Palladium(II) Schiff base complexes derived from ... - Springer Link

Download PDF
5 downloads 0 Views 302KB Size Report
Comment
Yield: 65 mg (42%) of an orange solid; m.p. 242–244 °C (decomposition). Spectroscopic. n.m.r. data (in CDCl3): 1H d: 8.18 (s, 2H, CH@N), 7.89. (d, J = 8 Hz, 2H ...
 Springer 2005

Transition Metal Chemistry (2005) 30:411–418 DOI 10.1007/s11243-004-7625-4

Palladium(II) Schiff base complexes derived from sulfanilamides and aminobenzothiazoles Robin R. Coombs, Melissa K. Ringer, Johanna M. Blacquiere, Joshua C. Smith, J. Scott Neilsen, Yoon-Seo Uh, J. Bryson Gilbert, Lisa J. Leger, Haiwen Zhang, Alison M. Irving, Susan L. Wheaton, Christopher M. Vogels and Stephen A. Westcott* Department of Chemistry, Mount Allison University, Sackville, NB, Canada, E4L 1G8 Andreas Decken Department of Chemistry, University of New Brunswick, Fredericton, NB, Canada, E3B 5A3 Felix J. Baerlocher Department of Biology, Mount Allison University, Sackville, NB, Canada, E4L 1G7 Received 30 November 2004; accepted 6 December 2004

Abstract Schiff bases (HL) derived from sulfanilamides or aminobenzothiazoles add to Pd(OAc)2 to give complexes of the type PdL2 (1–7) in moderate to excellent yields. Reactions of Schiff bases containing pyrimidine groups, however, gave several products arising from competing coordination of the pyrimidine nitrogen. Palladium complexes and Schiff bases have been investigated as antifungal agents against Aspergillus niger and Aspergillus flavus.

Introduction

Experimental

Sulfa drugs are chemotherapeutic agents whose molecular structures contain a sulfanilamide (4-aminobenzenesulfonamide) moiety (Figure 1a). The antibacterial activity of these drugs is believed to arise from the structural resemblance between the sulfanilamide group and p-aminobenzoic acid, where the sulfa drug mimics this metabolite and blocks folic acid synthesis in bacteria, thereby causing cell death [1]. Although over 15,000 sulfa derivatives have been synthesized and screened for potential antibacterial activity, such as the thiazoline derivative Sulfathiazole (Figure 1b), their medicinal use has greatly diminished due to the advent of new generations of antibiotics [2–6]. The topical application of metal complexes of 2-sulfanilamidopyrimidine (sulfadiazine), however, has recently revived the usefulness of these compounds in medicine [7]. Indeed, metal sulfadiazine complexes are now widely used to prevent bacterial infection during burn treatments [8–11]. As part of our investigation into designing new chelating agents from biologically active compounds, we decided to examine the synthesis, reactivity, and antifungal properties of Schiff base palladium complexes derived from sulfanilamides and aminothiazoles.

Materials and measurements

* Author for correspondence

Reagents and solvents used were obtained from Aldrich Chemicals. Palladium acetate was purchased from Precious Metals Online Ltd. Schiff bases were prepared using established procedures [12]. N.m.r. spectra were recorded on a JEOL JNM-GSX270 FT-n.m.r. spectrometer. 1Hn.m.r. chemical shifts are reported in p.p.m. and are referenced to residual protons in deuterated solvent at 270 MHz. 13C-n.m.r. chemical shifts are referenced to solvent carbon resonances as internal standards at 68 MHz. Multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), sextet (sext), septet (sept), multiplet (m), broad (br), and overlapping (ov). I.r. spectra were obtained using a Mattson Genesis II FT-IR spectrometer and are reported in cm)1. Melting points were measured uncorrected with a Mel-Temp apparatus. Microanalyses for C, H, and N were carried out at Guelph Chemical Laboratories Ltd. (Guelph, ON). Preparation of compounds General ligand synthesis To a 10-cm3 EtOH solution of salicylaldehyde and a catalytic amount of formic acid was added a 5-cm3 EtOH solution of the appropriate amine (0.9 eq). The mixture was heated at reflux for 8 h and the solution

412 SULFONAMIDE GROUP SULFONAMIDE GROUP

H2 N

SO2NH2 (a)

H2 N

SO2NH (b)

S N

THIAZOLE GROUP

Fig. 1. (a) Sulfanilamide and (b) sulfathiazole.

stored at 5 C overnight. The resulting precipitate was collected by suction filtration and washed with Et2O (3 · 10 cm3). Ligand (a). Yield: 70% of an orange solid; m.p. 222 C. Spectroscopic n.m.r. data (in dmso-d6): 1H d: 12.66 (br s, 1H, OH), 8.98 (s, 1H, CH@N), 7.89 (d, J ¼ 8 Hz, 2H, Ar), 7.69 (d, J ¼ 8 Hz, 1H, Ar), 7.56 (d, J ¼ 8 Hz, 2H, Ar), 7.47–7.43 (ov m, 3H, Ar & NH2), 7.02–6.97 (ov m, 2H, Ar); 13C{1H} d: 165.6, 160.8, 151.8, 142.5, 134.5, 133.2, 127.7, 122.4, 119.9, 119.8, 117.3. I.r. (nujol): 3338, 3300 (br, OH), 3242, 2953, 2910, 2858, 1614, 1589, 1571, 1525, 1485, 1456, 1410, 1373, 1309, 1279, 1155, 1093, 903, 851, 835, 769, 756, 725, 631, 555. Ligand (b). Yield: 80% of an orange solid; m.p. 162 C. Spectroscopic n.m.r. data (in dmso-d6): 1H d: 12.60 (br s, 1H, OH), 8.75 (s, 1H, CH@N), 7.83 (d, J ¼ 8 Hz, 2H, Ar), 7.53 (d, J ¼ 8 Hz, 2H, Ar), 7.50 (d, J ¼ 8 Hz, 1H, Ar), 7.39–7.32 (ov m, 3H, Ar & NH2), 6.95–6.88 (ov m, 2H, Ar), 4.88 (s, 2H, CH2); 13C{1H} d: 167.8, 160.9, 143.5, 143.3, 133.2, 132.4, 128.8, 126.6, 119.3, 119.2, 117.0, 62.0. I.r. (nujol): 3327, 3300 (br, OH), 3251, 2954, 2931, 2856, 1633, 1579, 1498, 1462, 1410, 1379, 1329, 1277, 1161, 1119, 1093, 908, 849, 812, 764, 534. Ligand (c). Yield: 65% of an orange solid; m.p. 141 C. Spectroscopic n.m.r. data (in dmso-d6): 1H d: 12.56 (br s, 1H, OH), 8.51 (s, 1H, CH@N), 7.74 (d, J ¼ 8 Hz, 2H, Ar), 7.45 (d, J ¼ 8 Hz, 2H, Ar), 7.38 (d, J ¼ 8 Hz, 1H, Ar), 7.34–7.28 (ov m, 3H, Ar & NH2), 6.90–6.83 (ov m, 2H, Ar), 3.87 (t, J ¼ 7 Hz, 2H, CH2), 3.03 (t, J ¼ 7 Hz, 2H, CH2); 13C{1H} d: 166.7, 161.1, 144.3, 142.6, 132.9, 132.2, 129.8, 126.2, 119.1 (2C), 117.0, 59.7, 36.8. I.r. (nujol): 3334, 3300 (br, OH), 3251, 2953, 2924, 2854, 1633, 1577, 1543, 1498, 1464, 1412, 1375, 1294, 1165, 1101, 1076, 1018, 968, 903, 835, 812, 762, 725, 536. Ligand (d). Yield: 75% of an orange solid; m.p. 168 C. Spectroscopic n.m.r. data (in dmso-d6): 1H d: 12.53 (br s, 1H, OH), 10.62 [br s, 1H, Ar-NHC(O)], 8.97 (s, 1H, CH@N), 7.96 (d, J ¼ 8 Hz, 2H, Ar), 7.70 (d, J ¼ 8 Hz, 1H, Ar), 7.56 (d, J ¼ 8 Hz, 2H, Ar), 7.46 (t, J ¼ 8 Hz, 1H, Ar), 7.03–6.97 (ov m, 2H, Ar), 6.50 [br t, J ¼ 6 Hz, 1H, C(O)NHBu], 2.94 (q, J ¼ 6 Hz, 2H, NHCH2CH2), 1.30 (quint, J ¼ 6 Hz, 2H, CH2CH2CH2), 1.13 (sext, J ¼ 6 Hz, 2H, CH2CH2CH3), 0.80 (t, J ¼ 6 Hz, 3H,

CH2CH2CH3); 13C{1H} d: 165.9, 160.8, 153.0, 151.9, 138.4, 134.6, 133.1, 129.8, 129.3, 122.4, 120.0, 119.9, 117.3, 112.8, 39.3, 31.8, 19.9, 14.1. I.r. (nujol): 3291, 3300 (br, OH), 3246, 2953, 2922, 2856, 1682, 1618, 1570, 1549, 1456, 1375, 1331, 1284, 1252, 1190, 1157, 1086, 1011, 889, 835, 760, 681, 623, 581. Ligand (e). Yield: 70% of a yellow-orange solid; m.p. 249–250 C. Spectroscopic n.m.r. data (in dmso-d6): 1H d: 12.53 (s, 1H, OH), 11.85 (br s, 1H, NH), 8.95 (s, 1H, CH@N), 8.51 (d, J ¼ 8 Hz, 2H, Ar), 8.04 (d, J ¼ 8 Hz, 2H, Ar), 7.69–7.44 (ov m, 4H, Ar), 7.05–6.96 (ov m, 3H, Ar). I.r. (nujol): 3300 (br, OH), 3076, 3026, 2953, 2914, 2856, 1620, 1581, 1493, 1446, 1412, 1379, 1338, 1279, 1167, 1149, 1092, 943, 854, 798, 623. Ligand (f). Yield: 65% of a yellow-orange solid; m.p. 195–196 C. Spectroscopic n.m.r. data (in dmso-d6): 1H d: 12.65 (br s, 1H, OH), 8.97 (s, 1H, CH@N), 7.94 (d, J ¼ 8 Hz, 2H, Ar), 7.68 (d, J ¼ 8 Hz, 1H, Ar), 7.52 (d, J ¼ 8 Hz, 2H, Ar), 7.42 (t, J ¼ 8 Hz, 1H, Ar), 7.02–6.96 (ov m, 3H, Ar), 6.87 (br s, 1H, NH), 2.35 (s, 3H, CH3), 2.27 (s, 3H, CH3). I.r. (nujol): 3456, 3300 (br, OH), 2947, 2910, 2858, 1645, 1612, 1570, 1483, 1460, 1408, 1375, 1282, 1198, 908, 835, 810, 760, 723, 623. Ligand (g). Yield: 85% of a yellow-orange solid; m.p. 210–211 C. Spectroscopic n.m.r. data (in dmso-d6): 1H d: 12.80 (br s, 1H, NH), 12.62 (br s, 1H, OH), 8.95 (s, 1H, CH@N), 7.87 (d, J ¼ 8 Hz, 2H, Ar), 7.67 (d, J ¼ 8 Hz, 1H, Ar), 7.51 (d, J ¼ 8 Hz, 2H, Ar), 7.42 (t, J ¼ 8 Hz, 1H, Ar), 7.28 (d, J ¼ 5 Hz, 1H, Ar), 7.01–6.96 (ov m, 2H, Ar), 6.84 (d, J ¼ 5 Hz, 1H, Ar). I.r. (nujol): 3300 (br, OH), 3105, 2945, 2910, 2868, 1614, 1581, 1531, 1454, 1416, 1379, 1308, 1271, 1182, 1147, 1128, 1092, 1078, 937, 908, 856, 760, 741, 706, 644, 621, 567, 548. Ligand (h). Yield: 85% of an orange solid; m.p. 150 C. Spectroscopic n.m.r. data (in dmso-d6): 1H d: 11.57 (br s, 1H, OH), 9.42 (s, 1H, CH@N), 8.05 (d, J ¼ 8 Hz, 1H, Ar), 7.95–7.91 (ov m, 2H, Ar), 7.54–7.48 (ov m, 2H, Ar), 7.41 (t, J ¼ 8 Hz, 1H, Ar), 7.04–6.97 (ov m, 2H, Ar); 13 C{1H} d: 170.9, 166.5, 161.1, 151.8, 136.2, 134.5, 131.7, 127.3, 125.9, 123.2, 122.9, 120.4, 120.1, 117.5. I.r. (nujol): 3300 (br, OH), 3055, 2949, 2873, 1606, 1570, 1502, 1452, 1377, 1284, 1174, 1149, 1063, 901, 800, 754, 723, 679, 617. Ligand (i). Yield: 75% of an orange solid; m.p. 152 C. Spectroscopic n.m.r. data: 1H d (in CDCl3): 12.23 (br s, 1H, OH), 9.18 (s, 1H, CH@N), 7.84 (d, J ¼ 8 Hz, 1H, Ar), 7.50–7.42 (ov m, 2H, Ar), 7.28 (d, J ¼ 2 Hz, 1H, Ar), 7.09–6.95 (ov m, 3H, Ar), 4.09 (q, J ¼ 7 Hz, 2H, CH2CH3), 1.45 (t, J ¼ 7 Hz, 3H, CH2CH3); 13C{1H} d (in dmso-d6): 168.2, 165.5, 160.9, 157.2, 145.9, 135.9, 135.8, 131.8, 123.9, 120.4, 120.1, 117.5, 116.8, 106.2, 64.3, 15.2. I.r. (nujol): 3300 (br, OH), 3055, 2962, 2913, 2864, 1597, 1560, 1450, 1377, 1313, 1259, 1211, 1153, 1113, 1059, 947, 833, 796, 758, 667.

413 Ligand (j). Yield: 50% of an orange solid; m.p. 265– 268 C. Spectroscopic n.m.r. data (in dmso-d6): 1H d: 12.06 (br s, 1H, OH), 9.48 (s, 1H, CH@N), 9.16 (d, J ¼ 2 Hz, 1H, Ar), 8.35 (d of d, J ¼ 8, 2 Hz, 1H, Ar), 8.11 (d, J ¼ 8 Hz, 1H, Ar), 7.98 (d, J ¼ 8 Hz, 1H, Ar), 7.54 (t, J ¼ 8 Hz, 1H, Ar), 7.04–6.97 (ov m, 2H, Ar). I.r. (nujol): 3300 (br, OH), 3109, 2927, 2856, 1628, 1593, 1504, 1491, 1464, 1377, 1362, 1335, 1277, 1225, 1165, 1147, 1117, 1001, 903, 887, 835, 808, 766, 751, 675, 646, 553.

8.05 [s, 2H, C(H)@N], 7.78 (d, J ¼ 8 Hz, 4H, Ar), 7.51 (d, J ¼ 8 Hz, 4H, Ar), 7.32–7.27 (ov m, 8H, NH2 & Ar), 6.79 (d, J ¼ 8 Hz, 2H, Ar), 6.60 (t, J ¼ 8 Hz, 2H, Ar), 3.98 (t, J ¼ 7 Hz, 4H, CH2), 3.13 (t, J ¼ 7 Hz, 4H, CH2); 13C{1H} d: 164.1, 164.0, 143.6, 142.8, 135.3, 135.2, 129.8, 126.4, 120.7, 120.2, 115.6, 58.0, 38.5. I.r. (nujol): 3357, 3265, 2931, 2858, 1622, 1597, 1537, 1446, 1404, 1333, 1203, 1157, 1092, 1016, 910, 877, 756, 586. (Found: C, 50.1; H, 4.3; N, 7.6. C30H30N4O6S2Pd calcd.: C, 50.5; H, 4.3; N, 7.9%.)

Synthesis of (1) An EtOH (5 cm3) solution of ligand (a) (0.14 g, 0.50 mmol) was added to Pd(OAc)2 (0.05 g, 0.22 mmol) in EtOH (3 cm3) and the mixture was heated at reflux for 2 h. A precipitate formed upon cooling to room temperature and was collected by suction filtration and washed with EtOH (3 · 5 cm3) to afford (1). Yield: 110 mg (76%) of an orange solid; m.p. 250 C (decomposition). Spectroscopic n.m.r. data (in dmso-d6): 1H d: 8.15 [s, 2H, C(H)@N], 7.88 (d, J ¼ 8 Hz, 4H, Ar), 7.53 (d, J ¼ 8 Hz, 4H, Ar), 7.51 (s, 4H, NH2), 7.45 (d, J ¼ 8 Hz, 2H, Ar), 7.16 (t, J ¼ 8 Hz, 2H, Ar), 6.54 (t, J ¼ 8 Hz, 2H, Ar), 5.98 (d, J ¼ 8 Hz, 2H, Ar); 13C{1H} d: 164.7, 164.6, 152.0, 142.6, 136.1 (2C), 126.1, 125.9, 120.6 (2C), 115.7. I.r. (nujol): 3365, 3284, 2935, 2856, 1604, 1589, 1529, 1462, 1377, 1340, 1322, 1306, 1149, 1097, 970, 933, 908, 866, 845, 804, 766, 724, 621, 565. (Found: C, 46.8; H, 3.2; N, 8.0. C26H22N4O6S2Pd Æ 0.5 H2O calcd.: C, 46.9; H, 3.5; N, 8.4%.)

Synthesis of (4) An EtOH (5 cm3) solution of Schiff base (d) (0.18 g, 0.48 mmol) was added to Pd(OAc)2 (0.05 g, 0.22 mmol) in EtOH (3 cm3) and the mixture was heated at reflux for 2 h. A precipitate formed upon cooling to room temperature and was collected by suction filtration and washed with EtOH (3 · 5 cm3) to afford (4). Yield: 180 mg (96%) as an orange solid; m.p. 252 C (decomposition). Spectroscopic n.m.r. data (in dmso-d6): 1H d: 10.65 (br s, 2H, NH), 8.18 [s, 2H, C(H)@N], 7.95 (d, J ¼ 8 Hz, 4H, Ar), 7.56 (d, J ¼ 8 Hz, 4H, Ar), 7.44 (d, J ¼ 8 Hz, 2H, Ar), 7.12 (t, J ¼ 8 Hz, 2H, Ar), 6.60–6.50 (ov m, 4H, NHCH2 & Ar), 5.94 (d, J ¼ 8 Hz, 2H, Ar), 2.98 (q, J ¼ 6 Hz, 4H, NHCH2), 1.34 (quint, J ¼ 6 Hz, 4H, CH2CH2CH3), 1.22 (sext, J ¼ 6 Hz, 4H, CH2CH2CH3), 0.81 (t, J ¼ 6 Hz, 6H, CH2CH2CH3); 13 C{1H} d: 164.7, 164.5, 153.0, 151.9, 138.5, 136.1 (2C), 127.9, 126.0, 120.6, 120.5, 115.7, 39.5, 31.9, 20.0, 14.1. I.r. (nujol): 3350, 3122, 3067, 2926, 2856, 1664, 1606, 1525, 1462, 1377, 1340, 1163, 899, 758, 621, 573. (Found: C, 50.3; H, 4.7; N, 9.7. C36H40N6O8S2Pd calcd.: C, 50.6; H, 4.7; N, 9.8%.)

Synthesis of (2) An EtOH (5 cm3) solution of ligand (b) (0.14 g, 0.48 mmol) was added to Pd(OAc)2 (0.05 g, 0.22 mmol) in EtOH (3 cm3) and the mixture was heated at reflux for 2 h. A precipitate formed upon cooling to room temperature and was collected by suction filtration and washed with EtOH (3 · 5 cm3) to afford (2). Yield: 140 mg (93%) as an orange solid; m.p. 246 C (decomposition). Spectroscopic n.m.r. data (in dmso-d6): 1H d: 8.28 [s, 2H, C(H)@N], 7.77 (d, J ¼ 8 Hz, 4H, Ar), 7.56 (d, J ¼ 8 Hz, 4H, Ar), 7.38 (d, J ¼ 8 Hz, 2H, Ar), 7.32– 7.24 (ov m, 6H, NH2 & Ar), 6.79 (d, J ¼ 8 Hz, 2H, Ar), 6.59 (t, J ¼ 8 Hz, 2H, Ar), 5.01 (s, 4H, CH2); 13C{1H} d: 165.9, 164.0, 144.0, 143.2, 135.6, 135.5, 128.2, 126.3, 120.4, 120.2, 115.6, 58.7. I.r. (nujol): 3361, 3255, 2922, 2856, 1619, 1599, 1537, 1456, 1327, 1149, 1093, 1055, 889, 817, 762, 685, 600. (Found: C, 48.6; H, 3.7; N, 7.9. C28H26N4O6S2Pd calcd.: C, 49.1; H, 3.8; N, 8.2%.) Synthesis of (3) An EtOH (5 cm3) solution of Schiff base (c) (0.14 g, 0.46 mmol) was added to Pd(OAc)2 (0.05 g, 0.22 mmol) in EtOH (3 cm3) and the mixture was heated at reflux for 2 h. A precipitate formed upon cooling to room temperature and was collected by suction filtration and washed with EtOH (3 · 5 cm3) to afford (3). Yield: 130 mg (83%) as an orange solid; m.p. 246 C (decomposition). Spectroscopic n.m.r. data (in dmso-d6): 1H d:

Synthesis of (5) To a warm MeOH (5 cm3) solution of palladium(II) acetate (50 mg, 0.22 mol) was added a MeOH (5 cm3) solution of ligand (h) (123 mg, 0.48 mol). The mixture was heated at reflux for 4 h, at which point an orange solid was collected by suction filtration and washed with MeOH (3 · 5 cm3). Yield: 62 mg (46%) of an orange solid; m.p. 282–284 C (decomposition). I.r. (nujol): 2953, 2926, 2854, 1606, 1577, 1525, 1479, 1462, 1429, 1383, 1331, 1252, 1165, 1146, 1126, 1066, 895, 754. (Found: C, 52.7; H, 2.9; N, 8.9. C28H18N4O2PdS2 Æ H2O calcd.: C, 53.3; H, 3.2; N, 8.9%.) Synthesis of (6) To a warm MeOH (5 cm3) solution of palladium(II) acetate (50 mg, 0.22 mol) was added a MeOH (5 cm3) solution of ligand (i) (143 mg, 0.48 mol). The mixture was heated at reflux for 4 h, at which point an orange solid was collected by suction filtration and washed with MeOH (3 · 2 cm3). Yield: 65 mg (42%) of an orange solid; m.p. 242–244 C (decomposition). Spectroscopic n.m.r. data (in CDCl3): 1H d: 8.18 (s, 2H, CH@N), 7.89 (d, J ¼ 8 Hz, 2H, Ar), 7.30–7.25 (ov m, 4H, Ar), 7.16– 7.08 (ov m, 4H, Ar), 6.53 (t, J ¼ 8 Hz, 2H, Ar), 6.17 (d, J ¼ 8 Hz, 2H, Ar), 4.12 (q, J ¼ 7 Hz, 4H, CH2CH3),

414 1.48 (t, J ¼ 7 Hz, 6H, CH2CH3). I.r. (nujol): 2924, 2854, 1606, 1579, 1525, 1448, 1433, 1385, 1329, 1261, 1219, 1146, 1126, 1061, 818, 744. (Found: C, 54.3; H, 3.4; N, 7.9. C32H26N4O4PdS2 calcd.: C, 54.8; H, 3.7; N, 8.0%.)

flavus supplied by Ward’s Natural Science Ltd. (St. Catharines, Ontario, Canada). Cultures were maintained on Sabouraud dextrose agar. Six plugs (10-mm diameter) were cut from a 5–8-day-old colony and homogenized in distilled, sterilized water (3 cm3). From this suspension, 0.5 cm3 was transferred aseptically to a Petri plate with Sabouraud dextrose agar (15 cm3) and spread evenly over the entire surface. Each plate was provided with four evenly spaced paper disks (6 mm Fisherbrand P8) containing 100 lg of the compound. Each compound was applied to the disks as a solution (5 lg of compound per 1 cm3 of acetone) where control disks were treated with neat acetone (20 mm3). Amphotericin B acted as a standard (100 lg). Test plates with fungal homogenates were incubated at room temperature for 48 h. Four replicate plates were used for each test. Antifungal activity was taken by the diameter of the clear zone surrounding the disk.

Synthesis of (7) To a warm MeOH (5 cm3) solution of palladium(II) acetate (25 mg, 0.11 mol) was added a MeOH (5 cm3) solution of ligand (j) (72 mg, 0.24 mol). The mixture was heated at reflux for 4 h, at which point a black solid was collected by suction filtration and washed with CH2Cl2 (3 · 2 cm3) and MeOH (3 · 2 cm3). Yield: 23 mg (30%) of a black solid; m.p. 262–264 C (decomposition). I.r. (nujol): 2953, 2922, 2854, 1593, 1554, 1506, 1493, 1466, 1439, 1362, 1335, 1290, 1279, 1236, 1227, 1165, 1149, 1119, 1001, 887, 750. (Found: C, 43.3; H, 1.8; N, 11.5. C28H16N6O6PdS2 Æ CH2Cl2 calcd.: C, 44.2; H, 2.3; N, 10.7%.) X-ray crystallography

Results and discussion Crystals of (c) were grown from a saturated EtOH solution at room temperature and crystals of (1.2dmso) were grown from a saturated dmso solution at 20 C. Single crystals were coated with Paratone-N oil, mounted using a glass fiber and frozen in the cold stream of the goniometer. A hemisphere of data were collected on a Bruker AXS P4/SMART 1000 diffractometer using x and h scans with a scan width of 0.3 and 10 s (c) and 20 s (1.2dmso) exposure times. The detector distance was 5 cm. The data were reduced [13] and corrected for absorption [14]. The structures were solved by direct methods and refined by full-matrix least squares on F 2 [15]. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were located in Fourier difference maps and refined isotropically. Crystallographic information has been deposited with the Cambridge Crystallographic Data Centre (ccdc 241953 & 256300). Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033; or [email protected]).

Sulfanilamides Schiff bases are versatile intermediates in organic synthesis and have been used to prepare numerous pharmacologically important compounds [16–20]. In this study, we have found that sulfanilamide derivatives add to salicylaldehyde to give compounds having spectroscopic data consistent with the salicylaldimines (a–g) (Scheme 1), where addition occurs at the more nucleophilic NH2 group in cases containing two primary amine groups (a–c). As expected, a shift for the methine proton from 10 to ca. 9 p.p.m. is observed in the 1H-n.m.r. spectra and a resonance at ca. 169 p.p.m. in the 13 C-n.m.r. spectra corresponds to the N@CH carbon. Likewise, formation of these compounds can be monitored by the diagnostic C@N stretching band in the FT-IR spectra at ca. 1620 cm)1 [21]. We have also carried out a single crystal X-ray diffraction study on (c). Crystallographic data are shown in Table 1 and selected bond distances and angles provided in Table 2. There are two unique molecules of (c) in the asymmetric unit, shown in Figure 2, where one is the expected phenol–imine compound and the other molecule is the keto–enamine tautomer. N-Salicylaldimines are well known to exist in tautomeric forms due to the intramolecular proton shift between the phenolic

Antifungal testing New compounds were tested for antifungal activity against pure cultures of Aspergillus niger and Aspergillus H O

RHNO2S

EtOH

+ OH

(CH2)nNH2

cat. formic acid

N(CH2)n OH (a): n = 0, R = H (b): n = 1, R = H (c): n = 2, R = H (d): n = 0, R = C(O)NHBu (e): n = 0, R = 2-pyrimidinyl (f): n = 0, R = 2,6-dimethyl-4-pyrimidinyl (g): n = 0, R = 2-thiazolyl

Scheme 1. Synthesis of sulfanilamide ligands and palladium complexes.

SO2NHR

H

SO2NHR

H

Pd(OAc)2

N(CH2)n O O Pd

EtOH

n(H2C)N

RHNO2S

H (1): n = 0, R = H (2): n = 1, R = H (3): n = 2, R = H (4): n = 0, R = C(O)NHBu

415 Table 1. Crystallographic data collection parameters for (c) and (1Æ2dmso) Complex

(c)

(1 Æ 2dmso)

C26H22N4O6PdS2Æ2dmso Formula C15H16N2O3S fw 304.36 813.25 Crystal system Monoclinic Monoclinic Space group Pn P2(1)/c a (A˚) 8.2232(7) 19.6536(11) b (A˚) 9.5901(8) 10.5729(6) c (A˚) 18.2600(15) 8.2662(5) b (deg) 98.287(1) 96.916(1) V (A˚3) 1425.0(2) 1705.18(17) Z 4 2 qcalcd (g cm)3) 1.419 1.584 Crystal size (mm3) 0.45 · 0.40 · 0.30 0.025 · 0.25 · 0.4 Temperature (K) 198(1) 198(1) Radiation MoKa (k = 0.71073) MoKa (k = 0.71073) l (mm)1) 0.239 0.844 Total reflections 9678 11447 Total unique reflections 5617 3837 No. of variables 507 282 Rint 0.0229 0.0235 Theta range (deg) 2.12–27.50 2.19–27.49 Largest difference Peak/hole e (A˚)3) 0.361/)0.169 0.760/)0.442 S (GoF) on F2 1.054 1.048 R1a (I > 2r(I)) 0.0299 0.0277 0.0717 0.0746 wR2b (all data) P P P P a R1 = ||Fo|–|Fc||/ |Fo|.b wR2 = ( [w(Fo2-Fc2)2]/ [wFo4])1/2, where w = 1/[r2(Fo2) + (0.0385 * P)2 + (0.0864 * P)] (c) and 1/[r2(Fo2) + 2 Æ (0.0038 * P) + (1.3041 * P)] (1 2dmso), where P = (max (Fo2, 0) + 2 * Fc2)/3.

oxygen and the imine nitrogen (O–H  N « O  H–N). The molecular structure of D -2,3-bis(salicylideneamino)1,4-butanediol has been reported recently [22] and also Table 2. Selected bond lengths (A˚) and angles (o) for (c) Molecule 1 N(1)–S(2) O(2)–S(2) S(2)–O(3) S(2)–C(5) N(13)–C(14) N(13)–H(13) C(16)–O(21)

1.601(2) 1.4374(15) 1.4268(16) 1.775(2) 1.297(3) 0.92(3) 1.301(3)

O(3)–S(2)–O(2) O(3)–S(2)–N(1) O(2)–S(2)–N(1) O(3)–S(2)–C(5) O(2)–S(2)–C(5) N(1)–S(2)–C(5) C(14)–N(13)–C(12)

117.49(10) 108.79(10) 107.05(10) 107.27(9) 107.89(9) 108.02(10) 126.47(19)

Molecule 2 N(21)–S(22) O(22)–S(22) S(22)–O(23) S(22)–C(25) N(33)–C(34) C(36)–O(41)

1.623(2) 1.4343(15) 1.4312(15) 1.7718(19) 1.277(3) 1.359(2)

O(23)–S(22)–O(22) O(23)–S(22)–N(21) O(22)–S(22)–N(21) O(23)–S(22)–C(25) O(22)–S(22)–C(25) N(21)–S(22)–C(25) C(34)–N(33)–C(32)

119.79(10) 107.26(11) 106.05(11) 108.42(10) 107.85(9) 106.78(9) 118.09(19)

exists as a mixture of both tautomers. The reason for the mixture of tautomers in (c) presumably lies within the packing in the solid state and with the resulting hydrogen bonding. Indeed, there is a considerable amount of both intra- and intermolecular interactions within the two molecules of (c) (Table 3). Hydrogen bonding has been used recently to control molecules and ions in the solid state for applications in crystal engineering and supramolecular synthesis [23–25]. As Schiff bases are ubiquitous in transition metal chemistry, we decided to investigate the use of salicylaldimines (a–g) as ligands for biologically active metals. Our initial investigations have been directed at making palladium(II) complexes as related Schiff base Pd(II) complexes derived from S-alkyldithiocarbazates have recently shown considerable antimicrobial activity against a number of pathogenic bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and Bacillus subtilis [26]. We have found that addition of (a–d) to Pd(OAc)2 afforded bis(salicylaldiminato)palladium(II) complexes (1–4) in high to excellent yields (76–96%). Complexes (1–4) have been characterized by a number of physical methods, including multinuclear n.m.r. spectroscopy. A significant upfield shift in the 1H-n.m.r. spectra is observed for the imine methine proton, from ca. 9 p.p.m. to ca. 8 p.p.m., upon coordination of the ligand to the d8 metal centre. Most notable, however, is the absence of the broad OH stretch in the FT-IR spectra when the ligands are coordinated to the metal. Complex (1.2dmso) has also been characterized by an X-ray diffraction study; the molecular structure of which

416

Fig. 2. Molecular structure of (c), with displacement ellipsoids drawn at the 30% probability level and most hydrogen atoms omitted for clarity.

is shown in Figure 3 and confirms that the aryl amine, and not the SO2NH2 group, reacts with the salicylaldehyde. Crystallographic data are given in Table 1 and selected bond distances and angles in Table 4. The palladium atom lies on an inversion centre and assumes a slightly distorted square planar configuration with trans bis(salicylaldiminato) groups. The Pd–O and Pd–N distances of 1.9835(15) A˚ and 2.0286(17) A˚, respectively, are similar to those seen in related complexes [27–29]. A preliminary structure on (2) was obtained confirming a centrosymmetric L2Pd structure similar to that observed in (1). Crystals of (2) were twinned, however, and not refined further [Rhombohedral R-3, unit cell parameters a ¼ 30.912(2), b ¼ 30.912(2), c ¼ 12.3940(7), a ¼ 90, b ¼ 90, c ¼ 120, V ¼ 10256.5(10), Z ¼ 12]. Interestingly, addition of Schiff bases derived from sulfadiazine (e), sulfisomidine (f), and thiazol (g) gave several unidentified products, presumably arising from a competing coordination through the basic pyrimidine and thiazol nitrogen atoms. Indeed, the uncoordinated imine fragment of the Schiff base could be observed via 1 H-n.m.r. spectroscopy, which eventually decomposed by reaction with adventitious water to form the starting aldehyde and amine. That the pyrimidine nitrogens were coordinating to the metal centres was confirmed by independent addition of the starting amines to organic soluble [PdCl2(coe)]2 [30, coe ¼ cis-cyclooctene], which

Fig. 3. Molecular structure of (1Æ2dmso), with displacement ellipsoids drawn at the 30% probability level. Most hydrogen atoms and solvent molecules omitted for clarity.

gave a number of unidentified products also observed in reactions with Schiff bases.

Aminobenzothiazoles 2-Aminothiazoles are a remarkably versatile group of compounds that have found recent applications in drug development. For instance, these compounds have been used for the treatment of allergies [31], hypertension [32], inflammation [33], schizophrenia [34], and for bacterial [35] and HIV infections [36]. Likewise, the unusual antitumor activity of 2-(4-aminophenyl)benzothiazole was originally discovered in a program of screening for tyrosine kinase inhibitors [37]. Since this discovery, analogues based on the aminothiazole scaffold have been synthesized that display superior growth inhibitory properties. The simple structures of these compounds belie remarkable and intriguing pharmacological properties, and their biological profile is unlike that of any known biological agent [37]. More relevant to this study, however, is the observation that Schiff base compounds derived from aminothiazoles display significant antibacterial and antifungal behavior [38]. We therefore decided to examine the synthesis and antifungal properties of palladium Schiff base complexes derived from aminobenzothiazoles.

Table 3. Hydrogen bond lengths (A˚) and angles (o) for (c) D–H…A

d(D–H)

d(H…A)

d(D…A)