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1-Ethyl Gallate-2-Substituted Phenoxymethyl Benzimidazoles: Synthesis, Molecular Structure, Antimicrobial Activities and Complex with Cr(III).

Byline: Li Zhao, Guirong Qiu, Jiacheng Wu, Zhiyuan Wang and Haibin Gu

Summary: The design of gallate and benzimidazole containing derivatives is expected to produce new bioactive molecules with multiple applications. Here the synthesis of eight novel benzimidazole compounds containing ethyl gallate and substituted phenoxymethyl units are reported. Firstly, the ring closure reaction between o-phenylendiamine and substituted phenoxyacetic acids resulted in 2-substituted phenoxymethyl benzimidazoles that were then modified by the N-hydroxyethylation with 2-chloroethyl alcohol under a phase transfer catalysis condition. The obtained 1-hydroxyethyl-2-substituted phenoxymethyl benzimidazoles were finally translated into the target title compounds 8a-h by an indirect esterification method in which three O-H groups of gallic acid were first protected by acetyls and deprotected after the esterification reaction by adding hydrazine hydrate.

The structures of the title products 8a-h were fully characterized and confirmed by elemental analysis, MS, IR, 1H-NMR, 13C-NMR and single crystal X-ray diffraction techniques. Antimicrobial tests by inhibition zones indicated that these compounds exhibited diverse inhibitory effects against the test bacteria and fungi, and the type and position of the substituent groups in the phenoxymethyl moieties had obvious influence on their antimicrobial activities. Furthermore, the Cr(III) complex of 8h was synthesized, and various spectral, elemental and thermal analysis results confirmed that the central Cr(III) atom coordinated with adjacent hydroxyl groups of two 8h ligands, nitrate and H2O, respectively.

Keywords: Gallates, Benzimidazole derivatives, Phenoxyacetic acid, Antimicrobial activity, Cr(III) complex.

Introduction

Gallic acid [1], namely, 3, 4, 5-trihydroxybenzoic acid, exhibited many biological, physiological and pharmacological activities, and its derivatives, especially gallates that can be prepared by the esterification reaction with various alcohols, have attracted widely attentions from medical, food, agricultural and industrial communities [2]. In the last decades, considerable reports focused on the synthesis and application of gallate derivatives for their anti-inammatory [3], anticancer [2], antiarthritic [4], antiviral [5], antibacterial [6, 7], antifungal [6-9], antiangiogenic [10], antioxidative [11, 12], neuroprotective [13], and cholesterol-lowering effects [14].

Also, benzimidazole derivatives are well known for their diverse biological and pharmacological activities such as antimicrobial [15-19], anticancer [20-22], anti-inammatory [23], antiparasitic [24], antihypertensive [25], anti-HIV [26-28], anticonvulsant [29], antitubercular [26, 28, 30], antioxidant [28, 31], antidiabetic [26, 32], antihistaminic [23, 26, 28] and antimalarial properties [33], and have been used as starting compounds, intermediates or subunits for the development of functional molecules [34]. Modifications of benzimidazole molecule, which can be conducted on the phenyl ring or/and the imidazole ring, provided an important and effective synthetic strategy in the drug discovery process.

In this study, the carbon (or 1) positon in the imidazole ring was modified by the phenoxymethyl units with different substitution groups. Phenoxyacetic acid derivatives showed various bioactivities including antimicrobial [35-39], antiviral [40], antidiabetic [41, 42] and phytohormone effects [43], and as shown in Scheme 1, the ring closure reaction of their carboxyl groups with o-phenylendiamine resulted in the compounds 5 containing the two basic structural units of benzimidazole and phenoxymethyl. Then, the N-hydroxyethylation reaction was conducted in the imidazole ring of 5 by using 2-chloroethyl alcohol with the aid of tetrabutyl ammonium bromide (TBAB) as a solid-liquid phase transfer catalyst.

Finally, the obtained intermediates 6 containing hydroxyl groups were used to synthesize the target compounds 8 by an indirect esterification protocol in which the three phenolic hydroxyl groups of gallic acid were first protected by acetyls, and deprotected after the esterification reaction by using hydrazine hydrate. Thus, the obtained molecules 8 contain three bioactive units, namely, gallate, benzimidazole and phenoxymethyl, and their bioactivities can be adjusted by the type and location of substitute groups in the benzene ring of phenoxymethyl structure. To prove this point, eight compounds 8a-8h were prepared according to the route in Scheme 1, and their molecular structures were characterized by elementary analysis, MS, IR, 1H-NMR, 13C-NMR and X-ray single crystal diffraction, and the inhibition zone method was adopted to determine their antibacterial and antifungal activities.

Furthermore, the Cr(III) complex of 8h, which has potential applications such as DNA binders [44-45], superoxide radical scavengers[46], cancer chemopreventive agents [47] and tanning agents for collagen and hides [48], was successfully synthesized and well characterized by many techniques containing IR, UV-visible, 1H-NMR, 13C-NMR and TG.

Experimental

All the used reagents were analytic grade, commercially purchased and used as received. All the solvents used were dried and freshly distilled. Trisacetyl-galloyl chloride (3) and 1-hydroxyethyl-2-substituted phenoxymethyl benzimidazoles (6) and were synthesized according to previous reports [7, 49, 50].

A Shanghai Zhongguang WRS-2 melting point apparatus (uncorrected) was used to determine the melting points of compounds. Elemental analysis (C, H, N) were carried out on a Carlo-Erba 1106 analyser. The infrared spectra were recorded on a Magna. IR 506 (Nicolet Ltd, USA) FT-IR spectrophotometer using KBr disk in the range 4000-400 cm-1. 1H (400 MHz) and 13C-NMR (150 MHz) spectra were recorded at 25 AdegC with a Bruker AV II-400 and 600 MHz spectrometer. All the chemical shifts are reported in parts per million (I', ppm) with reference to tetramethylsilane (TMS). Mass spectra were measured using a GCMS-QP2010 Plus Model GC-MS spectrometer. UV-visible absorption spectra were measured with a Perkin-Elmer Lambda 19 UV visible spectrometer. Thermogravimetric (TG) analysis was conducted on a Netzsch TG 209 F1 thermal analyzer in the range 40-800 AdegC with the heating rate of 10 K/min.

The measurement of single crystal was carried out on a CCD X-ray single crystal diffractometer (Xcalibur, Eos, UK) with a graphite-monochromated MoK[alpha] radiation. A suitable single crystal was selected and mounted on a glass fiber, X-ray diffraction intensity data were collected using the I-2I, scan technique. The crystal was kept at 293(2) K during data collection. Using Olex2 [51], the structure was solved with the Superflip [52] structure solution program using Charge Flipping and refined with the ShelXL [53] refinement package using Least Squares minimisation.

Synthesis of 8a: Trisacetyl galloyl chloride (3, 0.3147 g, 1 mmol) was added into a mixture of 1-hydroxyethyl phenoxymethyl benzimidazole (6a, 0.2683 g, 1mmol) and triethylamine (0.7 mL, 5 mmol) dissolved in 20 mL dry dichloromethane (CH2Cl2) at an ice bath condition. The obtained mixture was stirred for 10 hours at room temperature (r. t., 25 AdegC), then 10 mL of 10% (v/v) HCl was added to remove the excess triethylamine. The CH2Cl2 layer was separated and washed with distilled water (3 x 10 mL). The 80% hydrazine monohydrate (0.1878 g, 3 mmol) was then added to the CH2Cl2 solution, and the mixture was stirred for 3 hours at r. t. and washed using the 0.3 mol L-1 acetic acid solution (10 mL). The formed precipitate was filtered and collected, while the filtrate was separated to remove the water layer.

The organic layer was vacuumed, and the obtained residue was combined with the above precipitate and then recrystallized in the mixed solvent of ethanol and distilled water (8: 2, v/v) to produce purified 1-ethyl gallate-2-phenoxymethyl benzimidazole (8a) as a white solid. Similar procedures were adopted for the synthesis of 8b-8h. Yield: 85.7%. m. p. 221.5-221.8 AdegC. Anal. calcd. (%) for C23H20N2O6: C, 65.71; H, 4.76; N, 6.67. Found (%): C, 65.70; H, 4.77; N, 6.65. MS (ESI, m/z), calcd. for C23H20N2O6: 420.41; found: 421.22 (M+H +).

1H-NMR (400 MHz, DMSO-d6), I'ppm: 9.30 (s, 2H, Ar-OH), 9.04 (s, 1H, Ar-OH), 7.68 (t, 2H, Ar-H), 7.33-7.27 (q, 3H, Ar-H), 7.23 (t, 1H, Ar-H), 7.09(d, 2H, Ar-H), 6.98 (t, 1H, Ar-H), 6.88 (s, 2H, Ar-H), 5.45 (s, 2H, CH2-O-Ar), 4.72 (t, 2H, N-CH2), 4.57 (t, 2H, CH2-OOC-Ar). 13C-NMR (100 MHz, DMSO-d6), I'ppm: 165.6(COO), 157.7, 149.5(N=C-N), 145.6, 141.8, 138.7, 135.4, 129.6, 123.0, 122.1, 121.4, 119.4, 118.7, 114.8, 110.8, 108.7, 63.0(CH2O-Ar), 62.4(CH2OOC-Ar), 42.6(N-CH2). Selected IR (KBr, cm-1): 3519.7, 3384.2 (OH), 1718.2 (C=O), 1614.7 (C=N), 1599.5, 1589.3, 1523.4, 1496.7, 1465.3 (C=C, Ar), 1450.5 (I'CH2), 1391.1, 1374.9, 1334.7 (C-N), 1310.2, 1232.8 (I'OH), 1205.5 (Ar-O-C), 1085.9, 1032.7, 1007.1 (Ar-O-C), 896.5, 879.3, 817.0, 765.1, 747.2 (I'Ar-H).

8b: white solid. Yield: 84.1%. m. p. 225.5-225.9 AdegC. Anal. calcd. (%) for C24H22N2O6: C, 66.35; H, 5.10; N, 6.45. Found (%): C, 66.34; H, 5.02; N, 6.43. MS (ESI, m/z), calcd. for C24H22N2O6: 434.44; found: 435.21 (M+H +). 1H-NMR (400 MHz, DMSO-d6), I'ppm: 9.30 (s, 2H, Ar-OH), 9.04(s, 1H, Ar-OH), 7.72-7.67 (q, 2H, Ar-H), 7.31 (t, 1H, Ar-H), 7.24 (t, 1H, Ar-H), 7.19-7.14 (m, 3H, Ar-H), 6.90-6.86 (m, 3H, Ar-H), 5.46 (s, 2H, CH2-O-Ar), 4.76 (t, 2H, N-CH2), 4.56 (t, 2H, CH2-OOC-Ar), 2.17 (s, 3H, CH3). 13C-NMR (100 MHz, DMSO-d6), I'ppm: 165.6 (COO), 155.8, 149.6 (N=C-N), 145.6, 141.6, 138.8, 135.4, 130.7, 127.0, 125.9, 123.1, 122.2, 121.1, 119.3, 118.7, 111.8, 110.9, 108.7, 63.0 (CH2O-Ar), 62.6 (CH2OOC-Ar), 42.6 (N-CH2), 16.0(CH3).

Selected IR (KBr, cm-1): 3515.5, 3463.1 (OH), 2961.2 (CH3), 1697.3 (C=O), 1614.3 (C=N), 1540.8, 1524.5 1494.2, 1465.2 (C=C, Ar), 1450.2 (I'CH3), 1395.8, 1365.3, 1347.2 (C-N), 1316.3, 1236.3 (I'OH), 1216.3 (Ar-O-C), 1120.2, 1043.3 1006.5 (Ar-O-C), 890.1, 870.3, 849.6, 766.3, 743.4 (I'Ar-H).

8c: white solid. Yield: 81.3%. m. p. 200.1-200.7 AdegC. Anal. calcd. (%) for C24H22N2O6: C, 66.35; H, 5.10; N, 6.45. Found (%): C, 66.33; H, 5.04; N, 6.48. MS (ESI, m/z), calcd. for C24H22N2O6: 434.44; found: 435.24 (M+H +). 1H-NMR (400 MHz, DMSO-d6), I'ppm: 9.30 (s, 2H, Ar-OH), 9.04 (s, 1H, Ar-OH), 7.68 (t, 2H, Ar-H), 7.31-7.16 (m, 3H, Ar-H), 6.90-6.88 (m, 4H, Ar-H), 6.79 (d, 1H, Ar-H), 5.41 (s, 2H, CH2-O-Ar), 4.71 (t, 2H, N-CH2), 4.57 (t, 2H, CH2-OOC-Ar), 2.26 (s, 3H, CH3). 13C-NMR (100 MHz, DMSO-d6), I'ppm: 165.6 (COO), 157.7, 149.5 (N=C-N), 145.6, 141.8, 139.2, 138.7, 135.4, 129.3, 123.0, 122.1, 122.0, 119.4, 118.7, 115.4, 111.7, 110.8, 108.7, 62.9 (CH2O-Ar), 62.4 (CH2OOC-Ar), 42.7 (N-CH2), 21.1(CH3).

Selected IR (KBr, cm-1): 3488.7, 3445.4 (OH), 2960.5 (CH3), 1722.9 (C=O), 1633.4 (C=N), 1603.3, 1593.5, 1551.5, 1520.8, 1489.7, 1456.1 (C=C, Ar), 1443.6 (I'CH3), 1384.7, 1368.7, 1345.5 (C-N), 1298.0, 1259.7, 1225.9(I'OH), 1204.8(Ar-O-C), 1169.4, 1045.3, 1036.1, 1004.8 (Ar-O-C), 885.0, 847.1, 796.2, 773.2, 761.9, 748.6 (I'Ar-H).

8d: white solid. Yield: 87.7%. m. p. 228.8-229.9 AdegC. Anal. calcd. (%) for C24H22N2O6: C, 66.35; H, 5.10; N, 6.45. Found (%): C, 66.29; H, 5.01; N, 6.46. MS (ESI, m/z), calcd. for C24H22N2O6: 434.44; found: 435.26 (M+H +). 1H-NMR (400 MHz, DMSO-d6), I'ppm: 9.29 (s, 2H, Ar-OH), 9.03 (s, 1H, Ar-OH), 7.67 (t, 2H, Ar-H), 7.29 (t, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.10 (d, 2H, Ar-H), 6.98 (d, 2H, Ar-H), 6.88 (s, 2H, Ar-H), 5.40 (s, 2H, CH2-O-Ar), 4.71 (t, 2H, N-CH2), 4.56 (t, 2H, CH2-OOC-Ar), 2.22 (s, 3H, CH3). 13C-NMR (100 MHz, DMSO-d6), I'ppm: 165.6 (COO), 155.6, 149.6 (N=C-N), 145.6, 141.8, 138.7, 135.4, 130.2, 129.9, 123.0, 122.0, 119.4, 118.7, 114.7, 110.8, 108.7, 62.9 (CH2O-Ar), 62.6 (CH2OOC-Ar), 42.6 (N-CH2), 20.1 (CH3).

Selected IR (KBr, cm-1): 3500.9, 3420.3 (OH), 2962.2 (CH3), 1696.4 (C=O), 1416.3(C=N), 1601.3, 1529.3, 1509.8, 1474.9 (C=C, Ar), 1449.0 (I'CH3), 1393.6, 1373.0, 1339.7 (C-N), 1310.8, 1229.4 (I'OH), 1210.2 (Ar-O-C), 1108.7, 1047.0 1004.1 (Ar-O-C), 891.0, 872.0, 819.6, 801.8, 770.3, 751.8 (I'Ar-H).

8e: white solid. Yield: 91.4%. m. p. 234.9-236.1 AdegC. Anal. calcd. (%) for C23H19N2O6Cl: C, 60.73; H, 4.21; N, 6.16. Found (%): C, 60.79; H, 4.23; N, 6.14. MS (ESI, m/z), calcd. for C23H19N2O6Cl: 454.86; found: 455.22 (M+H +). 1H-NMR (400 MHz, DMSO-d6), I'ppm: 9.29 (s, 2H, Ar-OH), 9.03 (s, 1H, Ar-OH), 7.71-7.66 (q, 2H, Ar-H), 7.46-7.22 (m, 5H, Ar-H), 7.00 (t, 1H, Ar-H), 6.87 (s, 2H, Ar-H), 5.57 (s, 2H, CH2-O-Ar), 4.77 (t, 2H, N-CH2), 4.59 (t, 2H, CH2-OOC-Ar). 13C-NMR (100 MHz, DMSO-d6), I'ppm: 165.6 (COO), 153.0, 148.8 (N=C-N), 145.6, 141.8, 138.7, 135.5, 130.1, 128.3, 123.2, 122.4, 122.2, 121.5, 119.5, 118.7, 114.5, 111.0, 108.7, 63.3 (CH2O-Ar), 63.1 (CH2OOC-Ar), 42.6 (N-CH2). Selected IR (KBr, cm-1): 3524.5, 3424.5 (OH), 2920.7(CH2), 1717.7 (C=O), 1612.6 (C=N), 1593.9, 1585.7, 1520.8, 1485.9, 1474.7, 1463.7 (C=C, Ar), 1449.7 (I'CH2), 1336.9 (C-N), 1373.1, 1336.7 (C-N), 1243.6 (I'OH), 1205.5 (Ar-O-C), 1084.2, 1060.3 (Ar-Cl), 1039.7, 1008.2 (Ar-O-C), 894.9, 879.6, 764.7, 753.1, 743.0 (I'Ar-H).

8f: white solid. Yield: 82.3%. m. p. 213.9-214.3 AdegC. Anal. calcd. (%) for C23H19N2O6Cl: C, 60.73; H, 4.21; N, 6.16. Found (%): C, 60.71; H, 4.13; N, 6.17. MS (ESI, m/z), calcd. for C23H19N2O6Cl: 454.86; found: 455.01 (M+H +). 1H-NMR (600 MHz, DMSO-d6), I'ppm: 9.28 (s, 2H, Ar-OH), 9.03 (s, 1H, Ar-OH), 7.69-7.65 (q, 2H, Ar-H), 7.35 (d, 2H, Ar-H), 7.29 (t, 1H, Ar-H), 7.23 (t, 1H, Ar-H), 7.11 (d, 2H, Ar-H), 6.87 (s, 2H. Ar-H), 5.45 (s, 2H, CH2-O-Ar), 4.71 (t, 2H, N-CH2), 4.56 (t, 2H, CH2-OOC-Ar). 13C-NMR (150 MHz, DMSO-d6), I'ppm: 165.6 (COO), 156.5, 149.2 (N=C-N), 145.6, 141.8, 138.7, 135.4, 129.3, 125.1, 123.0, 122.1, 119.4, 118.7, 116.6, 110.9, 108.7, 62.9 (CH2O-Ar), 62.8 (CH2OOC-Ar), 42.6 (N-CH2). Selected IR (KBr, cm-1): 3485.7, 3384.1 (OH), 2951.0(CH2), 1696.4 (C=O), 1607.3 (C=N), 1530.1, 1490.8, 1468.9 (C=C, Ar), 1450.0 (I'CH2), 1423.0, 1394.8, 1373.5, 1333.6 (C-N), 1236.7 (I'OH), 1210.2 (Ar-O-C), 1095.2 (Ar-Cl), 1041.0, 1007.0 (Ar-O-C), 883.0, 822.1, 766.4, 744.0 (I'Ar-H).

8g: white solid. Yield: 88.9%. Anal. calcd. (%) for C23H18N2O6Cl2: C, 56.46; H, 3.71; N, 5.73. Found (%): C, 56.31; H, 3.54; N, 5.83. MS (ESI, m/z), calcd. for C23H18N2O6Cl2: 489.30; found: 488.87 (M+), 490.84 (M+H +). 1H-NMR (400 MHz, DMSO-d6), I'ppm: 9.21 (s, broad, 3H, Ar-OH), 7.71-7.65 (q, 2H, Ar-H), 7.60 (d, 1H, Ar-H), 7.43-7.38 (m, 2H, Ar-H), 7.30 (t, 1H, Ar-H), 7.24 (t, 1H, Ar-H), 6.86 (s, 2H, Ar-H), 5.57 (s, 2H, CH2-O-Ar), 4.76 (t, 2H, N-CH2), 4.57 (t, 2H, CH2-OOC-Ar). 13C-NMR (100 MHz, DMSO-d6), I'ppm: 165.6 (COO), 152.1, 148.5 (N=C-N), 145.6, 141.7, 138.7, 135.5, 129.4, 128.1, 125.4, 123.2, 122.5, 122.2, 119.5, 118.7, 115.8, 111.0, 108.7, 63.6 (CH2O-Ar), 63.1 (CH2OOC-Ar), 42.6 (N-CH2).

Selected IR (KBr, cm-1): 3495.9, 3393.9 (OH), 2959.2 (CH2), 1712.0 (C=O), 1611.9 (C=N), 1591.8, 1533.7, 1524.5, 1484.3, 1471.6 (C=C, Ar), 1422.6 (I'CH2), 1393.1, 1372.4, 1335.0 (C-N), 1286.5, 1245.0 (I'OH), 1207.8 (Ar-O-C), 1103.2, 1089.4 (Ar-Cl), 1041.7, 1003.5 (Ar-O-C), 874.7, 809.9, 780.4, 765.1, 741.9 (I'Ar-H).

8h: white solid. Yield: 87.1%. m. p. 232.3-232.6 AdegC. Anal. calcd. (%) for C23H19N2O6Br: C, 55.33; H, 3.84; N, 5.61. Found (%): C, 55.31; H, 3.82; N, 5.65. MS (ESI, m/z), calcd. for C23H19N2O6Br: 499.31; found: 498.96 (M+), 500.96 (M+H +). 1H-NMR (600 MHz, DMSO-d6), I'ppm: 9.28 (s, 2H, Ar-OH), 9.03 (s, 1H, Ar-OH), 7.69-7.65 (q, 2H, Ar-H), 7.47 (d, 2H, Ar-H), 7.29 (t, 1H, Ar-H), 7.23 (t, 1H, Ar-H), 7.06 (d, 2H, Ar-H), 6.87 (s, 2H, Ar-H), 5.45 (s, 2H, CH2-O-Ar), 4.71 (t, 2H, N-CH2), 4.55 (t, 2H, CH2-OOC-Ar). 13C-NMR (150 MHz, DMSO-d6), I'ppm: 165.6 (COO), 157.0, 149.2 (N=C-N), 145.6, 141.8, 138.7, 135.4, 132.2, 123.0, 122.1, 119.4, 118.7, 117.2, 112.9, 110.9, 108.7, 62.9 (CH2O-Ar), 62.7 (CH2OOC-Ar), 42.6 (N-CH2). Selected IR (KBr, cm-1): 3499.0, 3380.3 (OH), 2951.0 (CH2), 1698.1 (C=O), 1608.0 (C=N), 1581.6, 1529.5, 1488.0, 1469.0 (C=C, Ar), 1444.4 (I'CH2), 1334.6 (C-N), 1318.4, 1236.3 (I'OH), 1212.2 (Ar-O-C), 1093.2, 1073.7(Ar-Br), 1042.0, 1004.6 (Ar-O-C), 883.5, 821.9, 804.1, 766.2, 749.3 (I'Ar-H).

Evaluation on the antimicrobial activities of 8: The inhibition zone method with filter paper [7] was used to determine the inhibitory effects of the synthesized gallates 8 against pathogenic microorganisms containing Escherichia coli, Staphylococcus aureus, Viscous red round yeast, Aspergillus niger and Penicillium citrinum, which were all isolated from mildewed leather [7]. The filter-paper discs with diameters of 25 mm were cut, sterilized and soaked for 24 hours in 20 mL dimethyl sulfoxide (DMSO) solution containing 4 mmol of 8. The obtained discs were air dried, and then put on plate media inoculated with the test microbial suspensions. The test microbial concentrations are 5-10 x 105 cfu/mL for bacteria/yeast and 5-10 x 104 cfu/mL for moulds. Nutrient agar was used as the culture media for bacteria, while moulds and yeast were incubated by the rose bengal media.

The obtained plate media were put into an incubator of 37AdegC for 24 hours (for bacteria), or 28 AdegC for 48 hours (for moulds and yeast), then, the diameters of inhibition zones were measured by a vernier caliper. The discs soaked by pure DMSO were used as controls, and all experiments were conducted in duplicate and the results were confirmed in three independent experiments.

Synthesis of Cr(III) complex of 8h: 0.4 g of chromium nitrate (Cr(NO3)3*9H2O) was dissolved in 50 mL of ethanol/water (9: 1, v/v) mixed solvent, and the prepared solution was added quickly into 50 mL of ethanol/water (9: 1, v/v) mixed solution containing 0.5 g of 1-ethyl gallate-2-(para-bromo) phenoxymethyl benzimidazole 8h. The obtained mixture was stirred at r. t. for 3 hours, and then the formed light-green Cr (OH)3 precipitate was remove by the suction filtration, and the filtrate was adjusted to pH 4.0-4.1 with diluted nitric acid solution, and vacuumed to remove most of ethanol solvent. The obtained suspension (10 mL or so) was cooled, filtered, washed with distilled water (3 x 10 mL), and dried to get the Cr(III) complex of 8h as a yellowish-brown solid. Yield: 0.87 g. m. p. 196.6-197.3 AdegC. Anal. calcd. (%) for C46H48N5O22Br2Cr: C, 44.75; H, 3.92; N, 5.67. Found (%): C, 46.14; H, 4.39; N, 6.02.

1H-NMR (600 MHz, DMSO-d6), I'ppm: 8.04 (d, 1H, Ar-H), 7.82 (d, 1H, Ar-H), 7.60-7.54 (m, 4H, Ar-H), 7.13 (d, 2H, Ar-H), 6.85 (s, 2H, Ar-H), 5.73 (s, 2H, CH2-O-Ar), 4.93 (t, 2H, N-CH2), 4.63 (t, 2H, CH2-OOC-Ar). 13C-NMR (150 MHz, DMSO-d6), I'ppm: 165.6 (COO), 156.4, 149.5 (N=C-N), 145.6, 138.8, 133.1, 132.4, 125.8, 125.8, 118.6, 117.3, 115.5, 113.8, 113.0, 108.7, 62.4 (CH2O-Ar), 61.4 (CH2OOC-Ar), 44.0 (N-CH2). Selected IR (KBr, cm-1): 3517.2, 3393.9, 3195.9 (OH), 1709.1(N=O), 1673.8 (C=O), 1615.5 (C=N), 1585.7, 1529.6, 1489.0, 1463.3 (C=C, Ar), 1447.6 (I'CH2), 1384.2 (NO3-), 1357.1(C-N), 1239.8 (I'OH), 1230.6 (Ar-O-C), 1181.6, 1147.8, 1040.9, 1095. 7, 1068.3 (Ar-Br), 1040.9, 1007.1 (Ar-O-C), 872.6, 826.5 (I'Ar-H), 815.8 (NO3-), 804.1, 770.1, 748.7 (I'Ar-H), 639.0 (Cr-O).

Results and Discussion

Synthesis and structure analysis for compounds 8

As shown in Scheme 1, an indirect esterification protocol [7] was adopted to synthesize the target gallates containing the benzimidazole moiety. The gallic acid was used as starting material, and its three phenolic hydroxyl groups was firstly protected by the reaction with acetic anhydride in the presence of concentrated sulfuric acid (H2SO4) at 90 AdegC. Then, the obtained trisacetyl gallic acid (2) was refluxed for 3 hours in thionyl chloride (SOCl2) with the aid of dimethyl formamide (DMF) to prepare the trisacetyl galloyl chloride (3) that can efficiently react with 2-substituted phenoxymethyl benzimidazoles (6)[49,50] in the presence of triethylamine as the acid binding agent. Finally, the protective acetyl groups of the key intermediate (7) were eliminated by adding hydrazine hydrate to get the final 1-ethyl gallate-2-substituted phenoxymethyl benzimidazoles (8). This route resulted in high yield up to 91%.

All the obtained gallates are white solids and exhibit good solubility in common organic solvents such as CH2Cl2, chloroform (CHCl3), tetrahydrofuran (THF), methanol, ethanol, acetone, acetonitrile, DMF and DMSO.

Elemental analysis, MS, 1H, 13C-NMR and IR techniques were used to characterize the molecular structures of the compounds 8. Similar 1H and 13C-NMR spectra in DMSO-d6 were observed for all the obtained gallates. For example, in the 1H-NMR spectrum of 1-ethyl gallate-2-bromine phenoxymethyl benzimidazoles (8h), the two single peaks at 9.28 and 9.03 ppm can be asigned to the three protons of its contiguous phenolic hydroxyls, and the single peak at 5.45 ppm corresponded to the two protons of methoxy group, while the ethyl protons were found at 4.71 ppm and 4.55ppm and both of them are triplet peaks. In the 13C-NMR spectrum of 8h, carbonyl carbon was observed at 165.6 ppm and methoxy carbon was located at 62.9 ppm, while the peaks at 62.7 and 42.6 ppm are assigned to the two ethyl carbons. Notably, the type and location of substituent groups on the phenoxymethyl units can result in moderate effect on the position of these charcteristic peaks.

All the other peaks of the 1H and 13C-NMR are well assigned and match well with the structures of the target compounds 8.

All the target compounds showed similar FT-IR spectra. The stretching vibration of phenolic hydroxyl groups (Ar-OH) were observed at 3400-3500 cm-1 or so as broad absorption bands. The strong peaks at 1700 cm-1 or so corresponded to the stretching vibration of ester C=O groups, while the peaks assigned to the stretching vibration of C=N groups of benzimidazole rings were found at 1620 cm-1 nearby. The absorption bands found in the range of 1333-1347 cm-1 were attributed to the C-N bond, and the peaks due to the presence of ether bond (Ar-O-C) were found at 1225-1244 cm-1. The substituent groups in the phenoxymethyl structures also exhibit obvious effect on the position of these peaks. Furthermore, the several absorption peaks at 1600-1450 cm-1 were the characteristic skeletal vibration of benzene rings.

For compound 8h, Single crystal suitable for the X-ray diffraction analysis was obtained by slow evaporation of its hydrous ethanol solution. Crystal data and structure refinements are given in Table-1, while Fig. 1 clearly shows the crystal molecular structure. Selected bond lengths and angles are listed in Table-2, and hydrogen bond lengths bond and angles were given in Table-3.

Single crystal X-ray analysis further confirmed the success of the esterification reaction between the gallic acid and 1-hydroxyethyl 2-substituted phenoxymethyl benzimidazole. As shown in Fig. 1, the carbonyl carbon (C17) is connected to the hydroxyl oxygen (O2) to form the ester bond. Notably, the three moieties of compound 8h, namely, benzimidazole, substituted phenoxymethyl and gallate units, are not co-plane, and the formed intersection angles between these three planes are 59.23o, 75.56o and 19.60o, respectively. The bond lengths of C16-O2, C17-O2 and C17-O3 are 1.445(3) A, 1.334(3) A and 1.208(3) A, respectively, while the bond angles of C17-O2-C16, O3-C17-O2 and O2-C17-C18 are 116.1(2) o, 122.2(3) o and 113.4(2) o, respectively.

Furthermore, many intramolecular and intermolecular hydrogen bonds were observed in the unit cell of 8h. Specifically, there exists an intramolecular oxy-hydrogen linkage (O6-H6...O5) between hydroxyl oxygen (O5) and adjacent hydrogen (H6) with bond length of 2.273 A and bond angle of 113.55o, while another oxy-hydrogen linkage (C16-H16A...O1) was found between ether oxygen (O1) atom and the methylene hydrogen (H16A) of ester group, and its bond length is 2.566 A and bond angle is 128.72o. Five intermolecular hydrogen bonds, namely oxy-hydrogen linkages of C6-H6...O61, C15-H15B.O52, C19-H19...O33 and O4-H4...O34, and nitrogen-hydrogen linkage of O5-H5...N25 were also observed, their bond lengths are successively 2.563 A, 2.604 A, 2.556 A, 2.047 A and 1.875 A, and their bond angles are 160.86 o, 139.70 o, 132.68 o, 168.61 o and 176.21 o, respectively.

Table-1: Crystal data and structure refinement details for 8h.

Formula###C23H19BrN2O6###Formula weight###499.31

Temperature/K###293.15###Crystal system###monoclinic

Space group, F(000)###P21/n, 1016.0###Icalcmg/mm3, u/mm-1###1.594, 2.021,

a/A, b/A, c/A###11.6438(8), 12.6705(5), 15.0164(8)###Crystal size/mm3###0.4 x 0.4 x 0.25

[alpha]/Adeg, [beta]/Adeg, I3/Adeg###90, 110.136(7), 90###Volume/A3, Z###2080.0(2), 4

Radiation###MoK[alpha](I>> = 0.71073 A)###2I, range for data collection###5.78 to 52.746Adeg

Index ranges###-13 a$? h a$? 14, -15 a$? k a$? 15, -17 a$? l a$? 18###Reflections collected###9123

Independent reflections###4250[Rint= 0.0238, Rsigma= 0.0464]###Data/restraints/parameters###4250/0/292

Final R indexes [all data]###R1=0.0835, wR2=0.0946###Goodness-of-fit on F2###1.004

Final R indexes [I[greater than or equal to]2I(I)]###R1=0.0434, wR2=0.0805###Largest diff. peak/hole/eA-3###0.38/-0.55

Table-2: Selected bond lengths (A) and angles (Adeg) for 8h.

Bond###Length (A)###Bond###Length (A)###Bond###Length (A)

Br 1-C12###1.897(3)###C16-O2###1.445(3)###C17-O2###1.334(3)

C17-O3###1.208(3)###C17-C18###1.481(4)###C7-N1###1.358(3)

C7-N2###1.324(3)###C15-N1###1.457(3)###C1-N1###1.391(3)

C2-N2###1.387(3)###C20-O4###1.376(3)###C21-O5###1.365(3)

C22-O6###1.369(3)###C9-O1###1.374(3)###C8-O1###1.423(3)

Angle###(Adeg)###Angle###(Adeg)###Angle###(Adeg)

C11-C12-Br 1###119.4(2)###C13-C12-Br 1###120.4(2)###O3-C17-O2###122.2(3)

O3-C17-C18###124.3(3)###O2-C16-C15###107.6(2)###C17-O2-C16###116.1(2)

O2-C17-C18###113.4(2)###N1-C15-C16###113.0(2)

Table-3: Hydrogen bond lengths (A) and bond angles (Adeg) for 8h.

D - H ... A###D-H(A)###H...A(A)###D...A(A)###max of the ligand 8h and Cr(NO3)3 are 300 and 299 nm, respectively. This absorption at 301 nm corresponds to the I-I* transition that is known for both substituted benzene and NO3 units. The peak corresponding to the d-d* transition of NO3 group was observed in the complex as two shoulders at 350 and 400 nm, respectively, which shows the existence of NO3 unit in the molecular structure of the complex.

The TG and DTG curves of the Cr(III) complex were drawn in the range of 40-800 AdegC, and six obvious weight-loss bands were observed (Fig. 4). The first weight-loss band was found at 100-106 AdegC with the weight-loss ratio of 4% or so, and probably caused by the loss of free water. In the range of 106-127 AdegC, another about 4% weight is decreased, and it can be assigned the loss of hydrogen-binding water in the complex. The weight-loss at 127-152 AdegC is also 4% and resulted from the split of NO3 units, while the 3% weight loss at 152-211 AdegC is a sign of losing water coordinating with chromium atom. The last two weight-loss bands, 211-271 AdegC and 271-341 AdegC, resepctivley, can be attributed to the loss of two ligand units. Finally, residual 8% weight is retained.

Also, elemental analysis provided helpful information for the structural deduction of the Cr(III) complex. As shown in Fig 5, a possible molecular structure for the Cr(III) complex of 8h was drawn according to the data analysis for the above various tests. The molecular formula is C46H48N5O22Br2Cr, and the calculated molecular weight is 1234.70. The contens of C, H and N are 44.75%, 3.92% and 5.67%, respectively, and these vaules are very close to the found results of 46.14%, 4.39% and 6.02%. The errors may be caused by the little residual ethanol whose presence was confirmed by the small peaks in the 1H-NMR spectrum of the complex. The sturcrtue in Fig. 5 can adequately explain the weight-loss features in Fig. 4, and the calculated residual weight is 6.2% as Cr2O3 [54] that is close to the observed 8% or so. Furthermore, the hydrogen bonds between the uncoordinated hydroxy group and water probably resulted in the lack of detection for these O-H protons in the 1H-NMR spectrum of the complex.

Conclusion

Following the successive N-hydroxyethylation and indirect esterification reactions, the active structure of gallic acid ester was successfully attached to the N (or 1) positon of benzimidazole to get eight target compounds of 1-ethyl gallate-2-substituted phenoxymethyl benzimidazoles. The antimicrobial activities of these compounds can be regulated by changing the substituent groups in the phenoxymethyl portion, and specifically, the electron-drawing groups such as Cl and Br at meta- or para-postions can improve their antimicrobial activities, while substituent groups with electron-donating property at ortho-position will exhibit the opposite effect. Moreover, a target compound 8h can be used as a ligand to coordinate with Cr(III) salt, and in the obtained complex, adjacent hydroxyl groups of two 8h molecules, nitrate and H2O take part in the direct coordination with Cr(III) atom.

Supplementary material

Crystallographic data for the compound 8h has been deposited in the Cambridge Crystallographic Data Centre with the deposition number of CCDC 1482283. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data request/cif, by e-mailing data request@ccdc.cam.ac.uk or by contacting the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033.

Acknowledgements

The project is financially supported by the National Science Foundation of China (No. 21106088) and the Ph. D. Programs Foundation of Ministry of Education of China (No. 20110181120079).

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Author:Zhao, Li; Qiu, Guirong; Wu, Jiacheng; Wang, Zhiyuan; Gu, Haibin
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Date:Aug 31, 2017
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