INTRODUCTION

Schiff bases have received remarkable attention in constructing complexes with various metal ions. In recent years, a large number of Schiff bases and their transition metal complexes have been prepared and studied for their magnetic [1-3], catalytic [4-6], luminescent [7-9], as well as biological properties [10-14]. Schiff bases derived from salicylaldehyde are of particular interest because of the chelate capability of phenol and imino donor sets [15-17]. Fluorine is a biologically active element. Some Schiff bases with fluoride groups are reported for their various biological activities, e.g. antibacterial [18-20]. However, compared with chloride, bromide, methyl, methoxy, ethoxy, and nitrate substituted Schiff bases, those with fluoride substituent groups are rarely reported. Although Schiff bases and their complexes have widely been studied, the relationship between the structures and properties is not definite. Moreover, the self-assembly of the ligands and metal ions cannot be fully anticipated. In pursuit of new and efficient antibacterial materials, in the present work, the syntheses and structures of three copper(II) complexes [Cu2(La)2] (1), [Cu(Lb)2] (2), and [Cu(Lc)2] (3), derived from Schiff bases 2-((cyclopropylimino)methyl)-4,6-difluorophenol (HLa), 2-((cyclohexylimino)methyl)-4,6-difluorophenol (HLb), and 2,4-difluoro-6-((2-hydroxyethylimino)methyl)phenol (HLc), respectively, are presented.

EXPERIMENTAL

Materials and methods. Starting materials, reagents, and solvents were purchased from commercial suppliers and used as received. Elemental analyses were performed on a PerkinElmer 240C elemental analyzer. IR spectra were recorded on a Jasco FTIR-4000 spectrometer as KBr pellets in the range 4000-400 cm–1. The UV-Vis spectrum was recorded on a LAMBDA 900 spectrometer. Single crystal X-ray diffraction was carried out on a Bruker SMART 1000 CCD diffractometer.

Caution! Although our samples never exploded during handling, perchlorate salt is potentially explosive. Only a small amount of copper perchlorate should be prepared and it should be handled with care.

Synthesis of [Cu2(La)2] (HLa = 2-((cyclopropylimino)methyl)-4,6-difluorophenol) (1). 3,5-Difluorosalicylaldehyde (1.6 g, 0.010 mol) and cyclopropylamine (0.57 g, 0.010 mol) were mixed in methanol (50 mL). The mixture was stirred at ambient temperature for 30 min to give a yellow solution. Then, a methanol solution (30 mL) of copper perchlorate hexahydrate (3.7 g, 0.010 mol) was added. The mixture was further stirred for 30 min to give a blue solution. Single crystals of the complex, suitable for X-ray diffraction, were obtained after five days. The yield was 0.72 g (32%) based on 3,5-difluorosalicylaldehyde. Anal. calcd for C40H32Cu2F8N4O4 (%): C 52.69, H 3.54, N 6.14. Found (%): C 52.55, H 3.61, N 6.23. IR data (ν, cm–1): 1627 s (C=N), 1561 w, 1478 s, 1358 m, 1317 w, 1267 m, 1185 w, 1116 m, 1051 w, 982 m, 913 w, 845 m, 751 w, 701 w, 585 w, 546 w, 465 w. UV (λ, nm (ε, L/mol·cm)): 273 (1.89·104), 372 (7.87·103).

Synthesis of [Cu(Lb)2] (HLb = 2-((cyclohexylimino)methyl)-4,6-difluorophenol) (2). 3,5-Difluorosalicylaldehyde (1.6 g, 0.010 mol) and cyclohexylamine (0.99 g, 0.010 mol) were mixed in methanol (50 mL). The mixture was stirred at ambient temperature for 30 min to give a yellow solution. Then, a methanol solution (30 mL) of copper perchlorate hexahydrate (3.7 g, 0.010 mol) was added. The mixture was further stirred for 30 min to give a blue solution. Single crystals of the complex, suitable for X-ray diffraction, were obtained after three days. The yield was 1.1 g (41%) based on 3,5-difluorosalicylaldehyde. Anal. calcd for C26H28CuF4N2O2 (%): C 57.82, H 5.23, N 5.19. Found (%): C 57.96, H 5.31, N 5.12. IR data (ν, cm–1): 1627 s (C=N), 1561 w, 1478 s, 1386 w, 1360 m, 1261 s, 1191 w, 1121 m, 1088 m, 1051 s, 985 w, 885 w, 837 m, 751 w, 660 w, 580 w, 527 w, 455 w. UV (λ, nm (ε, L/mol·cm)): 266 (1.78·104), 373 (7.72·103).

Synthesis of [Cu(Lc)2] (HLc = 2,4-difluoro-6-((2-hydroxyethylimino)methyl)phenol) (3). 3,5-Difluorosalicylaldehyde (1.6 g, 0.010 mol) and ethanolamine (0.61 g, 0.010 mol) were mixed in methanol (50 mL). The mixture was stirred at ambient temperature for 30 min to give a yellow solution. Then, a methanol solution (30 mL) of copper perchlorate hexahydrate (3.7 g, 0.010 mol) was added. The mixture was further stirred for 30 min to give a blue solution. Single crystals of the complex, suitable for X-ray diffraction, were obtained after a week. The yield was 1.5 g (64%) based on 3,5-difluorosalicylaldehyde. Anal. calcd. for C18H16CuF4N2O4 (%): C 46.61, H 3.48, N 6.04. Found (%): C 46.45, H 3.43, N 6.15. IR data (ν, cm–1): 3443 w (OH), 1628 s (C=N), 1561 w, 1476 s, 1386 w, 1360 m, 1317 w, 1266 s, 1211 w, 1127 w, 1088 m, 1053 s, 986 w, 919 w, 865 w, 837 m, 745 w, 720 w, 618 w, 570 w, 526 w, 455 w. UV (λ, nm (ε, L/mol·cm)): 265 (1.75·104), 370 (6.63·103).

X-ray crystallography. Single crystal X-ray data for the complexes were collected on a Bruker SMART 1000 CCD diffractometer. Intensity data were collected using graphite-monochromatized MoKα radiation (λ = 0.71073 Å) at 298(2) K by the ω scan mode. The SAINT program was used for integration of the diffraction profiles [21]. Semi-empirical absorption corrections were applied using the SADABS program [22]. All structures were solved by direct methods using the SHELXS program of the SHELXTL package and refined by full-matrix least-squares methods with SHELXL [23]. All non-hydrogen atoms were refined with anisotropic displacement coefficients. The hydrogen atoms were included in geometric positions and given thermal parameters equivalent to 1.2 or 1.5 times those of the atom to which they attached. Crystallographic data and refinement parameters are given in Table 1, and important interatomic distances and angles are given in Table 2.

Biological assay. A qualitative determination of the antibacterial activity was made using the disk diffusion method. Suspensions in sterile peptone water from 24 h cultures of microorganisms were adjusted to 0.5 McFarland. Muller–Hinton Petri dishes of 90 mm were inoculated using these suspensions. Paper disks (6 mm in diameter) containing 10 μL of the substance to be tested (at a concentration of 2048 μg/mL in DMSO) were placed in a circular pattern in each inoculated plate. The plates were incubated at 37 °C for 18-24 h. DMSO impregnated discs were used as negative controls. Toxicity tests of the solvent (DMSO) showed that the concentrations used in antibacterial activity assays did not interfere with the growth of the microorganisms. The results were read by measuring the diameters of inhibition zones generated by the test substance. Penicillin was used as the reference.

Table 1 Crystallographic Data and Refinement Parameters for the Complexes
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Table 2 Selected Bond Distances (Å) and Angles (deg) for the Complexes
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The minimum inhibitory concentration (MIC) was determined using serial dilutions in the liquid broth method. The materials used were 96-well plates, suspensions of microorganism, Muller–Hinton broth, and stock solutions of each substance to be tested (2048 μg/mL in DMSO). The following concentrations of the substances to be tested were obtained in the 96-well plates: 1024 μg/mL, 512 μg/mL, 256 μg/mL, 128 μg/mL, 64 μg/mL, 32 μg/mL, 16 μg/mL, 8 μg/mL, 4 μg/mL, 2 μg/mL, and 1 μg/mL. After incubation at 37 °C for 18-24 h, the MIC for each tested substance was determined by a microscopic observation of the microbial growth. It corresponds to the well with the lowest concentration of the tested substance where the microbial growth was clearly inhibited.

RESULTS AND DISCUSSION

Chemistry. The complexes were synthesized by the reaction of Schiff bases and copper perchlorate in methanol. Except for copper perchlorate, chloride, nitrate, and acetate copper salts can also be used to prepare the complexes and the same structures as described in this paper. Moreover, although azide and thiocyanate anions are good building blocks in the construction of polymeric complexes [24-28], and we have added equimolar quantities of them to the reaction mixture, they do not combine with the current complexes.

Interestingly, with similar Schiff bases, different structures of copper complexes were obtained. Complex 1 is dinuclear, while complexes 2 and 3 are mononuclear. This may be influenced by steric hindrance effects of the terminal groups of Schiff bases, viz. cyclopropyl HLa, cyclohexyl for HLb, and 2-hydroxyethyl for HLc.

Crystal structure description of complex 1. The molecular structure of complex 1 is shown in Fig. 1. The complex is a phenolate-bridged dinuclear copper(II) species. The molecule of the complex possesses a crystallographic inversion center. The inversion center is located at the midpoint of two Cu atoms at a distance of 3.315(2) Å. The Cu atom is penta-coordinated in a square pyramidal geometry, with the apical position being occupied by the phenolate O atom (O2A) of a Schiff base ligand. The basal plane is defined by two imino N atoms (N1 and N2) and two phenolate O atoms (O1 and O2) from two Schiff base ligands. The bond angles in the basal plane vary from 89.47(6)° to 90.43(6)°, and those between the apical and basal donor atoms vary from 80.32(5)° to 100.13(6)°, indicating that the square pyramidal coordination is distorted. The distortion can also be observed from the bond lengths among donor and Cu atoms. The Cu–O and Cu–N bond lengths are in the range 1.9109(14)-2.3931(14) Å, which are comparable to those observed in the copper complexes with Schiff bases [29-31]. The coordinate bond values are also similar to those reported in the copper complexes with a similar Schiff base ligand 4-bromo-2-(cyclopropyliminomethyl)phenolate [32]. The molecules of the complex are linked through intermolecular C–H⋯F hydrogen bonds (C10–H10A = 0.97 Å, H10A⋯F4#4 = 2.50 Å, C10⋯F4#4 = 3.451(3) Å, C10–H10A⋯F4#4 = 166(3)°; symmetry code #4 x, 1–y, 1/2+z), to form one-dimensional chains running along the c axis (Fig. 2).

Fig. 1
figure 1

A perspective view of the molecular structure of complex 1 with the atom labeling scheme. Thermal ellipsoids are drawn at the 30% probability level. All H atoms are omitted for clarity. Atoms labelled with the suffix A or unlabelled are at the symmetry position #1 1/2–x, 1/2–y, –z.

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Crystal structure description of complexes 2 and 3. The molecular structures of complexes 2 and 3 are shown in Figs. 3 and 4, respectively. The structures of both complexes are similar, so we described them simultaneously. Molecules of the complexes possess a crystallographic inversion center, and the center is located at the Cu atom. The Cu atom is tetra-coordinated in a square planar geometry. The donor atoms come from phenolate O (O1, O1A) and imino N (N1, N1A) from two Schiff base ligands. Due to the special centro-symmetry, all the bond angles are exactly 90°. A slight distortion of the square planar coordination is reflected by bond lengths among the donor and Cu atoms. The Cu–O and Cu–N bond lengths are in the range 1.8855(14)-2.0394(14) Å for complex 2 and 1.880(3)-2.000(3) Å for complex 3, which are comparable to those observed in the copper complexes with Schiff bases [33-36]. The coordinate bond values are also similar to those reported in the copper complexes with similar Schiff base ligands N-cyclohexyl-3,5-di-t-butylsalicylaldimine and 2-(o-vanillinamino)-1-hydroxyethane [37, 38]. The molecules of complex 2 are linked through intermolecular C–H⋯O hydrogen bonds (C6–H6 = 0.93 Å, H6⋯O1#5 = 2.57 Å, C6⋯O1#5 = 3.309(3) Å, C6–H6⋯O1#5 = 136(4)°; symmetry code #5 1–x, –1/2+y, 1/2–z), to form one-dimensional chains running along the c axis (Fig. 5). The molecules of complex 3 are linked through intermolecular O–H⋯O hydrogen bonds (O2–H2 = 0.82 Å, H2⋯O2#6 = 1.97 Å, O2⋯O2#6 = 2.699(4) Å, O2–H2⋯O2#6 = 148(3)°; symmetry code #6 1/3–x+y, 2/3–x, –1/3+z), to form a two- dimensional network parallel to the ab plane (Fig. 6). Interestingly, the threefold axis passes through the center of the O3H3 hydrogen ring.

Fig. 2
figure 2

The hydrogen bond (dashed lines) forming a one-dimensional chain structure of complex 1, viewed along the b axis. The H atoms not related to hydrogen bonds are omitted for clarity.

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Fig. 3
figure 3

A perspective view of the molecular structure of complex 2 with the atom labeling scheme. Thermal ellipsoids are drawn at the 30% probability level. Atoms labelled with the suffix A are at the symmetry position #2 1–x, 1–y, 1–z.

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Fig. 4
figure 4

A perspective view of the molecular structure of complex 3 with the atom labeling scheme. Thermal ellipsoids are drawn at the 30% probability level. Atoms labeled with the suffix A are at the symmetry position #3 2/3–x, 1/3–y, 4/3–z.

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IR and electronic spectra of the complexes. The medium and broad absorption centered at 3443 cm–1 in the spectrum of complex 3 substantiates the presence of O–H groups. The strong absorption bands at about 1627 cm–1 for the three complexes are assigned to the azomethine groups, ν(C=N) [39, 40]. Several weak bands corresponding to aromatic and aliphatic C–H stretchings are in the range 2815-3010 cm–1. The Ar–O stretching bands are in the range 1260-1270 cm–1 [41]. The weak bands at 585-455 cm–1 can be assigned to ν(M–O) [42].

In the electronic spectra of the complexes, the bands observed at 260-280 nm are assigned to intraligand π–π* transitions. The charge transfer bands are observed at about 370 nm [43, 44].

Fig. 5
figure 5

The hydrogen bond (dashed lines) forming a one-dimensional chain structure of complex 2 viewed along the b axis. The H atoms not related to hydrogen bonds are omitted for clarity.

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Fig. 6
figure 6

The hydrogen bond (dashed lines) forming a one-dimensional chain structure of complex 3 viewed along the b axis. The H atoms not related to hydrogen bonds are omitted for clarity.

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Table 3 Antibacterial Activities of the Compounds as MIC Values (μg/mL)
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Antibacterial activity. The antibacterial microbial activities of the complexes against the E. coli, P. aeruginosa, S. typhi and S. aureus organisms are listed in Table 3. The complex has better activities against E. coli, P. aeruginosa and S. typhi than penicillin. Complex 1 exhibits a better activity against S. aureus than penicillin. However, complexes 2 and 3 are less active against S. aureus than penicillin. Complexes 1 and 2 are more active against E. coli than complex 3. Complex 1 is more active against P. aeruginosa, S. typhi, and S. aureus than complexes 2 and 3. A detailed comparison between the structures of the complexes and their antibacterial activities indicates that the terminal groups of Schiff bases are a factor for the antibacterial process. Cyclopropyl is a preferred group for the exploration of new antibacterial materials.

CONCLUSIONS

A dinuclear copper(II) complex and two mononuclear copper(II) complexes derived from similar fluoro-containing Schiff bases were synthesized. Single crystal structures of the complexes indicate that the Schiff base ligands coordinate through the phenolate O and imino N atoms. The Cu atom in the dinuclear complex is in the square pyramidal coordination, and those in the mononuclear complexes have the square planar geometry. The complexes exhibit effective antibacterial activities against P. aeruginosa, S. typhi, and S. aureus.

ADDITIONAL INFORMATION

Crystallographic data for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication No. CCDC – 1445982 (1), 2007028 (2), and 2007029 (3). Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).