Half-sandwich d6 metal complexes comprising of 2-substituted-1,8-napthyridine ligands with unexpected bonding modes: Synthesis, structural and anti-cancer studies

Article abstract of DOI:10.1016/j.jorganchem.2017.11.011

The Friedl?nder condensation reaction between 2-aminonicotinealdehyde and acetophenone derivatives in presence of potassium hydroxide yielded 2-substituted-1,8-napthyridine derivatives viz. 2-(1,8-napthyridin-2-yl)phenol (PHNp), 2-(1,8-napthyridin-2-yl)an

Full text of DOI:10.1016/j.jorganchem.2017.11.011

Accepted Manuscript
6
Half-sandwich d metal complexes comprising of 2-substituted-1,8-napthyridine
ligands with unexpected bonding modes: Synthesis, structural and anti-cancer studies
Sanjay Adhikari, Omar Hussain, Roger M. Phillips, Mohan Rao Kollipara
PII:
S0022-328X(17)30660-5
10.1016/j.jorganchem.2017.11.011
JOM 20176
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 12 October 2017
Revised Date: 9 November 2017
Accepted Date: 10 November 2017
6
Please cite this article as: S. Adhikari, O. Hussain, R.M. Phillips, M.R. Kollipara, Half-sandwich d
metal complexes comprising of 2-substituted-1,8-napthyridine ligands with unexpected bonding modes:
Synthesis, structural and anti-cancer studies, Journal of Organometallic Chemistry (2017), doi: 10.1016/
j.jorganchem.2017.11.011.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
1
2
3
Half-sandwich d6 metal complexes comprising of 2-substituted-1,8-
napthyridine ligands with unexpected bonding modes: Synthesis,
structural and anti-cancer studies
4
5
6
7
Sanjay Adhikari[a], Omar Hussain[b], Roger M Phillips[b], Mohan Rao Kollipara[a*]
8
9
[a]Centre for Advanced Studies in Chemistry, North-Eastern Hill University, Shillong 793022,
India. E-mail: mohanrao59@gmail.com
10
11
[b]Department of Pharmacy, School of Applied Sciences, University of Huddersfield,
Huddersfield HD1 3DH, UK

ACCEPTED MANUSCRIPT
12
13
Graphical abstract
14
2

ACCEPTED MANUSCRIPT
15 Abstract
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
The Friedländer condensation reaction between 2-aminonicotinealdehyde and
acetophenone derivatives in presence of potassium hydroxide yielded 2-substituted-1,8-
napthyridine derivatives viz. 2-(1,8-napthyridin-2-yl)phenol (PHNp), 2-(1,8-napthyridin-2-
yl)aniline (AnNp) and 2-(pyridine-4-yl)-1,8-napthyridine (PyNp). Treatment of the chloro-
bridged dimers [(arene)MCl2]2 [arene =
equivalents of napthyridine ligands (PHNp, AnNp and PyNp) allowed the formation of
mononuclear napthyridine complexes having formula [(arene)M(PHNp)Cl2] ),
[(arene)M(AnNp)Cl]PF6 ( ) and [(arene)M(PyNp)Cl2] ( ). These napthyridine compounds
p-cymene, Cp*; M = Ru, Rh and Ir] with two
(1-3
4-
6
7-9
were isolated as neutral and cationic complexes which were further characterized by analytical
and spectroscopic techniques. The molecular structures of some of the respective napthyridine
complexes were established by carrying out the single crystal X-ray analysis. Single crystal X-
ray studies revealed the coordination of the napthyridine ligands to the metal center wherein
AnNp ligand coordinated metal in a bidentate chelating NN
ʹ manner and PHNp and PyNp ligand
coordinated metal in a monodentate fashion. In case of PHNp complexes the coordination occurs
through napthyridine nitrogen N(1) whereas in case of PyNp complexes the coordination takes
place through pyridine nitrogen N(1). These napthyridine complexes possessed cytotoxicity
against HCT-116 (human colorectal cancer) and MIA-PaCa-2 (pancreatic carcinoma) cancer cell
lines as compared to non-cancer cell line ARPE-19.
Keywords: Ruthenium, rhodium, iridium, napthyridine’s, cytotoxicity
3

ACCEPTED MANUSCRIPT
35
36
Introduction
Arene ruthenium complexes are a well-known class of organometallic compounds
generally referred to as half-sandwich complexes having potential applications in many arenas
[1]. These organometallic compounds have been found to possess clinical as well as industrial
applications [2]. Ruthenium complexes have also displayed remarkable activity in medicinal
chemistry and these complexes have the potential to act as metal based anti-cancer drugs [3, 4].
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
Two such complexes in particular namely [Ru(η
6-arene)Cl(en)]+ (en = ethylenediamine) and
[Ru(cymene)Cl2(PTA)], known as RAPTA-C (PTA = 1,3,5-triaza-7-phosphaadamantane), have
been found to possess excellent cytotoxic and anti-cancer activity both in vitro and in vivo
including activity against cisplatin resistant cancer cells [5, 6]. Analogous to arene ruthenium
complexes, Cp* rhodium and Cp* iridium complexes are also being studied as an alternative to
platinum based drugs because of the inert facial co-ligand Cp* which is expected to offer several
advantages such as water solubility and lability [7]. These complexes also serve as catalysts for
various organic transformations such as hydrogenation and C-H activation [8, 9].
1,8-napthyridines represents an important class of ligands containing two fused pyridine
rings and whose structure is closely related to bipyridines and phenanthrolines. These ligands
possess several donor sites thus allowing them to act as monodentate, bidentate chelating and
bridging coordinating ligand [10]. Substitution of an appropriate donor groups such as pyridyl,
thiazolyl, furyl and pyrrole at the 2-position of 1,8-napthyridine provides a ligand, which can
coordinate metal with the substituted ring in addition to the napthyridine ring [11]. The
napthyridine ligands acts as a bridge to communicate between the two metal centers to come
close to each other and which is expected to alter the bonding magnetic or energy transfer
interactions. In cases where the donor groups attached at the 2-position of the napthyridine ring
were substituted phenyl (F and OMe) and N-methyl pyrrole groups, interesting coordinating
4

ACCEPTED MANUSCRIPT
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
chemistry has been observed for diruthenium complexes [12]. Despite having a rich diversified
chemistry of napthyridine metal complexes, it is noteworthy that only a few half-sandwich
platinum group metal napthyridine complexes have been reported to date [10, 13]. Based on the
reactivity and different bonding modes of napthyridine ligands we anticipated that what would
be the outcome if we substitute donor group such as phenol, aniline and pyridine at the 2-
position of the napthyridine ring. We assumed that the formed ligand would display distinctly
unusual bonding modes and we have therefore explored this possibility in our present work.
Ligands used in the present study are 2-(1,8-napthyridin-2-yl)phenol (PHNp), 2-(1,8-
napthyridin-2-yl)aniline (AnNp) and 2-(pyridine-4-yl)-1,8-napthyridine (PyNp). To the best of
our knowledge the coordination chemistry of these ligands has not been explored previously.
Herein, we report the synthesis and anti-cancer studies of ruthenium, rhodium and
iridium half-sandwich complexes bearing phenol, aniline and 4-pyridyl groups substituted at 2-
position of 1,8-napthyridine moiety.
Experimental
Physical methods and materials
The reagents used were of commercial quality and used without further purification.
Metal chloride’s RuCl3.nH2O, RhCl3.nH2O and IrCl3.nH2O were purchased from Arora Matthey
Limited.
α-phellandrene, pentamethylcyclopentadiene and 2´-hydroxyacetophenone were
purchased from Sigma-Aldrich. 2-aminonicotinaldehyde and 4-acetyl pyridine were obtained
from Alfa Aesar and 2´-aminoacetophenone was obtained from Spectrochem. The solvents were
dried and distilled prior to use according to standard procedures [14]. Precursor metal complexes
[(p-cymene)RuCl2]2 and [Cp*MCl2]2 (M = Rh/Ir) were prepared according to the published
1
13
procedures [15, 16]. H and C NMR spectra were recorded on a Bruker Advance II 400 MHz
5

ACCEPTED MANUSCRIPT
82
83
spectrometer using CDCl3 and DMSO-d6 as solvents; chemical shifts were referenced to TMS.
Infrared spectra (KBr pellets; 400-4000 cm-1) were recorded on a Perkin-Elmer 983
spectrophotometer. Mass spectra were obtained from Waters ZQ 4000 mass spectrometer by ESI
method using acetonitrile as solvent. Elemental analyses of the complexes were carried out on a
Perkin-Elmer 2400 CHN/S analyzer.
84
85
86
87
Structure determination by X-ray crystallography
88
Solvent diffusion method was used for growing single crystals of compounds by layering
solutions of the compounds in dichloromethane or chloroform with a fourfold excess of hexane
and allowing them to stand undisturbed for one week. Suitable single crystal of compounds were
chosen and glued onto the tip of glass fiber which was centered in the X-ray beam. The data for
the complexes was collected on an Oxford Diffraction Xcalibur Eos Gemini diffractometer using
89
90
91
92
93
graphite monochromated Mo-Kα radiation (λ = 0.71073 Å). The strategy for the data collection
94
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 [17, 18]. The positions of all the atoms were obtained
by direct methods. Metal atoms in the complex were located from the E-maps and all non-
hydrogen atoms were refined anisotropically by full-matrix least-squares. Hydrogen atoms were
placed in geometrically idealized positions and constrained to ride on their parent atoms with C--
-H distances in the range 0.95-1.00 Angstrom. Isotropic thermal parameters Ueq were fixed such
that they were 1.2Ueq of their parent atom Ueq for CH's and 1.5Ueq of their parent atom Ueq in
case of methyl groups. Crystallographic and structure refinement parameters for the complexes
95
96
97
98
99
100
101
102
103
6

ACCEPTED MANUSCRIPT
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
are summarized in Table 1 and selected bond lengths and bond angles are presented in Table 2.
Figures 1-5 were drawn with ORTEP3 program [19].
The crystal structure of complex (
4
) contains disordered DCM molecule. Crystal
structure of complexes (8 and 9) contains CHCl3 molecule in their solved structure.
Cell line testing
The biological importance of the naphthyridines prompted us to study the cytotoxic
activity of the synthesized napthyridine ligands and complexes. The cytotoxicity was tested
against the HCT-116 colorectal carcinoma and MIA-PaCa-2 pancreatic carcinoma cell lines with
the IC50 result shown in Table 3. Both cell lines were originally purchased from the American
Type Culture Collection (ATCC) and all other reagents were purchased from Sigma Aldrich Co.
Ltd (Dorset, UK) unless otherwise stated. The ARPE-19 cell line which is a non-cancer, human
epithelial cell line derived from the retina and this was also obtained from ATCC. Cytotoxicity
of ligands and compounds were evaluated using the standard MTT 3-(4,5-Dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide cellular viability assay as follows. Cells were inoculated into
°
96 well plates at 1.5 x 103 cells per well and incubated at 37 C in an atmosphere of 5% CO2
prior to drug exposure. The napthyridine ligands (Scheme 1) and complexes (
were all dissolved in DMSO at a concentration of 25 mM and diluted further with medium to
obtain drug solutions ranging from 0.5 to 150 M. Cisplatin was dissolved in phosphate buffered
1-9) (Scheme 2)
µ
saline at a stock concentration of 25 mM. The final DMSO concentration was 0.2% (v/v), which
is nontoxic to cells. Cells were exposed to drug for 96 hours and cell survival was determined
using the MTT assay [20, 21]. Following drug exposure, 20 µL of MTT (0.5 mg/ml) in
°
phosphate buffered saline was added to each well and it was further incubated at 37 C for 4
hours in an atmosphere of 5% CO2. The solution was then removed and the formed formazan
7

ACCEPTED MANUSCRIPT
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
crystals was dissolved in 150 µM DMSO and the absorbance of the solution was recorded at 550
nm using an ELISA spectrophotometer. Percentage cell survival was calculated by dividing the
true absorbance of treated cell by the true absorbance for controls (exposed to 0.2% DMSO). The
IC50 values were determined from plots of % survival against drug concentration. Each
experiment was repeated three times and a mean value obtained and stated as IC50 (µM) ± SD.
Synthesis of 2-substituted-1,8-napthyridine ligands
The ligands 2-(1,8-napthyridin-2-yl)phenol (PHNp), 2-(1,8-napthyridin-2-yl)aniline
(AnNp) and 2-(pyridine-4-yl)-1,8-napthyridine (PyNp) were synthesized according to
Friedländer condensation (Scheme 1) [22]. Herein a detailed procedure is provided only for 2-
(1,8-napthyridin-2-yl)phenol (L1). A stirred solution of 2´-hydroxy acetophenone (408 mg, 3
mmol), 2-aminonicotinealdehyde (366 mg, 3 mmol) and KOH (336 mg, 6 mmol) in 50%
aqueous methanol (10 mL) was heated to 60 °C overnight. The reaction mixture was quenched
by the addition of water (20 mL) and the resulting precipitate was isolated by filtration. The
crude product was washed with water, dried in vacuum and collected.
2-(1,8-napthyridin-2-yl)phenol (PHNp)
Color: Orange crystals; Yield: 82 %; IR (KBr, cm-1): 3521(b), 3224(m), 2961(m), 2870(w),
1644(s), 1469(m), 1358(m); 1H NMR (400 MHz, CDCl3):
δ
= 14.7 (s, 1H, OH), 8.26 (d, 1H,
= 8 Hz), 7.90 (d, 1H, = 8 Hz), 7.43-7.46 (m, 1H),
= 8 Hz), 6.88-6.92 (m, 1H); Anal. Calc
J =
12 Hz), 8.15 (d, 1H,
J
= 8 Hz), 8.08 (d, 1H,
J
J
7.31-7.34 (m, 1H), 7.24 (d, 1H,
J
= 8 Hz), 7.06 (d, 1H, J
for C14H10N2O (222.24); C, 75.66; H, 4.54; N, 12.60. Found: C, 75.76; H, 4.67; N, 12.73 %.
2-(1,8-napthyridin-2-yl)aniline (AnNp)
Color: Yellow crystals; Yield: 86 %; IR (KBr, cm-1): 3402(s), 3293(m), 3058(w), 2922(w),
1
1611(s), 1566(m), 1541(m), 1499(m), 1257(m); H NMR (400 MHz, DMSO-d6):
δ = 8.84 (dd,
8

ACCEPTED MANUSCRIPT
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
1H,
Hz), 7.70 (d, 1H,
1H, = 8 Hz), 6.46 (t, 1H,
J
= 4 and 4 Hz), 8.28 (d, 1H,
= 8Hz), 7.38-7.41 (m, 1H), 7.34 (s, 2H, NH2), 6.98 (t, 1H,
= 8 Hz); Anal. Calc for C14H11N3 (221.25); C, 76.00; H, 5.01; N,
J
= 8 Hz), 8.25 (dd, 1H,
J
= 4 and 4 Hz), 8.00 (d, 1H,
J = 8
J
J
= 8 Hz), 6.65 (d,
J
J
18.99. Found: C, 76.09; H, 5.12; N, 19.08 %.
2-(pyridine-4-yl)-1,8-napthyridine (PyNp)
Color: White powder; Yield: 65 %; IR (KBr, cm-1): 3021(m), 2927(m), 2811(m), 1634(m),
1
1587(m), 1494(m), 1340(s); H NMR (400 MHz, CDCl3):
δ
= 9.21 (dd, 1H,
= 8 and 8 Hz), 8.20 (d, 2H,
= 8 Hz), 7.54-7.57 (m, 1H); Anal. Calc for C13H19N3 (207.23); C, 75.35; H,
J
= 4 and 4 Hz),
8.82 (d, 2H,
J
= 8 Hz), 8.38 (d, 1H,
J
= 8 Hz), 8.28 (dd, 1H,
J
J
= 8
Hz), 8.07 (d, 1H,
J
4.38; N, 20.28. Found: C, 75.47; H, 4.46; N, 20.41 %.
General procedure for preparation of neutral napthyridine complexes (1-3)
A mixture of metal precursor [(arene)MCl2]2 (arene = p-cymene, Cp*; M = Ru, Rh and
Ir) (0.1 mmol) and ligand 2-(1,8-napthyridin-2-yl)phenol (PHNp) (0.2 mmol) were dissolved in
dichloromethane and the reaction mixture was stirred overnight at room temperature. This
solution was then filtered over celite and the solvent was evaporated under reduced pressure to
afford yellow solid which was washed with diethyl ether (2 x 10 mL) and air dried (Scheme 2).
[(p-cymene)Ru(PHNp)Cl2] (1)
Yield: 69 mg (75%); IR (KBr, cm-1): 3411(b), 3056(m), 1611(m), 1585(m), 1548(m), 1508(m),
1473(m), 1249(m), 1155(s); 1H NMR (400 MHz, DMSO-d6):
= 4 Hz), 8.48 (d, 1H, = 8 Hz), 8.31 (t, 2H, = 8 Hz), 8.07 (d, 1H,
1H), 7.22 (t, 1H, = 8 Hz), 6.77-6.82 (m, 2H), 5.61 (d, 2H, = 4 Hz, CH(p-cym)), 5.57 (d, 2H,
8 Hz, CH(p-cym)), 2.61 (sept, 1H, CH(p-cym)), 1.86 (s, 3H, CH(p-cym)), 0.98 (d, 6H, = 8 Hz, CH(p-
δ
= 14.92 (s, 1H, OH), 8.89 (d, 1H,
J
J
J
J
= 8 Hz), 7.47-7.50 (m,
J
J
J =
J
cym)); 13C NMR (100 MHz, DMSO-d6):
δ
(ppm) = 160.60, 160.29, 155.19, 149.35, 138.65,
9

ACCEPTED MANUSCRIPT
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
135.10, 133.83, 128.16, 121.69, 121.11, 119.92, 118.16, (C-PHNp), 105.51, 103.91, 87.71,
84.21, 30.31, 23.81, 17.41 (C-p-cym); ESI-MS (m/z) [Found (Calcd)]: [456.96 (457.08)] [M-Cl-
HCl]+; Anal. Calc for C24H24Cl2N2ORu (528.43); C, 54.55; H, 4.58; N, 5.30. Found: C, 54.64; H,
4.67; N, 5.39 %.
[Cp*Rh(PHNp)Cl2] (2)
Yield: 82 mg (77%); IR (KBr, cm-1): 3434(b), 2137(m), 1608(m), 1503(m), 1475(m), 1384(m),
1
1137(m); H NMR (400 MHz, DMSO-d6):
δ = 15.12 (s, 1H, OH), 9.10 (d, 1H, J = 4 Hz), 8.68
(d, 1H,
J = 8 Hz), 8.51 (d, 2H, J = 8 Hz), 8.26 (d, 2H, J = 4 Hz), 7.67-7.70 (m, 1H), 7.42 (t, 1H, J
= 8 Hz), 6.97-7.02 (m, 1H), 1.60 (s, 15H, CH(Cp*)); 13C NMR (100 MHz, DMSO-d6):
δ
= 160.61,
160.29, 154.49, 152.35, 139.65, 137.30, 132.83, 128.16, 122.69, 121.11, 118.92, 118.83, 118.18
(C-PHNp), 98.68 (Cp*ipso), 8.51 (Cp*Me); ESI-MS (m/z) [Found (Calcd)]: [459.02 (459.09)] [M-
Cl-HCl]+; Anal. Calc for C24H25Cl2N2ORh (531.27); C, 54.26; H, 4.74; N, 5.27. Found: C, 54.37;
H, 4.87; N, 5.41 %.
[Cp*Ir(PHNp)Cl2] (3)
Yield: 98 mg (78%); IR (KBr, cm-1): 3401(b), 2918(w), 2150(m), 1632(m), 1608(m), 1503(m),
1
1475(m), 1137(m); H NMR (400 MHz, DMSO-d6):
δ = 15.12 (s, 1H, OH), 9.10 (dd, 1H, J = 4
and 4 Hz), 8.68 (d, 1H,
1H), 7.42 (t, 1H,
DMSO-d6):
J
= 8 Hz), 8.51 (t, 2H,
J
= 8 Hz), 8.27 (d, 1H,
J
= 8 Hz), 7.67-7.70 (m,
13
J
= 8 Hz), 6.98-7.02 (m, 2H), 1.61 (s, 15H, CH(Cp*)); C NMR (100 MHz,
δ
= 160.62, 160.30, 154.49, 152.36, 139.65, 137.30, 132.83, 128.17, 122.69, 121.11,
118.92, 118.26, 118.18 (C-PHNp), 92.01 (Cp*ipso), 8.17 (Cp*Me); ESI-MS (m/z) [Found
(Calcd)]: [549.10 (549.15)] [M-Cl-HCl]+; Anal. Calc for C24H25Cl2N2OIr (620.59); C, 46.45; H,
4.06; N, 4.51. Found: C, 46.58; H, 4.14; N, 4.62 %.
10

ACCEPTED MANUSCRIPT
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
General procedure for preparation of cationic napthyridine metal complexes (4-6)
A mixture of metal precursor [(arene)MCl2]2 (arene = p-cymene, Cp*; M = Ru, Rh and
Ir) (0.1 mmol) and 2-(1,8-napthyridin-2-yl)aniline (AnNp) were dissolved in dry methanol (5
mL) and stirred at room temperature for 1 hour. Then 4 equivalents of NH4PF6 dissolved in dry
methanol (2 mL) was added dropwise to the reaction mixture and stirring continued for further 5-
6 hours whereupon a yellow solid precipitated out from the reaction mixture. The precipitate was
filtered, washed with cold methanol (2 x 5 ml) and diethyl ether (2 x 10 ml) and air dried
(Scheme 2).
[(p-cymene)Ru(AnNp)Cl]PF6 (4)
Yield: 101 mg (79%); IR (KBr, cm-1): 3314(m), 3125(m), 1604(m), 1494(w), 1462(w), 1111(m),
842(s); 1H NMR (400 MHz, DMSO-d6):
(d, 1H, = 8 Hz), 8.27 (d, 1H, = 8 Hz), 8.00 (d, 1H,
(m, 2H), 7.31 (t, 2H, = 8 Hz), 5.99 (dd, 2H, = 4 and 4 Hz, CH(p-cym)), 5.59 (d, 1H,
CH(p-cym)), 5.54 (d, 1H,
0.98 (d, 3H,
d6):
117.16, (C-AnNp), 106.14, 103.41, 89.51, 87.11, 85.22, 30.71, 23.81, 20.21, 16.41 (C-
δ
= 9.86 (d, 1H,
J
= 12 Hz), 8.97 (d, 1H,
= 8 Hz), 7.51-7.57
= 8.0 Hz,
J = 4 Hz), 8.70
J
J
J
= 4 Hz), 7.86 (t, 1H,
J
J
J
J
J
= 8 Hz, CH(p-cym)), 2.19 (sept, 1H, CH(p-cym)), 1.98 (s, 3H, CH(p-cym)),
J
= 8 Hz, CH(p-cym)), 0.89 (d, 3H, J
= 4 Hz, CH(p-cym)); 13C NMR (100 MHz, DMSO-
δ
= 161.78, 158.61, 155.19, 148.13, 138.12, 137.32, 134.18, 129.14, 123.41, 120.05, 119.18,
-cym);
p
ESI-MS (m/z) [Found (Calcd)]: [492.06 (492.07)] [M-PF6]+, ESI-MS (m/z) [Found (Calcd)]:
[456.0 (456.10)] [M-PF6-HCl]+; Anal. Calc for C24H25ClN3F6PRu (636.96); C, 45.25; H, 3.96; N,
6.60. Found: C, 45.38; H, 4.07; N, 6.71 %.
[Cp*Rh(AnNp)Cl]PF6 (5)
Yield: 93 mg (72%); IR (KBr, cm-1): 3269(w), 2923(w), 1606(m), 1491(w), 1462(w), 843(s); 1H
NMR (400 MHz, DMSO-d6):
δ = 9.23 (d, 1H, J = 4 Hz), 8.81 (d, 1H, J = 8 Hz), 8.63 (d, 1H, J =
11

ACCEPTED MANUSCRIPT
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
8 Hz), 8.25 (d, 1H,
J
= 8 Hz), 7.93 (d, 1H,
J
= 8 Hz), 7.77-7.80 (m, 1H), 7.65 (t, 1H,
J
= 4 Hz),
13
7.47-7.54 (m, 2H), 7.40 (t, 1H,
NMR (100 MHz, DMSO-d6):
J
= 8 Hz), 6.71 (d, 1H,
J
= 4 Hz), 1.34 (s, 15H, CH(Cp*)); C
δ
= 161.34, 157.13, 153.61, 142.01, 140.24, 139.21, 135.47,
133.45, 126.14, 124.16, 123.12, 120.33, 118.23 (C-AnNp), 89.38 (Cp*ipso), 8.13 (Cp*Me); ESI-
MS (m/z) [Found (Calcd)]: [494.05 (494.08)] [M-PF6]+, ESI-MS (m/z) [Found (Calcd)]: [458.06
(458.11)] [M-PF6-HCl]+; Anal. Calc for C24H26ClN3F6PRh (639.80); C, 45.05; H, 4.10; N, 6.57.
Found: C, 45.15; H, 4.21; N, 6.63 %.
[Cp*Ir(AnNp)Cl]PF6 (6)
Yield: 110 mg (75%); IR (KBr, cm-1): 3316(w), 3254(w), 3065(w), 2923(w), 1606(m), 1462(w),
1
1154(w), 842(s); H NMR (400 MHz, CDCl3):
δ
= 9.34 (d, 1H,
J
= 12 Hz), 8.85 (d, 1H,
= 8 Hz), 8.01 (d, 1H, = 8 Hz),
= 4 Hz), 6.69
= 160.04, 153.63,
J = 8
Hz), 8.49 (d, 1H,
J
= 8 Hz), 8.18 (d, 1H,
J
= 4 Hz), 8.10 (d, 1H,
J
J
7.80 (d, 1H,
J = 8 Hz), 7.57 (t, 1H, J = 4 Hz), 7.34 (t, 1H, J = 8 Hz), 7.23 (d, 1H, J
(d, 1H,
J
= 12 Hz), 1.39 (s, 15H, CH(Cp*)); 13C NMR (100 MHz, DMSO-d6):
δ
152.89, 142.01, 141.33, 137.57, 131.89, 131.45, 125.84, 123.78, 123.62, 123.36, 119.22 (C-
AnNp), 86.38 (Cp*ipso), 8.07 (Cp*Me); ESI-MS (m/z) [Found (Calcd)]: [584.07 (584.14)] [M-
PF6]+, ESI-MS (m/z) [Found (Calcd)]: [548.15 (548.16)] [M-PF6-HCl]+; Anal. Calc for
C24H26ClN3F6PIr (729.11); C, 39.54; H, 3.59; N, 5.76. Found: C, 39.66; H, 3.68; N, 5.82 %.
General procedure for preparation of neutral napthyridine metal complexes (7-9)
A mixture of metal precursor [(arene)MCl2]2 (arene = p-cymene, Cp*; M = Ru, Rh and
Ir) (0.1 mmol) and ligand 2-(pyridine-4-yl)-1,8-napthyridine (PyNp) (0.2 mmol) were dissolved
in dry methanol (5 mL) and stirred at room temperature for 6 hours. A yellow compound
precipitated out from the reaction mixture. The precipitate was collected washed with cold
methanol (2 x 5 mL) and diethyl ether (3 x 10 mL) and air dried (Scheme 2).
12

ACCEPTED MANUSCRIPT
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
[(p-cymene)Ru(PyNp)Cl2] (7)
Yield: 72 mg (70%); IR (KBr, cm-1): 2965(m), 2870(m), 1637(m), 1615(m), 1384(w), 1124(m);
1H NMR (400 MHz, CDCl3):
δ
= 9.14 (s, 3H), 8.35 (d, 1H,
J
= 8 Hz), 8.24 (d, 1H,
J
= 8 Hz),
8.08 (d, 2H,
cym)), 5.22 (d, 2H,
6H,
J = 8 Hz), 7.95 (d, 1H, J = 8 Hz), 7.53-7.57 (m, 1H), 5.45 (d, 2H, J = 4 Hz, CH(p-
J
= 4 Hz CH(p-cym)), 2.94 (sept, 1H, CH(p-cym)), 2.06 (s, 3H, CH(p-cym)), 1.28 (d,
13
J
= 8 Hz, CH(p-cym)); C NMR (100 MHz, CDCl3):
δ
= 155.78, 154.16, 153.19, 148.23,
139.12, 136.21, 135.11, 130.14, 128.06, 123.05, 119.18, 118.16, (C-PyNp), 106.18, 103.41,
90.13, 88.41, 30.20, 21.84, 17.80 (C- -cym); ESI-MS (m/z) [Found (Calcd)]: [478.21 (478.06)]
p
[M-Cl]+, ESI-MS (m/z) [Found (Calcd)]: [442.15 (443.09)] [M-2Cl]+; Anal. Calc for
C23H23Cl2N3Ru (513.42); C, 53.80; H, 4.52; N, 8.18. Found: C, 53.93; H, 4.63; N, 8.29 %.
[Cp*Rh(PyNp)Cl2] (8)
Yield: 92 mg (89%); IR (KBr, cm-1): 2985(m), 2860(m), 1635(m), 1609(m), 1378(w), 1127(m);
1H NMR (400 MHz, CDCl3):
δ
= 9.19 (s, 1H), 9.15 (d, 2H,
J
= 4 Hz), 8.45 (d, 1H,
= 8 Hz), 7.56-7.59 (m, 1H),
= 156.31, 155.42, 154.34, 153.18,
J = 8 Hz),
8.31 (dd, 1H,
J = 4 and 4 Hz), 8.21 (d, 1H, J = 8 Hz), 8.04 (d, 2H, J
1.63 (s, 15H, CH(Cp*)); 13C NMR (100 MHz, CDCl3):
δ
148.33, 139.24, 137.14, 123.43, 123.35, 123.07, 118.14 (C-PyNp), 87.12 (Cp*ipso), 8.63 (Cp*Me);
ESI-MS (m/z) [Found (Calcd)]: [480.07 (480.15)] [M-Cl]+, ESI-MS (m/z) [Found (Calcd)]:
[444.16 (445.10)] [M-2Cl]+; Anal. Calc for C23H24Cl2N3Rh (516.26); C, 53.51; H, 4.69; N, 8.14.
Found: C, 53.62; H, 4.76; N, 8.23 %.
[Cp*Ir(PyNp)Cl2] (9)
Yield: 86 mg (71%); IR (KBr, cm-1): 2991(m), 2875(m), 1631(m), 1611(m), 1374(w), 1125(m);
1H NMR (400 MHz, CDCl3):
δ
= 9.20 (s, 1H), 9.13 (d, 2H,
J
= 8 Hz), 8.45 (d, 1H,
J
= 8 Hz),
8.31 (dd, 1H, = 4 and 4 Hz), 8.19 (d, 2H,
J
J
= 4 Hz), 8.06 (d, 1H, J = 8 Hz), 7.57-7.60 (m, 1H),
13

ACCEPTED MANUSCRIPT
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
1.58 (s, 15H, CH(Cp*)); 13C NMR (100 MHz, CDCl3):
δ = 155.70, 155.59, 154.74, 153.88,
147.30, 139.32, 137.14, 123.56, 123.10, 123.02, 119.83 (C-PyNp), 86.0 (Cp*ipso), 8.58 (Cp*Me);
ESI-MS (m/z) [Found (Calcd)]: [570.21 (570.12)] [M-Cl]+, ESI-MS (m/z) [Found (Calcd)]:
[534.23 (535.15)] [M-2Cl]+; Anal. Calc for C23H24Cl2N3Ir (605.07); C, 45.62; H, 3.99; N, 6.94.
Found: C, 45.79; H, 4.08; N, 7.05 %.
Results and discussion
Synthesis of napthyridine ligands and metal complexes
The napthyridine ligands were synthesized according to Friedländer condensation
reaction and the napthyridine metal complexes (1-9) were synthesized by the reaction of metal
precursors with respective napthyridine ligands. At first the reaction of PHNp with metal
precursor was carried out using triethylamine as base with an aim of deprotonating phenolic
hydrogen which would result in formation of NO chelated complex but no deprotonation
occurred as evidenced from the 1H NMR spectra of the complexes which showed the presence of
phenolic proton. So the reaction was carried out without using triethylamine and which resulted
in formation of the same compounds. X-ray studies revealed that the PHNp ligand coordinated
metal in a monodentate manner through napthyridine nitrogen. Reaction of AnNp with precursor
afforded mononuclear bidentate chelated complexes. Surprisingly substituting 4-pyridyl group at
the 2-position of 1,8-napthyridine in PyNp yielded complexes where PyNp is coordinated to
metal through pyridine nitrogen rather than napthyridine nitrogen as in case of PHNp complexes.
The three-napthyridine ligands used in this work exhibited interesting coordination modes.
Complexes of PHNp and PyNp ligands were isolated as neutral complexes whereas with AnNp
ligand, complexes were isolated as ionic salts with PF6 counter ion. The napthyridine ligands and
metal complexes were obtained in good yields. These complexes are soluble in organic solvents
14

ACCEPTED MANUSCRIPT
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
such as chloroform, dichloromethane, acetonitrile and DMSO but insoluble in diethyl ether and
hexane. The napthyridine ligands and the napthyridine metal complexes were characterized
spectroscopically and the molecular structures of some of the complexes were established by
single crystal X-ray analysis.
Spectroscopic characterization of napthyridine ligands
The infrared spectra of PHNp and AnNp ligands exhibited stretching frequencies for OH
at 3521 cm-1 and for the NH2 group at 3402 and 3293 cm-1. The C=N and C=C stretching
frequencies of the napthyridine ligands were observed in the range of 1450-1650 cm-1. The
proton NMR spectra of the napthyridine ligands displayed signals in the range of 6.46-9.21 ppm
for the protons of the napthyridine moiety and substituted rings. In addition to these resonances
the PHNp ligand displayed a singlet at 14.7 ppm for the phenolic proton and the AnNp ligand
1
exhibited a broad singlet for the NH2 proton at 7.34 ppm respectively. The respective H NMR
spectra of the napthyridine ligands are presented in the SI.
Spectroscopic characterization of napthyridine metal complexes
IR studies of metal complexes
The IR spectra of the metal complexes suggest the coordination of the napthyridine
ligands to the metal atom. The presence of a broad band for complexes (1-3) in the lower
frequency region around 3401-3434 cm-1 for the phenolic OH group suggests that the phenolic
group is not involved in coordination to the metal center. This was further supported by NMR
and single crystal analysis. Complexes (4-6) displayed characteristic stretching frequencies for
NH2 group at lower frequency region around 3125-3326 cm-1 as compared to the free ligand at
3402 and 3293 cm-1. This shift to lower frequency suggests the coordination of the NH2 group.
Further the C=N stretching frequencies of the complexes decreases slightly and was observed in
15

ACCEPTED MANUSCRIPT
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
the range of 1603-1615 cm-1 as compared to the free ligand which suggest the coordination of the
napthyridine and pyridine nitrogen’s. In addition to these bands a sharp band for the cationic
complexes (4-6
) was observed around 842-843 cm-1 attributed to the P-F stretching frequency of
the counter ion [23].
1H NMR studies of metal complexes
1
The H NMR spectra of the metal complexes further support the formation of the
complexes. The resulting spectra are depicted in the supplementary information and ensuing data
are summarized in the experimental section. The metal complexes exhibited signals associated
with the ligand protons and signals due to
p-cymene and Cp* ring protons. The signals
associated with the napthyridine and substituted ring protons were observed in the downfield
region around 6.65-9.86 ppm. This shifting of the ligand resonances indicates the coordination of
the napthyridine ligands to the metal atom. Also the appearance of the phenolic proton signals in
complexes (
coordination to the metal atom. Further confirmation of the binding of napthyridine ligands was
confirmed by the appearance of the -cymene and Cp* ring proton signals. The aromatic protons
of the -cymene ligand consisted of doublets around 5.22-5.99 ppm. The isopropyl group of the
-cymene ligand displayed doublet for complexes ( and ) whereas for complex ( ) it showed
two doublets around 0.89-1.28 ppm. The methyl and methine protons of the -cymene ligand
1-3) around 14.9-15.1 ppm confirms that the phenolic OH group is not involved in
p
p
p
1
7
4
p
were observed as a singlet around 1.98-2.07 ppm and septet around 2.19-2.94 ppm. The methyl
protons of the Cp* moiety was observed as a singlet around 1.34-1.61 ppm.
13C NMR studies of metal complexes
The 13C NMR spectra further justify the formation of the complexes. The 13C NMR
spectra of the complexes displayed signals associated with the napthyridine carbons and the
16

ACCEPTED MANUSCRIPT
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
appearance of the
p
-cymene moiety carbons, methyl carbon of Cp* and ring carbon of Cp*
confirms the formation of these complexes. In the 13C NMR spectra of the complexes the carbon
resonances associated with the napthyridine ligand were observed in the region around 118-161
ppm. The aromatic carbon resonances of the
p-cymene ligand were observed in the region
around 84-106 ppm. The methine, isopropyl and methyl carbon resonances of the
p-cymene
moiety were observed in the region around 16-31 ppm. In addition to these carbon resonances
the ring carbons of the Cp* ligand displayed signal around 86.0-98.6 ppm and the signal for the
methyl protons of the Cp* moiety was observed around 8.07-8.63 ppm. Overall results from
NMR spectral studies strongly support the formation of the metal complexes.
Mass spectral studies of metal complexes
The composition and formation of napthyridine metal complexes (1-9) have further been
justified by ESI-mass spectral studies. The mass spectra of the complexes are presented in the
supplementary information and the values are listed in the experimental section (2.5). The mass
spectra of the complexes (
1–3) displayed their molecular ion peaks at m/z: 456.96, m/z: 459.02
and m/z: 549.10 corresponding to [M-Cl-HCl]+ ion. Complexes (
4-6) displayed their molecular
ion peaks at m/z: 492.06, m/z: 494.05 and m/z: 584.07 which corresponds to [M-PF6]+ ion peak.
Also peaks were observed at m/z: 456.0, m/z: 458.06 and m/z: 548.15 which is due to [M-PF6-
HCl]+ ion. Similarly complexes (
7-9) displayed peaks at m/z: 478.21, m/z: 480.15 and m/z:
570.21 which is due to the loss of one chloride [M-Cl]+ ion and also it exhibited peaks at m/z:
442.15, m/z: 444.16 and m/z: 534.23 which is due to the loss of both the chloride [M-2Cl]+ ion.
Description of the crystal structures of complexes
Apart from spectroscopic analysis, the molecular structures of some of the respective
complexes were established by single crystal X-ray analysis. Our attempt to isolate the single
17

ACCEPTED MANUSCRIPT
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
crystal for all the complexes was unsuccessful; however we obtained single crystals for the
PHNp ligand and complexes
analyses we were able to confirm the various coordination modes of the napthyridine ligand and
the geometry of the complexes. The data and molecular structure of complexes and presented
3, 4, 5, 8 and 9 respectively. By carrying out the single crystal
3
9
here is to only confirm the structure and composition of the molecule. The ORTEP plot of PHNp
and the complexes along with atom numbering scheme are shown in (Figures 1-5) respectively.
The summary of the crystal data including data collection and structure refinement parameters
are summarized in Table 1 and geometrical parameters including bond lengths, bond angles and
metal atom involving ring centroid values are listed in Table 2. The molecular structure of PHNp
ligand is shown in (Figure 1). Complexes (
[(arene)M(PHNp)Cl2] and [(arene)M(PyNp)Cl2] [(arene) =
Rh ( ), ( ) and Ir ( ), ( )]. Complexes ( ) have the cationic species with general formula
[(arene)M(AnNp)Cl] [(arene) = -cymene, M = Ru ( ); Cp*, M = Rh ( ) and Ir ( )] and counter
anion PF6. These complexes adopts a familiar three legged piano-stool geometry around the
1
-3) and (
7
-9
) have the neutral species with formula
p
-cymene, M = Ru ( ), ( ); Cp*, M =
1
7
2
8
3
9
4-6
p
4
5
6
metal center with coordination sites occupied by arene/Cp* ring (arene =
p-cymene and Cp*) in
a
η6 η5 manner, nitrogen donor atoms from napthyridine ligand and terminal chloride. The
/
geometry at the metal atom is pseudo-octahedral wherein the polycyclic arene ligand acts as seat
and napthyridine ligand and terminal chloride form the legs. In complex ( ) iridium metal is
3
coordinated through Cp* ring, PHNp ligand in a monodentate fashion coordinating iridium
through napthyridine nitrogen (N1) and two chlorides thus possessing a three-legged piano-stool
structure (Figure 2). In complexes
4 and 5 the metal is coordinated through p-cymene and Cp*
ring, AnNp ligand in a bidentate manner and one chloride. The AnNp ligand acts as a chelating
ligand coordinating metal through aniline nitrogen N(1) and napthyridine nitrogen (N2) forming
18

ACCEPTED MANUSCRIPT
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
a six membered metallacycle (Figure 3). The napthyridine nitrogen N(3) is not involved in
coordination. Similarly in complex
8 the metal is coordinated through two chloride’s, Cp*
moiety and PyNp ligand wherein it acted as a neutral monodentate ligand coordinating rhodium
through pyridine nitrogen (N1) (Figure 4 and 5). The distance between the metal to centroid of
the arene/Cp* ring are {1.775 (3), 1.799 (4), 1.803 (5) and 1.773 (8) and 1.778 (9) Å}. The Metal
to nitrogen (M-N) bond distances in these complexes is found to be in the range of 2.11-2.17 Å
which are in close agreement for reported complexes with napthyridine ligands (Table 2) [10,
13]. It is to be noted that in complexes (4 and 5) the M-N bond distance {2.143(3) and 2.138(2),
Å} from aniline N(1) is comparatively shorter than the napthyridine N(2) nitrogen-metal
distances {2.164(3) and 2.179(3) Å}. The M-Cl bond lengths in these complexes shows no
significant differences and was found to be in the range of 2.405-2.447 Å which are comparable
with earlier reported complexes [24]. The bite angle values in in these napthyridine complexes
were observed in the range of 80.0-91.3° which are consistent with the piano stool arrangement
of various groups around the metal center (Table 2) [25, 26].
Further from the crystal packing diagram it was observed that complex (
dimeric unit via intermolecular van der Waal N-H·····Cl (2.647 Å) interaction between the
terminal chloride and amino hydrogen (Figure 6). Also in complex ( ) two different types of
4) formed a
5
weak intermolecular van der Waal N-H·····Cl (2.548 Å) between chloride and amino group of
AnNp and C-H·····Cl (2.815 Å) interactions between chloride and napthyridine hydrogen was
observed (Figure 7). Interestingly the crystal packing in complex (8) formed a dimeric unit via
intermolecular van der Waal C-H·····Cl (2.723 and 2.809 Å) interaction between the chloride ion
and H-atom from napthyridine and pyridine of PyNp (Figure 8). These weak interactions play a
significant role in the formation of supramolecular motifs with interesting features.
19

ACCEPTED MANUSCRIPT
403
404
405
406
407
Chemosensitivity studies
The response of HCT-116 and MIA-PaCa-2 cells to the napthyridine ligands and the
respective metal complexes ( ) are presented in Table 3. PHNp ligand was found to be
moderately active against both HCT-116 and MIA-PaCa-2 cell lines with IC50 values of
39.90±1.60 and 62.48±6.28 M respectively. In contrast, both AnNp and PyNp were found to be
inactive with IC50 value > 100 M against both the cell lines. Upon complexation of napthyridine
ligands complexes ( ) of PHNp ligand displayed less activity whereas PyNp complexes did not
display any cytotoxicity and iridium complex ( ) with AnNp ligand possessed the highest
activity against HCT-116 cells. Complexes ( ) were found to be active against HCT-116 cell
line with IC50 value in the range of 37.79±4.90 to 82.09±3.55 M as compared to PHNp ligand
whose IC50 value is 39.90±1.60 M. Against the Mia-PaCa-2 cell line, complex ( ) was the most
active with an IC50 of 25.13±6.07 M. Complexes ( ) and ( ) were moderately active against the
MIA-PaCa-2 cell line with IC50 values of 52.13±12.28 and 82.09±2.55 M. Differences between
1-9
µ
408
409
410
411
412
µ
1-3
6
1-3
µ
413
414
µ
2
µ
3
6
415
416
417
418
419
420
421
422
423
424
425
µ
the response of HCT116 and Mia-PaCa-2 cells exist suggesting that these complexes are
targeting inherent biochemical differences between these cells as opposed to having general
cytotoxic properties. However, all the compounds were found to be less cytotoxic as compared to
cisplatin whose IC50 value is 2.78
compounds tested exhibited a cytotoxic effect on the non-cancer ARPE-19 cell line (IC50 values
were > 100 M). The selectivity ratio for cisplatin (defined as the IC50 of ARPE-19 divided by
the IC50 of cancer cell lines) was 1.23 for HCT-116 cells whereas for complex ( ), the selectivity
µM. In contrast to cisplatin however, none of the novel
µ
3
index was >2.64. Similar values for the selectivity index were obtained for other complexes
tested suggesting that whilst potency is reduced compared to cisplatin, selectivity for cancer cells
in vitro under identical experimental conditions is enhanced.
20

ACCEPTED MANUSCRIPT
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
Conclusion
In this work, we report the coordination chemistry of 2-substituted-1,8-naphthyridine
ligands towards ruthenium, rhodium and iridium half-sandwich complexes. Complexes of PHNp
and PyNp were isolated as neutral complexes whereas AnNp complexes were isolated as ionic
salts with PF6 counter anion. The molecular structures of neutral complexes revealed that PHNp
and PyNp ligands acted as monodentate ligand coordinating metal through napthyridine nitrogen
(N1) and pyridine nitrogen N(1). Whereas the X-ray structures of cationic complexes with AnNp
ligand showed that it behaved as neutral chelating ligand coordinating metal atom in a bidentate
NN´ fashion through aniline nitrogen N(1) and napthyridine nitrogen (N2) forming a six-
membered chelated ring. Chemosensitivity activity of the complexes carried out against HCT-
116 and MIA-PaCa-2cancer cell lines showed that PHNp and its complexes are cytotoxic;
however iridium-based AnNp complex possessed the highest activity among all other
napthyridine complexes. The work presented here exhibits interesting coordination modes of the
2-substituted-1,8-napthyridine ligands that have cytotoxic activity against cancer cells in vitro
.
Whilst the potency of these compounds is less than cisplatin, there is evidence to suggest that
these complexes have greater selectivity for cancer as opposed to non-cancer cells in vitro than
cisplatin and therefore representing promising compounds for further development and
evaluation.
Acknowledgements
Sanjay Adhikari thanks, UGC, New Delhi, India for providing financial assistance in the form of
university fellowship (UGC-Non-Net). We thank DST-PURSE SCXRD, NEHU-SAIF, Shillong,
India for providing Single crystal X-ray analysis and other spectral studies.
21

ACCEPTED MANUSCRIPT
449
450
451
452
453
454
Supplementary material
CCDC 1568178
(4), 1568179 (5), 1568180 (8), 1568181 (PHNp), 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.
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
References
[1]
[2]
[3]
[4]
[5]
B. Therrien, Coord. Chem. Rev. 253 (2009) 493.
S. Y. Mudi, T. M. Usman, S. Ibrahim, Am. J. Chem. Appl. 2 (2015) 151.
G. Gasser, I. Ott, N. M-Nolte, J. Med. Chem. 54 (2011) 3.
A. A. Nazarov, C. G. Hartinger, P. J. Dyson, J. Organomet. Chem. 751 (2014) 251.
(a) H. Chen, J. A. Parkinson, S. Parsons, R. A. Coxall, R. O. Gould, P. J. Sadler, J. Am.
Chem. Soc. 124 (2002) 3064, (b) R. E. Morris, R. E. Aird, P. S. Murdoch, H. Chen, J.
Cummings, N. D. Hughes, S. Parsons, A. Parkin, G. Boyd, D. I. Jodrell, P. J. Sadler, J.
Med. Chem. 44 (2001) 3616, (c) R. E. Aird, A. A. Ritchie, M. Muir, R. E. Morris, H.
Chen, P. J. Sadler, D. I. Jodrell, Br. J. Cancer, 86 (2002) 1652.
[6]
(a) C. S. Allardyce, P. J. Dyson, D. J. Ellis, S. L. Heath, Chem. Comm. (2001) 1396, (b)
C. Scolaro, A. Bergamo, L. Brescacin, R. Delfino, M. Cocchietto, G. Laurenczy, T. J.
Geldbach, G. Sava, P. J. Dyson, J. Med. Chem. 48 (2005) 4161.
[7]
[8]
Y. Geldmacher, M. Oleszak, W. S. Sheldrick, Inorg. Chim. Acta, 393 (2012) 84.
O. Prakash, K. N. Sharma, H. Joshi, P. L. Gupta, A. K. Singh, Organometallics, 33
(2014) 2535.
[9]
N. Hofmann, L. Ackermann, J. Am. Chem. Soc. 135 (2013) 5877.
22

ACCEPTED MANUSCRIPT
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
[10] T. Suzuki, Inorg. Chim. Acta, 359 (2006) 2431.
[11] S. K. Patra, N. Sadhukhan, J. K. Bera, Inorg. Chem. 45 (2006) 4007.
[12] A. Sinha, M. Majumdar, M. Sarkar, T. Ghatak, J. K. Bera, Organometallics, 32 (2013)
340.
[13] K. T. Prasad, B. Therrien, K. M. Rao, J. Organomet. Chem. 693 (2008) 3049.
[14] D. D. Perrin, W. L. F. Armarego, Purification of Laboratory Chemicals, fourth ed.,
Butterworths Heinemann, London, 1996.
[15] M. A. Bennett, T. N. Huang, T. W. Matheson, A. K. Smith, S. Ittel, W. Nickerson,
Inorg. Synth. 21 (1982) 74.
[16] C. White, A. Yates, P. M. Maitlis, D. M. Heinekey, Inorg. Synth. 29 (2007) 228.
[17] G. M. Sheldrick, Acta Crysat. Sect. A 46 (1990) 467.
[18] G. M. Sheldrick, Acta Cryst. Sect. A 64 (2008) 112.
[19] L. J. Farrugia, J. Appl. Cryst. 32 (1999) 837.
[20] Z. Almodares, S. J. Lucas, B. D. Crossley, A. M. Basri, C. M. Pask, A. J. Hebden, R. M.
Phillips, P. C. McGowan, Inorg. Chem. 53 (2014) 727.
[21] S. J. Lucas, R. M. Lord, R. L. Wilson, R. M. Phillips, V. Sridharan, P. C. McGowan,
Dalton Trans. 41 (2012) 13800.
[22] Q. Zhao, S. Liu, M. Shi, C. Wang, M. Yu, L. Li, F. Li, T. Yi, C. Huang, Inorg. Chem.
45 (2006) 6152.
[23] S. Adhikari, D. Sutradhar, S. L. Shepherd, R. M. Phillips, A. K. Chandra, K. M. Rao, J.
Organomet. Chem. 820 (2016) 70.
[24] A. Pastuszko, K. Niewinna, M. Czyz, A. Jozwiak, M. Malecka, E. Budzisz, J.
Organomet. Chem. 745 (2016) 64.
23

ACCEPTED MANUSCRIPT
495
496
497
[25] C. M. Clavel, E. Paunescu, P. N-Sliwinska, A. W. Griffioen, R. Scopelliti, P. J. Dyson, J.
Med. Chem. 57 (2014) 3546.
[26] S. Adhikari, W. Kaminsky, M. R. Kollipara, J. Organomet. Chem. 848 (2017) 95.
498
499
500
Scheme 1 Synthetic routes of ligands
24

ACCEPTED MANUSCRIPT
501
502
Scheme 2 Synthesis of neutral and cationic napthyridine metal complexes (1-9)
503
504
505
Figure 1 ORTEP plot of PHNp with 50% probability thermal ellipsoids.
25

ACCEPTED MANUSCRIPT
506
507
Figure 2 ORTEP plot of complex (
3) with 50% probability thermal ellipsoids. Hydrogen atoms
508
509
(except on O1) are omitted for clarity.
510
511
Figure 3 (a) ORTEP plot of complex (4) and (b) ORTEP plot of complex (5) with 50%
512
513
probability thermal ellipsoids. Counter anions, hydrogen atoms (except on N1) are omitted for
clarity.
26

ACCEPTED MANUSCRIPT
514
515
Figure 4 ORTEP plot of complex (8) with 50% probability thermal ellipsoids. Solvent molecules
516
and hydrogen atoms are omitted for clarity.
517
518
519
Figure 5 ORTEP plot of complex (
9) with 50% probability thermal ellipsoids. Solvent molecule
and hydrogen atoms are omitted for clarity.
27

ACCEPTED MANUSCRIPT
520
521
522
Figure 6 Packing diagram of complex (
4
) showing a dimeric unit formed via intermolecular van
der Waal N-H·····Cl (2.647 Å) interaction between the terminal chloride and amino hydrogen.
523
524
Figure 7 Packing diagram of complex (5) showing two different types of weak intermolecular
525
van der Waal N-H·····Cl and C-H·····Cl interactions.
28

ACCEPTED MANUSCRIPT
526
527
Figure 8 Crystal packing diagram of complex (8) showing a dimeric unit formed via
528
529
intermolecular van der Waal C-H·····Cl interactions.
29