Synthesis, crystal structure and antibacterial activity of zinc(II) complexes with Schiff bases derived from 5-fluorosalicylaldehyde

Abstract By a condensation of aliphatic amine containing adamantyl groups (amantadine, memantine, or 3-amino-1-adamantanol) and 5-fluorosalicylaldehyde, three new Schiff base ligands, HL1 – 3 , were synthesized. One Schiff base, zinc(II) chloride, and NaOH were stirred in anhydrous methanol generating three new zinc(II) complexes, C34H38F2N2O2Zn (1), C38H46F2N2O2Zn (2), and C34H38F2N2O4Zn (3), respectively. These complexes were characterized by melting point, elemental analysis, infrared spectrum, ultraviolet–visible spectrum, 1H NMR analysis, thermal analysis, and single-crystal X-ray diffraction analysis. Single-crystal X-ray diffraction analysis shows that 1 and 3 crystallize in the monoclinic system with space group P2 1 /c, but 2 crystallizes in the orthorhombic system with space group Pbca. Each asymmetric unit in 1 is composed of one zinc(II) and two deprotonated ligands; each asymmetric unit in 2 is constituted of one zinc(II), two deprotonated ligands as well as one dichloromethane. Each asymmetric unit in 3 is made up of one zinc(II), two deprotonated ligands, one methanol, and one lattice water. The central zinc(II) in 1–3 is four-coordinate via two nitrogen atoms and two oxygen atoms from the corresponding Schiff base ligands, forming a distorted tetrahedral geometry. The antibacterial activities of the three Schiff base ligands and the corresponding complexes against two gram positive bacteria, Staphylococcus aureus and Bacillus subtilis, and a gram negative bacteria, Escherichia coli, were tested.


Materials and methods
All chemicals and solvents were analytical grade and used as received. Elemental analysis of ligands and complexes were performed on a Perkin Elmer Flash EA 1112. Melting points were measured on a WRS-1B micro-melting point apparatus and are uncorrected. Samples were scanned at room temperature from 4000 to 400 cm À1 with KBr pellets on a Nicolet NEXUS FT-IR 5700 spectrophotometer. Ultraviolet-visible spectrum (UV-vis) absorption spectra were measured on a Perkin Elmer Lambda 25 spectrophotometer. Chemical shifts (d) for 1 H NMR spectra were recorded at 300 MHz on a Varian Mercury-Vx300 spectrometer in CDCl 3 containing TMS as an internal standard. Thermal analyses were carried out on a METTLER TOLEDO TGA/SDTA851e.
Aliphatic amine hydrochloride (375, 432 mg, 2 mmol) and KOH (112 mg, 2.0 mmol) in 50 mL anhydrous ethanol were stirred for 1 h; white precipitate (KCl) was filtered out. The filtered transparent liquid or 3-amino-1-adamantanol (335 mg, 2.0 mmol) in 20 mL anhydrous ethanol was added dropwise to a solution of 5-fluorosalicylaldehyde (280 mg, 2.0 mmol) in 20 mL anhydrous ethanol. The resulting solution was refluxed for 2 h and cooled to room temperature. The yellow block Schiff base ligands were collected after 1 week of slow solvent evaporation.

Synthesis of 1-3
Complexes 1-3 were prepared in an analogous procedure using the corresponding Schiff base ligands, NaOH, and zinc(II) chloride in anhydrous methanol ( Figure 2). NaOH (80 mg, 2.0 mmol) in 20 mL anhydrous methanol was added to a solution of ligand (HL 1 , HL 2 , HL 3 ; 547, 603, 579 mg; 2.0 mmol) in 20 mL anhydrous methanol, stirred for 0.5 h, followed by addition of zinc(II) chloride (136 mg, 1.0 mmol) in 20 mL anhydrous methanol dropwise. The mixture was refluxed for 2 h and then cooled until massive precipitate was observed. The yellow solid was suction filtered, washed with anhydrous methanol, and dried.

X-ray crystallography
Crystals suitable for X-ray diffraction of 1-3 were grown from a solution of CH 3OH/CH2Cl2 (1:1 vol/vol) through solvent volatilization. The crystallographic data collections were conducted on a Bruker Smart Apex II CCD with graphite monochromated Mo-K a radiation (k ¼ 0.71073 Å) at 298(2) K using the x-scan technique. The data were integrated by using SAINT, which also adjusted the intensities for Lorentz and polarization effects [28]. The structural analyses and refinements were performed using SHELXL and all nonhydrogen atoms were refined anisotropically on F 2 by full-matrix least-squares using the SHELXL crystallographic software package [29]. Hydrogen atoms were generated geometrically. All computations were calculated on a personal computer with the SHELXL crystallographic software package. The details of the crystal data and refinement results for 1-3 are summarized in Table 1. Partial bond lengths and angles with their computed standard errors are presented in Table 2.

Elemental analysis
The computed values and found values of C, H, and N content in 1-3 (Table 3) are consistent with the formula ZnL n 2 (n ¼ 1, 2, 3), indicating that 1-3 are all composed of one zinc(II) and two deprotonated ligands, with the central zinc(II) four coordinate by coordinating with two nitrogen atoms and two oxygen atoms provided by the corresponding Schiff base ligands. Although all complexes are soluble in dichloromethane and chloroform, they are less soluble than their corresponding ligands in other solvents such as methanol, ethanol, acetone, and DMSO.

IR spectra
IR data of complexes and ligands for comparison are summarized in Table 4. HL [1][2][3] show the phenolic hydroxyl stretch at 3444, 3444, and 3302 cm À1 , respectively. However, there are no phenolic hydroxyl absorptions in 1-3, illustrating that phenolic OH groups are deprotonated as O!Zn coordination occurs. Complex 3 shows a strong stretching vibration of the alcoholic hydroxyl at 3321 cm À1 [30]. Intense absorption bands at 1611, 1610 and 1612 cm À1 for the complexes are assigned to the C ¼ N stretch. Absorption bands at 1242, 1241, and 1248 cm À1 in 1-3 are C-O stretch of phenyl carbon and phenolic oxygen atoms. These bands shift to lower energy for the complex with zinc(II). At lower frequencies, absorptions at 540-547 cm À1 and 450-466 cm À1 for 1-3 can be assigned to Zn-O and Zn-N vibrations, indicating that nitrogen atoms and phenolic oxygen atoms of Schiff base ligands are involved in coordination with zinc(II).

UV-vis spectra
The UV-vis spectra of ligands and complexes are provided in Table 5. Complexes 1-3 exhibit approximately the same curves, but completely different from their corresponding ligands. Bands at 220 nm for ligands and 270 nm for complexes are due to p-p Ã transitions of the benzene ring. Bands at 325 nm for HL 1 might be from n-p Ã transitions of the p-p conjugation. Bands at 324-325 nm of complexes are assigned to charge transfer transitions from HL 1 to Zn(II) (n-p Ã transition) of N!Zn and O!Zn.

1 H NMR analysis
1 H NMR data for complexes and ligands in CDCl 3 are summarized in Table 6. Single peaks at 14.13, 14.02, and 13.79 ppm for ligands are assigned to the phenolic hydroxyl protons at low field due to intramolecular hydrogen bond formation, -CH ¼ NÁÁÁHO-. In this range, the absence of a proton for complexes indicates that phenolic hydroxyls of ligands are deprotonated when the complexes are formed. In ligands, peaks at 8.26, 8.27, and 8.27 ppm can be assigned to HC ¼ N protons. The chemical shift values of HC ¼ N protons in complexes are at higher field compared with ligands, indicating that nitrogen also forms coordination bonds with zinc(II). Multiple peaks at 7.29-6.63 ppm can be assigned to aromatic protons in complexes and ligands. The CH and CH 2 groups from adamantyl group are at 2.27-0.73 ppm.

Thermal analysis of 1-3
The thermal stability and the mechanism of decomposition for 1-3 were investigated by Thermogravimetry-Derivative thermogravimetry (TG-DTG) measurements, carried out with a heating rate of 20 C min À1 under N 2 from 25 to 650 C. The TG-DTG curves are shown in Figures 3-5. Thermal decomposition was observed with two stages for 1, three stages for 2, and four stages for 3. The starting decomposition and weight loss (4.58%) for 2 was at 150 C corresponding to the loss of one methanol molecule; the initial decomposition and weight loss (7.22%) for 3 were at 150 C corresponding to the loss of one methanol molecule and one lattice water, indicating that the solvents were not coordinated. Rapid weight loss stages took place at 450 C for 1-3. When the complexes were heated above 550 C for 1-3, residues formed as oxides. Table 4. Main IR data for ligands and complexes (cm À1 ).

Crystal structures of 1-3
Single-crystal X-ray diffraction analysis shows that 1 and 3 crystallize in the monoclinic system with space group P2 1 /c, whereas 2 crystallizes in the orthorhombic system with space group Pbca. The asymmetric units in 1-3 are composed of one zinc(II) ion and two deprotonated ligands; in addition, one dichloromethane in 2 and one methanol and one lattice water in 3 are found in crystals. The zinc(II) in complexes lies on a twofold rotation axis and is bonded to oxygen and nitrogen donors of the two bidentate ligands. The geometries around zinc(II) in 1-3 are all distorted tetrahedral structures, where the dihedral angle between the two coordination planes defined by O1-Zn1-N1 and O2-Zn1-N2 is 64.26 for 1, by O1-Zn1-N1 and O2-Zn1-N2 is 75.87 for 2, and by O1-Zn1-N1 and O3-Zn1-N2 is 68.94 for 3.   (8) . The s 4 parameters for 2 and 3 are close to 1.00, which indicates a trans-arrangement of two ligands to zinc(II) [32], expected for a Schiff base ligand (with a C ¼ N bond distance of 1.294 Å for 2, 1.286 Å for 3) coordinated to zinc(II), where the imine form predominates. The s 4 parameter for 1 indicates a cis-arrangement of two ligands to zinc(II), with a short C ¼ N bond distance of 1.288 Å.
The molecular structures of 1-3 are displayed in Figures 6-8. The molecular structure of 1 is shaped like a butterfly due to the cis-arrangement of two ligands to  zinc(II); complexes 2 and 3 are shaped like a windmill due to a trans-arrangement of two ligands to zinc(II). The difference in shapes might be caused by steric hindrances of adjacent adamantyl cages and their substituent groups.
Bidentate coordination restricts the formation of intramolecular hydrogen bonds in 1 and 2 due to deprotonated ligands. Complex 1 has weak van der Waals forces to construct a reticular structure containing adamantine cages. In 2 the phenyl rings form strong C-HÁÁÁp interaction with hydrogens of dichloromethane, causing the solvent molecule to be in 2. Complex 3 can form three types of O-HÁÁÁO intermolecular hydrogen bonds, listed in Table 7

Antibacterial activity
Three Schiff base ligands and their zinc(II) complexes were tested against two gram positive and a gram negative bacteria by the zone of inhibition method [35]. The compounds were prepared in concentrations of 1.0 Â 10 À1 , 1.0 Â 10 À2 , 1.0 Â 10 À3 , and 1.0 Â 10 À4 mol L À1 in DMF. The diameters of growth inhibition zones were measured after 48 h and the results are presented in Table 8. Complex 3 showed the maximum antibacterial effect against Staphylococcus aureus. The Schiff bases demonstrated inferior antibacterial activity under the same testing conditions. The antibacterial ability of complexes was concentration-dependent, as all the complexes showed the maximum antibacterial effect against the above three bacteria in solutions of 1.0 Â 10 À1 mol L À1 and the minimum inhibition in dilute solutions of 1.0 Â 10 À4 mol L À1.   Compared with chlorine-or bromine-substituted salicylaldehyde Schiff bases and their corresponding metal complexes [13,24,36], under the same conditions, fluoro-substituted salicylaldehyde Schiff bases showed roughly the same antibacterial effect, however, their corresponding metal complexes demonstrated better bacteriostatic effect.

Conclusion
Three Schiff base ligands and their corresponding zinc(II) complexes were prepared and characterized by melting point, elemental analysis, IR, UV-vis, 1 H NMR analysis, thermal analysis, and single-crystal X-ray diffraction analysis. Single-crystal X-ray diffraction analysis shows that complexes are composed of one zinc(II) ion and two deprotonated ligands. Their single-crystal structures demonstrate that each Schiff base serves as a bidentate ligand coordinating through an oxygen atom and a nitrogen atom in 1-3.

Disclosure statement
No potential conflict of interest was reported by the authors.

Funding
This work was financially supported by Foundation of Liaoning Provincial Department of Education Innovation Team Projects (LT2015012), the Cause of Public Welfare Scientific Research Fund (2015005008), and Shenyang Science and Technology Plan Project (F13-289-1-00). Table 8. Inhibitory of bacteria growth (inhibition zone a /mm) by 1-3 and ligands. 6.0 6.0 6.0 6.0 6.0 6.0 a Filter paper diameter being 6.0 mm.