Ruthenium, rhodium and iridium complexes containing pyrimidine based thienyl pyrazoles: Synthesis and antibacterial studies

Article abstract of DOI:10.1016/j.jorganchem.2020.121155

The reaction of pyrimidine based electron-rich heterocyclic thiophene pyrazoles and halide bridged arene d⁶ metal precursors yielded a series of mononuclear and dinuclear half sandwich d⁶ metal complexes. Mononuclear and dinuclear complexes formed by the ratio-based reaction between ligand and metal precursor. All these cationic complexes have been characterized by IR, UV–Vis, ¹H NMR, ¹³C NMR spectroscopic techniques. Complex 5 has been established by single-crystal analysis. X-ray diffraction studies revealed the formation of mononuclear and dinuclear complexes and suggest that the vicinity around the metal atom is distorted octahedral. An in vitro study to screen the antibacterial potential of these complexes against pathogenic bacteria, S. aureus, K. pneumoniae, and E. coli was addressed. All the complexes display a better zone of inhibitions for both Gram-positive (S. aureus) and Gram-negative strains (K. pneumoniae, and E. coli). The minimum inhibitory concentrations (MICs) for the most active complex ranged from 0.125 to 0.25 mg/ml for S. aureus and Klebsiella Pneumoniae and 0.25–0.5 mg/ml for E. coli.

Full text of DOI:10.1016/j.jorganchem.2020.121155

Journal Pre-proof
Ruthenium, rhodium and iridium complexes containing pyrimidine based thienyl
pyrazoles: Synthesis and antibacterial studies
Agreeda Lapasam, Ibaniewkor L. Mawnai, Venkanna Banothu, Werner Kaminsky,
Mohan Rao Kollipara
PII:
S0022-328X(20)30056-5
DOI:
https://doi.org/10.1016/j.jorganchem.2020.121155
JOM 121155
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 23 November 2019
Revised Date: 3 February 2020
Accepted Date: 3 February 2020
Please cite this article as: A. Lapasam, I.L. Mawnai, V. Banothu, W. Kaminsky, M.R. Kollipara,
Ruthenium, rhodium and iridium complexes containing pyrimidine based thienyl pyrazoles: Synthesis
and antibacterial studies, Journal of Organometallic Chemistry (2020), doi: https://doi.org/10.1016/
j.jorganchem.2020.121155.
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Ruthenium, rhodium and iridium complexes containing pyrimidine based thienyl
pyrazoles: Synthesis and antibacterial studies
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Agreeda Lapasama, Ibaniewkor L. Mawnaia, Venkanna Banothub, Werner Kaminskyc,
Mohan Rao Kolliparaa*
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aCentre for Advanced Studies in Chemistry, North-Eastern Hill University, Shillong-793 022,
India.
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bCentre for Biotechnology (CBT), Institute of Science & Technology (IST), Jawaharlal Nehru
Technological University Hyderabad (JNTUH), Kukatpally-500 085, Hyderabad, Telangana
State, India.
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cDepartment of Chemistry, University of Washington, Seattle, WA 98195, USA
E-mail: mohanrao59@gmail.com
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Graphical abstract
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Abstract
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The reaction of pyrimidine based electron-rich heterocyclic thiophene pyrazoles and
halide bridged arene d6 metal precursors yielded a series of mononuclear and dinuclear half
sandwich d6 metal complexes. Mononuclear and dinuclear complexes formed by the ratio-based
reaction between ligand and metal precursor. All these cationic complexes have been
characterized by IR, UV–Vis, 1H NMR, 13C NMR spectroscopic techniques. Complex
5 has been
established by single-crystal analysis. X-ray diffraction studies revealed the formation of
mononuclear and dinuclear complexes and suggest that the vicinity around the metal atom is
distorted octahedral. An in vitro study to screen the antibacterial potential of these complexes
against pathogenic bacteria, S. aureus, K. pneumoniae, and E. coli was addressed. All the
complexes display a better zone of inhibitions for both Gram-positive (S. aureus) and Gram-
negative strains (K. pneumoniae, and E. coli). The minimum inhibitory concentrations (MICs)
for the most active complex ranged from 0.125 to 0.25 mg/ml for S. aureus and Klebsiella
Pneumoniae and 0.25 to 0.5 mg/ml for E. coli.
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Keywords: Ruthenium, Rhodium, Iridium, Antibacterial studies.
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1. Introduction
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Bacterial resistance to antimicrobial drugs is a significant threat to humans [1]. Infectious
diseases caused by drug-resistant bacteria are currently the second main cause of death
worldwide and the third leading cause of death in developed countries. Due to the increasing
resistance of bacteria to the current clinical drugs, there has been increasing interest in the
development of novel classes of antimicrobials agents that may not be as susceptible to the
bacterial mechanisms of resistance developed against the current range of drugs [2-6]. Based on
the comparative success of platinum group metal complexes as anticancer agents, there is a
rising attention in the use of metal complexes as antimicrobial agents [7-9]. Ruthenium
complexes exhibit a wide range of properties and a large variety of ruthenium complexes have
found applications in biological and pharmaceutical studies such as antibacterial, antifungal,
antimalarial, anti-proliferative, anti-inflammatory, antiviral and antipyretic activities [10-15].
Cp*Rh and Cp*Ir complexes have also been considered as alternatives to ruthenium-based drugs
because of their biological applications and their water solubility. A well-defined series of metal
complexes with antibacterial activity is that of rhodium(III) coordination compounds of formula
trans-[RhX2(Py)4]Y [16-17]. Pharmaceuticals focusing on metal complexes of iridium are still at
the early stages [18]. Medically, organometallic complexes of iridium(III) proved to have
potentials for anticancer and antimicrobial activities [19]. Cyclometallated iridium(III)
complexes bearing dithiocarbamate derivatives have been reported to possess antibacterial
activity [20]. The delocalization of the π-electrons over the chelate ring was proposed to increase
the lipophilicity of the complexes and facilitate their penetration into bacterial cell membranes,
thereby resulting in inhibition of bacterial growth.
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Since the development of coordination chemistry, various new chelating N heterocyclic
ligands have been synthesized. Because of wide range of applications, new ruthenium complexes
with different types of ligands are of particular interest. A family of nitrogen-containing pyrazole
based ligands has been widely studied and offered a diversity of applications [21]. There have
been reports on pyrimidyl pyrazole derivatives being used as antitumor agents and show the
antiproliferative effect on human lung cancer cell line as well as inhibited the polymerization of
tubulin. The most probable way in which pyrazole based compounds exhibit bioactivity is by the
formation of a hydrogen bond with biomolecules [22-24]. Organometallic complexes containing
such ligands are considered as potential DNA intercalators with the capability to inhibit the
synthesis of nucleic acid. When the strong σ-donor ability of pyrazole group and π-accepting
property of pyrimidine ring are joined together, it may give rise to properties different from those
of the isolated moieties.
In recent years, we have reported many organometallic complexes including half-
sandwich platinum group metal complexes containing pyrazole ligands [25]. In continuation to
our previous work, herein we report the synthesis of mono and binuclear arene ruthenium,
rhodium, and iridium complexes containing pyrazole derivatives. The ligand used in this study is
shown in (Chart 1).
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Chart 1: Ligand used in the present study.
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2. Experimental Section
2.1. Physical methods and materials
All reagents used in this work were purchased commercially and used without further
purification; Tetra-n-butylammonium bromide, 2 acetyl thiophene, 4, 6- dichloro pyrimidine
were purchased from Sigma Aldrich. N, N- dimethylformamide dimethyl acetal was obtained
from Spectrochem Pvt. limited, potassium carbonate was obtained from SD Fine-Chem limited,
and
hydrazine
hydrate
was
purchased
from
Qualigens
Fine
Chemicals.
Pentamethylcyclopentadiene and α-Terpinene were obtained from Sigma Aldrich. The solvents
were purified and dried according to standard procedures [26]. The starting precursor metal
complexes [(p-cymene)RuCl2]2, [(benzene)RuCl2]2, and [Cp*MCl2]2 (M = Rh/Ir) were prepared
according to the literature methods [27-29]. The syntheses of all the metal complexes were
performed at room temperature. Infrared (IR) spectra were recorded on a Bruker ALPHA II
FTIR spectrometer as KBr pellets in the range 4000 to 400 cm−1. H NMR spectra were
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recorded on a Bruker Avance II 400 MHz spectrometer using CDCl3 and DMSO-d6 as solvents,
with TMS as internal references. UV–Vis absorption spectra were obtained on a Perkin-Elmer
Lambda 25 UV/Vis spectrophotometer in acetonitrile solution. Elemental analyses of the
complexes were carried out on a Perkin-Elmer 2400 CHN analyzer.
2. 2
Single-crystal X-ray structures analyses
Suitable single crystals of complex were obtained by slow diffusion of hexane into
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acetone solution. Single crystal X-ray diffraction data for the complexes were collected on an
Oxford Diffraction Xcalibur Eos Gemini diffractometer at 293 K using graphite monochromated
Mo-Kα radiation (λ = 0.71073 Å). The strategy for the data collection was evaluated using the
CrysAlisPro CCD software. Crystal data were collected by standard ‘‘phi–omega scan’’
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techniques and were scaled and reduced using CrysAlisPro RED software. The structures were
solved with the SHELXT-2016 [30] solution program using the direct method and refined full-
matrix least-squares with SHELXL-2016 refining on F2 [31]. The positions of all the atoms were
obtained by direct methods. Metal atoms in the complex were located from the E-maps and non-
hydrogen atoms were refined anisotropically. Crystallographic and structure refinement
parameters for the complexes are summarized in Table 1, and selected bond lengths and bond
angles are presented in Table 2. The molecular structure of complex
ellipsoid plot in Figure 1 [32].
5 is presented as thermal
2.3
Antimicrobial activity
All the Gram-negative and Gram-positive bacterial strains used for the present study were
obtained from the Department of Microbiology, Osmania General Hospital, Hyderabad. All
strains were tested for purity by standard microbiological methods. The bacterial stock cultures
were maintained on Mueller-Hinton agar slants and stored at 4˚C. An agar-well diffusion method
was employed for the evaluation of antibacterial activities of test compounds [33]. DMSO was
used as a negative control. The bacterial strains were reactivated from stock cultures by
transferring into Mueller-Hinton broth and incubating at 37 ˚C for 18 h. A final inoculum
containing 106 colonies forming units (1 x 106 CFU/ml) was added aseptically to MHA medium
and poured into sterile Petri dishes. Different test compounds at a concentration of 100 µg per
well were added to wells (8 mm in diameter) punched on the agar surface. Plates were incubated
overnight at 37 ºC and the diameter of inhibition zone (DIZ) around each well was measured in
mm. Experiments were performed in triplicates (Error bars with percentage and standard
deviation)
2.4
MIC and MBC
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The minimum inhibitory concentration (MIC) and minimum bactericidal concentration
(MBC) was determined by the micro-broth dilution method done in 96 well plates according to
the standard protocol [34]. A 2-fold serial dilution of the compounds, with the appropriate
antibiotic, was prepared. Initially, 100 µl of MH broth was added to each well plate. Then 100 µl
of compound or antibiotic was taken from the stock solution and dissolved in the first well plate.
Serial dilution was done to obtain different concentrations. The stock concentrations of 2.0
mg/ml. 24 hr culture turbidity was adjusted to match 0.5 McFarland standards which correspond
to 1×108 CFU/ml. The standardized suspension (100 µl) of bacteria was added to all the wells
except the antibiotic control well and the 96 well plates were incubated at 37 °C for 24 h. After
24 h of incubation 40 µl of MTT (3-(4,5-dimethlthiazol-2-yl)-2,5-diphenyltetrazolium bromide)
reagent (0.1 mg/ml in 1x PBS) was added to all the wells. MIC was taken as the lowest
concentration which did not show any growth which was visually noted from the blue color
developed by MTT. Subcultures were made from clear wells and the lowest concentration that
yielded no growth after subculturing was taken as the MBC.
2.5. Synthesis of ligand (L1)
The ligand (L1) was synthesized following the reported method [25(a)]. 4,6-dichloro
pyrimidine (2 mmol), thienyl pyrazole (4 mmol), potassium carbonate (4.5 mmol) and
tetrabutylammonium bromide (4 mmol) were dissolved in 50 ml of acetone (Scheme-1). The
reaction mixture was heated to reflux for 48h after the reaction completed the solvent was
reduced, poured into distilled water and then extracted with DCM. The combined organic layer
was dried over sodium sulfate (Na2SO4). The solvent was removed under vacuum and the
resulting residue was purified by column chromatography using ethyl acetate and hexane (2:8
ratio) as eluent.
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1H NMR (400 MHz, CDCl3, ppm): 10.85 (s, 1H), 10.20(s, 1H), 8.19 (d, 2H, J = 4 Hz), 8.00 (s,
2H), 7.31 (d, 2H, J = 4 Hz), 7.11 (d, 2H, J = 4 Hz), 6.41(s, 2H).
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Scheme 1: Synthesis of ligand L1
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2.6. General procedure for the synthesis of mononuclear complexes 1-4
A mixture of starting metal precursor (0.1 mmol) and ligand pyrimidine based thienyl
pyrazoles (L1) (0.2 mmol) and 2.5 equivalents of NH4PF6 were dissolved in dry methanol (15
ml) and stirred at room temperature for 8 hours (Scheme-2). The solvent was evaporated to
dryness. The residue was then dissolved in dichloromethane and filtered through a bed of celite
to remove excess NH4Cl. The filtrate was concentrated to 1 ml and on the addition of excess
hexane yellow solid precipitates out. The precipitate was further washed with diethyl ether and
air-dried.
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Scheme 2: Synthesis of complexes 1-4
2.6.1. [(p-cymene)RuL1Cl]PF6 [1]
Yield: 80%; IR (KBr, cm-1): 2967 ν(C-H), 1587 ν(C=N), 1116 ν(C-N), 957 ν(N-N), 844ν(P-F), 789 ν(C-S); 1H
NMR (400 MHz, CDCl3, ppm) : 9.73 (s, 1H), 9.23 (s, 1H), 8.70 (t, 4H, J = 4 Hz), 8.21 (s, 1H),
7.86 (s, 1H), 7.67 (s, 1H), 7.57 (d, 2H, J = 4Hz), 6.92 (s,1H), 6.06 (d, 2H, J = 4 Hz), 6.03 (d, 2H,
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J = 4 Hz), 2.21 (sept, 1H), 1.79 (s, 3H), 1.12 (d, 6H, J = 4Hz); C NMR (100 MHz,CDCl3,
ppm): 161.92,157.45, 153.97, 146.18, 143.72, 141.47, 129.25, 128.25, 127.90, 126.74, 104.84,
102.15, 101.08, 100.59, 86.92, 85.83, 85.52, 84.50, 30.87, 22.00, 17.94; UV-Vis {Acetonitrile,
λmax nm (ε/10-4 M-1 cm-1)}: 275.98 (6.48). Anal. Calc for C28H26ClN6RuS2PF6 (792.16); C,
42.45; H, 3.31; N, 10.61. Found: C, 42.49; H, 3.29; N, 10.65 %.
2.6.2. [(benzene)RuL1Cl]PF6 [2]
Yield: 76%; IR (KBr, cm-1): 2972 ν(C-H), 1588 ν(C=N), 1122 ν(C-N), 959 ν(N-N), 835ν(P-F), 778 ν(C-S); 1H
NMR (400 MHz, CDCl3, ppm) : 11.39 (s, 1H), 8.68 (s, 1H), 7.92 (s, 1H), 7.85 (d, 1H, J = 4Hz),
7.51 (d, 1H, J = 4Hz), 7.23 (d, 1H, J = 4Hz), 7.01 (t, 1H, J = 4Hz), 6.69 (t, 1H, J = 4Hz), 6.57 (s,
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3H, J = 8Hz), 6.21 (s, 1H), 5.98 (s, 6H); C NMR (100 MHz,CDCl3, ppm): 161.40, 158.96,
150.22, 144.87, 131.92, 131.66, 129.28, 128.42, 127.16, 125.22, 121.58, 108.88, 106.45, 86.56;
UV-Vis {Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}: 274.99 (7.86). Anal. Calc for
C24H18ClN6RuS2PF6 (736.06); C, 39.16; H, 2.46; N, 11.42. Found: C, 39.20; H, 2.48; N, 11.41
%.
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2.6.3. [Cp*RhL1Cl]PF6 [3]
Yield: 78%; IR (KBr, cm-1): 2995 ν(C-H), 1606 ν(C=N), 1081 ν(C-N), 955 ν(N-N), 843ν(P-F), 720 ν(C-S); 1H
NMR (400 MHz, CDCl3, ppm) :11.24 (s, 1H), 7.97 (s, 2H), 7.73 (s, 1H), 7.56 (d, 1H, J = 4Hz),
7.15 (d, 1H, J = 4Hz), 7.08 (d, 1H, J = 4Hz), 6.97 (t, 1H, J = 4Hz), 6.86 (t, 1H, J = 4Hz), 6.65 (d,
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2H, J = 8Hz), 6.17 (s, 1H), 1.65 (s,15H); UV-Vis {Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}:
234.99 (2.78), 274.98 (4.98). Anal. Calc for C28H27ClN6RhS2PF6 (795.01); C, 42.30; H, 3.42; N,
10.57. Found: C, 42.28; H, 3.45; N, 10.60 %.
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2.6.4. [Cp*IrL1Cl]PF6 [4]
Yield: 69%; IR (KBr, cm-1): 2967 ν(C-H), 1577 ν(C=N), 1121 ν(C-N), 957 ν(N-N), 844ν(P-F), 786 ν(C-S); 1H
NMR (400 MHz, CDCl3, ppm): 11.24 (s, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.56 (d, 1H, J = 4Hz),
7.15 (d, 1H, J = 4Hz), 7.08 (d, 1H, J = 4Hz), 6.97 (t, 1H, J = 4Hz), 6.86 (t, 1H, J = 4Hz), 6.64 (s,
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3H, J = 8Hz), 6.17 (d, 1H), 1.79 (s,15H); C NMR (100 MHz,CDCl3, ppm): 166.26, 160.59,
154.00,145.09, 142.29, 138.93, 132.29, 129.09, 128.23, 123.89, 106.72, 104.84, 97.27, 13.42;
UV-Vis {Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}: 229.44 (4.05), 269.96 (2.35); Anal. Calc for
C28H27ClN6IrS2PF6 (884.32); C, 38.03; H, 3.08; N, 9.50. Found: C, 38.04; H, 3.05; N, 9.48 %.
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2.7. General procedure for the synthesis of dinuclear complexes 5-8
A mixture of starting metal precursor (0.1 mmol) and ligand pyrimidine based thienyl
pyrazoles (L1) (0.1 mmol) and 2.5 equivalents of NH4PF6 were dissolved in dry methanol (15
ml) and stirred at room temperature for 8 hours (Scheme-3). The solvent was evaporated to
dryness. The residue was then dissolved in dichloromethane and filtered through a bed of celite
to remove excess NH4Cl. The filtrate was concentrated to 1 ml and on the addition of excess
hexane yellow solid precipitates out. The precipitate was further washed with diethyl ether and
air-dried.
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Scheme 3: Synthesis of complexes 5-8
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2.7.1. [{(p-cymene)RuCl}2(
µ-L1)](PF6)2 [5]
Yield: 74%; IR (KBr, cm-1): 2971 ν(C-H), 1541 ν(C=N), 1094 ν(C-N), 960 ν(N-N), 840 ν(P-F), 776 ν(C-S)
;
1H NMR (400 MHz, CDCl3, ppm) : 11.55 (s, 1H), 9.58 (s, 1H), 8.20 (s, 2H), 7.39 (d, 2H, J =
4Hz), 7.35 (d, 2H, J = 4Hz), 7.08 (t, 2H, J = 4Hz), 6.57 (s, 2H), 5.98 (d, 4H, J = 4Hz), 5.87 (d,
4H, J = 4Hz), 2.48 (sept, 2H), 1.92 (s, 6H), 1.15 (d, 12H, J = 4Hz); UV-Vis {Acetonitrile, λmax
nm (ε/10-4 M-1 cm-1)}: 224.97 (6.33), 269.96 (5.13), 350.94 (0.32). Anal. Calc for
C38H40Cl2N6Ru2S2P2F12 (1207.87); C, 37.79; H, 3.34; N, 6.96. Found: C, 37.85; H, 3.40; N, 7.01
%.
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2.7.2. [{(benzene)RuCl}2(
µ-L1)](PF6)2 [6]
Yield: 71%; IR (KBr, cm-1): 2998 ν(C-H), 1588 ν(C=N), 1118 ν(C-N), 958 ν(N-N), 843 ν(P-F), 713 ν(C-S)
;
1H NMR (400 MHz, CDCl3, ppm) : 9.24 (s, 1H), 8.51 (s, 1H), 7.55 (d, 2H, J = 4Hz), 7.41 (t, 2H,
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J = 4Hz), 7.15 (s, 2H), 6.59 (s, 2H), 6.10 (s, 12H), 5.87 (s, 2H); C NMR (100 MHz, CDCl3,
ppm):160.56, 155.60, 144.95, 140.74, 128.85, 128.09, 127.26, 126.77, 105.56, 100.71, 85.71;
UV-Vis {Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}: 274.98 (5.99). Anal. Calc for
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C30H24Cl2N6Ru2S2P2F12 (1095.66); C, 32.89; H, 2.21; N, 7.67. Found: C, 32.88; H, 2.24; N, 7.71
%.
2.7.3. [{Cp*RhCl}2(µ-L1)](PF6)2 [7]
Yield: 68%; IR (KBr, cm-1): 2992 ν(C-H), 1605 ν(C=N), 1080 ν(C-N), 955 ν(N-N), 845ν(P-F), 719 ν(C-S); 1H
NMR (400 MHz, CDCl3, ppm) : 11.16 (s, 1H), 9.69 (s, 1H), 8.29 (s, 2H), 8.04 (d, 2H, J = 4Hz),
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7.29 (d, 2H, J = 4Hz), 7.11 (t, 2H, J = 4Hz), 6.48 (s, 2H), 1.63 (s, 30H); C NMR (100 MHz,
CDCl3, ppm): 161.96, 154.33, 143.47, 138.24, 134.90, 132.04, 127.48, 121.79, 108.98, 103.54,
98.11, 9.67; UV-Vis {Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}: 229.98 (5.94), 269.96 (5.13),
395.02 (0.15). Anal. Calc for C38H42Cl2N6Rh2S2P2F12 (1213.56); C, 37.61; H, 3.49; N, 6.93.
Found: C, 37.66; H, 3.52; N, 6.90 %.
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2.7.4. [{Cp*IrCl}2(µ-L1)](PF6)2 [8]
Yield: 60%; IR (KBr, cm-1): 2997 ν(C-H), 1613 ν(C=N), 1077 ν(C-N), 960 ν(N-N), 843ν(P-F), 722 ν(C-S); 1H
NMR (400 MHz, CDCl3, ppm) : 11.66 (s, 1H), 10.09 (s, 1H), 7.94 (s, 2H), 7.37 (d, 2H, J = 4Hz),
7.33 (d, 2H, J = 4Hz), 7.09 (t, 2H, J = 4Hz), 6.64 (s, 2H), 1.66 (s, 30H); 13C NMR (100
MHz,CDCl3, ppm): 162.69, 154.52, 149.93, 140.68, 134.80, 128.08, 127.37, 123.82, 106.63,
102.58, 99.33, 9.01; UV-Vis {Acetonitrile, λmax nm (ε/10-4 M-1 cm-1)}: 285.41 (2.20), 350.16
(1.69). Anal. Calc for C38H42Cl2N6Ir2S2P2F12 (1392.18); C, 32.78; H, 3.04; N, 6.04. Found: C,
32.84; H, 3.00; N, 6.01 %.
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3.
RESULT AND DISCUSSION
3.1
Synthesis of complexes
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Pyrimidine based ligands are widely used in medicinal chemistry for their anti-bacterial
and antifungal properties. These pyrimidine based ligands have a variety of binding modes when
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they coordinate with the metal atoms. In this work, we substituted thienyl pyrazole in the
pyrimidine moiety (Scheme 1) and studied the way of bonding towards the d6 metal complexes.
The synthetic routes to pyrimidine-based pyrazoles are illustrated in scheme 1. These ligands can
bind to the metal either through NN or NS but in these complexes sterically hindered N, N
bonding occurred instead of a less sterically bonding mode of N, S site. Treatment of L1 with the
d6 configured halo bridged metal dimers at room temperature in methanol results in the yellow-
colored solution. After being stirred for one hour subsequent adding of NH4PF6 gave the
complexes as yellow-colored precipitates. All these complexes are air and moisture stable, the
solubility of these complexes is good in polar organic solvents like DCM, chloroform and
acetonitrile whereas insoluble in solvents like hexane, and diethyl ether. All complexes are fully
characterized by elemental analysis, 1H NMR, 13C NMR, IR, UV-Vis spectroscopy.
3.2
IR studies of metal complexes
Complexes 1-8 exhibits characteristic stretching frequencies for ν(C-H), ν(C=N), ν(C-N), ν(N-N)
,
ν(C-S) and ν(P-F). The IR spectrum of the complexes was compared with that of the free ligand. The
free ligand shows a characteristic stretching frequency at 1559 cm-1 for the ν(C=N) whereas in the
metal complexes the ν(C=N) absorbs at higher frequency region in the range 1577-1613 cm-1.
Since all the complexes are cationic a characteristic stretching and bending frequencies for ν(P-F)
appeared as a sharp band around 844 cm-1 and 550 cm-1 respectively.
3.3
NMR studies of the complexes
1
The H NMR spectra of ligand and complexes are depicted in figures S1-S8. The
coordination of the ligand to the metal atom was further confirmed by carrying out the NMR
analysis. In the metal complexes, the signals associated with the aromatic ligand protons were
observed in the downfield region as compared to the free ligand which suggests the coordination
14

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267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
of the ligand to the metal atoms [35]. After the formation of complexes, the aromatic proton of
the ligand was observed in the range 6.17-11.66 ppm which are downfield shifts. The aromatic
proton signals of the p-cymene ligand in complexes
1 and 5 are observed as two doublets around
5.87- 6.06 ppm, one septet around 2.21-2.48 ppm for the methine protons of the isopropyl group
and a singlet at 1.79 and 1.92 ppm for the methyl protons and doublet at 1.12-1.15 ppm for the
isopropyl group. The benzene proton resonance in complexes
2 and 6 is observed as a singlet at
5.98 and 6.10 ppm respectively. In addition, a sharp singlet is observed for the rhodium and
iridium complexes around 1.63-1.79 ppm for the methyl protons of the Cp* ligand. Upon the
formation of mononuclear complexes, the two sides of the ligand are no longer equivalent as one
side of the ligand bind to the metal center so the proton for both sides of the ligand was observed
in different chemical shift whereas in dinuclear complexes the chemical environment for both
sides are equivalent so it exhibited same shift. Furthermore, the formation of mononuclear and
di-nuclear complexes is confirmed by the integral ratio of the ligand with respect to the precursor
complexes
The 13C NMR spectra of the complexes further justify the coordination of the ligands and
13
formation of complexes. The C NMR spectra of the representative complexes are provided in
the supplementary information (figures S9-S14). The 13C NMR spectra of the complexes
displayed signals associated with the ligand carbons, p-cymene ligand carbons, methyl carbon of
Cp* and ring carbon of Cp*. The aromatic carbons signals for the ligands were observed in the
range of 166.26 to 102.58 ppm. The methyl, methine, and isopropyl carbon resonances of the p-
cymene ligand were observed in the region around 17.94 - 30.87 ppm. Complex
2 and complex 6
displayed a sharp signal at 86.56 and 85.71 ppm for the carbon of the benzene ring. The signals
associated with the ring carbons of the Cp* ligand in complex 4, complex 7 and complex 8 were
15

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289
290
291
292
293
294
295
296
297
298
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300
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302
303
304
305
306
307
observed at 97.27, 98.11 and 99.33 ppm respectively, in contrast, the methyl carbon resonances
were observed as a sharp peak at 13.42, 9.67 and 9.01 ppm respectively. Overall results from the
NMR spectral studies strongly support the formation of the metal complexes.
3.4
Ultraviolet-Visible spectra of the complexes
The electronic spectra of the complexes 1-8 along with the corresponding ligands L1
have been recorded in acetonitrile solutions in the range 200-600 nm at a concentration of 10 µM
and were depicted in figure S15. The free ligands and complexes exhibit two characteristic high
intense absorption bands, peaks at around 277, 285 nm are due to n - π* transition, peaks in the
range 230 nm are tentatively assigned to π→π* transitions. In addition, the complexes 1-8
exhibit a weak band or a small hump in the visible region at around 410 nm of the spectrum,
which arises due to the excitation of electrons from metal t2g level to the empty π* level of the
ligand (MLCT). Such weak bands may be ascribed either from the low concentration of the
solutions or obscured by the high intense bands.
3.5
Single-crystal X-ray structure determination of complexes
The molecular structures of some complexes were established by carrying out the single
crystal analysis. The solid-state structures was established and the thermal ellipsoid plot along
with crystallographic numbering schemes is depicted in Figure 1. The summary of the crystal
data, data collection, and structure refinement parameters are summarized in Table 1, selected
bond lengths, bond angles values are listed in Table 2.
By single-crystal X-ray diffraction studies, we were able to establish the coordination
modes associated with these ligands. Complex
5
crystallized in the monoclinic crystal system
contained the
with space group C2/m. X-ray crystallographic studies showed that complex
5
cationic species of [{(p-cymene)RuCl}2(µ-L1)] and counter anion contained two molecules of
16

-
308
309
310
311
312
PF6 . The crystal structure of complex 5 contains the disordered of acetone molecule in their
solved structure. The coordination sites around the metal is occupied by the arene ligand (arene =
p-cymene/benzene/Cp*) in a η6/η5 manner, terminal chloride and a chelating NN´- ligand, arene
ligand occupies the three facial coordination sites acting as seat of “piano-stool” and nitrogen’s
donor atoms from pyrimidine and pyrazole ligand and terminal chloride acting as legs.
313
314
315
Figure 1. ORTEP plot of complex 5 with 50% probability thermal ellipsoids. Hydrogen atoms
-
and counter ion (PF6 ) are omitted for clarity
316
317
318
319
320
321
322
The molecular structure of this complex revealed that the ligands coordinated metal in a
bidentate chelating NN´ fashion through pyrimidine nitrogen and pyrazole nitrogen. This
coordination of the ligands in a bidentate manner led to the formation of a five-membered
chelate ring with the metal center. The molecular structures of complex 5 revealed that the ligand
is symmetry in which both sides of the ligand have essentially identical coordination geometry,
and the corresponding bond lengths and bond angles are exactly the same. The arene ring is
essentially planar and the metal to the centroid of the arene ring distances is { 1.682 (5) Å}. The
17

323
324
325
326
327
328
M-N1 bond length is shorter compared to M-N3 bond length which indicates that the metal binds
strongly to the Nitrogen atom of the pyrazole rather than the nitrogen atom of the pyrimidine.
The observed M-N and M-Cl bond lengths in these complexes are found to be in close agreement
with reported complexes with nitrogen donor ligands [36]. The bond angle values N-M-Cl (M =
Ru and Rh) are close to 90° which is consistent with the piano-stool arrangement of various
donor groups about the metal atom [37].
329
3.6
Antibacterial activity
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
Antibacterial activities of the ligand and complexes have been tested against the Gram-
positive Staphylococcus aureus and Gram-negative Escherichia coli, Klebsiella pneumoniae
strains. The result was compared to the corresponding positive controls and the zone of
inhibition (in mm) was given in Table 3. The histogram of the antibacterial activities of the
complexes is shown in figure 2 and the Agar plates of complexes against the tested bacterial
strains were shown in figure S16- S18. It has been observed that all the complexes displayed
effective antibacterial activity against the tested organisms but ruthenium chelates have high
antibacterial activity. The antibacterial activity of the starting metals precursor was found to be
inactive as previously reported [38]. This specified that the antibacterial activity ascribed to the
ligands and the metal complexes. The better activity for the metal chelates compared to the free
ligands can be elucidated on the basis of chelation theory [39]. The activity of the metal
complexes may also be engaged to the lipophilic character of the central metal atom which arose
from the chelation pattern; this consequently favors the permeation via the lipid layer of the cell
membrane [40]. The difference in the effectiveness of the complexes against the tested
organisms is based on the ribosome of the microbial cells or the impermeability of the cells of
microbes [41]. In-vitro assay results revealed that complex 2 (20 ± 0.76 mm), complex 6 (20 ±
18

346
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348
349
350
0.96 mm) and complex 7 (20± 1.09 mm), has the highest potential against Gram-positive
Staphylococcus aureus. Complex 6 showed the highest activity against Gram-negative
Escherichia coli (17 ± 0.56 mm) and Klebsiella pneumonia (17 ± 0.86 mm). Even though all the
studied complexes are active, but they did not reach the effectiveness of the positive control
ciprofloxacin.
351
352
Figure 2: Histogram of the zone of inhibition (mm) of the ligand and complexes 1-8 in
comparison with ciprofloxacin. All the complexes data are means (n = 3) ± Standard deviation of
three replicates.
353
354
355
3.7
MIC and MBC
356
357
358
359
The minimum inhibitory concentration (MIC) and minimum bactericidal concentration
(MBC) results were listed in Table 4 or Figure 3. The MIC and MBC values of ligand and
complexes 1-8 ranged from 0.125 to 1.0 mg/ml against all the three bacterial organisms. The
MIC and MBC values of complex 4, complex 5 and complex 7 values ranged from 0.125 to 0.25
19

360
361
362
363
364
365
mg/ml for S. aureus and Klebsiella Pneumoniae. The values of complex 7 ranged from 0.25 to
0.5 mg/ml for E. coli. The MIC and MBC values of standard ciprofloxacin range from 0.031 to
0.062 mg/ml and 0.062 to 0.0125 mg/ml against the tested organisms. It was found that the MBC
values attained for the ligand and complexes are twice higher than the corresponding MIC values. As
the MBC values were twice to MIC values it can be concluded that the ligand and complexes are
bacteriostatic rather than bactericidal.
366
367
368
369
370
371
372
Figure 3: MIC and MBC of the ligand and complexes 1-8.
Conclusion
In this study, we have successfully introduced a range of ruthenium, rhodium, and
iridium half-sandwich d6 metal complexes containing pyrimidine based thienyl pyrazoles ligand.
The complexes are fully characterized by analytical and various spectroscopic methods and the
20

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375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
solid-state structure of complex 5 has been determined by single-crystal X-ray diffraction studies
to confirm the binding mode of the ligand to the metal. All the complexes were isolated as
-
cationic salts with PF6 as the counterion. The ligand understudy preferably binds to the metal in
a bidentate NNʹ manner using pyrimidine and a pyrazole nitrogen atom. All the eight complexes
investigated in the present study were screened for their in vitro antibacterial activity against
three human pathogens viz., S. aureus, E. coli, and K. Pneumoniae. The antibacterial data
showed that all the complexes have the capacity of inhibiting the metabolic growth of the
investigated bacteria to different extents, which may indicate broad-spectrum properties;
Acknowledgments
Agreeda Lapasam acknowledges the financial support of CSIR-HRDG, New Delhi in the
form of SRF-NET award no. 09/347(0223)/2017-EMR-I. We thank DST-PURSE SCXRD,
NEHU-SAIF, Shillong, India for providing Single-crystal X-ray analysis and other spectral
studies.
Appendix A. Supplementary data
Crystallographic data for the structural analysis has been deposited with the Cambridge
Crystallographic Data Centre, CCDC 1967663 (Complex 5). Whole information can be attained
free of charge by e-mailing data_request@ccdc.cam.ac.uk, or by contacting from The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB21 EZ, UK(fax: +44
1223336033).
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401
402
403
404
405
406
407
408
409
410
411
412
413
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26

485
Table 1: Crystal data and structure refinement details of complexes
Complexes
Complex 5
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
C88 H104 Cl4 F24 N12 O4 P4 Ru4 S4
2648.03
294(2)
0.17073
Monoclinic
C 2/m
a (Å)/α (°)
b (Å)/β (°)
c (Å)/γ (°)
16.1473(7)/90
23.1541(8)/ 101.163(4)
14.4650(6)/90
5305.8(4)
2
volume (Å3)
Z
Density (calc) (Mg/m-3)
1.657
Absorption coefficient (µ) (mm-1)
0.894
F(000)
2664
Crystal size (mm3)
Theta range for data collection
Index ranges
0.25 x 0.21 x 0.12
3.954 to 28.923°
-20<=h<=21, -31<=k<=28,
-19<=l<11
Reflections collected
11322
Independent reflections
Completeness to theta = 25.00°
6230 [R(int) = 0.0231]
98.9 %
Absorption correction
Refinement method
Semi-empirical from equivalents
Full-matrix least-squares on F2
Data/restraints/parameters
Goodness-of-fit on F2
6230/23/363
1.059
Final R indices [I>2sigma(I)]
R1 = 0.0402, wR2 = 0.0966
R indices (all data)
Largest diff. peak and hole (e.Å-3)
R1 = 0.0589, wR2 = 0.1097
0.623 and -0.462
CCDC No.
1967663
2
2
2 2 1/2
2
486
487
Structures were refined on F0 : wR2 = [Σ[w(F0 - Fc2)2] / Σw(F0 ) ] , where w-1 = [Σ(F0 )+(aP)2+bP] and P =
2
[max(F0 , 0)+2Fc2]/3.
488
27

489
Table 2: Selected bond lengths (Å) and bond angles (°) of complex 5
Complex 5
Ru-CNT
1.682
Ru-N1/N6
Ru-N3 / N4
2.091(2)
2.117(2)
Ru-Cl1/ Cl2
2.388(9)
76.34(9)
85.81(7)
N1-Ru1-N3 / N6-Ru2-N4
N1-Ru1-Cl1 / N6-Ru2-Cl2
N3-Ru1-Cl1 / N4-Ru2-Cl2
85.09(7)
490
491
CNT represents the centroid of the p-cymene ring)
Table 3: Antibacterial activity (Agar well) of ligand and complexes
Zone of inhibition (Diameter in mm)
at concentration 200
E. coli
µg
S. No.
Compound Names
S. aureus
13 ± 0.16
13 ± 0.22
20 ± 0.76
18 ± 0.54
17 ± 0.48
19 ± 0.76
20 ± 0.96
21 ± 1.09
16 ± 0.35
32 ± 0.40
K. pneumoniae
14 ± 0.16
09 ± 0.10
15 ± 0.21
16 ± 0.38
16 ± 0.29
15 ± 0.36
17 ± 0.86
16 ± 0.73
16 ± 0.54
31 ± 0.20
1
2
17 ± 0.36
15 ± 0.28
15 ± 0.26
16 ± 0.34
16 ± 0.42
16 ± 0.39
17 ± 0.56
16 ± 0.85
13 ± 0.24
29 ± 0.15
Ligand
Complex 1
Complex 2
Complex 3
Complex 4
Complex 5
Complex 6
Complex 7
Complex 8
Ciprofloxacin
3
4
5
6
7
8
9
10
492
493
S. aureus = Staphylococcus aureus; E. coli = Escherichia coli; K. pneumoniae = Klebsiella
pneumoniae, and Data are means (n = 3) ± Standard deviation of three replicates.
494
28

495
Table 4: MIC & MBC of ligand and complexes
Stock concentration in 2.0 mg/ml
S. aureus E. coli K. pneumoniae
S.
No.
Compound
Names
MIC
0.5
MBC
1.0
MIC
MBC
0.5
MIC
0.5
MBC
1.0
1
2
Ligand
0.25
0.25
0.25
0.25
0.5
Complex 1
Complex 2
Complex 3
Complex 4
Complex 5
Complex 6
Complex 7
Complex 8
Ciprofloxacin
0.5
1.0
0.5
0.5
1.0
3
4
0.5
1.0
0.5
0.5
0.5
0.5
1.0
0.5
0.25
0.125
0.125
0.25
0.125
0.125
0.031
0.25
0.125
0.125
0.25
0.125
0.5
5
6
0.25
0.25
0.5
1.0
1.0
0.25
0.25
0.5
0.5
7
0.5
1.0
8
9
0.25
0.25
0.062
0.25
0.5
0.5
1.0
0.25
1.0
10
0.031
0.062
0.062
0.125
496
497
S.aureus = Staphylococcus aureus; E. coli = Escherichia coli; K. pneumoniae = Klebsiella
pneumoniae.
498
29