Synthesis, structural characterization, and antibacterial activity of tricyclohexyltin aryloxyacetates

Synthesis

The reaction of tricyclohexyltin hydroxide with phenoxyacetic acid or p-substituted phenoxyacetic acid in a 1:1 molar ratio in anhydrous benzene afforded products 1–3, with a yield of 65–81% (Scheme 2).

Scheme 2:

Synthesis of compounds 1–3.

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

Spectroscopic analysis

In the IR spectra of compounds 1–3, the bands at ~3450 and ~1760 cm^-1 assigned to ν (O-H) and ν (C=O), respectively, of free aryloxyacetic acid do not appear, and new strong bands at ~1660 and ~1350 cm^-1 are assigned to the asymmetrical, ν_as(CO₂^-), and symmetrical stretching vibrations, ν_s(CO₂^-), of the aryloxyacetate, respectively. The difference between the ν_as(CO₂^-) and the ν_s(CO₂^-) bands, Δν(CO₂^-), is 313 cm^-1 for 1, 272 cm^-1 for 2, and 331 cm^-1 for 3, which is larger than 200 cm^-1, suggesting that the carboxylate group is coordinated to tin in the monodentate mode in the solid state (Deacon and Phillips, 1980; Li et al., 2010).

In ¹H NMR spectra of 1–3, the single resonances of COOH in the spectra of the free ligands are not observed at ~12 ppm, which further confirms the replacement of the carboxylic acid protons by the tricyclohexyltin moiety on complex formation. The complexes show multiplets in the range of 1.17–1.97 ppm due to the cyclohexyl protons and singlets at 4.43–4.71 ppm assigned to the OCH₂ protons. The resonances in the range between 6.76 and 7.82 ppm are assigned to the aryl protons.

The ¹³C chemical shifts of the carboxyl and methylene carbon atoms in 1–3 appear at 172.21–173.36 and 65.56–66.41 ppm, respectively. The signals of the cyclohexyl carbon atoms are in the range of 26.97–36.49 ppm, and the ¹J(¹¹⁹Sn-¹³C), ²J(¹¹⁹Sn-¹³C), and ³J(¹¹⁹Sn-¹³C) coupling constants are ~330, 20, and 60 Hz, respectively. The coordination number of the tin atom in the organotin compounds has been related to the ¹J(¹¹⁹Sn-¹³C) coupling constants (Nadvornik et al., 1984). The ¹J(¹¹⁹Sn-¹³C) coupling of the compounds is close to that of other four-coordinate tricyclohexyltin carboxylates, such as 2-HOC₆H₄N=NC₆H₄COOSn(C₆H₁₁-c)₃ (335 Hz) (Willem et al., 1998), C₄H₃SCOOSn(C₆H₁₁-c)₃ (333 Hz) (Abbas et al., 2013), (c-C₆H₁₁)₃SnO₂CCH₂CH₂COCH₂CH₂CO₂Sn(C₆H₁₁-c)₃ (325 Hz) (Chalupa et al., 2006), and (2-C₆H₅C₂HN₃)COOSn(C₆H₁₁-c)₃ (330 Hz) (Tian et al., 2015). Data suggest that the tin atom in these compounds is four-coordinated in CDCl₃ solution.

The ¹¹⁹Sn chemical shifts primarily depend on the coordination number and the nature of the donor atom directly bonded to the central tin atom (Davis, 2004). The ¹¹⁹Sn chemical shifts of 1–3 (30.0–33.0 ppm) are in accord with the values of the four-coordinated tricyclohexyltin carboxyl ester in the solution of the non-coordinating solvent (Tian et al., 2005, 2015; Chalupa et al., 2006).

Structure analysis of 1 and 3

The structures of complexes 1 and 3 are shown in Figures 1–3, and the selected geometric parameters are given in Table 1. Compound 1 crystallizes with two independent molecules in the crystallographic asymmetric unit that do not differ from each other significantly. The coordination geometry of the tin atom is a distorted tetrahedron shaped by three carbon atoms from the cyclohexyl groups and one carboxyl O atom [O(1) and O(4)] from the carboxylate ligand. The separation between the other O atom of the carboxylate ligand and Sn atom is Sn(1)···O(2) 3.017(4) Å and Sn(2)···O(5) 2.994(4) Å. The weak interaction distorts the tetrahedral geometry by opening up the C(1)-Sn(1)-C(13) and C(33)-Sn(2)-C(39) to 117.2(4)° and 121.1(3)°, respectively, and reducing the O(1)-Sn(1)-C(7) and O(5)-Sn(2)-C(27) to 94.0(2)° and 95.65(17)°, respectively. The monodentate mode of the carboxylate coordination is expressed in two disparate C-O bond distances (Table 1). The four bond distances 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), and ferrocene carboxylate (Dong et al., 2014).

Figure 1:

The molecular structure of 1.

Hydrogen atoms are omitted for clarity.

Figure 2:

The molecular structure of 3.

Hydrogen atoms are omitted for clarity.

Figure 3:

The 2D supramolecular network of 3 formed by the intermolecular O-H···O hydrogen bonds.

Compound 3 crystallizes in the monoclinic space group P2₁, and the crystal structure reveals that there are two crystallographically non-equivalent molecules in the crystallographic asymmetric unit. The tin atom Sn(1) of one molecule (A) is five-coordinated, and the tin atom Sn(2) of the other molecule (B) is four-coordinated. In A, the coordination geometry of the tin center displays a distorted trans-O₂SnC₃ trigonal bipyramid with three carbon atoms [C(1), C(7), and C(13)] of cyclohexyl groups defining the trigonal plane and a unidentate carboxylate O(2) and a O(1) atom from the water molecule occupying the axial positions. The C-Sn-C angles were in the range of 116.2(2)–123.0(3)°. The O(1)-Sn(1)-O(2) angle is 174.52(15)°, which is similar to that observed in related tricyclohexyltin analogues, such as 3-C₅H₄NCO₂Sn(C₆H₁₁-c)₃(H₂O) [176.11(11)°] (Teoh et al., 1999), (4-MeC₆H₄)₃GeCH(C₆H₄OMe-4)CH₂CO₂Sn(C₆H₁₁-c)₃(H₂O) [170.35(6)°] (Din et al., 2003), and 2-Cl-3-C₅H₄NCO₂Sn(C₆H₁₁-c)₃(H₂O) [176.40(11)°] (Yu et al., 2012). The bond length of Sn(1)-O(1) [2.432(4) Å] is significantly longer than that of Sn(1)-O(2) [2.175(4)Å], so that the Sn(1) atom is displaced out of the C₃ trigonal plane of the trans-C₃SnO₂ trigonal bipyramidal polyhedron in the direction of O(2) by 0.155(2) Å.

The structure of molecule B is similar to compound 1, and Sn(2) has also a distorted tetrahedral geometry with the angles range of 97.3(2)–116.9(3)°. As expected, the C-O bond distances [C(19)-O(3) 1.222(7) Å and C(46)-O(7) 1.221(7) Å] associated with the non-coordinating carbonyl O atoms are shorter than the coordinating C-O bond distances [C(19)-O(2) 1.287(7) Å and C(46)-O(6) 1.282(7) Å]. Although not involved in coordination to tin, the O(3) and O(7) atoms form significant intermolecular contacts in the crystal lattice. Through the coordinated water molecules and the hydroxyl groups of ligands, the monomeric structures (A and B) get into contact with each other via hydrogen bonds (Table 2), and a two-dimensional (2D) network containing R₃³(30) and R₅⁵(28) hydrogen bonding patterns is formed (Figure 3).

Antibacterial activity

The antibacterial activities of the compounds and the reference drug (penicillin sodium and cefazolin sodium) are listed in Table 3. Results show that complexes 1–3 is active against Escherichia coli, which is comparable with the reported tricyclohexyltin 2-phenyl-1,2,3-triazole-4-carboxylate (MIC=13.50 μg/mL) (Tian et al., 2005) and ferrocenecarboxylate (MIC=23.98 μg/mL) (Dong et al., 2014). The activity of the three compounds against E. coli decreased in the order 3>2>1 under experimental conditions. However, the activity is lower than that of the reference drugs.

General

All chemicals used in the syntheses were of analytical grade and were purchased from commercial sources (Sinopharm Chemical Reagent Company, 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). The IR spectra were recorded on a Nicolet Nexus 470 FT-IR spectrophotometer using KBr discs in the range of 4000–400 cm^-1 (Thermo Nicolet, Madison, WI, USA). ¹H and ¹³C NMR spectral data were collected using a Bruker Avance DPX300 NMR spectrometer (Bruker, Fallanden, Switzerland) with CD₃SOCD₃ or CDCl₃ as solvent and TMS as internal standard. ¹¹⁹Sn NMR spectra were recorded in CDCl₃ on a Varian Mercury Vx300 spectrometer. Me₄Sn was used as external reference (Varian, Palo Alto, USA).

Synthesis of ligands

Synthesis of the complexes

X-ray crystallography

The colorless single crystals of 1 and 3 were obtained from methanol by slow evaporation at room temperature. Diffractions measurements were performed on a Bruker Smart Apex imaging plate area detector fitted with graphite monochromatized Mo-Kα radiation (0.71073 Å) using the φ and ω scan technique at 295(2) K. 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 the 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, O-H=0.82 Å for hydroxy H atoms, and O-H=0.85(1) Å for water H atoms. In complex 1, two cyclohexyl groups are disordered over two positions, and their site occupancies were refined to 0.54(6):0.46(6) for C(13)-C(18) and 0.70(2):0.30(2) for C(39)-C(44). In complex 3, the site occupancies of the cyclohexyls were refined to 0.802(10):0.198(10) for C(7)-C(12) and 0.65(2):0.35(2) for C(40)-C(45), respectively. In refinements, the C-C bonds and 1,3-distances of the disorderly cyclohexyl groups were restrained to 1.52(1) and 2.50(2) Å, respectively. Crystal data, collection procedures, and refinement results are shown in Table 4. The crystallographic data of compounds 1 and 3 were deposited at the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 1014268 and 1043087.

Antibacterial activity

The antibacterial activity of compounds 1–3 against E. coli was determined by the microcalorimetric method according to the literature (Zhang et al., 2004). A 2277 Thermal Activity Monitor (Thermometric AB, Jarfalla, Sweden) was used to determine the power-time curves of bacterial growth at 310 K. After a stable baseline was obtained, the bacterial sample, a beef-extract-soluble medium (pH=7.2–7.4) containing NaCl (1 g), peptone (2 g), beef extract (1 g), and different concentrations of organotin medicine in each 200 mL were pumped into the flow cell system and the monitor began to record the power-time curves of continuous growth for bacteria. When the recording pen returned to the baseline, the process of bacterial growth was completed. 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 the concentration (C) of the organotin medicine was fitted using a computer (μ=aC+b). When the growth rate constant is 0, the minimum inhibitory concentration (MIC) was confirmed.