Nov 22, 2017 - NMR (DMSO-d6, 100 MHz): δ (ppm): 177.82 (C9, thioamide carbon), 161.33 (C15), 158.92. 126. (C3, oxime carbon), 155.10 (C5, azomethine ...
Accepted Manuscript p-halo N4-phenyl substituted thiosemicarbazones: Crystal structure, supramolecular architecture, characterization and bio-assay of their Co(III) and Ni(II) complexes Avinash Kotian, Karthik Kumara, Vinayak Kamat, Krishna Naik, Dhoolesh G. Kokare, Anupama Nevarekar, Neratur Krishnappagowda Lokanath, Vidyanand K. Revankar PII:
S0022-2860(17)31586-7
DOI:
10.1016/j.molstruc.2017.11.098
Reference:
MOLSTR 24585
To appear in:
Journal of Molecular Structure
Received Date: 26 September 2017 Revised Date:
22 November 2017
Accepted Date: 23 November 2017
Please cite this article as: A. Kotian, K. Kumara, V. Kamat, K. Naik, D.G. Kokare, A. Nevarekar, N.K. Lokanath, V.K. Revankar, p-halo N4-phenyl substituted thiosemicarbazones: Crystal structure, supramolecular architecture, characterization and bio-assay of their Co(III) and Ni(II) complexes, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.11.098. 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.
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p-halo N4-phenyl substituted thiosemicarbazones: Crystal structure, Supramolecular
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architecture, Characterization and Bio-assay of their Co(III) and Ni(II) complexes
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Avinash Kotian a, Karthik Kumara b, Vinayak Kamat a, Krishna Naik a, Dhoolesh G. Kokare a,
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Anupama Nevarekar a, Neratur Krishnappagowda Lokanath b and Vidyanand K. Revankar a, * a
Department of Chemistry, Karnatak University, Dharwad-580 003, Karnataka, India.
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b
Department of Studies in Physics, University of Mysore, Manasagangotri, Mysuru-570 006,
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India.
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*
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Abstract
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Corresponding Author
In the present work, three potential metal ion chelating ligands, p-halo N4-phenyl
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substituted thiosemicarbazones are synthesized and characterized. The molecular structure of all
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(E)-4-(4-halophenyl)-1-(3-hydroxyiminobutan-2-ylidene) thiosemicarbazones (halo = F/Cl/Br)
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are determined by single crystal X-ray diffraction method. All the molecules have crystallized in
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monoclinic crystal system with P21/n space group. The ligands show C—H···S and N—H···S
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intermolecular interactions, which are responsible to form the supramolecular self-assemblies
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through R22(8), R22(12) and R22(14) ring motifs. Hirshfeld surface analysis is carried out to
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explore the intermolecular interactions. A series of Co(III) and Ni(II) mononuclear transition
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metal complexes derived from these ligands have been synthesized and characterized by various
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spectro-analytical methods. The metal to ligand stoichiometry has been found to be 1:2 in all the
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complexes. The synthesized compounds have been investigated for their in vitro antimicrobial
21
potencies. The compounds are found to be more active than the standard used, in the case of E.
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coli and A. niger. Additionally, they are also screened for their in vitro antitubercular activity.
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Keywords:
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Supramolecular assembly, Hirshfeld surface analysis, Bio-assay.
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1. Introduction
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Thiosemicarbazones,
Co(III)
and
Ni(II)
complexes,
Crystal
structure,
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Thiosemicarbazones, an important class of nitrogen–sulfur donor ligands, usually act as
27
chelating ligands with transition metal ions. They generally coordinate to the metal through
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either thione or thiolate sulfur and one of the hydrazinic nitrogen atoms [1]. A large number of
29
the thiosemicarbazone complexes have been found to exhibit wide-ranging medicinal 1
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applications owing to their potentially beneficial biological (viz., antibacterial, antifungal,
31
antimalarial, antiviral, antitumor and anti-inflammatory) activities [2-4]. These metal complexes
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have shown better activities as compared to the free thiosemicarbazones. Particularly, the first-
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row transition metal complexes with such ligands have a wide range of biological activities [5-
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8].
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The self-assembly of molecular species through weak intermolecular contacts
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(noncovalent interactions) is one of the fundamental techniques that has been used to construct
37
supramolecular architectures [9-13]. During the past few decades, supramolecular interactions of
38
aromatic systems have attracted considerable attention because of the utilization of
39
intermolecular noncovalent interactions which is relied upon for the design and development of
40
novel functional materials. Various weak dispersive interactions, such as hydrogen bonding [14],
41
π-π stacking [15], C-H…π [16] contacts represent the backbone of self-assembly process and
42
supramolecular building blocks. The Hirshfeld surface is becoming a valuable tool for analyzing
43
intermolecular interactions while maintaining a whole-of-molecule approach [17]. Graphical
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tools based on the Hirshfeld surface and the associated two-dimensional (2D) fingerprint plot 13
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offered considerable promise for exploring packing modes and intermolecular interactions in
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molecular crystals [18].
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In the recent past cobalt(III) and nickel(II) complexes of thiosemicarbazones have
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received considerable attention due to sulphur rich coordination environment and also due to its
49
potential biological activities [19-22]. We have been exploring the chemistry of first-row
50
transition metal complexes of the thiosemicarbazones [23-28], mainly because of the variable
51
binding mode displayed by these ligands in their complexes.
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Biacetyl monoxime thiosemicarbazones have been shown to be versatile tridentate
53
ligands [29-31], through their structural chemistry and magneto-structural correlations. Hence, it
54
was considered worthwhile to club diacetyl monoxime with p-halo substituted phenyl ring of
55
thiosemicarbazones. Although a plethora of work has been carried out in the past on p-halo N4-
56
phenyl substituted thiosemicarbazones [32], attempts to correlate the influence of p-substituted
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halogen on the supramolecular architecture, coordination behavior of the ligands, geometry of
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the complexes and their biological activities have been meagerly studied.
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The present work has emerged out of this exploration, in gaining a chemical control over
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the mode of binding, supramolecular assembly and applications of p-halo N4-phenyl substituted
62
thiosemicarbazones and their Co(III) and Ni(II) coordination complexes.
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2. Experimental
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2.1. Materials and Physical Measurements
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All the chemicals used in the current study were of reagent grade and were purchased
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commercially and used as supplied. Solvents were dried and distilled before use according to the
68
standard procedures[33]. The metal salts used were CoCl2.6H2O and NiCl2.6H2O. The 1H and 13C
69
NMR spectra were recorded on AGILENT VNMRS-400 spectrometer, in a DMSO-d6 solvent.
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Infrared spectra were recorded in KBr discs in the region 4000-400 cm-1 on a Nicolet-6700 FT-
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IR spectrometer. The CHN analysis was carried out using a Thermo quest elemental analyzer.
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The solution state electronic spectra of all the synthesized compounds in methanol were recorded
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on a JASCO V-670 50 UV–Vis spectrophotometer. The EI mass spectra of all the ligands were
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obtained with a Shimadzu GCMS-QP2010S spectrometer. The ESI mass spectral data for all the
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complexes were obtained using a Waters UPLCTQD mass spectrometer.
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2.2. Single crystal X-ray crystallography
Single crystals of suitable dimensions were chosen carefully for X-ray diffraction studies.
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The X-ray diffraction data were obtained on a Bruker SMART APEX2 CCD area detector
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diffractometer at 296.15 K, using a graphite monochromated Mo-Kα (λ = 0.71073 Å) radiation
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source. The frames were integrated with the Bruker SAINT Software package [34] using a
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narrow-frame algorithm. Using Olex2 [35], the structure was solved with the ShelXT [36]
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structure solution program using direct methods and refined with the XL [37] refinement
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package. All non-hydrogen atoms were refined anisotropically. Molecular graphics were
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generated using Mercury-3.8 package [38]. The crystal data and the structure refinement details
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of the three ligands are given in table 1. The corresponding crystallographic information files can
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be downloaded from the website http://www.ccdc.cam.ac.uk. (CCDC 1544183, CCDC 1544184
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and CCDC 1544185).
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Table 1. Crystal data and structure refinement statistics.
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Parameters
L1
L2
L3
CCDC 1544183
CCDC 1544184
CCDC 1544185
Empirical formula
C11H13FN4OS
C11H13ClN4OS
C11H13BrN4OS
Formula weight
268.31
284.76
329.22
Temperature
296 K
296 K
Wavelength
0.71073 Å
0.71073 Å
Crystal system, space
Monoclinic, P 21/n
Monoclinic, P 21/n
a = 5.7349(4) Å
a = 9.3377(4) Å
a = 9.3883(4) Å
b = 23.2974(15) Å
b = 5.6469(3) Å
b = 5.6436(3) Å
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296 K
0.71073 Å
Monoclinic, P 21/n
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c = 9.6505(6) Å
c = 25.6892(11) Å
c = 25.7909(13)Å
β = 94.113(4)o
β = 93.215(2)o
β = 94.072(4)o
1352.44(11) Å3
1363.05(12) Å3
4
4
1.399 Mgm−3
1.604 Mgm−3
0.430 mm−1
3.163 mm−1
1286.07(15) Å3
Z
4
Density(calculated)
1.386 Mgm−3
Absorption coefficient
0.258 mm−1
F000
560
592
664
θ range for data
1.75o to 27.77o
1.59o to 31.71o
1.58o to 27.05o
−7 ≤ h ≤ 7
−13 ≤ h ≤ 13
−11 ≤ h ≤ 12
−29 ≤ k ≤ 30
−8 ≤ k ≤ 8
−7 ≤ k ≤ 7
−12 ≤ l ≤ 12
−37 ≤ l ≤ 37
−31 ≤ l ≤ 32
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Reflections collected
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32926
10939
Independent reflections
3035 [Rint= 0.0398]
4537 [Rint= 0.0296]
2910 [ Rint = 0.0434]
Absorption correction
multi-scan
multi-scan
multi-scan
Refinement method
Full matrix least-
Full matrix least-
Full matrix least-
squares on F 2
squares on F 2
squares on F 2
3035 / 0 / 193
4537 / 0 / 166
2910 / 0 / 193
Data / restraints / parameters
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1.032
1.030
1.026
Final [I > 2σ(I)]
R1 = 0.0515,
R1 = 0.0443,
R1 = 0.0447,
wR2 = 0.1376
wR2 = 0.1210
wR2 = 0.1020
R1 = 0.0783,
R1 = 0.0604,
R1 = 0.0811,
wR2 = 0.1574
wR2 = 0.1329
wR2 = 0.1155
R indices (all data)
Largest diff. peak and
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0.389 and −0.223 eÅ-3 0.438 and −0.570 eÅ-3
hole 92
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d −0.999 eÅ-3
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0.650
2.3. Hirshfeld surface analysis
The Hirshfeld surfaces are mapped with dnorm and 2D fingerprint plots presented in this
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paper were generated using Crystal Explorer 2.1[39]. The sum of spherical atom electron
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densities was used to calculate the electron distribution based on which the molecular Hirshfeld
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surfaces in the crystal structure were constructed. The normalized contact distance (dnorm) based
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on both de (distance from the point to the nearest nucleus external to the surface) and di (distance
101
to the nearest nucleus internal to the surface), and the vdW radii of the atom, given by Eq. (1)
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enables identification of the regions of particular importance to intermolecular interactions [40].
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The 2D fingerprint plot provides the summary of intermolecular contacts in the crystal by the
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combination of de and di. Shape-index and Curvedness of the surfaces are specified on the basis
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of local curvature of the Hirshfeld surface [41].
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=
+
(1)
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2.4. Synthesis
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2.4.1. Synthesis of 4-(4-halophenyl)thiosemicarbazones of biacetyl monoxime
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The ligands have been synthesized according to the previous strategy [32], with slight
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modifications. The synthesis of the ligands involves two steps. In the first step, the fluoro/chloro
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/bromo substituted thiosemicarbazides were prepared and purified using the literature method
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[42]. In the second step, the methanolic solution of biacetyl monoxime (1 mmol) was added
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dropwise to a solution of 4-(4-halophenyl)thiosemicarbazides (1 mmol) in methanol (20 mL). 5
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The reaction mixture was then refluxed on a water bath for 4 h followed by the addition of 1-2
115
drops of dilute acetic acid. The progress of the reaction was monitored by TLC. The obtained
116
pale yellow shiny solid was filtered, washed with cold methanol and then dried in vacuo. Single
117
crystals suitable for X-ray diffraction of ligands were obtained from slow evaporation of their
118
methanolic solutions. The synthesis of the ligands has been depicted in Scheme 1.
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2.4.2. (E)-4-(4-fluorophenyl)-1-(3-hydroxyiminobutan-2-ylidene) thiosemicarbazone (L1)
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Isolated yield: 76 %; M.P.: 220 0C; Colour: white. Anal. Calc. for C11H13FN4OS: C, 49.24; H,
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4.88; N, 20.88. Found: C, 49.01; H, 4.81; N, 20.83. IR (cm-1): phenyl ν(NH) 3,321; hydrazine
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ν(NH) 3,231; ν(C=N) 1,608. 1H NMR (DMSO-d6, 400 MHz): δ (ppm): 11.61 (s, 1H, O1H,
123
oximato proton), 10.58 (s, 1H, N8H, hydrazone proton), 9.84 (s, 1H, N11H, phenyl proton),
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7.53-7.50 (m, 2H, C14H and C16H aromatic protons), 7.14-7.19 (m, 2H, C13H and C17H
125
aromatic protons), 2.15 (s, 3H, C4H, methyl proton), 2.06 (s, 3H, C6H, methyl proton).
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NMR (DMSO-d6, 100 MHz): δ (ppm): 177.82 (C9, thioamide carbon), 161.33 (C15), 158.92
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(C3, oxime carbon), 155.10 (C5, azomethine carbon), 148.90 (C12), 135.84-115.09 (aromatic
128
carbons), 12.43 (C4, methyl carbon), 9.91 (C6, methyl carbon). λmax (nm): 219 π→π*, 282
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n→π*. EI-MS (m/z): 268.
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2.4.3. (E)-4-(4-chlorophenyl)-1-(3-hydroxyiminobutan-2-ylidene) thiosemicarbazone (L2)
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Isolated yield: 68 %; M.P.: 218 0C; Colour: pale yellow. Anal. Calc. for C11H13ClN4OS: C,
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46.40; H, 4.60; N, 19.67. Found: C, 46.21; H, 4.51; N, 19.53. IR (cm-1): phenyl ν(NH) 3,308;
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hydrazine ν(NH) 3,220; ν(C=N) 1,585. 1H NMR (DMSO-d6, 400 MHz): δ (ppm): 11.65 (s, 1H,
134
O1H, oximato proton), 10.68 (s, 1H, N8H, hydrazone proton), 9.89 (s, 1H, N11H, phenyl
135
proton), 7.58 (d, J = 8 Hz, 2H, C14H and C16H aromatic protons), 7.39 (d, J = 8 Hz, 2H, C13H
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and C17H aromatic protons), 2.15 (s, 3H, C4H, methyl proton), 2.06 (s, 3H, C6H, methyl
137
proton). 13C NMR (DMSO-d6, 100 MHz): δ (ppm): 177.44 (C9, thioamide carbon), 155.07 (C3,
138
oxime carbon), 149.13 (C5, azomethine carbon), 138.45 (C12), 129.78-127.58 (aromatic
139
carbons), 12.51 (C4, methyl carbon), 9.94 (C6, methyl carbon). λmax (nm): 225 π→π*, 281
140
n→π*. EI-MS (m/z): 284.
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2.4.4. (E)-4-(4-bromophenyl)-1-(3-hydroxyiminobutan-2-ylidene) thiosemicarbazone (L3)
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Isolated yield: 71 %; M.P.: 230 0C; Colour: pale yellow. Anal. Calc. for C11H13BrN4OS: C,
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40.13; H, 3.98; N, 17.02. Found: C, 40.01; H, 3.81; N, 16.83. IR (cm-1): phenyl ν(NH) 3,307;
145
hydrazine ν (NH) 3,220; ν (C=N) 1,581. 1H NMR (DMSO-d6, 400 MHz): δ (ppm): 11.65 (s, 1H,
146
O1H, oximato proton), 10.68 (s, 1H, N8H, hydrazone proton), 9.88 (s, 1H, N11H, phenyl
147
proton), 7.53 (s, 4H, C13H, C14H, C16H and C17H aromatic protons), 2.14 (s, 3H, C4H, methyl
148
proton), 2.05 (s, 3H, C6H, methyl proton).
149
(C9, thioamide carbon), 155.06 (C3, oxime carbon), 149.16 (C5, azomethine carbon), 138.33
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(C12), 131.38-117.98 (aromatic carbons), 12.51 (C4, methyl carbon), 9.94 (C6, methyl carbon).
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λmax (nm): 210 π→π*, 301 n→π*. EI-MS (m/z): 328.
H N
+ S
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Reflux 4h, MeOH
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N
14
9
12 13
1
6 H N
8
OH
5 N
7 S
N
2
3 4
10 R = F, Cl, Br
Scheme 1: Synthetic route for the preparation of ligands, L1, L2 and L3.
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Acetic acid
16
R 18
R
H11 N
17
NH2
N
C NMR (DMSO-d6, 100 MHz): δ (ppm): 177.36
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2.4.5. Synthesis of complexes
The dropwise addition of methanolic solution of CoCl2.6H2O and NiCl2.6H2O (1 mmol)
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to a hot solution of ligand (1 mmol) in methanol immediately showed a color change. This
157
reaction mixture was refluxed on a water bath for about 4 h. The precipitate obtained was filtered
158
off, washed with cold methanol and dried in vacuo. Repeated attempts to grow single crystals of
159
the nickel complexes were not fruitful. However, in the case of cobalt(III) complexes, the slow
160
evaporation of the reaction mixture yielded fine brittle crystals, which were unfit for X-ray
161
crystallographic studies.
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[Co(L1)2]Cl – (Co-L1)
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Isolated yield: 51 %; Colour: brown. Anal. Calc. for C22H24ClF2N8O2S2Co: C, 42.01; H, 3.85; N,
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17.81. Found: C, 42.21; H, 3.51; N, 17.53. IR (cm-1): phenyl ν(NH) 3,242; ν(C=N) 1,617. 1H
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NMR (DMSO-d6, 400 MHz): δ (ppm): 10.20 (s, 1H, N11H, phenyl proton), 7.65-7.61 (m, 2H,
167
C14H and C16H aromatic protons), 7.20-7.15 (m, 2H, C13H and C17H aromatic protons), 2.56 7
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(s, 3H, C4H, methyl proton), 2.28 (s, 3H, C6H, methyl proton).
C NMR (DMSO-d6, 100
169
MHz): δ (ppm): 157.19, 137.01, 122.32, 115.89, 115.68, 17.07 and 14.84. λmax (nm): 224 π→π*,
170
355 n→π*, 447(LMCT transition). ESI-MS (m/z): 593.
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[Ni(L1)2]Cl2 – (Ni-L1)
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Isolated yield: 55 %; Colour: brown. Anal. Calc. for C22H26Cl2F2N8O2S2Ni: C, 39.66; H, 3.93; N,
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16.80. Found: C, 39.61; H, 3.91; N, 16.73. IR (cm-1): phenyl ν(NH) 3,327; hydrazone ν(NH)
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3,128; ν (C=N) 1,607, 1543. λmax (nm): 212 π→π*, 247, 294 n→π*, 511, 655 and 755 (d→d
175
transitions). ESI-MS (m/z): 593.
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[Co(L2)2]Cl – (Co-L2)
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Isolated yield: 45 %; Colour: maroon. Anal. Calc. for C22H24Cl3N8O2S2Co: C, 39.92; H, 3.65; N,
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16.93. Found: C, 39.81; H, 3.51; N, 16.83. IR (cm-1): phenyl ν(NH) 3,251; ν(C=N) 1,598, 1539.
179
1
180
Hz, 2H, C14H and C16H aromatic protons), 7.37 (d, J = 8 Hz, 2H, C13H and C17H aromatic
181
protons), 2.56 (s, 3H, C4H, methyl proton), 2.23 (s, 3H, C6H, methyl proton).
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(DMSO-d6, 100 MHz): δ (ppm): 173.19, 159.20, 139.82, 128.99, 126.62, 121.66, 16.89 and
183
14.43. λmax (nm): 208 π→π*, 262, 349 n→π*, 445 (LMCT transition). ESI-MS (m/z): 625.
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H NMR (DMSO-d6, 400 MHz): δ (ppm): 10.12 (s, 1H, N11H, phenyl proton), 7.66 (d, J = 8
C NMR
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[Ni(L2)2]Cl2 – (Ni-L2)
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Isolated yield: 48 %; Colour: brown. Anal. Calc. for C22H26Cl4N8O2S2Ni: C, 37.79; H, 3.75; N,
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16.03. Found: C, 37.71; H, 3.81; N, 16.13. IR (cm-1): phenyl ν(NH) 3,324; hydrazone ν(NH)
188
3,261; ν(C=N) 1,597, 1541. λmax (nm): 208 π→π*, 258, 294 n→π*, 521, 601 and 759 (d→d
189
transitions). ESI-MS (m/z): 627.
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[Co(L3)2]Cl – (Co-L3)
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Isolated yield: 53 %; Colour: brown. Anal. Calc. for C22H24ClBr2N8O2S2Co: C, 35.19; H, 3.22;
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N, 14.92. Found: C, 35.21; H, 3.31; N, 14.83. IR (cm-1): phenyl ν(NH) 3,256; ν(C=N) 1,592,
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1538. 1H NMR (DMSO-d6, 400 MHz): δ (ppm): 10.24 (s, 1H, N11H, phenyl proton), 7.61 (d, J
194
= 8 Hz, 2H, C14H and C16H aromatic protons), 7.50 (d, J = 8 Hz, 2H, C13H and C17H aromatic
195
protons), 2.57 (s, 3H, C4H, methyl proton), 2.27 (s, 3H, C6H, methyl proton).
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(DMSO-d6, 100 MHz): δ (ppm): 159.41, 139.97, 131.96, 122.25, 114.99, 17.16 and 14.82. λmax
197
(nm): 210 π→π*, 263, 358 n→π*, 445 (LMCT transitions). ESI-MS (m/z): 714.
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C NMR
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[Ni(L3)2]Cl2 – (Ni-L3)
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Isolated yield: 50 %; Colour: brown. Anal. Calc. for C22H26Cl2Br2N8O2S2Ni: C, 33.53; H, 3.33;
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N, 14.22. Found: C, 33.61; H, 3.21; N, 14.33. IR (cm-1): phenyl ν(NH) 3,327; hydrazone ν(NH)
201
3,259; ν(C=N) 1,632, 1545. λmax (nm): 214 π→π*, 258, 302 n→π*, 601, 688 and 753 (d→d
202
transitions). ESI-MS (m/z): 714.
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2.5. Bio-Assay
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2.5.1. Antimicrobial activity
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The antimicrobial activity has been performed using broth dilution method [43]. The
206
synthesized complexes have been tested for its activity against four microbial species; Bacillus
207
subtilis, Escherichia coli, Aspergillus niger, Candida albicans. The test was carried out in brain
208
heart infusion (BHI) froth from 0.2 to 100 µg/mL concentrations by serial dilution method. The
209
determination of MIC values of all the tested complexes was compared with the standard drugs,
210
Ciprofloxacin (antibacterial) and Fluconazole (antifungal).
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2.5.2. Antituberculosis activity
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The antituberculosis activity has been performed against Mycobacterium tuberculosis
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(H37RV strain) using Microplate Alamar Blue dye Assay (MABA)[44]. The determination of
215
MIC values of all the tested complexes was compared with the standard drug, Streptomycin.
216 217
3. Results and Discussion
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The various physicochemical parameters of the ligands and its cobalt(III) and nickel(II)
219
complexes are compiled in the experimental section. The synthesized compounds are found to be
220
non-hygroscopic and stable to air and moisture at room temperature. The complexes are soluble
221
in methanol, ethanol, acetonitrile, acetone, DMF and DMSO but are insoluble in water. The
222
analytical and spectroscopic data implies 1:2, metal to ligand stoichiometry in all the complexes.
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3.1. Crystallographic structures
225
The ligands have crystallized in the monoclinic crystal system with the space group
226
P21/n. Mercury generated ORTEP of the molecules with displacement ellipsoids drawn at 50 %
227
probability level are shown in Fig. 1, 2 and 3. The selected geometric parameters are summarised
228
in Table 1 of supplementary information (SI). The bond lengths and bond angles are in good 9
ACCEPTED MANUSCRIPT
agreement with the standard values. The structural conformation of the molecules can be
230
described based on their torsion angle values.
M AN U
SC
RI PT
229
231 232
Fig. 1. ORTEP diagram of the L1 molecule with 50 % probability displacement thermal
233
ellipsoids.
AC C
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235
TE D
234
236 237
Fig. 2. ORTEP diagram of the L2 molecule with 50 % probability displacement thermal
238
ellipsoids. 10
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M AN U
SC
RI PT
239
240 241
Fig. 3. ORTEP diagram of the L3 molecule with 50 % probability displacement thermal
242
ellipsoids.
The structures and conformations of the ligands are very similar, except the variations at
244
para halo substitution. All the molecules are non-planar, as confirmed by the torsion angles
245
between the benzene ring and the long chain substituted at the first position of the benzene ring.
246
The phenyl group (mean of C12-C17) along with halogen lies in one plane and all the other
247
atoms (mean of N11-C9-S10-N8-N7-C5-C6-C3-C4-N2-O1) of the ligand lie in another plane.
248
These two planes intersect at an angle of 67.15° (L1), 67.03° (L2) and 66.93° (L3). The newly
249
formed azomethine bond distances are 1.289 (2) Å (L1), 1.289 (17) Å (L2), 1.281 (4) Å (L3),
250
agrees well with the double bond value confirming the formation of imine bond. The torsion
251
angle values for C9-N11-C12-C13 and C9-N11-C12-C17 are −61.9°(3) and 120.8°(3) in L1,
252
63.77°(19) and −119.08°(17) in L2 and −63.9°(5) and −118.6°(4) in L3 confirming the non-
253
planarity of the molecules. The benzene ring adopts +Syn-Periplanar conformations with sp2
254
hybridization which is confirmed by the ring torsion angle value of 0.70°, 0.54° and 0.55° in L1,
255
L2 and L3 respectively.
AC C
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243
256
The ligands show intermolecular interactions (C—H···S and N—H···S), which are
257
responsible to form the supramolecular self-assemblies through R22(8), R22(12) and R22(14) ring
258
motifs [45-47]. L1 shows intermolecular halogen bond interactions of type C—H···F with a
11
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259
bond distance of 3.275(3) Å and bond angle of 150.2°(17). It has also exhibited C—H···N and
260
N—H···N intramolecular interactions. In L2, the molecules exhibit C—H··· π and π—π interactions apart from inter and
262
intramolecular hydrogen bonding interactions. The C—H··· π; C(14)—H(14)···Cg1 interaction
263
(Cg1 is the centroid of the ring C12/C13/C14/C15/C16/C17) is with a C—Cg distance of
264
3.4932(18) Å, H···Cg distance of 2.79 Å and C—H···Cg angle of 133° (symmetry code 1/2-x, -
265
1/2+y, 3/2-z). The π—π ; Cg(1)—Cg(1) interaction is with a Cg—Cg distance of 4.6920(10) Å, α
266
= 58°, β = 12.1°, γ = 66.8°, and a perpendicular distance of 3.3553(16) Å (symmetry code 1/2-x,
267
1/2+y, 3/2-z). This connects the molecules to form two-dimensional networks. L3 exhibits the C—H··· π ;
SC
268
RI PT
261
C(14)—H(14)···Cg1 (Cg1 is the centroid of the ring
C12/C13/C14/C15/C16/C17) interaction with a C—Cg distance of 3.520(4) Å, H···Cg distance
270
of 2.87(4) Å, C—H···Cg angle of 135° and with a symmetry code 3/2-x, -1/2+y, 1/2-z. The π—π
271
; Cg(1)—Cg(1) interaction (Cg1 is the centroid of the ring C12/C13/C14/C15/C16/C17) with
272
Cg—Cg distance of 4.6920(10) Å, α = 58°, β = 13.8 °, γ = 66.8°, a perpendicular distance of Cg1
273
on ring C12/C13/C14/C15/C16/C17 = 1.8589(15) Å of neighboring molecule, a perpendicular
274
distance of 4.5856(15) Å on ring C12/C13/C14/C15/C16/C17 from Cg1 of neighboring molecule
275
with symmetry code 3/2-x, 1/2+y, 1/2-z, which expanded to form two-dimensional network of
276
the molecules.
TE D
M AN U
269
The three-dimensional structural analysis and comparison of all the three ligands reveal
278
the conformational significance of the substituted halogen atom at para position in the molecule.
279
The C—H··· π and π—π interactions contribute to the stability of the crystal packing while weak
280
and strong hydrogen bond interactions such as N—H···N, C—H···N, C—H···S, N—H···S and
281
O—H···S help to stabilize the molecular structure by forming a three-dimensional network. The
282
corresponding hydrogen bonding geometries are listed in Table 2. The packing of L1 molecules
283
when viewed along 'a' axis, L2 and L3 molecules along 'b' axis are respectively depicted in SI
284
Figs. 1, 2 and 3. The supramolecular three-dimensional network through R22(8), R22(12) and
285
R22(14) ring motifs in L1 are illustrated in Fig. 4 (L2 and L3 in SI Figs. 4 and 5). The C—H··· π
286
and π—π interactions in L2 and L3 are shown in Figs. 5 and 6.
AC C
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287 288 289
12
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Table 2. Geometric parameters for hydrogen bond interactions (Å, o). D—H
H...A
D...A
D—H...A
Symmetry codes
O(1)---H(1)...S(10)i A
0.89
2.46
3.34(17)
168
-1+x, y, -1+z
N(8)---H(8)...S(10)iiA
0.88
2.74
3.62(19)
176
2-x, 1-y, 1-z
C(6)---H(6A)...S(10)iiA
0.96
2.70
3.40(3)
C(13)---H(13)...F(18)iiiA
0.99
2.38
3.28(3)
N(11)---H(11)...N(7)*A
0.75
2.18
2.58(2)
C(4)---H(4B)...N(7)*A
0.96
2.46
2.79(3)
100
-
C(6)---H(6B)...N(2)*A
0.96
2.36
2.75(3)
104
-
O(1)---H(1)...S(10)iv B
0.82
2.55
3.34 (13)
165
1+x, 1+y, z
N(8)---H(8)...S(10)v B
0.86
2.73
3.58 (13)
175
1-x, -y, 1-z
C(6)---H(6C)...S(10)v B
0.96
2.70
3.39 (18)
130
1-x, -y, 1-z
N(11)---H(11)...N(7)*B
0.86
2.16
2.57 (17)
109
-
C(4)---H(4B)...N(7)*B
0.96
2.46
2.78(2)
100
-
C(6)---H(6B)...N(2)*B
0.96
2.36
2.76(2)
104
-
O(1)---H(1)...S(10)viC
0.73
2.67
3.38(3)
165
1+x, 1+y, z
N(8)---H(8)...S(10)vii C
0.80
2.80
3.56(3)
176
2-x, 1-y, -z
C(6)---H(6C)...S(10)vii C
0.96
2.72
3.40(4)
128
2-x, 1-y, -z
N(11)---H(11)...N(7)*C
0.79
2.19
2.58(4)
111
-
C(6)---H(6B)...N(2)*C
0.96
2.35
2.76(5)
105
-
EP
292
AC C
291
RI PT
D—H...A
A:L1, B:L2 and C:L3.
130
2-x, 1-y, 1-z
150.2
1/2+x, 1/2-y, -1/2+z
114
-
SC
M AN U
TE D
290
Inter- i, ii, iii, iv, v, vi, vii and Intra-*.
293 294
13
296
Fig. 4. The intermolecular hydrogen bonds forming supramolecular self-assembly through R22(8), R22(12) and R22(14) ring motifs in L1 molecules.
AC C
295
EP
TE D
M AN U
SC
RI PT
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14
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297 298 299 300
RI PT
301 302 303 304
SC
305 306 307
F
M AN U
308 309
Fig. 5. C—H··· π and π—π interactions in L2 molecules.
AC C
EP
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310
311 312
Fig. 6. C—H··· π and π—π interactions in L3 molecules.
313 15
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314
3.2. Hirshfeld Surface studies Hirshfeld surface analysis (HSA) is used to explore the packing modes, intermolecular
316
interactions and molecular shapes in a crystalline environment. Surface features characteristics of
317
different types of intermolecular interactions can be identified, and these features can be revealed
318
by color coding distances from the surface to the nearest atom exterior (de plots) or interior (di
319
plots) to the surface. Further, 2D fingerprint plots (FP) provide a quantitative summary of the
320
types of intermolecular contacts in terms of a convenient color plot. The 2D fingerprint plots [48,
321
49] were displayed by using the expanded 0.6–2.8 Å view with the de and di distance scales
322
displayed on the graph axes.
SC
RI PT
315
Fingerprint plots in Fig. 7 illustrates the difference between the intermolecular interaction
324
patterns and the relative contributions to the Hirshfeld surface (in percentage: SI Fig. 6) for all
325
the three ligands. H...H bonding appears to be a major contributor in the crystal packing, whereas
326
the C...H, S...H, N...H and F/Cl/Br...H contributions being the minor. The plots also reveal the
327
information regarding the intermolecular hydrogen bonds in support of N—H...S, C—H...F and
328
C—H...S intermolecular interactions. These intermolecular contacts are highlighted by
329
conventional mapping of dnorm, shape index and curvedness on molecular Hirshfeld surfaces and
330
are shown in Figs. 8, 9 and 10 for L1, L2 and L3 respectively. The dnorm plots are mapped with a
331
color scale between −0.368 au (blue) and 1.404 au (red). The dark-red spots on the dnorm surface
332
arise as a result of the short interatomic contacts, i.e., strong hydrogen bonds, while the other
333
intermolecular interactions appear as light-red spots. The red concave region on shape index
334
(−1.0 au (blue) and 1.0 au(red)) is the surface around the acceptor atoms and the blue region is
335
the surface around the donor atoms. The adjacent red-blue triangles indicate the identical π ··· π
336
stacking interactions over the surface. The flat regions of the curvedness (−4.0 au (blue) and 4.0
337
au (red)) surface also indicates the π ··· π stacking interactions [50-52].
TE D
EP
AC C
338
M AN U
323
16
SC
RI PT
ACCEPTED MANUSCRIPT
340
TE D
M AN U
339
Fig. 7. Two-dimensional fingerprint plots of the compounds I-L1, II-L2 and III-L3 showing the
342
overall interactions of the molecules.
343
EP
341
AC C
344
345 346 347 348 349
350 351
Fig. 8. dnorm, shape index and curvedness mapped on Hirshfeld surface for visualizing the
352
molecular interactions of the L1 molecule. 17
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RI PT
353
354
Fig. 9. dnorm, shape index and curvedness mapped on Hirshfeld surface for visualizing the
356
molecular interactions of the L2 molecule.
SC
355
357
M AN U
358
359
Fig. 10. dnorm, shape index and curvedness mapped on Hirshfeld surface for visualizing the
361
molecular interactions of the L3 molecule.
TE D
360
362 363
3.3. Spectral characterisation
364
3.3.1. Infrared spectral studies
366
cm . The FT-IR spectra of the ligands (SI Figs. 7, 8 and 9) show peaks at 3321-3307 cm-1 and
367
3231-3220 cm-1, due to the stretching frequencies of phenyl NH groups and hydrazine NH
368
groups respectively. The absence of thiol stretching peaks around 2500-2600 cm-1 indicates the
369
presence of thioamide tautomer (H-N-C=S) in the solid state of all the ligands. The coupled
370
vibrations among the components of thioamide bands I [ν(CN) and ν(NH) + (CH)], II [ν(CN)
371
and ν(CS)], III [ν(CS) and ν(CS) + ν(CN)] and IV[ν(CS)] are distributed around 1,508, 1,451,
372
1,359 and 930 cm-1 [28]. Thioamide bands III and IV which have major contributions from
373
ν(C=S) have undergone a considerable reduction in intensities and low-frequency shifts in the
374
nickel complexes, indicating the involvement of thione sulfur in the coordination. In all the
375
cobalt(III) complexes, the thioamide band IV has completely disappeared upon complexation,
AC C
-1
EP
The IR spectra of the synthesized compounds were recorded in the region of 4000–400
365
18
ACCEPTED MANUSCRIPT
due to the coordination of sulphur via thioenolisation. This fact is further supported by the
377
disappearance of the ν(NH) hydrazine bands and appearance of weak bands around 700 cm-1
378
[53], due to ν(C–S). Further, the absence of ν(S–H) band in the cobalt(III) complexes also
379
suggest the coordination of sulfur to the metal ion via deprotonation. The band arising from the
380
C=N stretching in L1, L2 and L3 are observed at 1,608, 1,585 and 1,581 cm-1, respectively [54].
381
These have undergone frequency shifts by 9-18 cm-1and low-intensity shifts upon complexation.
382
In conclusion, IR data suggests that the ligands behave as a monobasic anionic NSN tridentate in
383
the case of cobalt(III) and neutral NSN tridentate in the case of nickel complexes. The FT-IR
384
spectra of the complexes are illustrated in Figs. 10-15 of SI.
385
3.3.2. 1H NMR and 13C NMR spectral studies
SC
RI PT
376
The 1H NMR spectrum of the ligands (SI Figs. 16-18) shows singlet peaks for oximato
387
protons in the region of 11.61-11.65 ppm, for hydrazone NH protons 10.58-10.68 ppm and
388
phenyl NH protons 9.84-9.89 ppm. The aromatic protons are resonating in the region 7.14 – 7.59
389
ppm. The singlet peaks for C4H and C6H methyl protons are observed in the range of 2.14-2.15
390
ppm and 2.05-2.06 ppm respectively.
M AN U
386
The peak corresponding to hydrazone NH proton has disappeared and the peak due to
392
phenyl NH proton has shifted to the downfield region in the 1H NMR spectra of the cobalt(III)
393
complexes (SI Figs. 19-21). This observation clearly indicates the coordination of sulphur in the
394
thiol form via deprotonation. The shift in phenyl proton signal in the cobalt(III) complexes
395
supports the coordination of thiol sulphur. The aromatic protons of cobalt(III) complexes are also
396
shifted slightly towards downfield, resonating in the region 7.66-7.37 ppm. The two singlet
397
peaks appearing in the region 2.56-2.57 ppm and 2.23-2.28 ppm are due to C4H and C6H methyl
398
protons also show downfield shift.
EP
AC C
399
TE D
391
In the
13
C NMR spectrum of the ligands (SI Figs. 22-24), the signals in the region
400
177.82-177.36 ppm correspond to thioamide carbon (HN-C=S) which shifts to 173.19 ppm in the
401
spectrum of Co-L2 complex, indicating the presence of thioamide functionality and the
402
coordination of sulphur. The peaks in the region of 158.92-155.06 and 155.10-149.13 ppm, are
403
assigned to azomethine carbons shows a downfield shift in the spectra of cobalt(III) complexes,
404
indicating the involvement of azomethine nitrogen in coordination. Similarly, the peaks of two
405
methyl carbons, assigned in the region of 12.51-12.43 and 9.94-9.91 ppm also show downfield
406
shifts in the spectra of cobalt(III) complexes (SI Figs. 25-27). 19
ACCEPTED MANUSCRIPT
407 408
In conclusion, 1H NMR and
13
C NMR spectra of Co(III) complexes suggest the
coordination through azomethine nitrogen, oxime nitrogen and thioamide sulfur.
409 410
3.3.3. Mass spectral studies The EI-mass spectra of the ligands (SI Figs. 28-30) show the molecular ion peaks, [M]+
412
at m/z 268, 284 and 328 for L1, L2 and L3 respectively. The [M]+ and [M+2]+ peaks are seen at
413
an m/z of 284, 286 for L2 and 328, 330 for L3 respectively. [M]+, [M+2]+ ratio of 3:1 in L2 and
414
1:1 in L3 are in accordance with the natural isotopic abundance of single chlorine and bromine
415
atoms per molecule. Similarly, the [M]+ and [M+2]+ peaks in the L3 ligand, are seen at m/z 328
416
and 330, lie in accordance with Br isotopic ratio of 1:1. Further, a loss of 58 units from the [M]+
417
is observed in all the ligands which are due to the loss of CH3-C=N-OH fragment indicating the
418
homolytic cleavage of C-C bond with ease.
M AN U
SC
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411
The ESI-mass spectra of all the complexes show several peaks due to the molecular
420
cations of the various fragments formed during electrospray ionization [51]. ESI-mass spectra of
421
cobalt(III) complexes have shown peaks at 593, 625 and 714, corresponding to the abundant
422
monoisotopic species of [Co(L)2-2H]+. Similarly, the intense peaks at 593, 627 and 714 have
423
been attributed to [Ni(L)2-H]+ species in all the nickel(II) complexes. Further, all these peaks are
424
supported by calculated isotopic distributions for the formed ML2 type species in all the
425
complexes.
427
Electronic spectral studies
EP
426
TE D
419
The electronic spectra of the ligands and its complexes were measured in methanol over
429
the range 200–1000 nm. The UV-visible spectra of the ligands exhibit two bands in the region of
430
210-225 nm and 281-301 nm, which corresponds to intra ligand π→π* transition of the aromatic
431
ring and n→π* transitions of the azomethine and thioamide [55] portions respectively. The
432
bathochromic shifts have been observed in all the complexes indicating the participation of
433
azomethine group in coordination and appeared in the region 358-258 nm [56]. In the case of
434
Co(III) complexes, an intense absorption band has been observed around 445 nm, assigned to the
435
ligand to metal charge transfer transition [57]. The electronic spectra of Ni(II) complexes display
436
three d→d bands in Oh symmetry in the range of 753-759 nm, 601-688 nm and 521-601 nm are
437
assigned to 3A2g → 3T2g, 3A2g → 3T1g and 3A2g → 3T1g (P) respectively.
AC C
428
20
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438
The observed spectral data of organic motifs clearly support the obtained crystal structures.
439
Whereas, all physicochemical investigations of the synthesized complexes suggest the following
440
structures for the complexes (Fig. 11). R
N
H N
NH N
N N
Cl
S OH
S
N
S
HN
M AN U
N H
R = F/Cl/Br
Fig. 11. Proposed structures of the complexes.
442 443
3.4. Bio-Assay
TE D
444
N
R
R
441
Cl2
OH
N
N N
HN
S
Ni
HO
Co
NH
SC
N HO
RI PT
R
The gram-positive bacterium, B. subtilis and the gram-negative bacterium, E. coli were
446
used to test the activity of the compounds by comparing them with the standard drug,
447
Ciprofloxacin. The synthesized compounds have shown excellent activity against both the
448
bacterial species. All the ligands and their metal complexes are hyperactive against the gram-
449
negative bacterium, E. coli. The ligand, L1, with MIC value 0.2 µg/mL is 10 times more potent
450
and its complexes with MIC value 0.4 µg/mL are 5 times more toxic than that of the standard
451
drug, Ciprofloxacin with MIC value 2 µg/mL. The nickel(II) complex of L2 is also 5 times more
452
toxic than the standard. All other ligands and their metal complexes have shown MIC 0.8 µg/mL.
453
In the case of B. subtilis, the activity of the ligands (MIC 12.5 - 25 µg/mL) has been enhanced on
454
coordination with the metal ions (MIC 0.8 - 12.5 µg/mL).
AC C
EP
445
455
The antifungal activity of synthesized compounds was performed against A. niger and C.
456
albicans. The activities of the compounds are compared with the standard drug, Fluconazole.
457
The synthesized compounds are highly active against A. niger. All the three halo derivatives of
458
ligands are 20 times more active with MIC value 0.4 µg/mL than the standard drug, Fluconazole 21
ACCEPTED MANUSCRIPT
459
with MIC value 8 µg/mL. Their respective metal complexes have also shown extraordinary
460
activity with MIC values ranging from 0.4 – 6.25 µg/mL. The ligands and their metal complexes
461
are moderately active in the case of C. albicans, with MIC 25 - 50 µg/mL. The results are
462
tabulated in Table 3 and are graphically represented in Fig. 33 of SI. The excellent antimicrobial activity exhibited by Co(III) and Ni(II) complexes in case of
464
E. coli and A. niger as compared to their respective standards could be attributed to the increase
465
in lipophilicity of the complexes. The increase in lipophilic character can be explained based on
466
the delocalization of electrons over the entire molecule. This increased lipophilicity of the
467
complexes favours their permeation through the lipid layer of the cell membrane which seems to
468
be responsible for their enhanced antimicrobial activity [58].
SC
RI PT
463
According to Overtone's concept of cell permeability, the surrounding lipid membrane of
470
the cell allows only the lipid-soluble materials to pass through it. Hence lipophilicity plays an
471
important role in antimicrobial activity. In the case of transition metal complexes, chelation
472
considerably reduces the polarity of the central metal ion due to the overlap of ligand orbital,
473
partial sharing of positive charge with donor groups and possible π-electron delocalization over
474
the chelate ring [59]. Such chelation increases the lipophilic character of the complexes
475
favouring penetration into the lipid layer which in turn blocks the metal binding sites on enzymes
476
of microorganisms [60]. Hence, the growth of the organism is restricted by disturbing the
477
respiration process of the cell and blocking their protein synthesis [61].
TE D
M AN U
469
The variation in the effectiveness of the different complexes against different organisms
479
depends on various factors namely the nature and size of the metal ion, labile and inert nature of
480
the complexes, positive charge of the complex, geometry of the complex, dipole moment,
481
solubility of the complex and impermeability of the cells of microbes or difference in ribosome
482
of the microbial cells [26].
AC C
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478
483
Table 3. Results of in vitro antimicrobial assay in MIC (µg/ml).
484
Sl.No.
1.
Compounds
L1
Antibacterial activity, MIC
Antifungal activity, MIC
(µg/mL)
(µg/mL)
Gram-positive
Gram-negative
B. subtilis
E. coli
A. niger
C. albicans
12.5
0.2
0.4
25 22
ACCEPTED MANUSCRIPT
Co-L1
12.5
0.4
6.25
50
3.
Ni-L1
12.5
0.4
0.8
50
4.
L2
25
0.8
0.4
50
5.
Co-L2
25
0.8
0.4
50
6.
Ni-L2
25
0.4
0.8
50
7.
L3
12.5
0.8
0.4
50
8.
Co-L3
1.6
0.8
3.12
25
9.
Ni-L3
3.12
0.8
0.4
25
10.
Ciprofloxacin
2.0
2.0
---
---
11.
Fluconazole
---
---
8.0
16.0
SC
RI PT
2.
M AN U
485 486
The antitubercular activity of synthesized compounds is compared with the standard
487
drug, Streptomycin. All the compounds are active against the strain used. The nickel(II)
488
complexes of chloro and bromo derivatives of the ligand have shown promising activity against
489
the bacterium. The results are tabulated in Table 4 and are graphically represented in Fig. 34 of
490
SI.
Table 4. Results of in vitro antitubercular activity in MIC (µg/ml). Sl. No.
Compounds
Antitubercular activity, MIC (µg/mL)
1.
L1
50
Co-L1
50
Ni-L1
50
L2
25
5.
Co-L2
50
6.
Ni-L2
25
7.
L3
50
8.
Co-L3
50
9.
Ni-L3
25
10.
Streptomycin
6.25
2. 3.
AC C
4.
EP
492
TE D
491
493
23
ACCEPTED MANUSCRIPT
494 495
Conclusions The molecular structures of the ligands were confirmed by single crystal X-ray
497
diffraction studies. The crystal structures reveal that all the ligands have crystallized in
498
monoclinic crystal system with P21/n space group. Significantly, the ligand, L1 shows
499
intermolecular halogen bond interactions of type C—H···F with a bond distance of 3.275(3) Å
500
and bond angle of 150.2(17)°. The crystal structures were stabilized by C—H··· π and π—π
501
molecular interactions, and various inter and intramolecular hydrogen bonds (C—H···S, C—
502
H···N, N—H···S, N—H···N and O—H···S). The ligands exhibit three-dimensional network
503
establishing the supramolecular self-assembly through R22(8), R22(12) and R22(14) ring motifs.
504
Further, the HSA and two-dimensional fingerprint plots provide the numerical estimation and
505
graphical visualization of the intermolecular interactions, which substantiates the X-ray findings.
506
The ligands bind to the metal centers in an NSN fashion through azomethine nitrogen,
507
oxime nitrogen and thioamide sulphur (thiol→Co & thione→Ni). It is monobasic anionic in the
508
case of cobalt(III) complexes and neutral in the case of nickel complexes, as evident from IR and
509
NMR spectra. Metal to ligand stoichiometry is 1:2 as revealed by mass spectra. During the
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complexation, in situ oxidation of Co(II) to Co(III) has been observed which is well supported by
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NMR spectra. But the fluoro derived metal complexes have shown better activity when
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compared to its analogs in case of E.coli. The antimicrobial results show that the complexes are
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hyperactive against E. coli and A. niger. L1 is 10 times and its complexes are 5 times more
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potent than the standard drug, Ciprofloxacin, while the ligands are 20 times more active than the
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standard drug, Fluconazole. However, Mycobacterium tuberculosis has offered some resistance
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against the tested compounds. Among the compounds, L2, NiL2 and NiL3 have offered better
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antitubercular activities. These results illustrate the potential of cobalt(III) and nickel(II)
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complexes for the development of chemotherapeutic agents against the antimicrobial activity.
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Needless to say, detailed in vivo studies, understanding the mechanism of biological action is still
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required in order to fully develop the utility of these compounds as potent metal-based drugs.
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Acknowledgements
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The authors thank USIC, Karnatak University, Dharwad, for providing spectral and XRD
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facilities. Recording of ESI-mass spectra from CDRI Lucknow is greatly acknowledged. The 24
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authors thank UGC-New Delhi for providing RFSMS (Avinash Kotian), SRF (Vinayak Kamat -
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101864/June 2013) and financial assistance in the form of Major Research Project (no. 37-
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Crystal structures, supramolecular assemblies and Hirshfeld surfaces of three p-halo N4-phenyl substituted thiosemicarbazones are explored. A series of cobalt(III) and nickel(II) complexes are synthesized and characterized. In vitro antimicrobial activities are presented for the synthesized compounds.
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