Polymeric zinc complexes with 2,2′-dipyridylamine and different benzenepolycarboxylato ligands: Synthesis, structure, characterization and antimicrobial activity

Accepted Manuscript Polymeric zinc complexes with 2,2’-dipyridylamine and different benzenepolycarboxylato ligands: Synthesis, structure, characterization and antimicrobial activity Lidija Radovanović, Jelena Rogan, Dejan Poleti, Milica Milutinović, Marko V. Rodić PII: DOI: Reference:

S0277-5387(16)30065-1 http://dx.doi.org/10.1016/j.poly.2016.03.054 POLY 11919

To appear in:

Polyhedron

Received Date: Accepted Date:

27 January 2016 18 March 2016

Please cite this article as: L. Radovanović, J. Rogan, D. Poleti, M. Milutinović, M.V. Rodić, Polymeric zinc complexes with 2,2’-dipyridylamine and different benzenepolycarboxylato ligands: Synthesis, structure, characterization and antimicrobial activity, Polyhedron (2016), doi: http://dx.doi.org/10.1016/j.poly.2016.03.054

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Polymeric zinc complexes with 2,2’-dipyridylamine and different benzenepolycarboxylato ligands: Synthesis, structure, characterization and antimicrobial activity Lidija Radovanović

a ,*

, Jelena Rogan b, Dejan Poleti b, Milica Milutinović c, Marko V.

Rodić d a

Innovation Center of Faculty of Technology and Metallurgy, University of Belgrade,

Karnegijeva 4, 11000 Belgrade, Serbia b

Department of General and Inorganic Chemistry, Faculty of Technology and

Metallurgy, University of Belgrade, Karnegijeva 4, 11000 Belgrade, Serbia c

Department of Biochemical Engineering and Biotechnology, Faculty of Technology

and Metallurgy, University of Belgrade, Karnegijeva 4, 11000 Belgrade, Serbia d

Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi

Sad, Serbia

Abstract A series of new zinc complexes containing the 2,2’-dipyridylamine (dipya) ligand and anions of four benzenepolycarboxylic (BPC) acids, namely phthalic (H2pht), isophthalic (H2ipht), terephthalic (H2tpht) and pyromellitic (H4pyr), have been synthesized by ligand exchange reactions. The complexes were characterized based on elemental analysis, FTIR spectroscopy and thermal (TG/DSC) analysis. The complexes were found to have the formulae [Zn(dipya)(pht)] (1), [Zn(dipya)(ipht)]n (2), {[Zn(dipya)(tpht)]·H2O}n (3) and [Zn2(dipya)2(pyr)] (4). Compounds 2 and 3 have been obtained as single crystals and their crystal structures were determined from X-ray diffraction data. In both structures the coordination number of the Zn atoms is five and they are linked by bridging BPC ligands. In 2, the ipht ligand is coordinated in a tridentate manner via chelate and monodentate COO groups, whereas two crystallographically different tpht ligands in 3 are coordinated as bischelate and bis-monodentate ligands, respectively. These combined modes of ipht and tpht anions resulted in zigzag chains of 2 and 3. Two-dimensional pseudo-layers in 2 and a threedimensional network in 3 are governed by hydrogen bonds and C–H···O interactions which are formed between the zigzag chains, and by additional C–H···π interactions in 3. The antimicrobial activity of complexes 1-4 was screened in vitro against some Gram-positive bacteria

(Bacillus

subtilis,

Enterococcus 1

faecalis,

Listeria

monocytogenes

and

Staphylococcus aureus), some Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Salmonella enteritidis) and yeast Candida albicans. Complex 2 showed the most potent inhibitory effect against the tested microorganisms. Keywords: Zn, benzenepolycarboxylato ligands, 2,2’-dipyridylamine, zigzag chain, antimicrobial activity

Introduction The synthesis of transition metal (TM) complexes containing O- and/or N-donor ligands has become very important and attractive in the field of medical research due to the discovery of the antimicrobial properties of these compounds [1-4]. TM complexes could act against different diseases and infections caused by microorganisms. Even with the speed of introducing new antimicrobial agents, microorganisms have shown a remarkable ability to develop resistance to these agents, and this is the reason why the search for new medicaments, such as TM complexes with specific properties and the possibility of being applied as antibiotics, is a continual progress. Historically, medicinal inorganic chemistry is rich in metal-based drugs for the treatment of various diseases [5]. Metal ions such as Mn(II), Fe(II), Fe(III), Cu(II) and Zn(II) are incorporated into a great number of processes in living organisms and facilitate numerous chemical reactions needed for life [6]. Zinc is one of the most important trace elements in organisms, with three major biological roles: catalytic, structural and regulatory [7]. Also, zinc compounds are used in the photodynamic therapy of cancer [8], treatment of diabetes [9] and as antimicrobial agents [10-12]. Many previous studies have shown considerable progress in the utilization of TM complexes in biological activities, especially those with Schiff base ligands [13], thiosemicarbazones [14], quinolones [15] etc., containing Mn(II), Co(II), Ni(II) or Cu(II) cations. Alaghaz reported the excellent antimicrobial activity of Zn(II) complexes with a 2-aminopyridine-cyclodiphosph(V)azane derivative against Escherichia coli, Staphylococcus aureus, Aspergillus niger and Penicillium chrysogenum [11]. It is not rare that the biological activities of TM complexes are different from those of the free ligands. For example, Kasuga and co-workers investigated the antimicrobial activity of 12 zinc complexes based on thiosemicarbazone and semicarbazone ligands and discovered that the complexes [Zn(atsc)(OAc)]n, [Zn(Hatsc)2](NO3)2·0.3H2O and [ZnCl2(Hatsc)] (Hatsc = 2-acetylpyridine(thiosemicarbazone)) have much better activity than the free Hatsc ligand. At the same time, free Hmtsc (Hmtsc = 2-acetylpyridine(4N-morpholyl thiosemicarbazone)) has an excellent inhibitory effect on some tested bacteria and yeasts, 2

which is not true for the corresponding [Zn(mtsc)2]·0.2EtOH complex [12]. It is common to compare the biological activity of TM complexes, as well as free ligands, with the biological activity of known standard drugs, such as tetracycline [3], gentamycin [16] and nystatin [17], which are usually used as antibiotics. As an illustration, Saha and co-workers published an in vitro antimicrobial study of Co(II), Ni(II) and Zn(II) complexes with a Schiff base ligand, the dianion of 2-((pyridin-2-(yl)methyleneamino)benzene-1,4-dioic acid [17], and observed that all the complexes showed a lower inhibitory influence on microbes than tetracycline. The use of N-donor ligands, like 1,10-phenanthroline (phen), 2,2’-bipyridine (bipy) and 2,2’dipyridylamine (dipya), in antimicrobial treatment gave different results. Phen, by itself, was noticed to be very powerful against microorganisms either as the “free” ligand [1] or coordinated in Mn(II) [1], Cu(II) [2] or Zn(II) [18] complexes. On the contrary, bipy and dipya have none or a very low inhibitory effect as “free” ligands [2,3], but coordinated in some TM complexes displayed an improvement in preventing the growth of microorganisms [1,3]. The biological activity of TM complexes with O-donor ligands, such as the anions of benzenepolycarboxylic (BPC) acids, such as 1,2-benzenedicarboxylic (phthalic, H2pht), 1,3benzenedicarboxylic (isophthalic, H2 ipht) and 1,4-benzenedicarboxylic (terephthalic, H2tpht), has also been studied [1,19,20]. El-Sherif and co-workers proved the excellent antibacterial activity of a Cu–pht complex against two Gram positive (Staphylococcus aureus and Bacillus subtillis) and two Gram negative bacteria (Pseudomonas aereuguinosa and Escherichia coli) [20]. Devereux and co-workers showed that Mn–phen–pht/ipht complexes significantly inhibit the growth of Candida albicans [1]. The antimicrobial activities of TM–tpht complexes were measured for five bacteria and six fungi by Aly and co-workers [19], who demonstrated

a

high

efficiency

of

{[Ni(tpht)(ABZ)(H2O)]·H2O}n

(ABZ

=

2-

aminobenzothiazole) against all the tested microorganisms. A survey of the literature did not give any results about the biological activity of TM complexes with anions of 1,2,4,5benzenetetracarboxylic (pyromellitic, H4pyr) acid. Our contribution to the discovery of some potential drugs is presented through a series of new Zn complexes based on dipya and pht, ipht, tpht or pyr as ligands. The chemistry of ternary TM complexes containing BPCs is of great importance, according to the variety of bridging abilities of BPCs in the formation of inorganic-organic frameworks. Such multidentate O-donor ligands have been intensively used as linkers in the construction of numerous TM complexes together with chelate N-donor ligands [see for example 21,22]. In a great variety of multiple coordination modes of pht, ipht, tpht and pyr [23], they provide an abundance of fascinating structural motifs, forming discrete [24], 1D [22], 2D [25] and 3D 3

[26] crystal structures. A survey of the Cambridge Structural Database (CSD, V5.36) [27], resulted in about 350 TM complexes composed of BPCs and phen, bipy or dipya described to date. Among them, no examples of Zn complexes with dipya and BPCs were found. It is also noticeable that TM complexes with dipya and BPCs are very infrequent and less than 15 such compounds have been structurally characterized so far [27]. In this paper the synthesis, spectral and thermal properties, as well as antimicrobial activity, of four compounds, namely [Zn(dipya)(pht)] (1), [Zn(dipya)(ipht)]n (2), {[Zn(dipya)(tpht)]·H2O}n (3) and [Zn2(dipya)2(pyr)] (4), are reported. The crystal structures of two complexes, 2 and 3, have also been determined by X-ray diffraction and are described in detail.

Experimental Materials and measurements All reagents, except dipya, which was of purum quality, were of analytical grade and used without further purification. FTIR spectra were recorded on a Bomem MB-100, Hartmann Braun FTIR spectrophotometer (4000-400 cm-1 region) using KBr pellets. The thermal properties of the complexes were examined from room temperature up to 700 ºC on an SDT Q600 TGA/DSC instrument (TA Instruments). The heating rate was 20 ºC min-1, using less than 10 mg sample mass. The furnace atmosphere consisted of dry nitrogen at a flow rate of 100 cm3 min-1.

Synthesis of the microcrystalline complexes 1-4 An aqueous solution of Zn(CH3COO)2·2H2O (m = 0.55 g, n = 2.5 mmol) in 50 cm3 of H2O and 5 cm3 of 1.0 M HNO3 were mixed. The pH value of this solution was about 3. Next, a solution of dipya (m = 0.43 g, n = 2.5 mmol) in 7.5 cm3 of EtOH was added and then 50 cm3 of an aqueous solution of Na2BDC (BDC = benzenedicarboxylate: pht2–, ipht2–, tpht2–; m = 0.52 g, n = 2.5 mmol) or Na4pyr (m = 0.35 g, n = 1.25 mmol) was added dropwise at room temperature under continuous magnetic stirring. The formed white microcrystalline precipitates were filtered off after standing overnight, washed with small amounts of water, EtOH and Et2O and dried at room temperature. The formulae of the complexes 1-4, yield and analytical data are listed in Table 1. Henceforth, the complexes will be denoted by the numbers in Table 1.

4

Table 1 Formula, yield and analytical data for complexes 1-4. No.

Complex

Yield (%)

1 2 3 4

[Zn(dipya)(pht)] [Zn(dipya)(ipht)]n {[Zn(dipya)(tpht)]·H2O}n [Zn 2(dipya)2(pyr)]

67.9 71.9 75.5 45.9

Analysis Found (Calc.) (%) C H 54.40 (53.95) 3.21 (3.27) 53.64 (53.95) 3.12 (3.27) 51.34 (51.63) 3.41 (3.61) 50.00 (49.82) 2.76 (2.71)

N 11.17 (10.49) 10.57 (10.49) 10.17 (10.04) 11.80 (11.62)

Synthesis of single crystals of [Zn(dipya)(ipht)]n (2) Into an aqueous solution of Zn(NO3)2·6H2O (m = 0.74 g, n = 2.5 mmol) in 100 cm3 of H2O, 5 cm3 of 1.0 M HNO3 was added and a solution with a pH value of about 1 was obtained. After that, a solution of 2.5 mmol dipya (m = 0.43 g) in 7.5 cm3 of EtOH was added, then 50 cm3 of an aqueous solution of Na2ipht (m = 0.52 g, n = 2.5 mmol) was added dropwise at room temperature under continuous stirring. A white precipitate was immediately formed, but it was filtered off and rejected. Colorless single crystals of a suitable size, insoluble in water, EtOH and DMSO were obtained by slow evaporation of the mother liquor at room temperature after 25 days.

Synthesis of single crystals of {[Zn(dipya)(tpht)]·H2O}n (3) A mixture of Zn(NO3)2·6H2O (m = 0.0298 g, n = 0.1 mmol), dipya (m = 0.0171 g, n = 0.1 mmol), H2tpht (m = 0.0166 g, n = 0.1 mmol), NaOH (m = 0.008 g, n = 0.2 mmol) and H2O (3 cm3) was placed in a Teflon-lined steel autoclave, heated at 140 °C for 5 days and cooled to room temperature for 24 h. Colorless single crystals, insoluble in water, EtOH and DMSO were obtained.

X-ray structure determinations Single-crystal X-ray diffraction data were collected at 293 K on an Oxford Gemini S diffractometer equipped with a CCD detector using monochromatized Mo Kα radiation (λ = 0.71073 Å) and a 0.8 mm collimator. Intensities were corrected for absorption by means of the multi-scan method. The structures were solved by direct methods (SIR92) [28] and refined on F2 by full-matrix least-squares using the programs SHELXL-97 [29] and WinGX [30]. All non-hydrogen atoms were refined anisotropically. The positions of H atoms connected to C atoms were calculated on geometric criteria and refined using the riding model with Uiso = 1.2Ueq(C). Hydrogen atoms bonded to N3 in 2 and 3 and water H atoms in 3 were found in ∆F maps and added to the structural models before the final cycle of

5

refinement with fixed positional and atomic displacement parameters. Selected crystal data and refinement results for 2 and 3 are listed in Table 2.

Antimicrobial test Quantitative tests of the antimicrobial activity of all the obtained microcrystalline compounds against four Gram-positive (G+) bacteria (B. subtilis (ATCC 3366), E. faecalis (ATCC 29812), L. monocytogenes (IM 2000) and S. aureus (ATCC 25923)), three Gramnegative (G–) bacteria (E. coli (ATCC 25922), P. aeruginosa (ATCC 27833) and S. enteritidis (ATCC 13076)) and yeast C. albicans (ATCC 10259) were performed according to the liquid challenge method in sterile normal saline solution. A mass of 0.02 g of each microcrystalline complex was suspended in a tube containing 0.9 cm3 of sterile normal saline and inoculated with 0.1 cm3 bacterial suspension to achieve a concentration of 5 x 105 cfu cm-1. The tubes were then incubated at 37 °C for 1 h. After incubation, 9 cm3 of sterile normal saline was added. Subsequently, 1 cm3 aliquots were taken as samples for viable cell determination. Sterile normal saline solution was used for dilution of the number of colonies and 0.1 cm3 of the appropriately diluted solution was placed in a Petri dish and overlaid with TSAY (Tripton soy agar with 0.6 % yeast extract). The Petri dishes were incubated at 37 °C for 24 h. As a control, a blank sterile normal saline solution without sample was used. The degree of reduction, R (%), was calculated according to Eq. (1): R (%) = (CFUcont - CFUM)/CFUcont⋅100

(1)

where CFUcont is the number of microorganism colonies in the control tube and CFUM is the number of microorganism colonies in the tubes with the samples. All analyses of the antimicrobial activity determination were run in triplicate and the mean value and standard deviation were calculated. Table 2 Crystal data and structure refinements for 2 and 3. Complex Formula Formula weight (g mol–1) Crystal size (mm3) Crystal system Space group a (Å) b (Å) c (Å) β (°) V (Å3) Z F(000)

2 C18H13N 3O4Zn 400.68 0.30 × 0.50 × 0.74 Monoclinic P21/n 11.322(2) 8.851(2) 17.675(4) 102.32(3) 1730.4(6) 4 816

6

3 C18 H15N3O5Zn 418.7 0.14 × 0.45 × 0.57 Monoclinic P2 1/n 9.875(2) 14.371(3) 12.264(3) 95.87(3) 1731.3(6) 4 856

µ (mm–1) ρc (g cm–3) θ range (º) Index ranges, h, k, l Reflections collected/unique Data/restraints/parameters R indices [I > 2σ(I)] R indices (all data) Goodness-of-fit Rint ∆ρmax, ∆ρmin (e Å–3) *

1.448 1.538 3.3–25.35 –12→13 –10→10 –21→21 7537/3172 2628/0/239 R = 0.0371, Rw = 0.0818* R = 0.0499, Rw = 0.0871 1.058 0.0300 0.331, –0.391

w = 1/[σ2· (Fo2) + (0.0417P)2 + 0.3449P], where P = (Fo 2 + 2Fc2 )/3 w = 1/[σ2·(Fo2) + (0.0271P)2 + 0.6640P], where P = (Fo2 + 2Fc 2)/3

1.455 1.606 2.9–25.35 –11→11 –17→11 –14→14 7338/3151 2604/0/256 R = 0.0346, Rw = 0.0663** R = 0.0478, Rw = 0.0703 1.039 0.0266 0.264, –0.277

**

Results and discussion Complexes 1-4 were obtained by ligand exchange reactions. The empirical formulae of the complexes based on analytical data (Table 1) were [Zn(dipya)(pht)] (1), [Zn(dipya)(ipht)] (2), [Zn(dipya)(tpht)]·H2O (3) and [Zn2(dipya)2(pyr)] (4). Since 2 and 3 were also obtained as single crystals, their crystal structures could confirm their assumed empirical formulae, and also proved that 2 and 3 are polymeric, so the final formulae of 2 and 3 are [Zn(dipya)(ipht)]n and {[Zn(dipya)(tpht)]·H2O}n, respectively. Because all compounds are insoluble in polar and non-polar solvents, it can be concluded that complexes 1 and 4 are also polymeric.

Description of the structures 2 and 3 Complexes 2 and 3 are very similar in shape, so their crystal structures will be described simultaneously and differences between them will be emphasized. In both structures, each Zn atom has a distorted square pyramidal environment: in 2, the equatorial plane is formed by two N atoms from dipya and two O atoms from a chelate (C18/O3/O4) carboxylate group, while the O1 atom from a monodentate (C11/O1/O2) carboxylate group occupies the apical position (Fig. 1); the equatorial plane in 3 is comprised of an N atom from dipya, two O atoms from a bis-chelate tpht ligand, and an O atom from a bis-monodentate tpht ligand, whereas the N2 atom from dipya is located in the apical position (Fig. 2). The bond distances and angles (Table 3) are normal for TM compounds with square pyramidal arrangements of the metal cation [21,31,32,34]. The Zn atom deviates from the equatorial plane in 2 by 0.0594(4) Å, while the deviation of Zn in 3 is bigger, with value of 0.0669(5) Å. Due to the bridging role of ipht in 2 and tpht in 3 (Figs. 1 and 2), both complexes are polymeric and take the form of 1D zigzag chains (Figs. 3 and 4). In 2, the ipht anion acts as a tridentate ligand with one monodentate and one chelate COO group, whereas in 3, two 7

crystallographically different tpht ions exist: one is coordinated as a bis-chelate ligand and the other as a bis-monodentate ligand.

Fig. 1. Asymmetric unit of 2 with the atomic numbering scheme. Hydrogen atoms are omitted for clarity. The thermal ellipsoids are plotted at the 30% probability level. Symmetry code (i): x – 1/2, –y + 1/2, z – 1/2.

Fig. 2. Structural fragment of 3 with the atomic numbering scheme. Hydrogen atoms are omitted for clarity. The thermal ellipsoids are presented at the 30% probability level. Symmetry codes (i): –x + 1, –y + 1, –z + 2, (ii): –x + 1, –y, –z + 1. Very similar chains are found in some ipht or substituted ipht complexes, namely {[Cu(dipya)(ipht)]· H2O}n [21], [Zn(atibdc)(dipya)]n (atibdc is 5-amino-2,4,6-triiodobenzene1,3-dicarboxylate) [31] and [Co(atibdc)(dipya)]n [32], as well as in some tpht complexes, [Ni(phen)(tpht)(H2O)]n

[22],

{[Ni(phen)(tpht)(H2O)]·0.5H2tpht}n

[22],

{[Zn(bipy)(tpht)]·bipy}n [33] and [Zn(tpht)(quin)]n (quin = 2,2’-diquinolyl) [34]. The dihedral angle between phenyl rings of the ipht ligands in 2 is 71.9 °, while the corresponding angle between two tphts ligands in 3 amounts to 76.6 °. The zigzag chains are extended along the [103] and [011] direction for 2 and 3, respectively (Figs. 3 and 4). 8

Fig. 3. The zigzag chain of the isotactic type in 2 running along the [103] direction. Hydrogen bonds are presented by dashed lines.

Fig. 4. The zigzag chain of the syndiotactic type in 3 running along the [011] direction. In 2, dipya ligands are located on the same side of the zigzag chains (Fig. 3), so the chains can be classified as isotactic. In 3, dipya ligands are situated on alternative sides of the chains, thus the polymeric chains are syndiotactic (Fig. 4). The ipht aromatic ring in 2 and phenyl ring of the bis-monodentate tpht ligand in 3 are nearly perpendicular to dipya, with similar dihedral angles of 89.2(1) and 85.0(1) °, respectively, whereas the analogous angle between dipya and the aromatic ring of the bis-chelate tpht ligand in 3 is smaller [61.2(2) °]. Furthermore in 2, the angle formed between the planes of the monodentate COO group and the aromatic ring amounts to 1.75 °, whereas the angle between the chelate COO group and aromatic ring has a value of 5.98 °. In the structure of 3, the dihedral angle between the monodentate COO group and the aromatic ring of the bis-monodentate tpht ligand is 8.52 °. In addition, the chelate COO group and the phenyl ring of the bis-chelate tpht ligand form an angle with a value of 6.31 °. In line with the aforementioned small values of the dihedral angles in 2 and 3, it can be concluded that overall the ipht and tpht anions are very close to having a planar conformation. These findings confirm that the most stable conformation of the ipht and tpht anions is planar, which is often found within numerous structurally characterized TM complexes and clarified in detail by quantum chemical calculations [35].

9

There is one hydrogen bond in 2 and three hydrogen bonds in 3 with D…A lengths in the range 2.828(3)-2.909(4) Å (Table S1, Supporting Information). The intermolecular hydrogen bond in 2 is formed between the uncoordinated O4 atom from a monodentate COO group and the amine N3 atom from the dipya ligand, which further connects adjacent chains and enables formation of pseudo-layers almost parallel to the ac-plane (Fig. 3). In 3, the water molecule is triply hydrogen bonded, connecting three adjacent chains and leading to the formation of a 3D framework structure (Fig. 5). Also, in both structures the chains are interconnected by C–H···O interactions. Additional stabilization of the crystal lattice of 3 is achieved by two non-covalent C–H···π interactions (Fig. 5): one is found between the aromatic ring of the bis-chelate tpht ligand from one chain and the H atom from a bismonodentate tpht ligand belonging to an adjacent chain (the H13···Cg distance is 2.893 Å), while the other is formed between the pyridyl ring of the dipya ligand and the H atom from a bis-chelate tpht ligand (the H17···Cg distance is 2.772 Å).

Spectral analysis of complexes 1-4 The presence of the water molecule, dipya and BPC ligands were confirmed in detail from the FTIR spectra (Fig. 6). A strong O–H stretching vibration at 3425 cm-1 in the spectrum of 3 corresponds to the lattice water molecule. Characteristic vibrations of the aromatic nuclei as [ν(C=C), ν(C=N)] and ν(N–H) bands are observed in the 1659-1655, 14931481 and 3435-3209 cm-1 regions, respectively, verifying the coordination of the dipya ligand in all the synthesized complexes.

10

Fig. 5. Structural fragment of 3 showing the hydrogen bonds and C–H…π interactions presented by dashed and dotted lines, respectively. Table 3 Selected bond lengths and angles for 2 and 3 (Å, °). 2 N1–Zn 2.034(2) N2–Zn 2.054(2) O1–Zn 1.955(2) O3i–Zn 2.058(2) O4i–Zn 2.322(3) N1–Zn–N2 91.76(9) N1–Zn–O1 116.4(1) N1–Zn–O3i 128.4(1) N1–Zn–O4i 92.11(9) N2–Zn–O1 110.6(1) N2–Zn–O3i 91.26(9) N2–Zn–O4i 143.8(1) O1–Zn–O3i 110.4(1) O1–Zn–O4i 99.66(8) O3i–Zn–O4i 58.95(9) Symmetry codes: 2, (i): x – 1/2, –y + 1/2, z – 1/2.

3 N1–Zn N2–Zn O1–Zn O3–Zn O4–Zn N1–Zn–N2 N1–Zn–O1 N1–Zn–O3 N1–Zn–O4 N2–Zn–O1 N2–Zn–O3 N2–Zn–O4 O1–Zn–O3 O1–Zn–O4 O3–Zn–O4

2.048(2) 2.053(2) 1.972(2) 2.462(2) 2.022(2) 91.19(8) 112.0(1) 153.2(1) 96.06(8) 102.2(1) 96.76(8) 113.7(1) 91.28(7) 133.6(1) 57.34(7)

The existence of coordinated BPC ligands caused the appearance of very intense asymmetrical (νas) and symmetrical (νs) COO vibrations, the wavenumbers of which are listed in Table 4. The difference between these vibrations, ∆ν, when compared with the ”purely ionic“ value, ∆νi, for alkaline metal salts K2pht [36], K2ipht [36], K2tpht [37] and Na4pyr (this study) could predict the coordination mode of the COO groups [38,39]. It is evident (Table 4) that ∆ν values for all complexes are higher than ∆νi, confirming that the BPC ligands are coordinated in a monodentate or strongly asymmetric chelate way. In the fingerprint region, the bands characteristic for the presence of dipya have been observed and very likely overlap with the corresponding C–H vibrations [40]. A weak band attributed to the Zn–O stretching vibration, found around 415 cm-1 in the FTIR spectra of all the complexes, verifies BPC coordination as O-donor ligands [39]. All the above results are in agreement with the crystal structure determination for 2 and 3, whereas the structures of 1 and 4 can be assumed on the basis of the spectroscopic properties (see below).

11

Fig. 6. FTIR spectra of complexes 1-4. Table 4 Spectral data for complexes 1-4, the initial decomposition temperatures and calculated molar dehydration enthalpy. Complex

1 2 3 4

νas(COO) (cm–1) 1587 1566 1593 1587

νs(COO) (cm–1) 1382 1373 1364 1375

∆ν (cm–1) 205 193 229 212

∆νi (cm–1) 157 176 173 173

Tdec,i (°C) 178 361 187 235

∆dehHom (kJ mol–1) – – 49.8 –

Thermal properties of complexes 1-4 The thermal behavior of the complexes was investigated by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) from room temperature up to 700 °C (Fig. 7). Complex 1 is thermally stable up to 178 °C, whereas the decomposition of 2 did not begin before 361 °C. Further, degradation of 3 starts at 187 °C, while 4 is stable under 235 °C. The dehydration of 3 is not a single step process and it is partially overlapped with decarboxylation, as shown by the difference between the found and calculated values of mass loss (found 4.30, calc. 5.62%). A DSC peak maximum corresponding to dehydration, Tmax, is at 177 °C and the molar enthalpy of dehydration, ∆dehHom, is 49.8 kJ mol–1, calculated by measuring the area under the peak. According to the crystal structure of 3, the water molecule participates in three hydrogen bonds which result in an energy value per one hydrogen bond of 16.6 kJ mol–1. This energy value for a single hydrogen bond per 1 mol of water is comparable to those found from the thermal behavior of similar TM complexes [41-43]. The decomposition of 1-4 follows a similar pattern: it starts with decarboxylation which is further followed by the removal of C5H5N2 fragments of the dipya ligand. The only difference is that 12

during the decarboxylation of 1 and 2, two CO molecules were removed, while in the cases of 3 and 4, the elimination of CO2 molecules occurred. During further decomposition up to 550 °C, the residuals of BPCs were removed from 1 and 3, the remaining part of dipya was eliminated from 2, while the C5H5N2 fragment from the second dipya ligand was lost for 4. After 550 °C, all compounds showed a slow weight loss up to 700 °C, though at this temperature none of the complexes reach the expected formation of ZnO. All the degradation processes of 1-4 were accompanied by a sharp endothermic maximum in DSC curves (Fig. 7 b). As is seen from the initial decomposition temperatures, Tdec, i, (Table 4), the thermal stability decreases in the order: 2 > 4 > 3 > 1.

Fig. 7. TG (a) and DSC curves (b) of complexes 1-4 (exo up). If we now consider the structures of complexes 1 and 4, based on the performed analysis and a comparison with the known crystal structures, 2 and 3, as well as with literature data [42,44], the following conclusions could be assumed: both complexes 1 and 4 are polymeric due to their non-solubility in typical polar or non-polar solvents; the pht/pyr anions are coordinated at least in a bis-monodentate manner; the coordination number of Zn atom in 1 and 4 is five. The formula of 1 is very similar to polymeric heteronuclear [CoNi(dipya)2(pht)2]n [44], but the coordination mode of pht is different – bis-monodentate in 1, while in [CoNi(dipya)2(pht)2]n it is bis-chelate. The spectral data for 4 indicated the same coordination mode of the COO groups as in [Ni2(dipya)2(pyr)(H2O)3]·H2O [42]. Regardless of the presence of discrete complex units in the later compound, 4 is polymeric. Therefore, the proposed structural formulae for 1 and 4 are [Zn(dipya)(pht)]n and [Zn2(dipya)2(pyr)]n, respectively, and their possible structures are presented in Scheme 1.

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Scheme 1. The assumed structural formulae for 1 and 4.

Antimicrobial activity of complexes 1-4 The main aim of the synthesis of antimicrobial compounds is to inhibit the microbial cultures without any side effects on human cells. In testing the antimicrobial activity of compounds 1-4, we used eight microorganisms to increase the opportunity for discovering the antibiotic effect of the investigated compounds. The in vitro antimicrobial activity of the complexes was screened against B. subtilis, E. faecalis, L. monocytogenes and S. aureus (as G+ bacteria), E. coli, P. aeruginosa and S. enteritidis (as G– bacteria), and also their antifungal activity against C. albicans. These bacteria and yeast have been selected as the most frequent sources of human infections. The obtained results are presented in Table 5. It has already been proven that the biological activities of Zn(CH3COO)2·2H2O [12], free dipya [3] and BPC acids [1], as reactants and components, are very weak or even non-existent, so their inhibitory effects were not tested. Complex 2 was found to be the most active among all the tested complexes, showing an inhibitory effect against four out of the eight examined microorganisms (Table 5). It exhibits high activity against L. monocytogenes, E. coli and P. aeruginosa, and moderate activity against S. enteritidis. Thus, 2 is active against all tested G– bacteria, but the best activity is shown against the G+ bacteria L. monocytogenes with an R value of 96.30 %. It is not rare that TM complexes are more active against G– bacteria than against G+ bacteria, or vice versa. Some authors have claimed [45] that similar differences in antimicrobial activity could be associated with the differences in the structure of cell walls and membranes of G+ and G– bacteria. In contrast to 2, complexes 1, 3 and 4 were generally less effective, showing moderate to low antibacterial effect against S. enteritidis only. None of the compounds exhibit any activity against S. aureus, E. faecalis, B. subtilis and the yeast C. albicans.

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Since the crystal structures of 2 and 3 are reliably known, we compared in detail their activities with the aim to identify the structural features related to the antimicrobial activity of these compounds. Due to the insolubility of 2 and 3 in sterile normal saline solution, it is possible to assume that during the in vitro tests, the structures of 2 and 3 remain the same, as they were in the solid state. If the biological activity of TM complexes is examined, the following factors should be considered: a) the presence of ligands chelate coordinated to the central metal ion, whose influence could be explained by Tweedy’s chelation theory [46] and Overtone’s concept of cell permeability [47]; b) an increase/decrease in polarity of the COO groups due to coordination to the metal ions [10]; c) the nature of the N-donor ligands [48]; d) the total charge of the complex [48]; e) the coordination number of metal ions [48] and f) the nature of counter ions if they exist [48]. Because of a great similarity between the structures of 2 and 3, the above mentioned factors could not explain the better activity of 2 over 3, and additional criterion related to the steric hindrance has to be taken into account. Xie and co-workers [10] claimed that certain types of geometry could facilitate contact with a microorganism and inhibit its growth quickly, due to the reduction of steric hindrance from the ligands. Therefore, the higher antibacterial activity of 2 is predetermined by the fact that the distortion of square pyramid in 2 is smaller than in 3, which is confirmed by τ5 values of 0.26 and 0.33, for 2 and 3, respectively [49]. This further indicates that there is less steric hindrance from the ligand on one side of the Zn atom in 2. In addition, we compared the angle between two planes (comprised of O1/Zn/O4 and N1/Zn/N2 for 2; and O1/Zn/O2 and N1/Zn/N2 for 3) in the coordination polyhedron of 2 and 3 (Fig. 8). It can be seen that the aforementioned angle is smaller in 2, implying that the Zn atom in 2 is more accessible for interaction with microorganisms. According to the literature [50] and in line with the better activity against G– bacteria, complex 2 could also have a possible antitumor effect, but that must be taken with caution until its effect could be proven in future examinations.

15

Fig. 8. Availability (presented by the sphere of arbitrary radius) of the metal centers in 2 and 3 for the interaction with the microorganisms.

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Table 5 Testing the antimicrobial effects of complexes 1-4. Sample

Control 1 2 3 4

No. of colonies and R (%) Gram-positive bacteria, G+ B. subtilis E. faecalis 4.20·107 1.05·108 8 6.52·10 – 3.12·108 – 5.40·107 – 3.98·108 – 4.40·107 – 3.07·108 – 3.20·108 – 6.56·108 –

L. monocytogenes 2.74· 106 7.00· 106 – 7.00· 104 96.30±1.10 7.00· 106 – 2.00· 108 –

S. aureus 9.10· 107 2.80· 108 1.10· 108 1.50· 108 2.80· 108

– – – –

Gram-negative bacteria, G– E. coli P. aeruginosa 1.40·108 8.30·108 8 1.40·10 – 1.69·109 – 6 3.32·10 95.75±1.72 2.19·108 71.67±2.22 2.84·108 – 1.08·109 – 8 1.42·10 – 1.53·109 –

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S. enteritidis 6.02·108 2.50·108 57.28±1.77 2.00·108 64.30±2.20 2.50·108 56.80±2.60 2.50·108 33.22±1.73

Yeast C. albicans 4.41·106 5.00·106 – 6.50·106 – 8.00·106 – 7.00·106 –

Conclusion In this work, the synthesis and characterization of four zinc complexes with dipya and various

BPC

ligands,

namely

[Zn(dipya)(pht)]

(1),

[Zn(dipya)(ipht)]n

(2),

{[Zn(dipya)(tpht)]·H2O}n (3) and [Zn2(dipya)2(pyr)] (4), have been described. All the complexes were obtained as polycrystalline compounds and 2 and 3 were also prepared as single crystals. In 2, the ipht ligand is coordinated with one COO group as monodentate and with another COO group as a chelate ligand, while in 3 two crystallographically different tpht ligands exist: one is coordinated as bis-monodentate and the other as bis-chelate. These coordination modes of the COO groups in 2 and 3 allow the formation of zigzag chains. Due to the different positions of the dipya ligands in 2 and 3, the chains are classified as isotactic and syndiotactic, respectively. The geometry around the Zn atom in both complexes is a deformed square pyramid. Two-dimensional pseudo-layers of 2 are governed by intermolecular hydrogen bonds, whereas three-dimensional crystal packing of 3 is achieved by both hydrogen bonds and non-covalent C–H···π interactions. Additional stabilization of the structures 2 and 3 is also achieved with C–H···O interactions between the chains. With regard to antimicrobial activity, complex 2 showed the highest inhibitory activity, reaching more than 95 % inhibition against L. monocytogenes and E. coli, making this compound promising in the search for new antibiotic medicaments. By a comparison of the structural characteristics of 2 and 3, the better biological activity of 2 is explained by taking into account the reduction of steric hindrance on one side of the central metal atom.

Acknowledgement We are indebted to Dr. Suzana Dimitrijević from the Department of Biochemical Engineering and Biotechnology, Faculty of Technology and Metallurgy, University of Belgrade for her help with analyses of antimicrobial activity. This work was supported financially by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No. III45007).

Appendix A. Supporting information CCDC Nos. 1447374 and 1447375 contains the supplementary crystallographic data for this

paper.

These

data

can

be

obtained

free

of

charge

via

http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail:

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[email protected]. Supplementary data associated with this article can be found, in the online version.

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Synopsis Four novel polycrystalline zinc(II) complexes with 2,2’-dipyridylamine (dipya) and benzenepolycarboxylate, BPC, ligands were synthesized by ligand exchange reactions and characterized by elemental and TG/DSC analyses, IR spectroscopy and screened for antimicrobial activity against several microorganisms. Two complexes were obtained as single crystals, whose structures were solved from X-ray diffraction data.

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