Abstract
Six Schiff base compounds have been prepared from the condensation of o-vanillin, 2,3-dihydroxybenzaldehyde and 2,3,4-trihydroxybenzaldehyde with 4-aminosalicylic acid and 5-aminosalicylic acid (5-ASA). Addition of these Schiff bases to [Pd(OAc)2] afforded the corresponding bis(salicylaldiminato)palladium(II) complexes in moderate to excellent yields. All new palladium complexes have been characterized fully using standard spectroscopic methods, elemental analyses and a single-crystal X-ray diffraction study in the case of 2e, the palladium complex containing Schiff base ligands derived from 5-ASA and 2,3-dihydroxybenzaldehyde. All derivatives of 5-ASA were examined for potential antimicrobial activities against two species of fungi, Aspergillus niger and Saccharomyces cerevisiae, as well as two species of bacteria, Bacillus cereus (Gram-positive) and Pseudomonas aeruginosa (Gram-negative).
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Introduction
Although metals and their coordination complexes have been recognized for their therapeutic properties for many years, it was not until the serendipitous discovery that cis-diamminedichloroplatinum(II) (cisplatin, or cis-DDP; Fig. 1) inhibited cellular division in Escherichia coli that research into designing new metal complexes truly emerged as an important area of bioinorganic and pharmaceutical chemistry [1–5]. Unfortunately, cisplatin, although effective for treating various cancers, has limited efficacy due to numerous side effects arising from the compound’s poor solubility in physiological media and for its lack of selectivity for cancerous cells. To overcome these problems associated with cisplatin, a significant amount of research over the past few decades has focused on generating and testing second and third generation platinum-based drugs based upon altering the nature of the ligands bound to the metal center. Notable examples include carboplatin and cis-[PtCl2(1,4-DACH)] (DACH = diaminocyclohexane) (Fig. 1). Unfortunately, significant advances in platinum-based chemotherapy have yet to be realized and, as such, there has also been a considerable amount of effort directed toward examining the bioactivities of other metal complexes for various diseases and ailments [1].
Cisplatin, carboplatin, and cis-[PtCl2(1,4-DACH)]
Although once overlooked for their bioactivity, complexes of palladium have emerged in recent years as promising antimicrobial and anticancer candidates [6–25]. The readers are encouraged to read an excellent review by Hadjiliadis [19] summarizing the field of bioactive palladium complexes. As part of our study aimed at generating palladium compounds for their antimicrobial properties, we have recently focussed on the synthesis and testing of palladium(II) complexes containing Schiff base ligands. Schiff bases are easily prepared from any number of salicylaldehyde derivatives with simple primary amines. Variation of both the starting salicylaldehyde and the primary amine provides a synthetic strategy that readily allows for fine-tuning of the physicochemical properties of the Schiff base ligand and hence the corresponding metal complex. In a previous report, we have disclosed our initial findings on designing two palladium Schiff base complexes derived from 5-ASA (5-aminosalicylic acid; Fig. 2) [26]. 5-ASA has traditionally been used in the treatment of inflammatory bowel disease, ulcerated colitis and Crohn’s disease [27]. The isomeric analogue 4-ASA also has significant bioactivities and has been used in the treatment of tuberculosis [28, 29]. In this study, we have expanded our initial work and prepared a number of hydrophilic Schiff base derivatives containing both 4- and 5-ASA appendages, along with their corresponding palladium(II) complexes, and investigated their preliminary antimicrobial activities.
4-ASA and 5-ASA
Experimental section
Materials and methods
Reagents and solvents used were obtained from Aldrich Chemicals. Compounds 1b [30], 1c [30], and 1d [31] have been previously reported, and additional data are presented below. NMR spectra were recorded on a JEOL JNM-GSX400 FT NMR spectrometer (1H: 400 MHz and 13C: 100 MHz). Chemical shifts (δ) are reported in ppm (relative to residual solvent peaks). Multiplicities are reported as singlet (s), doublet (d), triplet (t), multiplet (m), broad (br), and overlapping (ov) with coupling constants (J) reported in Hz. FT-IR spectra were obtained with a Thermo Fisher Scientific Nicolet iS5 FT-IR spectrometer in ATR mode and are reported in cm−1. Decomposition and melting points were measured uncorrected with a Stuart SMP30 apparatus. Elemental analyses for carbon, hydrogen, and nitrogen were carried out at Guelph Chemical Laboratories (Guelph, Ontario).
General procedure for ligand synthesis
To a stirred colorless MeOH (25 mL) solution of the appropriate aminosalicylic acid (1.00 g, 6.53 mmol) was added a pale brown MeOH (25 mL) solution of the desired amine (6.53 mmol). The reaction mixture was heated at reflux for 1 h, and upon cooling to room temperature, the resulting precipitate was collected by suction filtration and washed with cold MeOH (3 × 10 mL) to afford the desired Schiff base. All ligands were spectroscopically pure and used as obtained for the synthesis of the corresponding palladium complexes.
(E)-2-Hydroxy-4-((2-hydroxy-3-methoxybenzylidene)amino)benzoic acid (1a) Bright orange solid. Yield: 1.76 g (94%); m.p.: 169 °C. IR: 3444 (br, νOH), 2842 (w), 1663 (m), 1601 (s, νC=N), 1451 (m), 1353 (m), 1253 (m), 1219 (s), 1153 (m), 1095 (w), 965 (m), 793 (s), 738 (s). Compound 1a decomposes rapidly in solution negating the possibility of obtaining solution NMR data.
(E)-4-((2,3-dihydroxybenzylidene)amino)-2-hydroxybenzoic acid (1b) Burgundy solid. Yield: 1.64 g (92%); m.p.: 156–157 °C. Compound 1b decomposes rapidly in solution negating the possibility of obtaining solution NMR data.
(E)-2-hydroxy-4-((2,3,4-trihydroxybenzylidene)amino benzoic acid (1c) Orange solid. Yield: 1.78 g (94%); m.p.: 178–179 °C. Compound 1c decomposes rapidly in solution negating the possibility of obtaining solution NMR data.
(E)-2-hydroxy-5-((2-hydroxy-3-methoxybenzylidene)amino)benzoic acid (1d) Orange solid. Yield: 1.69 g (90%); m.p.: 218–220 °C. 1H NMR (DMSO-d6) δ: 13.16 (v br s, 1H, CO2 H), 12.31 (br s, 1H, OH), 8.93 (s, 1H, CH=N), 7.79 (d, J = 2.3 Hz, 1H, Ar), 7.63 (dd, J = 8.4, 2.3 Hz, 1H, Ar), 7.19 (dd, J = 7.6, 1.5 Hz, 1H, Ar), 7.06 (d, J = 8.4 Hz, 1H, Ar), 7.01 (d, J = 8.4 Hz, 1H, Ar), 6.86 (ov dd, J = 8.4, 7.6 Hz, 1H, Ar), 3.77 (s, 3H, OCH 3). 13C{1H} NMR (DMSO-d6) δ: 172.1, 162.6, 160.7, 150.8, 148.3, 139.7, 129.3, 124.3, 123.1, 119.7, 119.1, 118.7, 115.7, 114.1, 56.3. IR: 3053 (br), 2834 (w), 1653 (m), 1617 (m, νC=N), 1495 (m), 1354 (m), 1221 (s), 999 (m), 911 (m), 838 (m), 730 (s).
(E)-5-((2,3-Dihydroxybenzylidene)amino)-2-hydroxybenzoic acid (1e) Orange solid. Yield: 1.62 g (91%); decomposes above 250 °C. 1H NMR (DMSO-d6) δ: 13.09 (v br s, 1H, CO2 H), 9.16 (br s, 1H, OH), 8.90 (s, 1H, CH=N), 7.78 (d, J = 2.3 Hz, 1H, Ar), 7.63 (dd, J = 8.4, 2.3 Hz, 1H, Ar), 7.06 (dd, J = 7.6, 1.5 Hz, 1H, Ar), 7.02 (d, J = 8.4 Hz, 1H, Ar), 6.89 (dd, J = 7.6, 1.5 Hz, 1H, Ar), 6.74 (app t, J = 7.6 Hz, 1H, Ar). 13C{1H} NMR (DMSO-d6) δ: 172.1, 163.1, 160.6, 149.5, 146.1, 139.8, 129.4, 123.2, 123.0, 120.0, 119.3 (2C), 118.7, 114.0. IR: 3324 (br, νOH), 3062 (w), 1659 (w), 1622 (m, νC=N), 1493 (m), 1355 (m), 1271 (w), 1209 (s), 1005 (w), 846 (w), 732 (m).
(E)-2-Hydroxy-5-((2,3,4-trihydroxybenzylidene)amino)benzoic acid (1f) Yellow solid. Yield: 1.62 g (86%); decomposes above 250 °C. 1H NMR (DMSO-d6) δ: 12.98 (v br s, 1H, CO2 H), 9.70 (br s, 1H, OH), 8.75 (s, 1H, CH=N), 8.47 (br s, 1H, OH), 7.72 (d, J = 3.1 Hz, 1H, Ar), 7.56 (dd, J = 8.4, 3.1 Hz, 1H, Ar), 6.98 (d, J = 8.4 Hz, 1H, Ar), 6.92 (d, J = 8.4 Hz, 1H, Ar), 6.38 (d, J = 8.4 Hz, 1H, Ar). 13C{1H} NMR (DMSO-d6) δ: 172.1, 162.5, 160.1, 151.4, 150.7, 139.8, 132.8, 129.0, 124.5, 122.5, 118.6, 114.1, 112.9, 108.2. IR: 3437 (br, νOH), 3083 (w), 1606 (m, νC=N), 1494 (m), 1439 (w), 1216 (s), 1150 (s), 981 (w), 772 (w), 700 (m).
Synthesis of metal complexes
Synthesis of 2a To a stirred EtOH (20 mL) suspension of 1a (525 mg, 1.83 mmol) was added Pd(OAc)2 (200 mg, 0.89 mmol) as a solid. The reaction mixture was gently heated at 60 °C for 2 h at which point an orange solid was collected by suction filtration. The solid was washed with EtOH (2 × 10 mL) and hexane (20 mL) to afford 2a as a pale orange solid. Yield: 523 mg (86%); decomposes at 225 °C. 1H NMR (DMSO-d6) δ: 13.87 (v br s, 2H, CO2 H), 11.45 (v br s, 2H, OH), 8.00 (s, 2H, CH=N), 7.75 (d, J = 8.4 Hz, 2H, Ar), 6.98 (d, J = 7.6 Hz, 2H, Ar), 6.88–6.85 (ov m, 4H, Ar), 6.64 (d, J = 6.9 Hz, 2H, Ar), 6.38 (ov dd, J = 8.4, 7.6 Hz, 2H, Ar), 3.24 (s, 6H, OCH 3). 13C{1H} NMR (DMSO-d6) δ: 172.4, 163.8, 161.8, 155.7, 155.5, 150.5, 130.6, 126.7, 119.7, 116.8, 115.2, 114.5, 113.7, 111.3, 55.1. IR: 3533 (br, νOH), 3436 (br, νOH), 2942 (w), 1660 (m), 1594 (m, νC=N), 1427 (s), 1353 (m), 1295 (m), 1210 (s), 1145 (m), 986 (w), 864 (m), 780 (m), 734 (s). Anal. calcd. for C30H24N2O10Pd (678.94) (%): C 53.07, H 3.56, N 4.13; found: C 52.79, H 3.42, N 4.43.
Synthesis of 2b To a stirred THF (30 mL) solution of Pd(OAc)2 (250 mg, 1.11 mmol) was added 1b (609 mg, 2.23 mmol) as a solid. The reaction was gently heated at 60 °C for 2 h at which point an orange solid was collected by suction filtration. The solid was washed with EtOH (2 × 10 mL), THF (2 × 5 mL) and hexane (20 mL) to afford 2b as an orange solid. Yield: 613 mg (86%); decomposes at 320 °C. 1H NMR (DMSO-d6) δ: 14.11 (v br s, 2H, CO2 H), 11.55 (v br s, 2H, OH), 8.13 (s, 2H, CH=N), 7.85 (d, J = 8.4 Hz, 2H, Ar), 7.06 (d, J = 1.5 Hz, 2H, Ar), 7.01 (dd, J = 8.7, 2.3 Hz, 2H, Ar), 6.97 (dd, J = 8.2, 1.5 Hz, 2H, Ar), 6.70 (dd, J = 7.8, 2.3 Hz, 2H, Ar), 6.43 (app t, J = 7.8 Hz, 2H, Ar), 5.03 (s, 2H, OH). 13C{1H} NMR (DMSO-d6) δ: 171.7, 164.4, 161.9, 155.0, 151.9, 146.5, 130.9, 125.6, 118.8, 116.4, 116.3, 115.9, 113.3, 112.0. IR: 3409 (br, νOH), 3075 (w), 2980 (w), 2875 (w), 1662 (m), 1597 (m, νC=N), 1547 (m), 1450 (s), 1320 (m), 1232 (s), 1198 (s), 1148 (s), 1043 (m), 985 (m), 772 (m), 781 (m), 738 (s), 700 (m). Anal. calcd. for C28H20N2O10Pd (650.89) (%): C 51.67, H 3.10, N 4.30; found: C 51.54, H 3.28, N 4.19.
Synthesis of 2c To a stirred EtOH (20 mL) suspension of 1c (258 mg, 0.89 mmol) was added Pd(OAc)2 (100 mg, 0.45 mmol) as a solid. The reaction mixture was gently heated at 60 °C for 1 h at which point an orange–brown solid was collected by suction filtration. The solid was washed with EtOH (2 × 5 mL) and CH2Cl2 (20 mL) to afford 2c as an orange–brown solid. Yield: 150 mg (49%); m.p.: 290–292 °C. 1H NMR (DMSO-d6) δ: 13.97 (v br s, 2H, CO2 H), 11.57 (br s, 2H, OH), 9.67 (s, 2H, OH), 7.87 (s, 2H, CH=N), 7.84 (d, J = 8.4 Hz, 2H, Ar), 7.01–6.97 (ov m, 4H, Ar), 6.84 (d, J = 8.4 Hz, 2H, Ar), 6.12 (d, J = 8.4 Hz, 2H, Ar), 4.48 (s, 2H, OH). 13C{1H} NMR (DMSO-d6) δ: 172.1, 163.1, 162.2, 155.9, 152.9, 148.9, 132.9, 131.0, 126.6, 117.0, 113.6, 113.1, 111.8, 108.3. IR: 3366 (br, νOH), 3102 (br, νOH), 1672 (m), 1594 (m, νC=N), 1553 (s), 1495 (m), 1455 (m), 1408 (m), 1280 (m), 1215 (s), 1098 (s), 971 (m), 767 (m), 696 (m). Anal. calcd. for C28H20N2O12Pd.CH2Cl2 (767.91) (%): C 45.36, H 2.89, N 3.65; found: C 45.33, H 2.36, N 3.75.
Synthesis of 2d To a stirred EtOH (20 mL) suspension of 1d (525 mg, 1.83 mmol) was added Pd(OAc)2 (200 mg, 0.89 mmol) as a solid. The reaction mixture was gently heated at 60 °C for 2 h at which point an orange solid was collected by suction filtration. The solid was washed with EtOH (2 × 10 mL) and hexane (2 × 10 mL) to afford 2d as an orange solid. Yield: 580 mg (96%); m.p.: 290–291 °C. 1H NMR (DMSO-d6) δ: 13.88 (v br s, 2H, CO2 H), 11.35 (v br s, 2H, OH), 8.02 (s, 2H, CH=N), 7.63 (d, J = 2.3 Hz, 2H, Ar), 7.45 (dd, J = 8.4, 2.3 Hz, 2H, Ar), 6.97 (d, J = 6.9 Hz, 2H, Ar), 6.92 (d, J = 8.4 Hz, 2H, Ar), 6.63 (d, J = 6.9 Hz, 2H, Ar), 6.38 (app t, J = 7.6 Hz, 2H, Ar), 3.27 (s, 6H, OCH 3). 13C{1H} NMR (DMSO-d6) δ: 172.5, 164.4, 160.1, 155.7, 150.9, 141.1, 132.8, 126.7, 126.5, 119.9, 117.2, 115.0, 114.5, 112.7, 55.3. IR: 3043 (br, νOH), 2946 (w), 1664 (m), 1599 (m, νC=N), 1424 (s), 1287 (m), 1248 (s), 1207 (s), 1078 (m), 990 (m), 734 (s). Anal. calcd. for C30H24N2O10Pd (678.94) (%): C 53.07, H 3.56, N 4.13; found: C 52.92, H 3.38, N 4.39.
Synthesis of 2e To a stirred EtOH (20 mL) suspension of 1e (500 mg, 1.83 mmol) was added Pd(OAc)2 (200 mg, 0.89 mmol) as a solid. The reaction mixture was gently heated at 60 °C for 2 h at which point an orange solid was collected by suction filtration. The solid was washed with EtOH (2 × 10 mL) and Et2O (2 × 10 mL) to afford 2e as an orange solid. Yield: 551 mg (95%); m.p.: 260–262 °C. 1H NMR (DMSO-d6) δ: 14.10 (v br s, 2H, CO2 H), 11.43 (v br s, 2H, OH), 8.12 (s, 2H, CH=N), 7.76 (d, J = 2.3 Hz, 2H, Ar), 7.61 (dd, J = 8.4, 2.3 Hz, 2H, Ar), 7.04 (d, J = 8.4 Hz, 2H, Ar), 6.95 (d, J = 7.6 Hz, 2H, Ar), 6.68 (d, J = 6.9 Hz, 2H, Ar), 6.41 (app t, J = 7.6 Hz, 2H, Ar), 5.03 (s, 2H, OH). 13C{1H} NMR (DMSO-d6) δ: 171.7, 165.1, 160.2, 152.0, 146.9, 140.5, 132.5, 125.7 (2C), 119.1, 117.7, 116.3, 115.9, 113.3. IR: 3418 (br, νOH), 3098 (w), 1694 (m), 1597 (m, νC=N), 1552 (m), 1458 (s), 1425 (m), 1316 (s), 1206 (m), 1182 (s), 827 (m), 725 (s), 679 (m). Anal. calcd. for C28H20N2O10Pd (650.89) (%): C 51.67, H 3.10, N 4.30; found: C 51.88, H 3.13, N 4.58.
Synthesis of 2f To a stirred EtOH (20 mL) suspension of 1f (528 mg, 1.83 mmol) was added Pd(OAc)2 (200 mg, 0.89 mmol) as a solid. The reaction mixture was gently heated at 60 °C for 1 h at which point an orange–brown solid was collected by suction filtration. The solid was washed with EtOH (2 × 10 mL) and Et2O (20 mL) to afford 2f as an orange–brown solid. Yield: 500 mg (82%); m.p.: 277–279 °C. 1H NMR (DMSO-d6) δ: 13.69 (v br s, 2H, CO2 H), 11.43 (br s, 2H, OH), 9.57 (s, 2H, OH), 7.88 (s, 2H, CH=N), 7.72 (s, 2H, Ar), 7.58 (d, J = 7.6 Hz, 2H, Ar), 7.01 (d, J = 8.4 Hz, 2H, Ar), 6.82 (d, J = 9.2 Hz, 2H, Ar), 6.11 (d, J = 9.2 Hz, 2H, Ar), 4.44 (s, 2H, OH). 13C{1H} NMR (DMSO-d6) δ: 171.8, 163.6, 159.9, 152.8, 148.6, 141.0, 133.1, 132.8, 126.3, 125.8, 117.7, 113.3, 113.1, 108.3. IR: 3477 (br, νOH), 3441 (br, νOH), 1663 (m), 1599 (m, νC=N), 1560 (s), 1444 (m), 1188 (s), 1090 (w), 834 (m), 767 (m), 683 (m). Anal. calcd. for C28H20N2O12Pd (682.88) (%): C 49.25, H 2.95, N 4.10; found: C 49.63, H 3.11, N 4.06.
Stability of ligands and palladium complexes in dimethyl sulfoxide
Solutions of ligands 1a–f and palladium complexes 2a–f in wet DMSO-d6 were monitored by 1H NMR spectroscopy over a period of 2 days at RT. Compounds 1a–c and 2a–c were found to decompose over this time period; therefore, they were not included in the bioactivity studies. While 1a–c reacted reversibly with wet DMSO-d6 to generate the starting aldehyde and amines, complexes 2a–c decomposed to give a number of unidentified products.
X-ray crystallography
Crystals of 2e were grown from a saturated solution of dimethyl sulfoxide stored at RT. Crystals were attached to the tip of a 400 μm MicroLoop with paratone-N oil. Measurements were made on a Bruker APEXII CCD equipped diffractometer (30 mA, 50 mV) using monochromated Mo–Kα radiation (λ = 0.71073 Å) at 125 K. The initial orientation and unit cell were indexed using a least-squares analysis of a random set of reflections collected from three series of 0.5° wide scans, 10 s per frame and 12 frames per series that were well distributed in reciprocal space. For data collection, four ω-scan frame series were collected with 0.5° wide scans, 60 s frames and 366 frames per series at varying φ angles (φ = 0°, 90°, 180°, 270°). The crystal to detector distance was set to 6 cm and a sphere of data was collected. Cell refinement and data reduction were performed with the Bruker SAINT software, which corrects for beam inhomogeneity, possible crystal decay, Lorentz and polarization effects. Data processing and a multiscan absorption correction were applied using the APEX2 software package [32]. The structure was solved using direct methods [33], and all non-hydrogen atoms were refined anisotropically using ShelXle [34] graphical user interface and SHELXL [35]. Hydrogen atoms were included at geometrically idealized positions and were fixed (Ar–H, CH) or in the case of methyl groups, the dihedral angle of the idealized tetrahedral CH3 fragment was allowed to refine. In the case of O–H bonding environments, hydrogen atoms were allowed to freely refine.
Cultures
Pure cultures of Aspergillus niger, Saccharomyces cerevisiae, Bacillus cereus, and Pseudomonas aeruginosa were revived from strains maintained at −70 °C. A. niger was maintained on Sabouraud dextrose agar, S. cerevisiae was maintained on yeast malt agar, and B. cereus and P. aeruginosa were maintained on tryptic soy agar.
Inoculations
Using aseptic techniques, a small amount (1 cm2) of agar culture was removed from a plate via scalpel and placed into a sterile tissue homogenizer tube. Approximately 3–4 mL of doubly distilled H2O was then added followed by gentle homogenization. Homogenate (200 μL) was added to an agar plate (Sabouraud dextrose agar for fungi; Mueller–Hinton II agar for bacteria) and spread evenly to ensure uniform growth.
Compound testing
Disks (5 mm diameter) created from filter paper (Fisherbrand® Filter paper, diameter of 15.0 cm, porosity: coarse, flow rate: fast (09-795F)) were placed equidistantly on an inoculated agar plate (diameter 9 cm) at four points. Set concentrations of compound (0, 25, 50, and 100 μg for disks 1–4, respectively) in DMSO were added to the disks and the cultures were allowed to grow over 48 h at which point caliper measurements were obtained, measuring from the center of the disk to the nearest presence of fungus. Plates were done in triplicate and mean results calculated and reported. Control plates with a known antibiotic were performed with amphotericin B (Sigma A9528) at a concentration of 100 µg for the fungal species. Control plates for B. cereus were performed with erythromycin (BD BBL Sensi-Disc #230793) at 15 μg and for P. aeruginosa, streptomycin (BD BBL Sensi-Disc #230942) at 10 μg was used. Negative controls were disks provided with DMSO but without compound.
Results and discussion
Synthesis and characterization
o-Vanillin, or 2-hydroxy-3-methoxybenzaldehyde, is a natural product found in the extracts and oils of many plants. Although it only displays moderate antimicrobial properties, its use in Schiff base chemistry is well-documented [36]. We decided to use o-vanillin, along with the alcohol derivatives, 2,3-dihydroxybenzaldehyde and 2,3,4-trihydroxybenzaldehyde, in an attempt to increase the solubility of the resulting palladium complexes in aqueous media. Poor solubility in physiological media is a recurring problem associated with designing novel therapeutic metal complexes. Addition of the aminosalicylic acids 4-ASA and 5-ASA readily afforded the corresponding Schiff base compounds 1a–c and 1d–f, respectively (Fig. 3). Unfortunately, albeit stable in the solid state, compounds 1a–c decomposed rapidly in solution (DMSO) and thus negated the possibility of obtaining solution NMR data. It is not clear at this point why these compounds are unstable with respect to decomposition and attempts to get single crystals of these compounds for X-ray diffraction studies proved unsuccessful. For the more stable Schiff bases 1d–f, a peak for the aldehyde proton at 10 ppm disappeared upon formation of the imine and a new resonance was observed at around 9 ppm in the 1H NMR spectra. Likewise, a resonance at ca. 160 ppm in the 13C NMR spectra indicated the formation of the N=CH methine carbon. Generation of these Schiff base compounds was also confirmed by the diagnostic C=N stretching band in the IR spectra at ca. 1620 cm−1 [26].
Schiff base ligands 1a–f
We then decided to investigate the ligating properties of 1a–f and were pleased to observe that all reacted readily with Pd(OAc)2 in ethanol to give the corresponding bis(salicylaldiminato)palladium(II) species 2a–f (Scheme 1) in moderate to high yields. All new metal complexes have been characterized by a number of physical methods including multinuclear NMR spectroscopy, FT-IR spectroscopy and elemental analyses, and all data are consistent with a bis-Schiff base formulation. For instance, the C=N stretch in the FT-IR spectra shifted from ca. 1620 to ca. 1595 cm−1 upon coordination to palladium. Likewise, as typical for these species, a significant upfield shift in the 1H NMR spectra was observed for the imine methine proton, from ca. 9 to ca. 8 ppm. To unambiguously assign the solid-state structure of these complexes, we carried out a single-crystal X-ray diffraction study on the 5-ASA derivative 2e, the molecular structure of which is shown in Fig. 4. Crystallographic data are provided in Table 1 and selected bond distances and angles are shown in Table 2. Complex 2e crystallized in the P21/c space group along with two molecules of DMSO. The palladium atom lies on a center of inversion and the environment around the metal center is roughly square planar. The Pd–O and Pd–N distances of 1.9839(13) and 2.0178(16) Å, respectively, are similar to those observed in related complexes. For instance, the corresponding bis(salicylaldiminato)palladium(II) complex derived from 2-(3,4-dimethoxyphenyl)ethanamine and 2-hydroxybenzaldehyde has Pd–O and Pd–N distances of 1.984(11) and 2.020(12) Å, respectively [23]. Likewise, the C(1)–N(1) bond distance of 1.293(2) Å in 2e is typical for Schiff base ligands bound to a metal that retain the predominant imine form containing a formal C=N double bond.
Synthesis of palladium(II) complexes 2a–f
Molecular structure of 2e drawn with 50% probability ellipsoids showing atoms generated by symmetry. Hydrogen atoms and a molecule of solvent removed for clarity
Antimicrobial testing
As mentioned previously, there has been considerable recent interest in palladium Schiff base complexes for their potential antimicrobial activities. As part of our investigation into this area, we therefore decided to examine the initial antifungal and antibacterial activities of both the Schiff base ligands 1d–f and their corresponding palladium(II) complexes 2d–f against two species of fungi, Aspergillus niger and Saccharomyces cerevisiae, as well as two species of bacteria, Bacillus cereus (Gram-positive) and Pseudomonas aeruginosa (Gram-negative). Unfortunately, we were unable to examine the antimicrobial properties of the 4-ASA derivatives as they were not stable under the test conditions. The results from this study are provided in Table 3 and shown in Fig. 5 using known controls and Na2PdCl4 as a metal control. As expected, the simple palladium salt Na2PdCl4 displayed no appreciable activities. The most promising results were with Schiff base 1e and palladium complexes 2e and 2f, which showed considerable activity against Saccharomyces cerevisiae. Schiff bases 1d and 1e and palladium complex 2d displayed only moderate activities against Aspergillus niger. Although 1e and 2d displayed weak activities against the Gram-positive bacterium Bacillus cereus, no compound tested showed any activity against the Gram-negative bacterium Pseudomonas aeruginosa. Unfortunately, poor solubilities and stabilities preclude both the Schiff bases and the corresponding bis(salicylaldiminato)palladium(II) complexes from being potential candidates as practical antimicrobial agents.
Comparison of antimicrobial activity of ligands and palladium complexes (100 μg)
Conclusion
We have prepared six Schiff base compounds from the condensation of o-vanillin, 2,3-dihydroxybenzaldehyde and 2,3,4-trihydroxybenzaldehyde with 4-aminosalicylic acid (4-ASA) and 5-aminosalicylic acid (5-ASA). Although a significant amount of research has focussed on generating derivatives of 5-ASA, much less is known about the analogous chemistry of isomeric 4-ASA. Addition of the generated Schiff bases to [Pd(OAc)2] afforded the corresponding bis(salicylaldiminato)palladium(II) complexes in excellent yields. All new palladium complexes have been characterized fully using standard spectroscopic methods, elemental analyses, and a single-crystal X-ray diffraction study in the case of 2e, the palladium complex containing Schiff base ligands derived from 5-ASA and 2,3-dihydroxybenzaldehyde. All derivatives of 5-ASA were examined for potential antimicrobial activities against two species of fungi, Aspergillus niger and Saccharomyces cerevisiae, as well as two species of bacteria, Bacillus cereus (Gram-positive) and Pseudomonas aeruginosa (Gram-negative). Problems associated with stability and solubility with the 4-ASA derivatives negated biological testing of these species.
Supplemental material
Full supplemental crystallographic data in CIF format have been deposited with the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 UK (fax: + 44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk) and are available on request, quoting deposition number 1528913).
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Acknowledgements
Thanks are gratefully extended to Mount Allison University, Saint Mary’s University, and the Canada Research Chair Program (S.A.W.) for financial support. We also thank Cuthumb Durant (Mount Allison University) for his expert technical assistance and anonymous reviewers thanked for their helpful comments.
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Klaus, J.A., Brooks, T.M., Zhou, M. et al. Synthesis, characterization, and antimicrobial activities of palladium Schiff base complexes derived from aminosalicylic acids. Transit Met Chem 42, 263–271 (2017). https://doi.org/10.1007/s11243-017-0130-3
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DOI: https://doi.org/10.1007/s11243-017-0130-3