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Metal Complexes of Multidentate N2S2 Heterocyclic Schiff-base Ligands;Formation, Structural Characterisation and Biological Activity

The synthesis of ligands with N2S2 donor sets that include imine, an amide, thioether, thiolate moieties and their metal complexes were achieved. The new Schiff-base ligands; N-(2-((2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-ylidene)amino)ethyl)-2-((2-mercaptoethyl)thio)-acetamide (H2L1) and N-(2-((2,4-di-p-tolyl-3-azabicyclo[3.3.1]nonan-9-ylidene)amino)ethyl)-2-((2-mercaptoethyl)thio) acetamide (H2L2) were obtained from the reaction of amine precursors with 1,4-dithian-2-one in the presence of triethylamine as a base in the CHCl3 medium. Complexes of the general formula K2[M(Ln)Cl2], (where: M = Mn (II), Co(II) and Ni(II)) and [M(Ln)], (where: M = Cu(II), Zn(II) and Cd(II); n =1-2, expect [Cu(HL2)Cl]) were isolated. The entity of ligands and complexes including their purity were confirmed using elemental microanalysis (C.H.N.S), atomic absorption (A.A), chloride content, conductivity measurement’s, melting point and thermal analysis technique. The molecular structures were elucidated with FT-IR, UV-Vis, magnetic susceptibility, 1H-and 13C-NMR and mass spectroscopy. The synthesised compounds were evaluated for their activity against bacterial strains (G+ and G-) and fungi species. The tested compounds indicated that; the ligands have not shown any antimicrobial activity against Escherichia coli. The Cd(II) complexes, for ligands H2L1 and H2L2, display the higher antimicrobial activity, compared with the other complexes. The H2L1 and H2L2 have not shown any activity against Candida albicans. All complexes for ligands (H2L1 and H2L2) exhibited less activity against Candida albicans, compared with other types of fungi.


Introduction
Compounds incorporate nitrogen and sulfur in their frameworks are a class of organic species that attracted a range of chemist researchers (organic, inorganic and bioinorganic chemists) [1]. The impact of these species on chemistry stimulated researches to investigate and implementing a range of synthetic protocols to increase yields and stability of these materials. These species have shown a range of potential applications, including their role as useful chelating agents for radio-metals of transition and representative elements [2]. They have also used as biomedical agents, in radiopharmaceutical [2], medicine [3] and as a mimic for bioactive molecules, in catalysis, analytical chemistry, coordination chemistry [4], environmental, materials and supramolecular chemistry [5]. Mannich-bases are an important organic species that pronounced a range of uses and applications in chemistry. Compounds derived from 2,4-bis(R-phenyl)-3-azabicyclo[3.3.1]nonan-9-one are interesting materials that used as organic reagents in the fabrication of natural-based blocks including the synthesis of  3 A solution of benzaldehyde (1.33ml, 13mmol), ammonium acetate (0.5g, 6.500mmol) and cyclohexanone (0.674ml, 6.500mmol) [2:1:1] in ethanol (20ml) was mixed together. The reaction mixture was allowed heating between 30-40 ºC for 6h, during which time a yellow solid was formed. However, upon using MeOH medium for 4h reflux the reaction yielded an identical compound. The solid was collected by filtration, washed with ethanol (5ml), and diethylether (10ml) and then dried under vacuum. Yield: 1.26g (93%), m.p = 108-110 ºC. FT-IR data (cm -1 ), 3313 ν(N-H), 3032 ν(C-H) arom , 2920 and 2850 ν(C-H) alip

Synthesis of the complexes with H 2 L 1 and H 2 L 2
A mixture of the title ligand (0.1g, 0.180mmol) in 20ml of a mixture solution of ethanol:chloroform 1:1 and potassium hydroxide (0.03g, 0.541mmol) in ethanol (5ml) was stirred for 10 min. To the above mixture was added dropwise an ethanolic solution (10ml) of the metal chloride (0.043g, 0.180mmol). The resulting mixture was refluxed under N 2 atmosphere for 3h. A solid that formed was filtered, washed by ethanol and diethyl ether, and dried under vacuum. Elemental analysis data, colours, and yields for the ligands and their complexes are given in Table (2).

Determination of biological activity
The evaluation of compounds (ligands and complexes) against four bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus) and four fungi species (Candida albicans, Candida glabrata, Candida tropicalis and Candida parapsilsis) were performed using agar-well diffusion. In this method, the wells were dug in the media with the help of a sterile metallic borer with centres at least 6 mm. A 100 μL concentration of the title specimen 1 mg/mL in DMSO was placed in the individual wells [13]. The Petri dishes were incubated in the incubator for 24h at 37 ºC. The biological activity was observed by measuring the diameter of inhibition zones (mm).

Results and discussion
Ligands were prepared from the reaction of amine precursors with 1,4-dithian-2one. The preparation of the precursors was achieved into two steps; the first step includes Mannich-reaction of benzaldehyde or its derivative with ammonium acetate and cyclohexanone in the presence of ethanol to isolate precursors M 1 and M 2 . The second step focused on the reaction of precursors with ethylenediamine to obtain amine compounds A 1 and A 2 . The ligands were synthesised from the reaction of 1,4-dithian-2-one and amine precursors in the presence of triethylamine as a base in CHCl 3 medium, which gave the title ligands (H 2 L 1 and H 2 L 2 ), see Scheme (1). Elemental analysis Table 1, FT-IR (Table 3), NMR ( 1 H-and 13 C-NMR) and mass spectra were implemented to determine the entity of compounds (precursors and ligands).  Table 4. Physico-chemical data agree well with the proposed formulas. The prominent infrared peaks and their assignments for the ligands and complexes are included in Table 3. The electronic data (UV-Vis) with their assignments for ligands and complexes are placed in Table 4. General synthetic route of (H 2 L 1 and H 2 L 2 ) complexes.

FT-IR and NMR spectra
The FT-IR spectra of free ligands display bands due to ν(C=O) amide , ν(C=N) imine and ν(C-N) groups. The distinct frequency around 2555-2619 cm 1 related to ν(S-H), confirms the presence of the ligands in the thiol form [14]. The FT-IR spectra of the complexes exhibited H 2 L 1 and H 2 L 2 bands with the proper shifts due to complex formation (Table 3). Band assigned to ν(S-H) in the free ligands was disappeared in the spectra of complexes, due to the involvement of sulfur atom, as a thiolate moiety, in complex formation. The ν(C=O) amide and ν(C=N) imine at ca. 1662,1674 cm 1 and at ca. 1604-1616 cm 1 in the free ligands were recorded at lower frequencies, indicated a reduced bond order, and observed around 1631-1651; 1600 and 1639-1651; 1600 cm 1 for H 2 L 1 and H 2 L 2 complexes, respectively. This shift confirmed the involvement of the N atoms of these moieties in the coordination to the metal centre. Bands detected around 1056-1029; 898-855 cm -1 and 1083-1033; 898-855 cm -1 were attributed to ν(C-S) for complexes of H 2 L 1 and H 2 L 2 , respectively indicating the involvement of sulfur atoms upon coordination to metal centre [15]. At lower frequency, the complexes exhibited bands around 416-493 and 333-383 cm 1 [16]. The appearance of two bands indicated the coordination of the Cl atoms in the cis conformation. Table 3. Infrared spectral data (wavenumber, ν¯) cm -1 of (H 2 L 1 -H 2 L 1 ) and their complexes

Mass spectra
The obtained mass spectra of the ligands agreed with the suggested structural formula (see experimental section and ' Figure 4'.

Electronic spectra, magnetic moments, and conductivity measurements
The electronic data of H 2 L 1 and H 2 L 2 display absorption peak at 206, 205 and 345, 360 nm, respectively related to overlaps of π → π * and n → π * transitions. The spectra of H 2 L 1 complexes showed hypsochromic shift peaks correlated to the ligand field transitions (π→π * and n→π * ) [17][18][19], bar Cu(II) complex that exhibited a bathochromic shift. The electronic spectrum of Mn(II) complex revealed peaks in the d-d region at 441 and 762 nm assigned to 6 A 1 g (F) → 4 T 2 g (G) and 6 A 1 g→ 4 T 1 g (G) transitions, respectively indicating a distorted octahedral geometry about Mn(II) ion [20][21]. These data with the magnetic moment value confirmed an octahedral geometry around the Mn(II) atom. The Co(II) complex displays more peaks in the d-d region at 413, 537 and 674 nm due to 2 Eg→ 2 T 1 g or 2 T 2 g, 2 Eg→ 4 T 1 g (F) and 4 T 1 g (F) → 4 A 2 g (F) , respectively. This spectrum is characteristic for Co(II) complexes with distorted octahedral geometries around Co atom [22][23][24]. The  eff value for this complex is included at the range of octahedral confirming octahedral geometry about metal centre. The Ni(II) complex showed peaks at 417, 610 and 681 nm related to 3 A 2 g→ 1 T 1 g (P) , 3 A 2 g→ 3 T 1 g (p) and 3 A 2 g→ 3 T 1 g (F) transitions, respectively confirmed a distorted octahedral geometry around Ni atom [16]. The paramagnetic behaviour of the Ni(II) complex suggested a distorted octahedral geometry. The Cu(II) complex displayed a peak in the d-d region at 828 nm attributed to d-d transition attributed to 2 B 1 g→ 2 A 2 g, confirming a distorted square planar arrangement about Cu atom [25][26][27]. The proposed distorted square planar arrangement for the pale-green Cu(II) complex is supported by its magnetic measurement value and other analytical data. The spectra of the Zn(II) and Cd(II) complexes revealed peaks related to ligand field (π→π * and n→π * ). These diamagnetic complexes (d 10 system) normally prefer tetrahedral structures. The conductance values of the Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes were in the range of 13.1-76.99 Ω -1 cm 2 mol -1 indicating 2:1 electrolytic behaviour of the Mn(II), Co(II) and Ni(II), while those of the Cu(II), Zn(II) and Cd(II) complexes were indicating nonelectrolytes [27][28]. The electronic spectra of H 2 L 2 complexes revealed peaks that attributed to the ligand field (π→π * and n→π * transitions) [16][17][18]. The electronic spectrum of Mn(II) complex displayed peaks at 434 and 639 nm correlated to 6 A 1 g (F) → 4 T 2 g (G) and 6 A 1 g→ 4 T 2 g (G) transitions, respectively confirming a distorted octahedral structure around Mn atom [23]. These data with the value of magnetic moment support an octahedral geometry around the Mn atom. The Co(II) complex displays additional peaks in the d-d area at 438 and 680 nm due to 4 T 1 g (F) → 4 A 2 g (F) and 4 T 1 g→ 4 T 2 g (F) transitions, respectively. This spectrum is characteristic for Co(II) complexes that adopt distorted octahedral structures [23]. The magnetic moment value of the Co(II) complex is in the agreement of octahedral structure with a high spin configuration around Co(II) ion. The Ni(II) complex displayed a peak at 641 nm related to 3 A 2 g→ 3 T 1 g transition, confirming a distorted octahedral sphere about Ni atom [23]. The Ni(II) complex is paramagnetic with a value consists of the distorted octahedral geometry. The electronic spectrum of this complex was in agreement with this assignment. Cu(II) complex showed a peak in the d-d region at 794 nm attributed to d-d transition 2 B 1 g→ 2 B 2 g demonstrating a distorted square planar geometry about Cu atom [14]. The suggested distorted square planar geometry of the blue Cu(II) complex is supported by magnetic moment value  13 and other analytical data. The spectra of the Zn(II) and Cd(II) compounds indicated peaks attributed to ligand field (π→π * and n→π * ). These diamagnetic complexes (d 10 system) normally prefer tetrahedral structures. The molar conductance values of the Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes were in the range of 7.07-78.21 Ω -1 cm 2 mol -1 indicating 2:1 electrolytic behaviour of the Mn(II), Co(II) and Ni(II), while those of the Cu(II), Zn(II) and Cd(II) complexes were indicating nonelectrolytes, except Cu(II) complex that indicated a 1:1 electrolytic behaviour [27][28]. This technique was implemented to study the thermal properties of compounds (stability and chemical composition of ligands and some complexes). TGA analysis supported the determination of the melting points of compounds and identifying their decomposition steps, see Table (5). The TGA peak of the ligand Figure 6; observed at 399.9 ºC indicated the loss of (C 20 H 22 N 2 ) fragment, (det. = 12.364 mg, 60.904 %; calc. = 12.357 mg). The other step occurred at 521.8 ºC revealed the loss of (CH 3 NO) portion, (det. = 1.941 mg, 9.562 %; calc. = 1.921 mg). The third step of the decomposition of the compound at 593.3 ºC is linked to the evolving of (CH 2 S) segment, (obs. = 1.956 mg, 9.633 %; calc. = 1.958 mg). The remaining deposit of the compound above 598.0 ºC is associated with the loss of (C 4 H 6 S), (obs. = 4.040 mg, 19.901%; calc. = 3.668 mg). The differences in the weight may be related to a sublimation process that occurred at high temperature. The DSC curve recorded peaks at 317.1, 337.0, 524.1 and 593.3 ºC, which refer to an endothermic decomposition process. While the peak at 344.0 ºC was referred to an exothermic decomposition process. The exothermic and endothermic peaks may specify combustion of the organic ligand in an argon environment [29][30]. The thermogram for K 2 [Co(L 1 )Cl 2 ] Figure 7; which confirmed the Co(II) complex is stable up to 285.0 ºC. In the TGA curve, peak detected at 408.6 ºC is related to the loss of (C 7 H 4 , C 7 H 7 NO and 2HCl) segments, (det. = 9.954 mg, 54.997 %; calc. = 9.941 mg). The second step at 594.0 ºC that indicated the loss of (2C) fragment, (obs. = 0.619 mg, 3.429%; calc. = 0.646 mg). The final residue of the compound that recorded above 598.0 ºC is correlated to the (Co, 2K, N 2 , 2H 2 S, CH 4 [29][30]. The last endothermic peak may indicate the braking of the metal-ligand bond. The thermogram for [Cu(L 1 )] Figure 8; which shows the Cu(II) complex is stable up to 220.0 ºC. The TGA peak at 259.9 ºC attributed to the loss of (C 2 H 2 ) group, (det. = 0.835 mg, 4.347 %; calc. = 0.946 mg). The differences between the observed and calculated weight may be related to the sublimation process. The second step occurred at 391.9 ºC account for the loss of (C 4 H 6 S 2 , C 6 H 6 and NH 3 [29][30]. The last endothermic peak may signify the metal-ligand bond breaking. While the thermogram for H 2 L 2 is shown in Figure 9; The analysis chart indicated the ligand is intact up to 325.0 ºC. The TGA curve measured at 336.9 ºC attributed to the mass loss of (C 5 H 7 NO) segment, (obs. = 3.845 mg, 19.612 %; calc. = 3.844 mg). The second step took place at 399.3 ºC confirmed the loss of (C 5 H 6 S 2 , C 5 H 5 N and C 3 H 4 ) portions, (obs. = 12.979 mg, 66.217 %; calc. = 12.985 mg). The third decomposition step of the compound at 577.5 ºC is assigned to the mass loss of (C 2 H 4 ) fragment, (obs. = 1.146 mg, 5.8471 %; calc. = 1.110 mg). The final residue that observed above 598.0 ºC is attributed to the elimination of (C 3 H 6 ) portion, (obs.  [29][30]. The last endothermic peak may signify the metal-ligand bond breaking. The thermogram for K 2 [Ni(L 2 )Cl 2 ], Figure 11; which revealed the Ni(II) complex is stable up to 288. 8 ). The second and third step occurred at 443.9 and 594.8 ºC indicated the loss of (C 2 H 4 and HCN) fragments, (det. = 1.663 mg, 7.919 %; calc. = 1.655 mg). The remaining residue above 598.0 ºC related to the (NiO, 2K, Cl 2 , HCN and 4C), (det. = 9.267 mg, 44.128 %; calc. = 8.978 mg). The DSC analysis shows peaks at 288.8, 347.7, 502.7 and 594.8 ºC refer to endothermic decomposition processes. The peak at 477.0 ºC refers to an exothermic decomposition step. The exothermic and endothermic peaks may conclude combustion of the organic compound in the inert atmosphere [29][30]. The final endothermic peak attributed to the metal-ligand bond breaking.

Antimicrobial activity
The compounds (ligands and complexes) were screened against four bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus) and four fungi species (Candida albicans, Candida glabrata, Candida tropicalis and Candida parapsilsis). The measured areas of inhibition against the growth of different microorganisms were listed in Tables (6 and 7). These data show the inhibition capacity of the prepared compounds on the tested bacteria and fungi species. It is found that metal complexes have antimicrobial activity against bacterial strains and fungi species. This attributed to the complexation influence that allows the participation of the inherent positive charge of the metal ion in complexes with the negative charge provided by the donor atoms of the ligand. Subsequently, the π-electron will distribute over the entire chelate ring resulting in the increases of the lipophilic character of the metal chelate system. This shall help its mobility through the cell membranes [31][32]. Table 6. The bacterial activity of (H 2 L 1 -H 2 L 2 ) and their complexes.

Conclusions
In the present publication, we have investigated the synthesis, structural characterisation and coordination bonding mode of metal complexes isolated from the reaction of multidentate N 2 S 2 heterocyclic ligands (H 2 L 1 and H 2 L 2 ) with a range of metal ions. The coordination chemistry and overall structure of the complexes were concluded using a range of analytical and spectroscopic techniques. Further, thermal properties of the ligands and some complexes were established using TGA, DTA and DSC analyses. Biological activities revealed that the ligands and their metal complexes showed different