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Synthesis, structural, DFT calculations and biological studies of rhodium and iridium complexes containing azine Schiff-base ligands
University of Huddersfield Repository
Adhikari, S., Sutradhar, D., Shepherd, S.L., Phillips, Roger M., Chandra, A.K. and Rao, K.M.
Synthesis, structural, DFT calculations and biological studies of rhodium and iridium complexes
containing azine Schiff-base ligands
Original Citation
Adhikari, S., Sutradhar, D., Shepherd, S.L., Phillips, Roger M., Chandra, A.K. and Rao, K.M.
(2016) Synthesis, structural, DFT calculations and biological studies of rhodium and iridium
complexes containing azine Schiff-base ligands. Polyhedron, 117. pp. 404-414. ISSN 0277-5387
This version is available at http://eprints.hud.ac.uk/id/eprint/28693/
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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:
DOI:
Reference:
S0277-5387(16)30218-2
http://dx.doi.org/10.1016/j.poly.2016.06.001
POLY 12039
To appear in:
Polyhedron
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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1
Synthesis, structural, DFT calculations and biological studies of rhodium and
2
iridium complexes containing azine Schiff-base ligands
3
4
5
Sanjay Adhikaria, Dipankar Sutradhara, Samantha L. Shepherdb, Roger M Phillipsb,
6
Asit K. Chandraa, K. Mohan Raoa*
7
8
9
a
10
Shillong 793 022, India.
11
E-mail: mohanrao59@gmail.com
12
Telephone Number: +91 364 2722620
13
Fax Number: +91 364 2550076
14
b
15
HD1 3DH, UK
Centre for Advanced Studies in Chemistry, North-Eastern Hill University,
Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield
16
1
17
Graphical abstract
18
Half-sandwich Cp*Rh(III) and Cp*Ir(III) complexes have been synthesized with N-Nʹ azine
19
Schiff-base ligands and characterized by spectroscopic techniques. The molecular structures of
20
some of the representative complexes have been confirmed by single crystal X-ray analysis.
21
Chemo-sensitivity activities of the complexes were evaluated against HT-29 (human colorectal
22
cancer) cell line and non-cancer cell line ARPE-19 (human retinal epithelial cells).
23
24
25
Complex 1
26
2
27
Abstract
28
The reaction of [Cp*MCl2]2 (M = Rh/Ir) with N-Nʹ azine Schiff-base ligands (L1-L4)
29
leads to the formation of mononuclear cationic half-sandwich complexes having the general
30
formula [Cp*M(L)Cl]+ (1–8), (M = Rh/Ir and L = (2-hydroxy-4-methoxybenzylidene)2-
31
pyridylamidrazone
32
hydroxyphenyl)ethylidene)2-pyridylamidrazone
33
pyridylamidrazone (L4). All these complexes were isolated as their hexafluorophosphate salts
34
and fully characterized by spectroscopic and analytical techniques. The molecular structure of
35
complexes (1), (3), (4), (7) and (8) have been determined by single crystal X-ray crystallographic
36
studies which displayed the coordination of the ligand to the metal in a bidentate N∩N fashion
37
through nitrogen atom of pyridine and one azine nitrogen. The chemo-sensitivity activities of the
38
complexes were evaluated against HT-29 (human colorectal cancer) cell line and non-cancer cell
39
line ARPE-19 (human retinal epithelial cells) which revealed that the complexes are moderately
40
cytotoxic to cancer cells over human cells although complex 5 was the most potent among all the
41
compounds. Theoretical studies carried out using DFT and TD-DFT at B3LYP level shows good
42
agreement with the experimental results.
43
Keywords: Rhodium, Iridium, Azine Schiff-base ligands, Cytotoxicity
(L1),
(2-hydroxybenzylidene)2-pyridylamidrazone
(L3)
44
3
and
(L2),
(1-(2-
(1-phenylethylidene)2-
45
1.
Introduction
46
The chemistry of half-sandwich organometallic complexes has evolved as a versatile
47
subject of research during the past few decades due to its wide application in biological and
48
medicinal fields [1-4]. Organometallic half-sandwich compounds of the general formula
49
[Cp*MCl(LLʹ)] (M = Rh, Ir and LL' = N,N or N,O donor ligands) have been extensively studied
50
for their cytostatic activity, DNA binding, cellular uptake and as DNA intercelators [5-9].
51
Rhodium and iridium complexes have also been investigated as an alternative to platinum based
52
drugs mainly because of their water solubility and lability towards ligand exchange [10, 11].
53
Recently Therrien et.al reported dinuclear dithiolato bridged rhodium and iridium complexes
54
which exhibit cytotoxicity against human ovarian cancer cells lines (A2780 and A2780cisR)
55
[12]. C-H activated cyclometallated Rh(III) and Ir(III) complexes can effectively bind to DNA
56
and protein through electrostatic and hydrophobic interactions [13]. Iridium complexes of
57
dihydroxybipyridine are active catalysts for homogenous water oxidation under mild reaction
58
conditions [14]. Rh(III) and Ir(III) polypyridyl complexes exhibits strong antiproliferative
59
activity towards human cancer cell lines and are also capable of binding to DNA [15]. A number
60
of half-sandwich Ir(III) complexes have been reported by Sadler et al with chelating C, N and
61
pyridine ligands and N, N donor ligands which showed strong antiproliferative activity [16, 17].
62
Pyridyl azines represent an important class of organic compounds with interesting
63
properties having wide applications in various areas [18]. Open chain diazine Schiff base ligands
64
linked by a single N-N bond are of great interest due to its rotational flexibility around the N-N
65
bond and potential donor sites which can give rise to a rich variety of coordination compounds
66
with different binding modes [19]. The N-N bridging ligand plays a crucial role in
67
communicating the metal centers to form mononuclear, dinuclear or polynuclear complexes [20].
4
68
The diazine ligand has been employed into several transition metal azido and thiocyanato
69
systems namely Mn(II)-azido, Cd(II)-NCS to obtain several 1D, 2D and 3D polymers which
70
exhibit interesting magnetic properties [21, 22]. Dinuclear transition metal complexes of Cu, Zn,
71
Mn and Ni have been reported with bridging N-N diazine ligands which give rise to strong
72
ferromagnetic and antiferromagnetic coupling [23]. In the recent years our group has reported
73
many half-sandwich Ru(II), Rh(III) and Ir(III) complexes with azine ligands [24, 25]. In
74
continuation with our interest of these ligands herein we report four new azine Schiff base
75
ligands derived from 2-pyridylamidrazone and its corresponding rhodium and iridium half-
76
sandwich metal complexes. The complexes were tested for their cytotoxic property to selectively
77
kill HT-29 cancer cell line against normal ARPE-19 cells.
78
2. Experimental Section
79
2. 1.
Physical methods and materials
80
All the reagents were purchased from commercial sources and used as received. Starting
81
materials RhCl3.nH2O, IrCl3.nH2O were purchased from Arora Matthey limited. 2-
82
cyanopyridine, 2-hydroxybenzaldehyde, 2-hydroxyacetophenone, were obtained from Aldrich,
83
acetophenone and 2-hydroxy-4-methoxybenzaldehyde were obtained from Alfa-Aesar. The
84
solvents were purified and dried according to standard procedures [26]. All the reactions were
85
carried out under normal conditions. The starting precursor metal complexes [Cp*MCl2]2 (M =
86
Rh/Ir) were prepared according to the literature methods [27]. Infrared spectra were recorded on
87
a Perkin-Elmer 983 spectrophotometer by using KBr pellets in the range of 400-4000 cm-1. 1H
88
NMR spectra were recorded on a Bruker Avance II 400 MHz spectrometer using DMSO-d6 and
89
CDCl3 as solvents. Absorption spectra were recorded on a Perkin-Elmer Lambda 25 UV/Visible
90
spectrophotometer in the range of 200-800 nm at room temperature in acetonitrile. Elemental
5
91
analyses of the complexes were performed on a Perkin-Elmer 2400 CHN/S analyzer. Mass
92
spectra were recorded using Q-Tof APCI-MS instrument (model HAB 273). All these
93
mononuclear metal complexes were synthesized and characterized by using FT-IR, 1H NMR,
94
UV-Vis, and Single-crystal X-ray diffraction techniques.
95
2. 2.
Single-crystal X-ray structures analyses
96
The orange crystals of complexes (1), (3), (7) and (8) were obtained by slow diffusion of
97
hexane into acetone or DCM solution and yellow crystals of complex (4) was obtained by
98
diffusing hexane into DCM solution. Single crystal X-ray diffraction data for all the complexes
99
(1), (3) (4), (7) and (8) were collected on a Oxford Diffraction Xcalibur Eos Gemini
100
diffractometer at 293 K using graphite monochromated Mo-Kα radiation (λ = 0.71073 Å). The
101
strategy for the data collection was evaluated using the CrysAlisPro CCD software. Crystal data
102
were collected by standard ‘‘phi–omega scan’’ techniques and were scaled and reduced using
103
CrysAlisPro RED software. The structures were solved by direct methods using SHELXS-97
104
and refined by full-matrix least squares with SHELXL-97 refining on F2 [28, 29]. The positions
105
of all the atoms were obtained by direct methods. Metal atoms in the complex were located from
106
the E-maps and non-hydrogen atoms were refined anisotropically. The hydrogen atoms bound to
107
the carbon were placed in geometrically constrained positions and refined with isotropic
108
temperature factors, generally 1.2 Ueq of their parent atoms. Crystallographic and structure
109
refinement details for the complexes are summarized in Table 1, and selected bond lengths and
110
bond angles are presented in Table S1. Figures 1-3 were drawn with ORTEP3 program. Figure 4
111
and Figures S3-S6 were drawn with MERCURY3.6 program [30].
112
2.3.
Biological studies
6
113
All complexes (1-8) were dissolved in DMSO at 100 mM and stored at -20 °C until
114
needed. The complexes were tested against cancer cell line HT-29 (human colorectal cancer),
115
and one non-cancer cell line ARPE-19 (human retinal epithelial cells). Cells were seeded into 96
116
well plates at 1 x 103 cells per well and incubated at 37 °C in a CO2 enriched (5%), humidified
117
atmosphere overnight to adhere. The cells were exposed to a range of drug concentrations in the
118
range of 0-100 µM for four days before cell survival was determined using the MTT assay [31].
119
To each well MTT (0.5 mg/ml) was added and was further incubated at 37 °C for 4 h. After this
120
the MTT was removed from each well and the formazan crystals formed were dissolved in 150
121
µM DMSO. The absorbance of the resulting solution was recorded at 550 nm using an ELISA
122
spectrophotometer. The percentage of cell inhibition was calculated by dividing the absorbance
123
of treated cell by the control value absorbance (exposed to 0.1 % DMSO). The results were
124
expressed in terms of IC50 values (concentration required to kill 50 % cell) and all studies were
125
performed in triplicate. The results were also expressed in terms of a ‘selectivity index’ defined
126
as the IC50 of the non-cancer cell line ARPE divided by the IC50 of cancer cell lines [32]. Values
127
greater than 1 demonstrate that the compound is preferentially active against tumor cell
128
compared to normal cell lines.
129
2.4.
Computational methodology
130
All the electronic structure calculations of the metal complexes (1-8) were carried out
131
using the Gaussian 09 suite of program [33]. The geometries of the rhodium and iridium
132
complexes were optimized in the gas phase employing the DFT-based B3LYP method with 6-
133
31G** basis set for (H, C, N, O, Cl, F and P atoms and LANL2DZ [34, 35] for (Rh and Ir)
134
atoms. Harmonic frequency calculations were carried out at the same level of theory to ensure
135
that the optimized geometries were true minima on the potential energy surface (PES). Natural
7
136
Bond Orbital (NBO) analysis [36] was used to obtain the charge distribution on individual atoms
137
and the d-orbital occupations of the metal present in the complexes. Time dependent-Density
138
Functional Theory (TD-DFT) [37] has been employed to evaluate the absorption spectra and the
139
electronic transitions of the metal complexes. In order to incorporate the effect of the solvent
140
around the molecule, the Polarizable Continuum Model (PCM) [38] was used in TD-DFT
141
calculations. The percentage contribution of molecular orbital analysis was carried out using
142
Chemissian software package [39].
143
2.4. General procedure for preparation of ligands 1-4
144
2.4.1. The azine Schiff base ligands (L1-L4) were prepared by two step procedure.
145
In the first step 2-pyridylamidrazone was prepared, by following a reported procedure
146
[40]. 2-cyanopyridine and hydrazine hydrate were dissolved and stirred in absolute ethanol
147
overnight to give 2-pyridylamidrazone as yellow crystalline solid which was used in the next
148
step without further purification (Scheme-1). In the second step (5 mmol) of aldehyde or ketone
149
and 2-pyridylamidrazone (5 mmol) was refluxed in 10 ml ethanol for 5 hours (Scheme-2). The
150
products obtained after cooling the solution were filtered off washed with cold methanol and
151
diethyl ether and dried in vacuum.
152
Data for ligands (L1-L4)
153
2.4.2. (2-hydroxy-4-methoxybenzylidene)2-pyridylamidrazone (L1)
154
Color: Yellow needles; Yield: 88%; IR (KBr, cm-1): 3487(s), 3380(s), 3333(m), 2964(m),
155
1627(s), 1587(m), 1566(m), 1394(m), 1340(s); 1H NMR (400 MHz, CDCl3): δ = 11.82 (s, 1H,
156
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)),
157
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,
158
CH(Ar)), 3.80 (s, 3H, OMe); HRMS-APCI (m/z): 271.11 [M+H]+; UV–Vis {Acetonitrile, λmax,
8
159
nm (ε/10-4 M-1 cm-1)}: 218 (0.84), 314 (0.68), 342 (0.92), 355 (0.94); Anal. Calc. for C14H14N4O2
160
(270.29): C, 62.21; H, 5.22; N, 20.73. Found: C, 62.36; H, 5.35; N, 20.86%.
161
2.4.3. (2-hydroxybenzylidene)2-pyridylamidrazone (L2)
162
Color: Yellow needles; Yield: 92%; IR (KBr, cm-1 ): 3477(s), 3363(s), 3340(s), 3043(m), 1626(s),
163
1576(m), 1567(m), 1473(m), 1337(m); 1H NMR (400 MHz, CDCl3): δ = 11.61 (s, 1H, OH), 8.59
164
(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,
165
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)),
166
6.87 (t, 2H, CH(Ar)); HRMS-APCI (m/z): 241.10 [M+H]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4
167
M-1 cm-1)}: 219 (0.84), 247 (0.55), 349 (1.30), 361 (1.29); Anal. Calc. for C13H12N4O (240.26):
168
C, 64.99; H, 5.03; N, 23.32. Found: C, 65.12; H, 5.18; N, 23.44%.
169
2.4.4. (1-(2-hydroxyphenyl)ethylidene)2-pyridylamidrazone (L3)
170
Color: Yellow crystalline solid; Yield: 95%; IR (KBr, cm-1): 3482(s), 3339(s), 3056(m),
171
3003(m), 1615(s), 1562(m), 1507(m), 1300(m); 1 H NMR (400 MHz, CDCl3): δ = 13.73 (s, 1H,
172
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
173
(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,
174
CH(Ar)), 2.62 (s, 3H, CH3); HRMS-APCI (m/z): 255.12 [M+H]+; UV–Vis {Acetonitrile, λmax, nm
175
(ε/10-4 M-1 cm-1)}: 217 (1.21), 303 (0.74), 344 (0.95); Anal. Calc. for C14H14N4O (254.29): C,
176
66.13; H, 5.55; N, 22.03. Found: C, 66.25; H, 5.68; N, 22.21%.
177
2.4.5. (1-phenylethylidene)2-pyridylamidrazone (L4)
178
Color: Yellow crystalline solid; Yield: 92%; IR (KBr, cm-1): 3450(s), 3331(s), 3056(m),
179
3009(m), 1604(s), 1568(m), 1445(m), 1362(m); 1 H NMR (400 MHz, CDCl3): δ = 8.58 (d, 1H, J
180
= 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-
181
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-
9
182
APCI (m/z): 239.13 [M+H]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 225 (0.21), 327
183
(0.29); Anal. Calc. for C14H14N4 (238.29): C, 70.57; H, 5.92; N, 23.51. Found: C, 70.72; H, 6.03;
184
N, 23.62%.
185
2.5.
186
A mixture of metal precursor [Cp*MCl2]2 (M = Rh/Ir) (0.1 mmol), azine Schiff-base ligands (L1-
187
L4) (0.2 mmol) and 2.5 equivalents of NH4PF6 in dry methanol (10 ml) was stirred at room
188
temperature for 8 hours (Scheme-3). The solvent was evaporated under reduced pressure, and the
189
residue was dissolved in dichloromethane and filtered over celite to remove excess salt. The
190
filtrate was reduced to 2 ml and diethyl ether was added to induce precipitation. The yellow
191
colored precipitate, which formed, was filtered and washed with diethyl ether and dried in
192
vacuum.
193
2.5.1. [Cp*Rh(L1)Cl]PF6 (1)
194
Yield: 56 mg (40%); IR (KBr, cm-1): 3460(m), 3237(m), 2926(w), 1630(s), 1595(m), 1296(m),
195
846(s); 1H NMR (400 MHz, CDCl3): δ = 10.5 (s, 1H, OH), 9.02 (s, 1H, CH(imine)), 8.76 (d, 1H, J
196
= 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
197
(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,
198
CH(Ar)), 3.81 (s, 3H, OMe), 1.58 (s, 15H, CH(Cp*)); HRMS-APCI (m/z): 507.12 [M-PF6-HCl]+;
199
UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1 )}: 233 (0.98), 277 (0.57), 352 (0.42); Anal.
200
Calc. for C24H29ClF6N4O2PRh (688.84): C, 41.85; H, 4.24; N, 8.13. Found: C, 41.96; H, 4.16; N,
201
8.23%.
202
2.5.2. [Cp*Ir(L1)Cl]PF6 (2)
203
Yield: 70 mg (45%); IR (KBr, cm-1): 3447(m), 3241(m), 2925(m), 1630(s), 1610(m), 1293(m),
204
846(s); 1H NMR (400 MHz, CDCl3): δ = 10.4 (s, 1H, OH), 9.02 (s, 1H, CH(imine)), 8.77 (d, 1H, J
General procedure for preparation of metal complexes (1-8)
10
205
= 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
206
(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,
207
CH(Ar)), 3.87 (s, 3H, OMe), 1.62 (s, 15H, CH(Cp*)); HRMS-APCI (m/z): 597.18 [M-PF6-HCl]+;
208
UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 266 (0.36), 347 (0.29); Anal. Calc. for
209
C24H29ClF6N4O2PIr (778.14): C, 37.04; H, 3.76; N, 7.20. Found: C, 37.19; H, 3.89; N, 7.31%.
210
2.5.3. [Cp*Rh(L2)Cl]PF6 (3)
211
Yield: 52 mg (39%); IR (KBr, cm-1): 3422(m), 3310(w), 2923(w), 1636(s), 1603(m), 1457(m),
212
845(s); 1H NMR (400 MHz, CDCl3): δ = 10.1 (s, 1H, OH), 9.11 (s, 1H, CH(imine)), 8.78 (d, 1H, J
213
= 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
214
(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*));
215
HRMS-APCI (m/z): 477.12 [M-PF6-HCl]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}:
216
235 (1.55), 283 (0.79), 348 (1.00); Anal. Calc. for C23H27ClF6N4OPRh (658.81): C, 41.93; H,
217
4.13; N, 8.50. Found: C, 42.08; H, 4.25; N, 8.68%.
218
2.5.4. [Cp*Ir(L2)Cl]PF6 (4)
219
Yield: 52 mg (34%); IR (KBr, cm-1): 3479(s), 3329(s), 2924(w), 1642(s), 1618(m), 1602(m),
220
842(s); 1H NMR (400 MHz, CDCl3): δ = 10.1 (s, 1H, OH), 9.13 (s, 1H, CH(imine)), 8.80 (d, 1H, J
221
= 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
222
(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*));
223
HRMS-APCI (m/z): 567.17 [M-PF6-HCl]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}:
224
291 (0.62), 344 (0.78); Anal. Calc. for C23H27ClF6N4OPIr (748.12): C, 36.93; H, 3.64; N, 7.49.
225
Found: C, 37.11; H, 3.83; N, 7.62%.
226
2.5.5. [(Cp*Rh(L3)Cl]PF6 (5)
11
227
Yield: 58 mg (43%); IR (KBr, cm-1): 3452(s), 3318(s), 2924(m), 1648(s), 1600(m), 1566(m),
228
1489(m), 842(s); 1H NMR (400 MHz, DMSO-d6): δ = 12.5 (s, 1H, OH), 8.96 (d, 1H, J = 4.0 Hz,
229
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,
230
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,
231
CH(Cp*)); HRMS-APCI (m/z): 491.14 [M-PF6-HCl]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1
232
cm-1)}: 229 (0.95), 268 (0.59), 332 (0.32); Anal. Calc. for C24H29ClF6N4OPRh (672.84): C,
233
42.84; H, 4.34; N, 8.33. Found: C, 42.98; H, 4.26; N, 8.48%.
234
2.5.6. [Cp*Ir(L3)Cl]PF6 (6)
235
Yield: 65 mg (42%); IR (KBr, cm-1): 3460(m), 3237(m), 2926(w), 1630(s), 1595(m), 1296(m),
236
846(s), 3456(m), 3369(m), 2925(m), 1649(s), 1618(m), 1598(m), 1306(m), 845(s); 1H NMR
237
(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 =
238
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,
239
1H, CH(Ar)), 7.01-7.06 (m, 3H, NH2, CH(Ar)), 2.46 (s, 3H, CH3), 1.58 (s, 15H, CH(Cp*)); HRMS-
240
APCI (m/z): 581.19 [M-PF6-HCl]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 209
241
(1.27), 263 (0.66), 330 (0.36); Anal. Calc. for C24H29ClF6N4OPIr (762.15): C, 37.82; H, 3.84; N,
242
7.35. Found: C, 37.96; H, 3.96; N, 7.44%.
243
2.5.7. [(Cp*Rh(L4)Cl]PF6 (7)
244
Yield: 54 mg (41%); IR (KBr, cm-1): 3441(s), 3137(m), 2961(w), 1640 (s), 1593(m), 1464(m),
245
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,
246
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,
247
2H, CH(Ar)), 6.97-7.02 (m, 3H, NH2, CH(Ar)), 2.47 (s, 3H, CH3), 1.59 (s, 15H, CH(Cp*)); HRMS-
248
APCI (m/z): 511.12 [M-PF6]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 229 (1.37),
12
249
265 (0.37), 400 (0.22); Anal. Calc. for C24H29ClF6N4PRh (656.84): C, 43.89; H, 4.45; N, 8.53.
250
Found: C, 44.02; H, 4.39; N, 8.61%.
251
2.5.8. [Cp*Ir(L4)Cl]PF6 (8)
252
Yield: 65 mg (43%); IR (KBr, cm-1): 3458(s), 3383(s), 2922(m), 1643(s), 1603(m), 1567(m),
253
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
254
(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-
255
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*));
256
HRMS-APCI (m/z): 601.17 [M-PF6]+; UV–Vis {Acetonitrile, λmax, nm (ε/10-4 M-1 cm-1)}: 256
257
(0.53), 361 (0.20); Anal. Calc. for C24H29ClF6N4PIr (746.15): C, 38.63; H, 3.92; N, 7.51. Found:
258
C, 38.74; H, 4.03; N, 7.63%.
259
3.
Results and discussion
260
3.1.
Synthesis of ligands and complexes
261
The azine Schiff-base ligands (L1-L4) were prepared by the reaction of 2-
262
pyridylamidrazone and the respective aldehyde or ketone in absolute ethanol medium. The
263
complexes (1-8) were synthesized by the reaction of Rh/Ir metal precursors with the azine
264
Schiff-base ligands. The cationic complexes were isolated with PF6 counter ion. All these metal
265
complexes were obtained in good yields and are yellow in color. They are stable in air as well as
266
in solid state, and are non-hygroscopic. These complexes are soluble in common organic
267
solvents such as dichloromethane, acetonitrile and acetone but insoluble in diethyl ether and
268
hexane. All the synthesized ligands and complexes were fully characterized by spectroscopic
269
techniques.
270
3.2.
Spectroscopic characterization of ligands
13
271
The infrared spectra of the free ligand shows characteristic stretching frequencies for
272
NH2, OH, C=N and C=C groups. The NH2 and OH stretching frequencies for the azine ligand
273
appeared in the range of 3300-3500 cm-1. The C=C and C=N stretching frequencies were
274
observed in the range of 1550-1626 cm-1. The proton NMR spectra of the ligands displayed
275
signals in the range of 7.30-8.57 ppm assignable to the protons of the pyridine ring. The imine
276
protons for L1 and L2 are located at 8.60 and 8.59 ppm respectively. The methoxy proton signal
277
was observed as a singlet for L1 at 3.80 ppm. The methyl protons of L3 and L4 were observed as
278
a singlet at 2.62 and 2.39 ppm respectively. The hydroxyl proton resonance for the ligands
279
appeared in the range of 11.5-11.9 ppm. The aromatic protons of the ligand appeared as doublet,
280
triplet and multiplet in the range of 6.21-7.29 ppm. The [M+H]+ molecular ion peak for the
281
ligands are shown in the experimental section which are found to be in good agreement with the
282
expected range. The electronic spectra of the free ligands are shown in (Figure S1). The
283
electronic spectra of the free ligands show absorption bands in the range of 210-360 nm. The
284
band in the range of 210-250 nm can be assigned as π-π* and n-π * transition. The band around
285
300-370 nm is due to the intermolecular charge transfer transition within the whole molecule
286
[41].
287
3.3.
Spectroscopic characterization of complexes
288
The IR spectra of the complexes show sharp bands around 842-846 cm-1 due to the P-F
289
stretching frequency of the counter ion [42]. The OH and NH2 stretching vibrations in the
290
complexes were found around 3300-3500 cm-1. The retaining of the OH and NH2 stretching
291
frequencies indicates that they are not involved in bonding to the metal center. The strong
292
absorption band for νC=N around 1630-1650 cm-1 at higher wave numbers as compared to the free
14
293
ligand around 1615-1626 cm-1 suggest that the coordination to the metal occurs through the
294
imine and pyridine nitrogen.
295
The proton NMR spectra of the metal complexes show that the ligand resonance signals
296
are shifted downfield as compared to that of the free ligand. These signals are shifted downfield
297
because of the ligand coordination to the metal atom. The imine proton signal was observed in
298
the range of 9.0-9.13 ppm for complexes (1-4). The hydroxyl proton resonance for the
299
complexes appeared in the range of 10.1-12.5 ppm respectively. The appearance of the hydroxyl
300
proton signal indicates that the hydroxyl group is not involved in bonding to the metal atom. The
301
pyridine ring protons also showed downfield signals comprising of doublet and triplet in the
302
range of 7.75-8.96 ppm. The NH2 protons were observed as a singlet for complexes (1-4) in the
303
range of 7.35-7.37 ppm respectively. The methoxy proton resonance for complexes (1 and 2)
304
appeared as a singlet at 3.81 and 3.83 ppm. The aromatic proton signals for complexes appeared
305
in the range of 6.50-7.86 ppm as doublet, triplet and multiplet. The methyl proton signal for
306
complexes (5-8) appeared as a singlet around 2.46-2.48 ppm respectively. In addition to the
307
signals for the ligand protons, a sharp singlet was observed for all the complexes between 1.58-
308
1.63 ppm respectively corresponding to the methyl protons of the Cp* ring. In the mass spectra
309
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:
310
491.13 and m/z: 581.20 can be assigned as [M-PF6-HCl]+ ion peaks respectively. Whereas, the
311
mass spectra of the complex 7 and 8 displayed molecular ion peaks at m/z: 511.12 and 601.17
312
which corresponds to the [M-PF6]+ ion.
313
The electronic spectra of the complexes were recorded in acetonitrile at 10-4 M
314
concentration at room temperature and the plot is shown in (Figure S2). The electronic spectra of
315
complexes display two absorption band in the higher energy region around 210-330 nm. The
15
316
bands in the higher energy UV region can be assigned as ligand centered or intra ligand π-π* and
317
n-π*transition. The Rh(III) and Ir(III) complexes provides filled dπ (t2g) orbitals which can
318
interact with low lying π* orbitals (C=N) of the ligand. The band in the lower energy region
319
around 345-405 nm can be assigned as Rh (dπ) or Ir (dπ) to π* ligand metal to ligand charge
320
transfer (MLCT) transition [43].
321
3.4.
Molecular structures of complexes
322
The molecular structures of some of the respective complexes have been elucidated by
323
single crystal X-ray analysis. Suitable single crystals were attached to a glass fibre and
324
transferred into the Oxford Diffraction Xcalibur Eos Gemini diffractometer. The crystallographic
325
details and structure refinement details are summarized in Table 1. The geometrical parameters
326
around the metal atom involving ring centroid are listed in Table S1. In all these complexes the
327
ligand is coordinated to the metal atom in a similar manner with N∩N binding mode. Complex
328
(1) and (8) crystallized in triclinic system with space group P 1͞ . Complex (8) crystallized with
329
one PF6 and one chloride counter ion. Complex (3) and (4) crystallized in monoclinic system
330
with space group P21/c whereas complex (7) crystallized in monoclinic system with space group
331
P21.
332
All these complexes display a typical three-legged piano stool geometry around the metal
333
center with coordination sites occupied by one chloride group, two σ bonded nitrogen atoms
334
from chelating azine ligand and the pentamethylcyclopentadienyl (Cp*) ring in η5 manner. The
335
metal atom in all these complexes is situated in a pseudo-octahedral arrangement with the azine
336
ligand coordinating through the pyridine and azine nitrogen atoms forming a five membered
337
metallocycle. In complexes (1), (3), (4) and (7) the M-N bond length {2.088(5), 2.099(3),
338
2.098(4) and 2.102(4) Å} from pyridine is comparatively shorter than the azine nitrogen-metal
16
339
distances {2.135(5), 2.116(3), 2.105(4) and 2.159(4) Å}, which are similar to those, reported
340
with similar complexes [24, 44]. However in complex (8) the metal-nitrogen distance from
341
pyridine {2.102(5) Å} is comparatively larger than azine nitrogen-metal distance, which is
342
{2.096(5) Å}. The C=N bond length of the coordinated nitrogen in complex (1), (3), (4) and (8)
343
is longer than that of the uncoordinated C=N (Table S1) which could be due to the back bonding
344
of electron from metal (dπ) to π* orbital of the ligand. But in complex (7), a reverse pattern has
345
been observed where the C=N bond length of the coordinated nitrogen {1.346(7) Å} is shorter
346
than uncoordinated C=N {1.358(7) Å} bond. The average M-C distances are {2.159 (1), 2.1534
347
(3), 2.1616 (4), 2.1528 (7) and 2.1726 (8) Å} while the distance between the metal to Cp*
348
centroid ring is in the range of 1.758–1.793 Å respectively. The M-Cl bond lengths {2.3976(15)
349
(1), 2.4172(9) (3), 2.4190(12) (4), 2.4242(16) (7) and 2.4220(17) (8) shows no significant
350
differences and is comparable to previously reported values (Table 1) [45-48]. The bite angle
351
N(1)-Rh(1)-N(2) values are 75.10(19) (1), 75.09(11) (3), and 75.44(17) (7) whereas in complex
352
(4) and (8) the bite angle values are N(1)-Ir(1)-N(2) values are 74.99(14) (4) and 75.26(18)
353
respectively which probably indicates an inward bending of the coordinated pyridyl and azine
354
group [49]. The bond angles N(1)-M-Cl(1) and N(2)-M-Cl(1) in complexes are comparable to
355
the piano stool arrangement about the metal atom and is comparable to reported values for
356
closely related systems [50-52]. Further the crystal packing in complex (1) is stabilized by weak
357
intermolecular hydrogen bonding C-H·····O (2.702 Å) between the hydrogen atom from methoxy
358
group and oxygen atom of the hydroxyl group and C-H·····Cl (2.793 Å) interaction between CH3
359
group of Cp* and chloride atom (Figure S3). These interactions play a significant role in the
360
formation of supramolecular motifs.
17
361
On the other hand in the crystal structure of complex (3) and (4) two types of
362
intramolecular hydrogen bonding has been observed; the first one between the uncoordinated
363
nitrogen atom of the azine linkage with the hydrogen atom of the hydroxyl group O-H·····N
364
(1.916 and 1.908 Å) and the second between the hydrogen atom from NH2 and uncoordinated
365
azine nitrogen atom N-H·····N (2.323 and 2.328 Å) (Figure 4). The selected hydrogen bonding
366
distances and angles for complex (3) and (4) are given in (Table 2). Also the crystal packing in
367
complex (3) and (4) is further stabilized by two different C-H·····Cl interaction between the Cl
368
atom attached to metal M (where M = Rh/Ir) with hydrogen atom of pyridine ring and NH2
369
(Figure S4). Complex (7) shows C-H·····π (2.832 and 2.937 Å) interactions between the methyl
370
hydrogen atom and Cp* moiety and between pyridine ring and hydrogen atom of Cp* group
371
respectively (Figure S5). Interestingly the crystal packing in complex (8) leads to a dimeric unit
372
via intermolecular C-H·····Cl interaction between the chloride counter ion and hydrogen atom
373
from pyridine ring, NH2 and Cp* group (Figure S6).
374
3.5.
Chemosensitivity studies
375
The complexes (1-8) were tested for their cytotoxicity against cancer cell line HT-29
376
(human colorectal cancer), and non-cancer cell line ARPE-19 (human retinal epithelial cells).
377
The response of the cell lines HT-29 to the test complexes and cisplatin (1-8) is presented in
378
graphical form in Figure 5 and in tabular form in Table 3. All the complexes tested were found to
379
be active against HT-29 cancer cell line (IC50< 30 µM). Complex (5) was the most potent among
380
all the complexes with (IC50 value of 96.93 ± 5.31 µM). However all the complexes were less
381
potent than cisplatin (IC50 value of 0.25 ± 0.11 µM against HT-29). The selectivity index (SI)
382
defined as the ratio of IC50 values in ARPE19 cells divided by the IC50 value of cancer cell line
383
demonstrates that all the complexes are effective against cancer cell with SI values ranging from
18
384
1.01 to 2.11 (Table S2). Moreover although complex (5) showed more selectivity than other
385
complexes for HT-29 cancer cell, however its selectivity was significantly lower than cisplatin
386
where SI value is 25.64 (Figure 6).
387
3.6.
Optimized geometry
388
The comparison of the geometric parameters (selected bond lengths and bond angles) of
389
the optimized structures and the crystal structures of the complexes (1, 3, 4, 7 and 8) are listed in
390
Table S3. All the metal complexes are found to be closed shell structures. The calculated bond
391
lengths and the bond angles of the complexes are in good agreement with the experimental data
392
indicating the reliability of the theoretical method (B3LYP/6-31G**/LanL2DZ) used in the
393
present study. It should be noted that for complexes (3, 4, 7 and 8), the M(1)-N(2) (where M =
394
Rh/Ir) bond length is slightly longer than the M(1)-N(1) bond length whereas for complex (1), a
395
reverse pattern has been observed (Table S3).
396
3.7.
Charge distribution
397
The charges on the individual atoms for the metal complexes obtained from NBO
398
analysis are listed in Table S4. The charges on the Rh atom in the complexes (1), (3), (5) and (7)
399
are 0.136, 0.200, 0.216 and 0.214 e whereas the charges on Ir for complexes (2), (4), (6) and (8)
400
are 0.186, 0.252, 0.268 and 0.214 e respectively. These NBO charges on Rh and Ir are
401
comparatively lower than their formal charge of +3 which suggests that the ligand transfers their
402
negative charge to the respective rhodium and iridium metal on complex formation. In metal
403
complexes (1-8), the charge on Cl ranges between -0.439 e (Complex-1) to -0.394 e (Complex-
404
4). In isolated ligands, the charge on N(1) ranges between -0.416 and –0.417 e whereas for N(2)
405
it ranges between -0.324 e and -0.348 e. It should be noted that for isolated ligands as well as for
406
complexes (1-8), the negative charges on N(1) (-0.385, -0.381, -0.372, -0.373, -0.369, -0.398, -
19
407
0.368 and -0.373 e) are slightly higher than the charges on N(2) (-0.258, -0.253, -0.284, -0.283, -
408
0.305, -0.297, -0.311 and -0.305 e). On complex formation, the negative charge on the N(1) and
409
N(2) reduces slightly giving an indication of the charge transfer on Rh and Ir in metal
410
complexes. The population of the 4d (4dxy, 4dxz, 4dyz, 4dx2 -y2 and 4dz2) orbital of Rh complexes
411
and 5d orbital of Ir complexes are shown in Table S5. The orbital occupations of each orbital
412
(ndxy, ndxz, ndyz, ndx2-y2 and ndz2) for all the complexes are comparatively higher in rhodium
413
complexes than iridium complexes. In free Rh(III) and Ir(III) state, the population of ndxy, ndxz and
414
ndyz are 2.0, 2.0 and 2.0 e and the other two orbitals remain vacant. But on complex formation, the
415
population on ndxy, ndxz and ndyz orbital gets reduced whereas the ndx2-y2 and ndz2 orbitals gain
416
some population as indicated in Table S5. For most of the complexes, the population of 4d and
417
5d orbital containing the same ligand follow similar pattern of filling, except for the complexes
418
containing ligand L1 where the ndxz orbital population is slightly lower and ndx2-y2 is higher as
419
compared to the other complexes.
420
3.8.
Frontier molecular orbitals and absorption spectra
421
The molecular orbital representation of the complexes along with their HOMO, LUMO
422
energies and HOMO-LUMO energy gaps are shown in Figure 7. The HOMO-LUMO energy gap
423
can be used as an important parameter in analyzing the chemical reactivity and kinetic stability
424
of a molecule. This energy gap is also related to the hardness/softness of a chemical species [53].
425
The lower HOMO-LUMO energy gap is a suitable condition where a molecule can be excited
426
easily and thereby increasing its reactivity and decreasing its kinetic stability whereas higher
427
energy gap can lead to more kinetic stability but less reactivity. The HOMO-LUMO energy gaps
428
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
429
respectively. The gap is slightly lower for the iridium complexes as compared to rhodium
20
430
complexes containing the same ligand indicating the reactivity of Ir complexes over the
431
complexes containing Rh metal. The % contribution of molecular orbital analysis as shown in
432
Table S6, predicts that the most percentage of HOMO is located on the ligand itself except for
433
complex (2) and (8) where as it is mostly present on the Ir metal. On the other hand, LUMO is
434
located on the ligand for complexes (1) (about 97%), (2) (91%), (4) (89%), (6) (92%) and (8)
435
(69%) whereas for complexes (3) (40%), (5) (35%) and (7) (38%), it is located on the Rh metal.
436
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), (4) and (6) occurring at 417, 444 and 441 nm corresponds to
440
ILCT character, for complexes (2) and (8) at 463 and 440 nm corresponds to MLCT character
441
whereas for complexes (3), (5) and (7) at 532, 519 and 518 nm corresponds to LMCT character.
442
These MLCT character can be assigned for dπ(M)→π∗(L) transitions whereas the ILCT
443
character are for π→π∗ transitions. It should be noted that all LMCT transitions are occurring at
444
higher wavelength regions (i.e. > 500 nm). In good agreement with the experimental data, the
445
TD-DFT calculations shows few MLCT transitions at 358 nm complex (2), 332 nm, complex
446
(4), 334 nm complex (6) and 372, 358 nm complex (8). However, in the range between 340-400
447
nm, few LMCT, ILCT and LLCT transitions have also been observed (Table 4).
448
4.
Conclusion
449
In summary, we have synthesized four new azine Schiff-base ligands and its rhodium and
450
iridium half-sandwich complexes. All these complexes and ligands were full characterized by
451
various spectroscopic techniques. The ligands under study preferably bind to the metal in a
452
bidentate N∩N fashion using pyridine and one azine nitrogen atom. Our attempt to synthesize
21
453
dinuclear rhodium and iridium complexes with NNʹ and NO bonding was however unsuccessful
454
irrespective of molar ratio of metal to ligand where as in the presence of base, it leads to
455
decomposition of the reaction. These complexes possess some important intramolecular and
456
intermolecular hydrogen bonding and also possess some weak non-covalent interactions,
457
particularly C-H·····Cl and C-H·····π interactions. Chemosensitivity activity of the complexes
458
against HT-29 cancer cell demonstrates that the complexes are active however complex (5) was
459
found to be the most potent among all other complexes. Theoretical studies reveal that the
460
HOMO-LUMO energy gap is lower for iridium complexes indicating better reactivity over the
461
rhodium complexes. TD-DFT calculations were carried out in order to evaluate the electronic
462
transitions occurring in the metal complexes, which are in good agreement with the experimental
463
results. The charge distribution analysis (using NBO analysis) of these complexes helps to
464
understand how the charges on nitrogen atom (which are coordinating to the metal) are
465
delocalized on complex formation. Especially, the NBO charges, on rhodium and iridium
466
confirm that the ligands transfer their negative charge to the respective metal on complex
467
formation. The lower HOMO-LUMO energy gap leads to greater chemical reactivity but lesser
468
kinetic stability and vice versa. Furthermore, the nature of HOMO and LUMO illustrate the
469
electronic origin of the lowest energy transition and the resulting electronic reorganization.
470
Moreover, the molecular orbital analysis was helpful to understand and locate the % contribution
471
of HOMO and LUMO on different fragments of the complexes, which is otherwise not possible
472
to predict from experimental data.
473
Acknowledgements
474
Sanjay Adhikari and Dipankar Sutradhar thanks UGC, New Delhi, India for providing financial
475
assistance in the form of university fellowship (UGC-Non-Net). We thank DST-PURSE
22
476
SCXRD, NEHU-SAIF, Shillong, India for providing Single crystal X-ray analysis and other
477
spectral studies. AKC thanks Computer centre, NEHU, for computational facilities.
478
Supplementary material
479
CCDC 1477976 (1), 1477977 (3), 1477978 (4), 1477979 (7) and 1477980 (8) contains
480
the supplementary crystallographic data for this paper. These data can be obtained free of charge
481
via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing data_request@ccdc.cam.ac.uk, or by
482
contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
483
UK; Fax: +44 1223 336033.
484
485
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486
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571
572
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
584
complex [Cp*IrCl(L2)Cl]PF6 (4) with 50% probability thermal ellipsoids. Hydrogen atoms and
585
counter ions are omitted for clarity.
29
586
587
588
589
590
Figure 3 (a) ORTEP diagram of complex [Cp*Rh(L4)Cl]PF6 (7) and (b) ORTEP diagram, of
591
complex [Cp*IrCl(L4)Cl]PF6 (8) with 50% probability thermal ellipsoids. Hydrogen atoms and
592
counter ions are omitted for clarity.
593
594
Figure 4 Crystal structure of complexes (3) and (4) showing intramolecular hydrogen bonding.
30
595
596
Figure 5 Response of HT-29 (human colorectal cancer) to compounds (1-8) and cisplatin. Cell
597
were exposed to compounds (1-8) for 96 hours. Each value represents the mean ± standard
598
deviation from three independent experiments.
599
600
Figure 6 Graph showing selectivity index of complex 5 and cisplatin against HT-29 cancer cell
601
line. The selectivity index is defined as the IC50 of ARPE19 cell divided by the IC50 of tumour
602
cell line.
31
603
604
605
Figure 7 HOMO, LUMO energies and their energy gap of complexes (1–8)
32
606
Table 1. Crystal structure data and refinement parameters of complexes.
Complexes
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
a (Å)/α (°)
b (Å)/β (°)
c (Å)/γ (°)
Volume (Å3)
Z
Density (calc) (Mg/m-3)
[1] PF6
C24H29ClN4O2F6PRh
688.84
298(2)
0.71073
triclinic
P ͞1
8.3893(7)/89.370(6)
10.5533(7)/86.439(6)
16.6554(11)/71.182(7)
1393.00(18)
2
1.642
[3] PF6
C23H27ClF6N4OPRh
658.82
293(2)
0.71073
monoclinic
P21/c
10.6710(6)/90
17.0730(8)/92.708(4).
14.5390(8)/90
2645.8(2)
4
1.654
[4] PF6
C23H27ClF6N4OPIr
748.11
293(2)
0.71073
monoclinic
P21/c
10.7019(5)/90
17.0860(9)/93.062(4)
14.6118(9)/90
2668.0(2)
4
1.862
[7] PF6
C24H29ClF6N4PRh
656.84
293(2)
0.71073
monoclinic
P21/c
38.850(5)/90
7.9488(5)/98.027(4)
28.562(4)/90
1344.83(10)
2
1.622
[8] PF6 Cl
C24H29Cl2F6N4PIr
781.58
293(2)
0.71073
triclinic
P ͞1
7.9976(4)/87.496
12.4774(4)/82.086(4)
14.6442(6)/72.596(4)
1381.15(10)
2
1.879
Absorption coefficient (µ) (mm-1)
F(000)
Crystal size (mm3)
0.836
696
0.23 x 0.21 x 0.21
0.874
1328
0.21 x 0.19 x 0.04
5.231
1456
0.23 x 0.23 x 0.21
0.857
664
0.22 x 0.20 x 0.120
5.148
762
0.19 x 0.12 x 0.09
Theta range for data collection
Index ranges
3.174 to 28.654°.
-11<=h<=10, -12<=k<=13, 22<=l<=20
10811
6286 [R(int) =0.0717]
99.57 %
Semi-empirical from
equivalents
Full-matrix least-squares on
F2
6286/0/362
1.197
R1 = 0.0703, wR2 = 0.1706
R1 = 0.0855, wR2 = 0.1772
0.583 and -0.461
1477976
3.33 to 26.73°.
-13<=h<=10, -10<=k<=21, 12<=l<=18
9506
5375 [R(int) = 0.0268]
99.5 %
Semi-empirical from
equivalents
Full-matrix least-squares on
F2
2375/0/330
1.063
R1 = 0.0440, wR2 = 0.0895
R1 = 0.0592, wR2 = 0.0968
0.520 and -0.543
1477977
3.31 to 26.37°.
-13<=h<=7, -21<=k<=19, 16<=l<=18
10081
5422 [R(int) = 0.0277]
99.2 %
Semi-empirical from
equivalents
Full-matrix least-squares on
F2
5422/0/340
1.026
R1 = 0.0340, wR2 = 0.0630
R1 = 0.0500, wR2 = 0.0683
1.102and -1.143
1477978
3.386 to 28.842°.
-9<=h<=9, -12<=k<=22, 14<=l<8
5614
4000 [R(int) = 0.0268]
99.2 %
Semi-empirical from
equivalents
Full-matrix least-squares on
F2
4000/1/340
1.041
R1 = 0.0394, wR2 = 0.0822
R1 = 0.0462, wR2 = 0.0858
0.512 and -0.478
1477979
3.23 to 26.37°.
-8<=h<=9, -15<=k<=15, 17<=l<18
7889
5335 [R(int) = 0.0296]
94.8 %
Semi-empirical from
equivalents
Full-matrix least-squares on
F2
5335/0/349
1.046
R1 = 0.0368, wR2 = 0.0875
R1 = 0.0431, wR2 = 0.0912
1.828 and -1.071
1477980
Reflections collected
Independent reflections
Completeness to theta = 25.00°
Absorption correction
Refinement method
Data/restraints/parameters
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.
607
Structures were refined on F02: wR2 = [Σ[w(F02 - Fc2)2] / Σw(F02)2]1/2, where w-1 = [Σ(F02)+(aP)2+bP] and P = [max(F02, 0)+2Fc2]/3.
33
608
Table-2. Selected hydrogen bonding distances (Å) and angles (°) of complexes 3 and 4.
Complexes
3
D-H·····A
O(1)-H(1A)·····N(4)
N(3)-H(3A)·····N(4)
H····A (Å)
1.916
2.323
D·····A (Å)
2.638
2.624
D·····H (Å)
0.820
0.860
∠D─H···A(°)
146.39
100.76
4
O(1)-H(1A)·····N(4)
N(3)-H(3A)·····N(4)
1.908
2.328
2.634
2.629
0.820
0.860
146.90
100.78
609
610
Table-3 Response of HT-29 (human colorectal cancer) to complexes (1-8) and cisplatin. Each
611
value represents the mean ± standard deviation from three independent experiments.
Complexes
IC50 (µM)
HT-29
56.95 ± 11.76
89.42 ± 18.33
82.32 ± 15.55
96.93 ± 5.31
46.17 ± 12.78
83.74 ± 28.17
93.16 ± 11.84
88.09 ± 20.63
0.25 ± 0.11
1
2
3
4
5
6
7
8
Cisplatin
ARPE-19
85.31 ± 14.86
93.45 ± 11.34
83.03 ± 14.76
>100
97.39 ± 4.53
>100
>100
>100
6.41 ± 0.95
612
613
Table 4. The energy gap, theoretical and experimental absorption bands, electronic transitions
614
and dominant excitation character for various singlet states of the complexes (1-8) calculated
615
with TD-DFT method.
The most
important orbital
excitations
Calculated
λ (nm)
Energy
gap E
(eV)
Oscillator Dominant excitation
strength
Character
(f)
Complex (1)
H→L
H-2→L
H→L+2
H-4→L+2
H-1→L+4
H-6→L
H-6→L+2
H-11→L
H-5→L+4
417.16
359.64
355.41
338.40
278.91
282.81
275.41
235.62
233.62
3.20
3.53
4.03
4.89
4.73
4.54
5.37
5.08
5.74
0.2051
0.0542
0.0120
0.0139
0.0248
0.0073
0.0050
0.0216
0.0480
34
L1→L1(ILCT)
Cl→L1(LLCT)
L1→L1(ILCT)
L1→L1(ILCT)
L1→L1(ILCT)
L1→L1(ILCT)
L1→L1(ILCT)
Rh→L1(MLCT)
Cl→L1(LLCT)
Experimental
λ (nm)
352.21
276.0
233.3
H-6→L+3
232.46
5.46
H→L
H→L+3
H-4→L
H-5→L+1
H-2→L+4
462.76
358.38
340.55
273.73
266.79
2.98
4.64
4.01
5.11
5.33
H→L
H-2→L+1
H→L+2
H-1→L+2
H-3→L
H→L+4
H-6→L
H-5→L+1
H-4→L+4
H-5→L+3
532.04
348.95
345.72
344.68
336.07
289.42
285.32
282.59
237.16
234.58
3.63
4.11
3.84
4.10
4.24
4.85
5.14
4.98
5.74
5.74
H→L
H-2→L
H-1→L+1
H→L+3
H-4→L
H-4→L+2
H-1→L+2
H-8→L+3
H-6→L+4
H-2→L+5
444.09
362.56
332.29
329.46
324.35
294.35
288.71
212.19
210.71
210.22
3.46
3.91
3.80
4.48
4.53
5.47
4.74
6.47
6.56
6.26
H→L
H-2→L+2
H-4→L+1
H-1→L+4
H-2→L+4
H-5→L+4
H-10→L+2
519.01
338.46
326.16
271.36
267.30
232.84
229.44
3.61
4.30
4.56
5.01
5.21
5.83
6.14
H→L
H-2→L+1
H-1→L+1
H-7→L
H-6→L
H-1→L+4
441.76
334.33
328.24
268.58
264.64
260.56
3.60
4.45
4.33
5.42
5.25
5.17
H→L
H-1→L
H-1→L+1
H-1→L+4
H-2→L+3
518.07
448.90
397.25
269.94
262.52
3.68
4.05
4.09
5.23
5.20
0.0105
Complex (2)
0.0644
0.0191
0.0075
0.0470
0.1540
Complex (3)
0.0087
0.0369
0.0128
0.0089
0.0047
0.0063
0.0163
0.0391
0.0422
0.0161
Complex (4)
0.0355
0.0077
0.0076
0.0468
0.0265
0.0164
0.0048
0.0387
0.0399
0.0669
Complex (5)
0.0076
0.0120
0.0052
0.265
0.0177
0.0498
0.0127
Complex (6)
0.0160
0.0109
0.1160
0.0159
0.0304
0.0350
Complex (7)
0.0071
0.0132
0.0148
0.0297
0.0465
35
L1→L1(ILCT)
Ir→L1(MLCT)
Ir→Cp*(MLCT)
L1→L1(ILCT)
Cp*→L1(LLCT)
L1→Ir(LMCT)
L2→Rh(LMCT)
L2→L2(ILCT)
L2→Rh(LMCT)
Cl+L2→Rh(LMCT)
Cl→Rh(LMCT)
L2→L2(ILCT)
Cl+L2→Rh(LMCT)
L2→L2(ILCT)
L2→L2(ILCT)
L2→L2(ILCT)
L2→L2(ILCT)
L2→L2(ILCT)
Rh+L2→L2(MLCT/ILCT)
L2→L2(ILCT)
Cl+Cp*→L2(LLCT)
Cl+Cp*→L2(LLCT)
Rh+L2→Rh+L2
L2→L2(ILCT)
Cl→L2(LLCT)
L2→L2(ILCT)
L3→Rh(LMCT)
Cl→L3(LLCT)
L3→Rh(LMCT)
L3→L3(ILCT)
Cl→L3(LLCT)
L3→L3(LLCT)
Rh+L3→L3(MLCT/ILCT)
L3→L3(ILCT)
Ir→L3(MLCT)
L3→L3(ILCT)
Ir→L3(MLCT)
Cl→L3(LLCT)
L3→L3(ILCT)
L4→Rh(LMCT)
Cl→Rh(LMCT)
Cl→Rh(LMCT)
Cl→L4(LLCT)
Cl→L4(LLCT)
347.0
266.0
344.10
286.1
234.30
346.1
292.21
210.9
332.0
268.0
229.0
330.0
256.0
400.0
265.0
H→L+5
231.04
5.66
H→L
H-1→L+2
H-1→L
H-2→L+3
H-4→L+3
439.65
371.55
358.22
257.57
255.65
3.59
4.79
4.0
5.29
5.61
0.0547
Complex (8)
0.0196
0.0381
0.0349
0.0359
0.0142
616
36
L4→L4(ILCT)
Ir→L4(MLCT)
Ir→L4(MLCT)
Ir→L4(MLCT)
Cl→Cp*(LLCT)
L4→Cp*(LLCT)
229.0
361.0
256.0