (L1), (2-hydroxybenzylidene)2-pyridylamidrazone (L2), (1-(2-hydroxyphenyl)ethylidene)2-pyridylamidrazone (L3) and (1-phenylethylidene)2-pyridylamidrazone (L4). All these complexes were isolated as their hexafluorophosphate salts and fully characterized by spectroscopic and analytical techniques. The molecular structure of complexes (1), (3), (4), (7) and (8) have been determined by single crystal X-ray crystallographic studies which displayed the coordination of the ligand to the metal in a bidentate N∩N fashion through nitrogen atom of pyridine and one azine nitrogen. The chemo-sensitivity activities of the complexes were evaluated against HT-29 (human colorectal cancer) cell line and non-cancer cell line ARPE-19 (human retinal epithelial cells) which revealed that the complexes are moderately cytotoxic to cancer cells over human cells although complex 5 was the most potent among all the compounds. Theoretical studies carried out using DFT and TD-DFT at B3LYP level shows good agreement with the experimental results.

Full text of DOI:10.1016/j.poly.2016.06.001

Accepted Manuscript
Synthesis, structural, DFT calculations and biological studies of rhodium and
iridium complexes containing azine Schiff-base ligands
Sanjay Adhikari, Dipankar Sutradhar, Samantha L. Shepherd, Roger M.
Phillips, Asit K. Chandra, K. Mohan Rao
PII:
S0277-5387(16)30218-2
DOI:
http://dx.doi.org/10.1016/j.poly.2016.06.001
POLY 12039
Reference:
Polyhedron
To appear in:
Received Date:
Accepted Date:
4 May 2016
1 June 2016
Please cite this article as: S. Adhikari, D. Sutradhar, S.L. Shepherd, R.M. Phillips, A.K. Chandra, K. Mohan Rao,
Synthesis, structural, DFT calculations and biological studies of rhodium and iridium complexes containing azine
Schiff-base ligands, Polyhedron (2016), doi: http://dx.doi.org/10.1016/j.poly.2016.06.001
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Synthesis, structural, DFT calculations and biological studies of rhodium and
iridium complexes containing azine Schiff-base ligands
Sanjay Adhikaria, Dipankar Sutradhara, Samantha L. Shepherdb, Roger M Phillipsb,
Asit K. Chandraa, K. Mohan Raoa*
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aCentre for Advanced Studies in Chemistry, North-Eastern Hill University,
Shillong 793 022, India.
E-mail: mohanrao59@gmail.com
Telephone Number: +91 364 2722620
Fax Number: +91 364 2550076
bDepartment of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield
HD1 3DH, UK
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Graphical abstract
Half-sandwich Cp*Rh(III) and Cp*Ir(III) complexes have been synthesized with N-Nʹ azine
Schiff-base ligands and characterized by spectroscopic techniques. The molecular structures of
some of the representative complexes have been confirmed by single crystal X-ray analysis.
Chemo-sensitivity activities of the complexes were evaluated against HT-29 (human colorectal
cancer) cell line and non-cancer cell line ARPE-19 (human retinal epithelial cells).
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Complex 1
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Abstract
The reaction of [Cp*MCl2]2 (M = Rh/Ir) with N-Nʹ azine Schiff-base ligands (L1-L4)
leads to the formation of mononuclear cationic half-sandwich complexes having the general
formula [Cp*M(L)Cl]+ (1–8), (M = Rh/Ir and L = (2-hydroxy-4-methoxybenzylidene)2-
pyridylamidrazone
(L1),
(2-hydroxybenzylidene)2-pyridylamidrazone
(L2),
(1-(2-
hydroxyphenyl)ethylidene)2-pyridylamidrazone
(L3) and (1-phenylethylidene)2-
pyridylamidrazone (L4). All these complexes were isolated as their hexafluorophosphate salts
and fully characterized by spectroscopic and analytical techniques. The molecular structure of
complexes (1), (3), (4), (7) and (8) have been determined by single crystal X-ray crystallographic
studies which displayed the coordination of the ligand to the metal in a bidentate N∩N fashion
through nitrogen atom of pyridine and one azine nitrogen. The chemo-sensitivity activities of the
complexes were evaluated against HT-29 (human colorectal cancer) cell line and non-cancer cell
line ARPE-19 (human retinal epithelial cells) which revealed that the complexes are moderately
cytotoxic to cancer cells over human cells although complex 5 was the most potent among all the
compounds. Theoretical studies carried out using DFT and TD-DFT at B3LYP level shows good
agreement with the experimental results.
Keywords: Rhodium, Iridium, Azine Schiff-base ligands, Cytotoxicity
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1.
Introduction
The chemistry of half-sandwich organometallic complexes has evolved as a versatile
subject of research during the past few decades due to its wide application in biological and
medicinal fields [1-4]. Organometallic half-sandwich compounds of the general formula
[Cp*MCl(LLʹ)] (M = Rh, Ir and LL' = N,N or N,O donor ligands) have been extensively studied
for their cytostatic activity, DNA binding, cellular uptake and as DNA intercelators [5-9].
Rhodium and iridium complexes have also been investigated as an alternative to platinum based
drugs mainly because of their water solubility and lability towards ligand exchange [10, 11].
Recently Therrien et.al reported dinuclear dithiolato bridged rhodium and iridium complexes
which exhibit cytotoxicity against human ovarian cancer cells lines (A2780 and A2780cisR)
[12]. C-H activated cyclometallated Rh(III) and Ir(III) complexes can effectively bind to DNA
and protein through electrostatic and hydrophobic interactions [13]. Iridium complexes of
dihydroxybipyridine are active catalysts for homogenous water oxidation under mild reaction
conditions [14]. Rh(III) and Ir(III) polypyridyl complexes exhibits strong antiproliferative
activity towards human cancer cell lines and are also capable of binding to DNA [15]. A number
of half-sandwich Ir(III) complexes have been reported by Sadler et al with chelating C, N and
pyridine ligands and N, N donor ligands which showed strong antiproliferative activity [16, 17].
Pyridyl azines represent an important class of organic compounds with interesting
properties having wide applications in various areas [18]. Open chain diazine Schiff base ligands
linked by a single N-N bond are of great interest due to its rotational flexibility around the N-N
bond and potential donor sites which can give rise to a rich variety of coordination compounds
with different binding modes [19]. The N-N bridging ligand plays a crucial role in
communicating the metal centers to form mononuclear, dinuclear or polynuclear complexes [20].
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The diazine ligand has been employed into several transition metal azido and thiocyanato
systems namely Mn(II)-azido, Cd(II)-NCS to obtain several 1D, 2D and 3D polymers which
exhibit interesting magnetic properties [21, 22]. Dinuclear transition metal complexes of Cu, Zn,
Mn and Ni have been reported with bridging N-N diazine ligands which give rise to strong
ferromagnetic and antiferromagnetic coupling [23]. In the recent years our group has reported
many half-sandwich Ru(II), Rh(III) and Ir(III) complexes with azine ligands [24, 25]. In
continuation with our interest of these ligands herein we report four new azine Schiff base
ligands derived from 2-pyridylamidrazone and its corresponding rhodium and iridium half-
sandwich metal complexes. The complexes were tested for their cytotoxic property to selectively
kill HT-29 cancer cell line against normal ARPE-19 cells.
2. Experimental Section
2. 1. Physical methods and materials
All the reagents were purchased from commercial sources and used as received. Starting
materials RhCl3.nH2O, IrCl3.nH2O were purchased from Arora Matthey limited. 2-
cyanopyridine, 2-hydroxybenzaldehyde, 2-hydroxyacetophenone, were obtained from Aldrich,
acetophenone and 2-hydroxy-4-methoxybenzaldehyde were obtained from Alfa-Aesar. The
solvents were purified and dried according to standard procedures [26]. All the reactions were
carried out under normal conditions. The starting precursor metal complexes [Cp*MCl2]2 (M =
Rh/Ir) were prepared according to the literature methods [27]. Infrared spectra were recorded on
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a Perkin-Elmer 983 spectrophotometer by using KBr pellets in the range of 400-4000 cm-1. H
NMR spectra were recorded on a Bruker Avance II 400 MHz spectrometer using DMSO-d6 and
CDCl3 as solvents. Absorption spectra were recorded on a Perkin-Elmer Lambda 25 UV/Visible
spectrophotometer in the range of 200-800 nm at room temperature in acetonitrile. Elemental
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analyses of the complexes were performed on a Perkin-Elmer 2400 CHN/S analyzer. Mass
spectra were recorded using Q-Tof APCI-MS instrument (model HAB 273). All these
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mononuclear metal complexes were synthesized and characterized by using FT-IR, H NMR,
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UV-Vis, and Single-crystal X-ray diffraction techniques.
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2. 2. Single-crystal X-ray structures analyses
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The orange crystals of complexes (1), (3), (7) and (8) were obtained by slow diffusion of
hexane into acetone or DCM solution and yellow crystals of complex (4) was obtained by
diffusing hexane into DCM solution. Single crystal X-ray diffraction data for all the complexes
(1), (3) (4), (7) and (8) were collected on a Oxford Diffraction Xcalibur Eos Gemini
diffractometer at 293 K using graphite monochromated Mo-Kα radiation (λ = 0.71073 Å). The
strategy for the data collection was evaluated using the CrysAlisPro CCD software. Crystal data
were collected by standard ‘‘phi–omega scan’’ techniques and were scaled and reduced using
CrysAlisPro RED software. The structures were solved by direct methods using SHELXS-97
and refined by full-matrix least squares with SHELXL-97 refining on F2 [28, 29]. The positions
of all the atoms were obtained by direct methods. Metal atoms in the complex were located from
the E-maps and non-hydrogen atoms were refined anisotropically. The hydrogen atoms bound to
the carbon were placed in geometrically constrained positions and refined with isotropic
temperature factors, generally 1.2 Ueq of their parent atoms. Crystallographic and structure
refinement details for the complexes are summarized in Table 1, and selected bond lengths and
bond angles are presented in Table S1. Figures 1-3 were drawn with ORTEP3 program. Figure 4
and Figures S3-S6 were drawn with MERCURY3.6 program [30].
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2.3. Biological studies
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All complexes (1-8) were dissolved in DMSO at 100 mM and stored at -20 °C until
needed. The complexes were tested against cancer cell line HT-29 (human colorectal cancer),
and one non-cancer cell line ARPE-19 (human retinal epithelial cells). Cells were seeded into 96
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well plates at 1 x 103 cells per well and incubated at 37 C in a CO2 enriched (5%), humidified
atmosphere overnight to adhere. The cells were exposed to a range of drug concentrations in the
range of 0-100 µM for four days before cell survival was determined using the MTT assay [31].
To each well MTT (0.5 mg/ml) was added and was further incubated at 37 °C for 4 h. After this
the MTT was removed from each well and the formazan crystals formed were dissolved in 150
µM DMSO. The absorbance of the resulting solution was recorded at 550 nm using an ELISA
spectrophotometer. The percentage of cell inhibition was calculated by dividing the absorbance
of treated cell by the control value absorbance (exposed to 0.1 % DMSO). The results were
expressed in terms of IC50 values (concentration required to kill 50 % cell) and all studies were
performed in triplicate. The results were also expressed in terms of a ‘selectivity index’ defined
as the IC50 of the non-cancer cell line ARPE divided by the IC50 of cancer cell lines [32]. Values
greater than 1 demonstrate that the compound is preferentially active against tumor cell
compared to normal cell lines.
2.4. Computational methodology
All the electronic structure calculations of the metal complexes (1-8) were carried out
using the Gaussian 09 suite of program [33]. The geometries of the rhodium and iridium
complexes were optimized in the gas phase employing the DFT-based B3LYP method with 6-
31G** basis set for (H, C, N, O, Cl, F and P atoms and LANL2DZ [34, 35] for (Rh and Ir)
atoms. Harmonic frequency calculations were carried out at the same level of theory to ensure
that the optimized geometries were true minima on the potential energy surface (PES). Natural
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Bond Orbital (NBO) analysis [36] was used to obtain the charge distribution on individual atoms
and the d-orbital occupations of the metal present in the complexes. Time dependent-Density
Functional Theory (TD-DFT) [37] has been employed to evaluate the absorption spectra and the
electronic transitions of the metal complexes. In order to incorporate the effect of the solvent
around the molecule, the Polarizable Continuum Model (PCM) [38] was used in TD-DFT
calculations. The percentage contribution of molecular orbital analysis was carried out using
Chemissian software package [39].
2.4. General procedure for preparation of ligands 1-4
2.4.1. The azine Schiff base ligands (L1-L4) were prepared by two step procedure.
In the first step 2-pyridylamidrazone was prepared, by following a reported procedure
[40]. 2-cyanopyridine and hydrazine hydrate were dissolved and stirred in absolute ethanol
overnight to give 2-pyridylamidrazone as yellow crystalline solid which was used in the next
step without further purification (Scheme-1). In the second step (5 mmol) of aldehyde or ketone
and 2-pyridylamidrazone (5 mmol) was refluxed in 10 ml ethanol for 5 hours (Scheme-2). The
products obtained after cooling the solution were filtered off washed with cold methanol and
diethyl ether and dried in vacuum.
Data for ligands (L1-L4)
2.4.2. (2-hydroxy-4-methoxybenzylidene)2-pyridylamidrazone (L1)
Color: Yellow needles; Yield: 88%; IR (KBr, cm-1): 3487(s), 3380(s), 3333(m), 2964(m),
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1627(s), 1587(m), 1566(m), 1394(m), 1340(s); H NMR (400 MHz, CDCl3): δ = 11.82 (s, 1H,
OH), 8.60 (s, 1H, CH(imine)), 8.57 (d, 1H, J = 4.0 Hz, CH(py)), 8.34 (d, 1H, J = 8.0 Hz, CH(py)),
7.76 (t, 1H, CH(py)), 7.35 (t, 1H, CH(py)), 7.20 (d, 2H, J = 8.0 Hz, CH(Ar)), 6.46-6.50 (m, 3H, NH2,
CH(Ar)), 3.80 (s, 3H, OMe); HRMS-APCI (m/z): 271.11 [M+H]+; UV–Vis {Acetonitrile, λmax
,
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nm (ε/10-4 M-1 cm-1)}: 218 (0.84), 314 (0.68), 342 (0.92), 355 (0.94); Anal. Calc. for C14H14N4O2
(270.29): C, 62.21; H, 5.22; N, 20.73. Found: C, 62.36; H, 5.35; N, 20.86%.
2.4.3. (2-hydroxybenzylidene)2-pyridylamidrazone (L2)
Color: Yellow needles; Yield: 92%; IR (KBr, cm-1): 3477(s), 3363(s), 3340(s), 3043(m), 1626(s),
1576(m), 1567(m), 1473(m), 1337(m); 1H NMR (400 MHz, CDCl3): δ = 11.61 (s, 1H, OH), 8.59
(s, 1H, CH(imine)), 8.54 (d, 1H, J = 4.0 Hz, CH(py)), 8.28 (d, 1H, J = 8.0 Hz, CH(py)), 7.74 (t, 1H,
CH(py)), 7.33 (t, 1H, CH(py)), 7.24-7.27 (m, 3H, NH2, CH(Ar)), 6.96 (d, 1H, J = 8.0 Hz, CH(Ar)),
6.87 (t, 2H, CH(Ar)); HRMS-APCI (m/z): 241.10 [M+H]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4
M-1 cm-1)}: 219 (0.84), 247 (0.55), 349 (1.30), 361 (1.29); Anal. Calc. for C13H12N4O (240.26):
C, 64.99; H, 5.03; N, 23.32. Found: C, 65.12; H, 5.18; N, 23.44%.
2.4.4. (1-(2-hydroxyphenyl)ethylidene)2-pyridylamidrazone (L3)
Color: Yellow crystalline solid; Yield: 95%; IR (KBr, cm-1): 3482(s), 3339(s), 3056(m),
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3003(m), 1615(s), 1562(m), 1507(m), 1300(m); H NMR (400 MHz, CDCl3): δ = 13.73 (s, 1H,
OH), 8.59 (d, 1H, J = 4.0 Hz, CH(py)), 8.36 (d, 1H, J = 8.0 Hz, CH(py)), 7.79 (t, 1H, CH(py)), 7.58
(t, 1H, CH(py)), 7.21-7.28 (m, 3H, NH2, CH(Ar)), 6.98 (d, 2H, J = 8.0 Hz, CH(Ar)), 6.89 (t, 1H,
CH(Ar)), 2.62 (s, 3H, CH3); HRMS-APCI (m/z): 255.12 [M+H]+; UV–Vis {Acetonitrile, λmax, nm
(ε/10-4 M-1 cm-1)}: 217 (1.21), 303 (0.74), 344 (0.95); Anal. Calc. for C14H14N4O (254.29): C,
66.13; H, 5.55; N, 22.03. Found: C, 66.25; H, 5.68; N, 22.21%.
2.4.5. (1-phenylethylidene)2-pyridylamidrazone (L4)
Color: Yellow crystalline solid; Yield: 92%; IR (KBr, cm-1): 3450(s), 3331(s), 3056(m),
3009(m), 1604(s), 1568(m), 1445(m), 1362(m); 1H NMR (400 MHz, CDCl3): δ = 8.58 (d, 1H, J
= 4.0 Hz, CH(py)), 8.23 (d, 1H, J = 8.0 Hz, CH(py)), 7.71 (t, 1H, CH(py)), 7.30 (t, 1H, CH(py)), 7.21-
7.28 (m, 3H, NH2, CH(Ar)), 6.93 (m, 3H, CH(Ar)), 6.89 (t, 1H, CH(Ar)), 2.39 (s, 3H, CH3); HRMS-
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APCI (m/z): 239.13 [M+H]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 225 (0.21), 327
(0.29); Anal. Calc. for C14H14N4 (238.29): C, 70.57; H, 5.92; N, 23.51. Found: C, 70.72; H, 6.03;
N, 23.62%.
2.5. General procedure for preparation of metal complexes (1-8)
A mixture of metal precursor [Cp*MCl2]2 (M = Rh/Ir) (0.1 mmol), azine Schiff-base ligands (L1-
L4) (0.2 mmol) and 2.5 equivalents of NH4PF6 in dry methanol (10 ml) was stirred at room
temperature for 8 hours (Scheme-3). The solvent was evaporated under reduced pressure, and the
residue was dissolved in dichloromethane and filtered over celite to remove excess salt. The
filtrate was reduced to 2 ml and diethyl ether was added to induce precipitation. The yellow
colored precipitate, which formed, was filtered and washed with diethyl ether and dried in
vacuum.
2.5.1. [Cp*Rh(L1)Cl]PF6 (1)
Yield: 56 mg (40%); IR (KBr, cm-1): 3460(m), 3237(m), 2926(w), 1630(s), 1595(m), 1296(m),
846(s); 1H NMR (400 MHz, CDCl3): δ = 10.5 (s, 1H, OH), 9.02 (s, 1H, CH(imine)), 8.76 (d, 1H, J
= 4.0 Hz, CH(py)), 8.54 (d, 1H, J = 4.0 Hz, CH(py)), 8.13 (t, 1H, CH(py)), 7.76 (t, 1H, CH(py)), 7.41
(d, 1H, J = 8.0 Hz, CH(Ar)), 7.38 (s, 2H, NH2), 6.53 (d, 1H, J = 8.0 Hz, CH(Ar),), 6.50 (s, 1H,
CH(Ar)), 3.81 (s, 3H, OMe), 1.58 (s, 15H, CH(Cp*)); HRMS-APCI (m/z): 507.12 [M-PF6-HCl]+;
UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 233 (0.98), 277 (0.57), 352 (0.42); Anal.
Calc. for C24H29ClF6N4O2PRh (688.84): C, 41.85; H, 4.24; N, 8.13. Found: C, 41.96; H, 4.16; N,
8.23%.
2.5.2. [Cp*Ir(L1)Cl]PF6 (2)
Yield: 70 mg (45%); IR (KBr, cm-1): 3447(m), 3241(m), 2925(m), 1630(s), 1610(m), 1293(m),
846(s); 1H NMR (400 MHz, CDCl3): δ = 10.4 (s, 1H, OH), 9.02 (s, 1H, CH(imine)), 8.77 (d, 1H, J
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= 4.0 Hz, CH(py)), 8.51 (d, 1H, J = 4.0 Hz, CH(py)), 8.17 (t, 1H, CH(py)), 7.78 (t, 1H, CH(py)), 7.42
(d, 1H, J = 8.0 Hz, CH(Ar)), 7.39 (s, 2H, NH2), 6.56 (d, 1H, J = 8.0 Hz, CH(Ar)), 6.54 (s, 1H,
CH(Ar)), 3.87 (s, 3H, OMe), 1.62 (s, 15H, CH(Cp*)); HRMS-APCI (m/z): 597.18 [M-PF6-HCl]+;
UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 266 (0.36), 347 (0.29); Anal. Calc. for
C24H29ClF6N4O2PIr (778.14): C, 37.04; H, 3.76; N, 7.20. Found: C, 37.19; H, 3.89; N, 7.31%.
2.5.3. [Cp*Rh(L2)Cl]PF6 (3)
Yield: 52 mg (39%); IR (KBr, cm-1): 3422(m), 3310(w), 2923(w), 1636(s), 1603(m), 1457(m),
845(s); 1H NMR (400 MHz, CDCl3): δ = 10.1 (s, 1H, OH), 9.11 (s, 1H, CH(imine)), 8.78 (d, 1H, J
= 4.0 Hz, CH(py)), 8.49 (d, 1H, J = 8.0 Hz, CH(py)), 8.14 (t, 2H, CH(py)), 7.78 (t, 1H, CH(Ar)), 7.60
(d, 1H, J = 8.0 Hz, CH(Ar)), 7.38 (s, 2H, NH2), 6.92-7.01 (m, 2H, CH(Ar)), 1.58 (s, 15H, CH(Cp*));
HRMS-APCI (m/z): 477.12 [M-PF6-HCl]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}:
235 (1.55), 283 (0.79), 348 (1.00); Anal. Calc. for C23H27ClF6N4OPRh (658.81): C, 41.93; H,
4.13; N, 8.50. Found: C, 42.08; H, 4.25; N, 8.68%.
2.5.4. [Cp*Ir(L2)Cl]PF6 (4)
Yield: 52 mg (34%); IR (KBr, cm-1): 3479(s), 3329(s), 2924(w), 1642(s), 1618(m), 1602(m),
842(s); 1H NMR (400 MHz, CDCl3): δ = 10.1 (s, 1H, OH), 9.13 (s, 1H, CH(imine)), 8.80 (d, 1H, J
= 4.0 Hz, CH(py)), 8.56 (d, 1H, J = 8.0 Hz, CH(py)), 8.18 (t, 2H, CH(py)), 7.80 (t, 1H, CH(Ar)), 7.64
(d, 1H, J = 8.0 Hz, CH(Ar)), 7.40 (s, 2H, NH2), 6.99-7.35 (m, 2H, CH(Ar)), 1.63 (s, 15H, CH(Cp*));
HRMS-APCI (m/z): 567.17 [M-PF6-HCl]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}:
291 (0.62), 344 (0.78); Anal. Calc. for C23H27ClF6N4OPIr (748.12): C, 36.93; H, 3.64; N, 7.49.
Found: C, 37.11; H, 3.83; N, 7.62%.
2.5.5. [(Cp*Rh(L3)Cl]PF6 (5)
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Yield: 58 mg (43%); IR (KBr, cm-1): 3452(s), 3318(s), 2924(m), 1648(s), 1600(m), 1566(m),
1489(m), 842(s); 1H NMR (400 MHz, DMSO-d6): δ = 12.5 (s, 1H, OH), 8.96 (d, 1H, J = 4.0 Hz,
CH(py)), 8.33-8.38 (m, 3H, CH(py)), 7.91 (t, 1H, CH(Ar)), 7.86 (d, 1H, J = 8.0 Hz, CH(Ar)), 7.48 (t,
1H, J = 8.0 Hz, CH(Ar)), 7.01-7.06 (m, 3H, NH2, CH(Ar)), 2.48 (s, 3H, CH3), 1.59 (s, 15H,
CH(Cp*)); HRMS-APCI (m/z): 491.14 [M-PF6-HCl]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1
cm-1)}: 229 (0.95), 268 (0.59), 332 (0.32); Anal. Calc. for C24H29ClF6N4OPRh (672.84): C,
42.84; H, 4.34; N, 8.33. Found: C, 42.98; H, 4.26; N, 8.48%.
2.5.6. [Cp*Ir(L3)Cl]PF6 (6)
Yield: 65 mg (42%); IR (KBr, cm-1): 3460(m), 3237(m), 2926(w), 1630(s), 1595(m), 1296(m),
1
846(s), 3456(m), 3369(m), 2925(m), 1649(s), 1618(m), 1598(m), 1306(m), 845(s); H NMR
(400 MHz, DMSO-d6): δ = 12.3 (s, 1H, OH), 8.94 (d, 1H, J = 4.0 Hz, CH(py)), 8.44 (d, 1H, J =
4.0 Hz, CH(py)), 8.35 (t, 2H, CH(py)), 7.90 (t, 1H, CH(Ar)), 7.86 (d, 1H, J = 8.0 Hz, CH(Ar)), 7.48 (t,
1H, CH(Ar)), 7.01-7.06 (m, 3H, NH2, CH(Ar)), 2.46 (s, 3H, CH3), 1.58 (s, 15H, CH(Cp*)); HRMS-
APCI (m/z): 581.19 [M-PF6-HCl]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 209
(1.27), 263 (0.66), 330 (0.36); Anal. Calc. for C24H29ClF6N4OPIr (762.15): C, 37.82; H, 3.84; N,
7.35. Found: C, 37.96; H, 3.96; N, 7.44%.
2.5.7. [(Cp*Rh(L4)Cl]PF6 (7)
Yield: 54 mg (41%); IR (KBr, cm-1): 3441(s), 3137(m), 2961(w), 1640 (s), 1593(m), 1464(m),
841(s); 1H NMR (400 MHz, DMSO-d6): δ = 8.96 (d, 1H, J = 4.0 Hz, CH(py)), 8.33-8.37 (m, 2H,
CH(py)), 7.88 (t, 1H, CH(py)), 7.81 (d, 1H, J = 8.0 Hz, CH(Ar)), 7.46 (t, 1H, CH(Ar)), 7.23-7.28 (m,
2H, CH(Ar)), 6.97-7.02 (m, 3H, NH2, CH(Ar)), 2.47 (s, 3H, CH3), 1.59 (s, 15H, CH(Cp*)); HRMS-
APCI (m/z): 511.12 [M-PF6]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 229 (1.37),
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265 (0.37), 400 (0.22); Anal. Calc. for C24H29ClF6N4PRh (656.84): C, 43.89; H, 4.45; N, 8.53.
Found: C, 44.02; H, 4.39; N, 8.61%.
2.5.8. [Cp*Ir(L4)Cl]PF6 (8)
Yield: 65 mg (43%); IR (KBr, cm-1): 3458(s), 3383(s), 2922(m), 1643(s), 1603(m), 1567(m),
1447(m), 844(s); 1H NMR (400 MHz, DMSO-d6): δ = 8.97 (d, 1H, J = 4.0 Hz, CH(py)), 8.31-8.34
(m, 2H, CH(py)), 7.85 (t, 1H, CH(py)), 7.79 (d, 1H, J = 8.0 Hz, CH(Ar)), 7.44 (t, 1H, CH(Ar)), 7.19-
7.23 (m, 2H, CH(Ar)), 6.99-7.03 (m, 3H, NH2, CH(Ar)), 2.46 (s, 3H, CH3), 1.59 (s, 15H, CH(Cp*));
HRMS-APCI (m/z): 601.17 [M-PF6]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 256
(0.53), 361 (0.20); Anal. Calc. for C24H29ClF6N4PIr (746.15): C, 38.63; H, 3.92; N, 7.51. Found:
C, 38.74; H, 4.03; N, 7.63%.
3.
Results and discussion
3.1. Synthesis of ligands and complexes
The azine Schiff-base ligands (L1-L4) were prepared by the reaction of 2-
pyridylamidrazone and the respective aldehyde or ketone in absolute ethanol medium. The
complexes (1-8) were synthesized by the reaction of Rh/Ir metal precursors with the azine
Schiff-base ligands. The cationic complexes were isolated with PF6 counter ion. All these metal
complexes were obtained in good yields and are yellow in color. They are stable in air as well as
in solid state, and are non-hygroscopic. These complexes are soluble in common organic
solvents such as dichloromethane, acetonitrile and acetone but insoluble in diethyl ether and
hexane. All the synthesized ligands and complexes were fully characterized by spectroscopic
techniques.
3.2. Spectroscopic characterization of ligands
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The infrared spectra of the free ligand shows characteristic stretching frequencies for
NH2, OH, C=N and C=C groups. The NH2 and OH stretching frequencies for the azine ligand
appeared in the range of 3300-3500 cm-1. The C=C and C=N stretching frequencies were
observed in the range of 1550-1626 cm-1. The proton NMR spectra of the ligands displayed
signals in the range of 7.30-8.57 ppm assignable to the protons of the pyridine ring. The imine
protons for L1 and L2 are located at 8.60 and 8.59 ppm respectively. The methoxy proton signal
was observed as a singlet for L1 at 3.80 ppm. The methyl protons of L3 and L4 were observed as
a singlet at 2.62 and 2.39 ppm respectively. The hydroxyl proton resonance for the ligands
appeared in the range of 11.5-11.9 ppm. The aromatic protons of the ligand appeared as doublet,
triplet and multiplet in the range of 6.21-7.29 ppm. The [M+H]+ molecular ion peak for the
ligands are shown in the experimental section which are found to be in good agreement with the
expected range. The electronic spectra of the free ligands are shown in (Figure S1). The
electronic spectra of the free ligands show absorption bands in the range of 210-360 nm. The
band in the range of 210-250 nm can be assigned as π-π* and n-π * transition. The band around
300-370 nm is due to the intermolecular charge transfer transition within the whole molecule
[41].
3.3. Spectroscopic characterization of complexes
The IR spectra of the complexes show sharp bands around 842-846 cm-1 due to the P-F
stretching frequency of the counter ion [42]. The OH and NH2 stretching vibrations in the
complexes were found around 3300-3500 cm-1. The retaining of the OH and NH2 stretching
frequencies indicates that they are not involved in bonding to the metal center. The strong
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absorption band for νC=N around 1630-1650 cm-1 at higher wave numbers as compared to the free
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ligand around 1615-1626 cm-1 suggest that the coordination to the metal occurs through the
imine and pyridine nitrogen.
The proton NMR spectra of the metal complexes show that the ligand resonance signals
are shifted downfield as compared to that of the free ligand. These signals are shifted downfield
because of the ligand coordination to the metal atom. The imine proton signal was observed in
the range of 9.0-9.13 ppm for complexes (1-4). The hydroxyl proton resonance for the
complexes appeared in the range of 10.1-12.5 ppm respectively. The appearance of the hydroxyl
proton signal indicates that the hydroxyl group is not involved in bonding to the metal atom. The
pyridine ring protons also showed downfield signals comprising of doublet and triplet in the
range of 7.75-8.96 ppm. The NH2 protons were observed as a singlet for complexes (1-4) in the
range of 7.35-7.37 ppm respectively. The methoxy proton resonance for complexes (1 and 2)
appeared as a singlet at 3.81 and 3.83 ppm. The aromatic proton signals for complexes appeared
in the range of 6.50-7.86 ppm as doublet, triplet and multiplet. The methyl proton signal for
complexes (5-8) appeared as a singlet around 2.46-2.48 ppm respectively. In addition to the
signals for the ligand protons, a sharp singlet was observed for all the complexes between 1.58-
1.63 ppm respectively corresponding to the methyl protons of the Cp* ring. In the mass spectra
of the complexes (1–6) the peaks at m/z: 507.12, m/z: 597.18, m/z: 477.12, m/z: 567.17, m/z:
491.13 and m/z: 581.20 can be assigned as [M-PF6-HCl]+ ion peaks respectively. Whereas, the
mass spectra of the complex 7 and 8 displayed molecular ion peaks at m/z: 511.12 and 601.17
which corresponds to the [M-PF6]+ ion.
The electronic spectra of the complexes were recorded in acetonitrile at 10-4
M
concentration at room temperature and the plot is shown in (Figure S2). The electronic spectra of
complexes display two absorption band in the higher energy region around 210-330 nm. The
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bands in the higher energy UV region can be assigned as ligand centered or intra ligand π-π* and
n-π*transition. The Rh(III) and Ir(III) complexes provides filled dπ (t2g) orbitals which can
interact with low lying π* orbitals (C=N) of the ligand. The band in the lower energy region
around 345-405 nm can be assigned as Rh (dπ) or Ir (dπ) to π* ligand metal to ligand charge
transfer (MLCT) transition [43].
3.4. Molecular structures of complexes
The molecular structures of some of the respective complexes have been elucidated by
single crystal X-ray analysis. Suitable single crystals were attached to a glass fibre and
transferred into the Oxford Diffraction Xcalibur Eos Gemini diffractometer. The crystallographic
details and structure refinement details are summarized in Table 1. The geometrical parameters
around the metal atom involving ring centroid are listed in Table S1. In all these complexes the
ligand is coordinated to the metal atom in a similar manner with N∩N binding mode. Complex
(1) and (8) crystallized in triclinic system with space group P 1͞ . Complex (8) crystallized with
one PF6 and one chloride counter ion. Complex (3) and (4) crystallized in monoclinic system
with space group P21/c whereas complex (7) crystallized in monoclinic system with space group
P21.
All these complexes display a typical three-legged piano stool geometry around the metal
center with coordination sites occupied by one chloride group, two σ bonded nitrogen atoms
from chelating azine ligand and the pentamethylcyclopentadienyl (Cp*) ring in η5 manner. The
metal atom in all these complexes is situated in a pseudo-octahedral arrangement with the azine
ligand coordinating through the pyridine and azine nitrogen atoms forming a five membered
metallocycle. In complexes (1), (3), (4) and (7) the M-N bond length {2.088(5), 2.099(3),
2.098(4) and 2.102(4) Å} from pyridine is comparatively shorter than the azine nitrogen-metal
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distances {2.135(5), 2.116(3), 2.105(4) and 2.159(4) Å}, which are similar to those, reported
with similar complexes [24, 44]. However in complex (8) the metal-nitrogen distance from
pyridine {2.102(5) Å} is comparatively larger than azine nitrogen-metal distance, which is
{2.096(5) Å}. The C=N bond length of the coordinated nitrogen in complex (1), (3), (4) and (8)
is longer than that of the uncoordinated C=N (Table S1) which could be due to the back bonding
of electron from metal (dπ) to π* orbital of the ligand. But in complex (7), a reverse pattern has
been observed where the C=N bond length of the coordinated nitrogen {1.346(7) Å} is shorter
than uncoordinated C=N {1.358(7) Å} bond. The average M-C distances are {2.159 (1), 2.1534
(3), 2.1616 (4), 2.1528 (7) and 2.1726 (8) Å} while the distance between the metal to Cp*
centroid ring is in the range of 1.758–1.793 Å respectively. The M-Cl bond lengths {2.3976(15)
(1), 2.4172(9) (3), 2.4190(12) (4), 2.4242(16) (7) and 2.4220(17) (8) shows no significant
differences and is comparable to previously reported values (Table 1) [45-48]. The bite angle
N(1)-Rh(1)-N(2) values are 75.10(19) (1), 75.09(11) (3), and 75.44(17) (7) whereas in complex
(4) and (8) the bite angle values are N(1)-Ir(1)-N(2) values are 74.99(14) (4) and 75.26(18)
respectively which probably indicates an inward bending of the coordinated pyridyl and azine
group [49]. The bond angles N(1)-M-Cl(1) and N(2)-M-Cl(1) in complexes are comparable to
the piano stool arrangement about the metal atom and is comparable to reported values for
closely related systems [50-52]. Further the crystal packing in complex (1) is stabilized by weak
intermolecular hydrogen bonding C-H·····O (2.702 Å) between the hydrogen atom from methoxy
group and oxygen atom of the hydroxyl group and C-H·····Cl (2.793 Å) interaction between CH3
group of Cp* and chloride atom (Figure S3). These interactions play a significant role in the
formation of supramolecular motifs.
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On the other hand in the crystal structure of complex (3) and (4) two types of
intramolecular hydrogen bonding has been observed; the first one between the uncoordinated
nitrogen atom of the azine linkage with the hydrogen atom of the hydroxyl group O-H·····N
(1.916 and 1.908 Å) and the second between the hydrogen atom from NH2 and uncoordinated
azine nitrogen atom N-H·····N (2.323 and 2.328 Å) (Figure 4). The selected hydrogen bonding
distances and angles for complex (3) and (4) are given in (Table 2). Also the crystal packing in
complex (3) and (4) is further stabilized by two different C-H·····Cl interaction between the Cl
atom attached to metal M (where M = Rh/Ir) with hydrogen atom of pyridine ring and NH2
(Figure S4). Complex (7) shows C-H·····π (2.832 and 2.937 Å) interactions between the methyl
hydrogen atom and Cp* moiety and between pyridine ring and hydrogen atom of Cp* group
respectively (Figure S5). Interestingly the crystal packing in complex (8) leads to a dimeric unit
via intermolecular C-H·····Cl interaction between the chloride counter ion and hydrogen atom
from pyridine ring, NH2 and Cp* group (Figure S6).
3.5. Chemosensitivity studies
The complexes (1-8) were tested for their cytotoxicity against cancer cell line HT-29
(human colorectal cancer), and non-cancer cell line ARPE-19 (human retinal epithelial cells).
The response of the cell lines HT-29 to the test complexes and cisplatin (1-8) is presented in
graphical form in Figure 5 and in tabular form in Table 3. All the complexes tested were found to
be active against HT-29 cancer cell line (IC50< 30 µM). Complex (5) was the most potent among
all the complexes with (IC50 value of 96.93 5.31 µM). However all the complexes were less
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potent than cisplatin (IC50 value of 0.25 0.11 µM against HT-29). The selectivity index (SI)
defined as the ratio of IC50 values in ARPE19 cells divided by the IC50 value of cancer cell line
demonstrates that all the complexes are effective against cancer cell with SI values ranging from
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1.01 to 2.11 (Table S2). Moreover although complex (5) showed more selectivity than other
complexes for HT-29 cancer cell, however its selectivity was significantly lower than cisplatin
where SI value is 25.64 (Figure 6).
3.6. Optimized geometry
The comparison of the geometric parameters (selected bond lengths and bond angles) of
the optimized structures and the crystal structures of the complexes (1, 3, 4, 7 and 8) are listed in
Table S3. All the metal complexes are found to be closed shell structures. The calculated bond
lengths and the bond angles of the complexes are in good agreement with the experimental data
indicating the reliability of the theoretical method (B3LYP/6-31G**/LanL2DZ) used in the
present study. It should be noted that for complexes (3, 4, 7 and 8), the M(1)-N(2) (where M =
Rh/Ir) bond length is slightly longer than the M(1)-N(1) bond length whereas for complex (1), a
reverse pattern has been observed (Table S3).
3.7. Charge distribution
The charges on the individual atoms for the metal complexes obtained from NBO
analysis are listed in Table S4. The charges on the Rh atom in the complexes (1), (3), (5) and (7)
are 0.136, 0.200, 0.216 and 0.214 e whereas the charges on Ir for complexes (2), (4), (6) and (8)
are 0.186, 0.252, 0.268 and 0.214 e respectively. These NBO charges on Rh and Ir are
comparatively lower than their formal charge of +3 which suggests that the ligand transfers their
negative charge to the respective rhodium and iridium metal on complex formation. In metal
complexes (1-8), the charge on Cl ranges between -0.439 e (Complex-1) to -0.394 e (Complex-
4). In isolated ligands, the charge on N(1) ranges between -0.416 and –0.417 e whereas for N(2)
it ranges between -0.324 e and -0.348 e. It should be noted that for isolated ligands as well as for
complexes (1-8), the negative charges on N(1) (-0.385, -0.381, -0.372, -0.373, -0.369, -0.398, -
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0.368 and -0.373 e) are slightly higher than the charges on N(2) (-0.258, -0.253, -0.284, -0.283, -
0.305, -0.297, -0.311 and -0.305 e). On complex formation, the negative charge on the N(1) and
N(2) reduces slightly giving an indication of the charge transfer on Rh and Ir in metal
2
complexes. The population of the 4d (4dxy, 4dxz, 4dyz, 4dx -y2 and 4dz2) orbital of Rh complexes
and 5d orbital of Ir complexes are shown in Table S5. The orbital occupations of each orbital
2
2
(ndxy, ndxz, ndyz, ndx -y2 and ndz ) for all the complexes are comparatively higher in rhodium
complexes than iridium complexes. In free Rh(III) and Ir(III) state, the population of ndxy, ndxz and
ndyz are 2.0, 2.0 and 2.0 e and the other two orbitals remain vacant. But on complex formation, the
population on ndxy, ndxz and ndyz orbital gets reduced whereas the ndx2-y2 and ndz2 orbitals gain
some population as indicated in Table S5. For most of the complexes, the population of 4d and
5d orbital containing the same ligand follow similar pattern of filling, except for the complexes
2
containing ligand L1 where the ndxz orbital population is slightly lower and ndx -y2 is higher as
compared to the other complexes.
3.8. Frontier molecular orbitals and absorption spectra
The molecular orbital representation of the complexes along with their HOMO, LUMO
energies and HOMO-LUMO energy gaps are shown in Figure 7. The HOMO-LUMO energy gap
can be used as an important parameter in analyzing the chemical reactivity and kinetic stability
of a molecule. This energy gap is also related to the hardness/softness of a chemical species [53].
The lower HOMO-LUMO energy gap is a suitable condition where a molecule can be excited
easily and thereby increasing its reactivity and decreasing its kinetic stability whereas higher
energy gap can lead to more kinetic stability but less reactivity. The HOMO-LUMO energy gaps
for all the complexes (1-8) are found to be 3.20, 2.98, 3.63, 3.46, 3.61, 3.60, 3.68 and 3.59 eV
respectively. The gap is slightly lower for the iridium complexes as compared to rhodium
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complexes containing the same ligand indicating the reactivity of Ir complexes over the
complexes containing Rh metal. The % contribution of molecular orbital analysis as shown in
Table S6, predicts that the most percentage of HOMO is located on the ligand itself except for
complex (2) and (8) where as it is mostly present on the Ir metal. On the other hand, LUMO is
located on the ligand for complexes (1) (about 97%), (2) (91%), (4) (89%), (6) (92%) and (8)
(69%) whereas for complexes (3) (40%), (5) (35%) and (7) (38%), it is located on the Rh metal.
The electronic absorption spectra were calculated using the TD-DFT method in
acetonitrile solvent employing PCM model. The calculated and the experimental absorption data,
HOMO-LUMO energy gaps, and the character of electronic transitions are listed in Table 4. The
H→L transitions for complexes (1), (4) and (6) occurring at 417, 444 and 441 nm corresponds to
ILCT character, for complexes (2) and (8) at 463 and 440 nm corresponds to MLCT character
whereas for complexes (3), (5) and (7) at 532, 519 and 518 nm corresponds to LMCT character.
These MLCT character can be assigned for dπ(M)→π∗(L) transitions whereas the ILCT
character are for π→π∗ transitions. It should be noted that all LMCT transitions are occurring at
higher wavelength regions (i.e. > 500 nm). In good agreement with the experimental data, the
TD-DFT calculations shows few MLCT transitions at 358 nm complex (2), 332 nm, complex
(4), 334 nm complex (6) and 372, 358 nm complex (8). However, in the range between 340-400
nm, few LMCT, ILCT and LLCT transitions have also been observed (Table 4).
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4.
Conclusion
In summary, we have synthesized four new azine Schiff-base ligands and its rhodium and
iridium half-sandwich complexes. All these complexes and ligands were full characterized by
various spectroscopic techniques. The ligands under study preferably bind to the metal in a
bidentate N∩N fashion using pyridine and one azine nitrogen atom. Our attempt to synthesize
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dinuclear rhodium and iridium complexes with NNʹ and NO bonding was however unsuccessful
irrespective of molar ratio of metal to ligand where as in the presence of base, it leads to
decomposition of the reaction. These complexes possess some important intramolecular and
intermolecular hydrogen bonding and also possess some weak non-covalent interactions,
particularly C-H·····Cl and C-H·····π interactions. Chemosensitivity activity of the complexes
against HT-29 cancer cell demonstrates that the complexes are active however complex (5) was
found to be the most potent among all other complexes. Theoretical studies reveal that the
HOMO-LUMO energy gap is lower for iridium complexes indicating better reactivity over the
rhodium complexes. TD-DFT calculations were carried out in order to evaluate the electronic
transitions occurring in the metal complexes, which are in good agreement with the experimental
results. The charge distribution analysis (using NBO analysis) of these complexes helps to
understand how the charges on nitrogen atom (which are coordinating to the metal) are
delocalized on complex formation. Especially, the NBO charges, on rhodium and iridium
confirm that the ligands transfer their negative charge to the respective metal on complex
formation. The lower HOMO-LUMO energy gap leads to greater chemical reactivity but lesser
kinetic stability and vice versa. Furthermore, the nature of HOMO and LUMO illustrate the
electronic origin of the lowest energy transition and the resulting electronic reorganization.
Moreover, the molecular orbital analysis was helpful to understand and locate the % contribution
of HOMO and LUMO on different fragments of the complexes, which is otherwise not possible
to predict from experimental data.
Acknowledgements
Sanjay Adhikari and Dipankar Sutradhar thanks UGC, New Delhi, India for providing financial
assistance in the form of university fellowship (UGC-Non-Net). We thank DST-PURSE
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SCXRD, NEHU-SAIF, Shillong, India for providing Single crystal X-ray analysis and other
spectral studies. AKC thanks Computer centre, NEHU, for computational facilities.
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Supplementary material
CCDC 1477976 (1), 1477977 (3), 1477978 (4), 1477979 (7) and 1477980 (8) contains
the supplementary crystallographic data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; Fax: +44 1223 336033.
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Scheme-1 Synthesis of 2-pyridylamidrazone
573
574
575
Scheme-2 Preparation of ligands (L1-L4)
576
577
578
Scheme-3 Preparation of metal complexes (1-8)
28

579
580
Figure 1 ORTEP diagram of complex [Cp*RhCl(L1)Cl]PF6 (1) with 50% probability thermal
581
ellipsoids. Hydrogen atoms and counter ions are omitted for clarity.
582
583
Figure 2 (a) ORTEP diagram of complex [Cp*RhCl(L2)Cl]PF6 (3) and (b) ORTEP diagram of
complex [Cp*IrCl(L2)Cl]PF6 (4) with 50% probability thermal ellipsoids. Hydrogen atoms and
counter ions are omitted for clarity.
584
585
29