Synthesis, crystal structure, and antibacterial activity of tricyclohexyltin salicylates

Synthesis

Compounds 1–3 are prepared by the reaction of tricyclohexyltin hydroxide with salicylic acid in equal mole ratio in anhydrous toluene with the yield of 85%–91% (Scheme 1).

These compounds are white or yellow crystals, air stable, and soluble in common polar organic solvents such as methanol, chloroform, acetone, and N,N-dimethylformamide, but insoluble in water and saturated hydrocarbons such as n-hexane and petroleum ether.

Spectroscopic characterization

In the IR spectra of compounds 1–3, the ν(O-H) band of phenolic hydroxyl appears at ~3200 cm^-1, whereas the broad band of 3300–2600 cm^-1 assigned to ν(O-H) of COOH of free salicylic acid does not appear, which indicates the deprotonation of the carboxyl of salicylic acid on complexation with the tin atom (Deacon and Phillips, 1980; Tian et al., 2015a,b). The strong bands at ~1635 and ~1315 cm^-1 are assigned to the asymmetrical stretching vibration, ν_as(COO^-), and symmetrical stretching vibration, ν_s(COO^-), of the salicylate, respectively. The difference between the ν_as(COO^-) and ν_s(COO^-) bands, Δν(COO^-), is 326 cm^-1 for 1, 318 cm^-1 for 2, and 320 cm^-1 for 3, which is obviously larger than that observed in the sodium salt of free acid (227 cm^-1 for sodium salicylate, 249 cm^-1 for sodium 5-nitrosalicylate, and 240 cm^-1 for 3,5-dinitrosalicylate), indicating that the carboxylate group is coordinated to tin in monodentate mode in the solid state (Deacon and Phillips, 1980; Szorcsik et al., 2004; Li et al., 2010).

In the ¹H NMR spectra of 1–3, the single resonances of phenolic OH appear at ~12 ppm, and the resonances of COOH of the free ligands are not observed at ~15 ppm, which further confirms the replacement of the carboxylic acid protons by the tricyclohexyltin moiety on complex formation (Tian et al., 2015a,b; Zhang et al., 2015). Complexes 1–3 show the multiplets in the range of 1.25–2.09 ppm due to the cyclohexyl protons. The proton resonances of the benzene ring of 1–3 appear in the range of 6.86–9.02 ppm.

Crystal structure of 1–3

The structures of complexes 1–3 are shown in Figures 1–3, and the selected geometric parameters are given in Table 1. Compound 1 crystallizes in the monoclinic space group P2₁/c. The tin atom is four-coordinated, and the coordination geometry is a distorted tetrahedron shaped by three carbon atoms of cyclohexyl groups and one carboxyl O(1) from the carboxylate ligand. The bond angles around the tin atom are in the range of 94.74(7)°–117.80(8)°. The separation between the carbonyl O(2) atom of the carboxylate ligand and the Sn atom is Sn(1)···O(2) 2.971(4) Å. This distance is shorter than the sum of the Van der Waals radii of tin and oxygen (3.73 Å) and much longer than the sum of the covalent radii of tin and oxygen (2.14 Å) (Hu et al., 2003). Distortions from the ideal geometry may be rationalized partly by the weak Sn(1)···O(2) interaction. The monodentate mode of coordination of carboxylate is also reflected in two disparate C-O bond lengths (C(19)-O(1) 1.293(3) Å, C(19)-O(2) 1.235(3) Å) of the carboxylate ligand (Table 1). The four bond lengths around Sn are similar to those found in other reported tricyclohexyltin carboxylates, such as tricyclohexyltin indole-3-acetate (Molloy et al., 1986), 2-(4-chlorophenyl)-3-methylbutyrate (Song et al., 2003), ferrocenecarboxylate (Dong et al., 2014), and phenoxyacetate (Zhang et al., 2015).

Figure 1:

The molecular structure of 1.

Hydrogen atoms are omitted for clarity.

Figure 2:

The molecular structure of 2.

Hydrogen atoms are omitted for clarity.

Figure 3:

The molecular structure of 3.

Hydrogen atoms are omitted for clarity.

Compounds 2 and 3 crystallize in the monoclinic space group C2/c and P2₁/n, respectively. The structures of 2 and 3 are similar to compound 1, and the tin atom also has a distorted tetrahedral geometry with the angles in the range of 94.66(14)°–125.61(17)° for 2 and 90.80(12)°–122.40(17)° for 3, respectively. In 2 and 3, there is a long Sn(1)···O(4)ⁱ contact (3.090(4) Å for 2 and 3.039(4) Å for 3) (symmetry operation i=1.5-x, 0.5+y, 0.5-z for 2 and 1.5-x, -0.5+y, 1.5-z for 3) between the tin atom and the O(4) atom of nitro (N(1)O(4)O(5)) from an adjacent molecule. Through the intermolecular interaction molecules are connected to each other into a one-dimensional supramolecular chain (Figures 4 and 5). The atom O(4)ⁱ exerts a steric influence on the atom Sn(1) from the opposite side of the atom O(1), and thus contributes to the distortion of the tetrahedral geometry around the Sn atom, by opening up the C-Sn(1)-C angles (111.52(15)°–125.61(17)° for 2 and 112.47(19)°-122.40(17)° for 3) and contracting the O(1)-Sn(1)-C angles (94.66(14)°–101.60(15)° for 2 and 90.80(12)°–102.66(16)° for 3). The hydroxy group (O(3)H) in each molecule of compounds 1–3 forms an intramolecular hydrogen bond with the carboxylate carbonyl oxygen atom (O(2)) of the same ligand (Table 2), and the O(2)-C(19)-C(20)-C(21)-O(3) in each molecule is essentially planar.

Figure 4:

The zigzag chain of 2 formed by the intermolecular Sn···O interaction.

Figure 5:

The zigzag chain of 3 formed by the intermolecular Sn···O interaction.

Antibacterial activity

The antibacterial activity of compounds 1–3, tricyclohexyltin hydroxide, the free acids and the reference drugs, penicillin sodium (sodium (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate) and cefazolin sodium (sodium (6R,7R)-7-amino-8-oxo-3-[[(1H-1,2,3-triazol-4-yl)-sulphanyl]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate), is listed in Table 3. The results showed that compounds 1–3 against Escherichia coli are active, and the activity is better than that of the substrate (Cy₃SnOH), the ligand (free acid), and penicillin sodium, but is weaker than that of cefazolin sodium. Compared with the reported tricyclohexyltin carboxylates such as 2-phenyl-1,2,3-triazole-4-carboxylate [minimum inhibitory concentration (MIC)=13.50 μg mL^-1] (Tian et al., 2005), ferrocenecarboxylate (MIC=23.98 μg mL^-1) (Dong et al., 2014), and phenoxyacetate (MIC=25.22 μg mL^-1) (Zhang et al., 2015), these salicylates are more active. The activity of the three compounds decreased in the order 3>2>1 under experimental conditions. Thus, the carboxylate ligand of trioganotin carboxylates appears to play an important role in determining their antibacterial activity, and further structure modification of organotin compounds by selecting a suitable carboxylate ligand is valuable for enhancing activity.

General

All chemicals used in the syntheses were of analytical grade and purchased from commercial sources (Sinopharm Chemical Reagent Company Limited, Shanghai, China) and used as received. Carbon and hydrogen analyses were determined using a Perkin Elmer 2400 Series II elemental analyzer (Perkin Elmer, Waltham, MA, USA). IR spectra were recorded on a Nicolet Nexus 470 FT-IR spectrophotometer using KBr disks in the range of 4000–400 cm^-1 (Thermo Nicolet Corporation, Madison, WI, USA). ¹H NMR spectral data were collected using a Bruker Avance DPX300 NMR spectrometer (Bruker Corporation, Switzerland) with CDCl₃ as solvent and tetramethylsilane as internal standard.

Synthesis of the complexes

X-ray crystallography

The colorless single crystals of 1–3 were obtained from methanol by slow evaporation at room temperature. Diffraction measurements were performed on a Bruker Smart Apex imaging-plate area detector fitted with graphite monochromatized MoK_α radiation (0.71073 Å) using the φ and ω scan technique at 295(2) K. Empirical corrections for absorption effects were made using the SADABS program (Sheldrick, 1996). The structures were solved by direct methods and refined by a full-matrix least-squares procedure based on F² using SHELXL-97 (Sheldrick, 2008). The non-hydrogen atoms were refined anisotropically and hydrogen atoms were placed at calculated positions in the riding model approximation, with C-H=0.93 Å for aromatic and formyl H atoms, C-H=0.97 Å for methylene H atoms, C-H=0.98 Å for methine H atoms, and O-H=0.82 Å for hydroxy H atoms. Crystal data, collection procedures, and refinement results are shown in Table 4. The crystallographic data of compounds 1–3 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 1471305, 1471306, and 1471307.

Antibacterial activity

The antibacterial activity of compounds 1–3 against Escherichia coli was determined by a microcalorimetric method according to the literature (Zhang et al., 2004, 2015). A 2277 Thermal Activity Monitor (Thermometric AB, Sweden) was used to determine the power-time curves of bacterial growth at 310 K. Based on the data of power-time curves and theoretical model, the growth rate constants were calculated (Zhang et al., 2004). The relationship between the growth rate constants (μ) and concentration (C) of organotin medicine was fitted by using a computer (see the μ-C curves in Figures S-1–S-7 in the online supplementary material). When the growth rate constant was 0, the MIC was confirmed.