YANG Go-Shn LIU Chong-Bo② LI Heng-Nong

CHEN Yuana HUANG De-Hea WEN Hui-Liangb

a (College of Environment and Chemical Engineering,Nanchang Hangkong University, Nanchang 330063, China)

b (State Key Laboratory of Food Science and Technology,Nanchang University, Nanchang 330047, China)

1 INTRODUCTION

Schiff bases were widely investigated because of their excellent pharmaceutical activities as antibacterial[1-6], antifungal[1,3], anticancer[7,8], antitubercular[9], antiviral[7,10], anticonvulsant[11]and antimalarial agents[12]. Many researchers studied the synthesis, characterization and structure-activity relationships of Schiff base compounds[13,14]. In particular, more attention has been paid to heterocyclic Schiff base compounds with pyridine or furanyl rings owning to their superb biological activities.For example, pyridine-2,6-carboxamide-derived Schiff bases had significant antibacterial activities against the Bacillus subtilis, Staphylococcus aureus,Escherichia coli, Candida albicans and Aspergillus niger[15]; Schiff bases derived from 2,6-bis(2- and 4-formylaryloxymeth-yl)pyridines exhibited favourable activity against the human malignant tumors[16];N,N-bis(furan-2-ylmethylene)benzene-1,2-diamine and their metal compounds showed a remarkable biological activity against different types of grampositive and gram-negative bacteria[17]; and furan-2-carboxaldehyde4-phenyl-3-thiosemicarbazone and their metal compounds were tested for their antitumour activity against the human cervical cancer cell line[18]. Recently, in our previous work, four heterocyclic Schiff base compounds have been synthesized and studied for their antibacterial activities on Escherichia coli, Staphylococcus aureus and Bacillus subtilis[19]. In view of these observations and in continuation of our previous work in heterocyclic chemistry, we synthesized two Schiff base derivatives containing pyridine and furanyl rings for the evaluation of antimicrobial activity, and the crystal structures of them were also studied in the article.

2 EXPERIMENTAL

2. 1 Reagents and apparatus

All reagents were commercially available and used without further purification. Melting points were determined on a Micromelting point apparatus without correction. Elemental analyses of C, H and N were carried out with an Elementar Vario EL analyzer. Infrared spectra were recorded with a Nicolet Avatar 360 FT-IR spectrometer using the KBr pellet technique. Mass spectra were taken on an Agilent Liquid chromatography-mass spectrometry 6340 series instrument in the electrospray ionization(positive electrospray ionization)mode.

2. 2 Synthesis of 1

Compound 1 was prepared according to the literature[20]. Yellow crystals were obtained upon recrystallization from ethanol in 83.5% yield. m.p.: 191～193 ℃. Anal. Calcd. (%)for C12H10N2O: C, 72.71;H, 5.08; N, 14.13. Found (%): C, 72.65; H, 5.14; N,14.33. IR (KBr pellet, cm-1): 3421 (m, -OH), 3331(w), 1630 (vs, -C=N), 1594 (m), 1570 (m), 1516 (s),1232 (w), 1140 (w), 1053 (w), 756 (w), 654 (w).ESI-MS: m/z 199.1 [M+H+].

2. 3 Synthesis of 2

A mixture of 3-(2-furyl)acrolein (3.05 g, 25 mmol)and p-phenylenediamine (1.08 g, 10 mmol)in ethanol (30 mL)was stirred under reflux for 2 h at 50 ℃. The precipitated product was filtered, and large yellow organic crystals suitable for X-ray structure determination were obtained by recrystallization in ethanol by the slow evaporation at room temperature. Yield: 77.2%, m.p.: 199～201 ℃.Anal. Calcd. (%)for C20H16N2O2: C, 75.93; H, 5.10;N, 8.86. Found (%): C, 75.77; H, 5.12; N, 8.43. IR(KBr pellet, cm-1): 3136 (w, C=C), 1624 (m, -C=N),1590 (vs), 1487 (s), 1385 (w), 1259 (m), 1203 (w),1156 (s), 1073 (w), 1016 (m), 983 (m), 807 (m), 746(m). ESI-MS: m/z 317.1 [M+H+].

2. 4 X-ray crystal structure determination

The X-ray single-crystal data of compounds 1 and 2 were recorded on a Bruker APEX II area detector diffractometer equipped with a graphite-monochromatic Mo-Ka radiation (λ = 0.71073 ?)at 296(2)K.Semi-empirical absorption corrections were applied to the title compounds using the SADABS program[21]. The structures were solved by direct methods[22]and refined by full-matrix least-squares on F2using SHELXL-97[23]. All non-hydrogen atoms were refined anisotropically. The hydroxy hydrogen atom was located from difference Fourier maps, and the other hydrogen atoms were placed in the geometrically calculated positions. For 1, a yellow crystal with dimensions of 0.25mm × 0.22mm ×0.17mm was selected for X-ray analyses and a total of 7487 reflections were collected with 1890 unique ones (Rint= 0.0271)in the range of 2.90≤θ≤25.50o.The final R = 0.0371, wR = 0.0929 (w = 1/[σ2(Fo2)+(0.0530P)2+ 0.1049P], where P = (Fo2+ 2Fc2)/3)for 1497 observed reflections with I ＞ 2σ(I)), S = 1.060,(Δ/σ)max= 0.001, (Δρ)max= 0.148 and (Δρ)min=–0.243 e/?3. For 2, a yellow crystal with dimensions of 0.40mm × 0.30mm × 0.20mm was selected for X-ray analyses and a total of 8569 reflections were collected with 2883 unique ones (Rint= 0.0349)in the range of 2.96≤θ≤25.99o. The final R = 0.0526,wR = 0.1267 (w = 1/[σ2(Fo2)+ (0.0605P)2+8.2959P], where P = (Fo2+ 2Fc2)/3)for 2059 observed reflections with I ＞ 2σ(I)), S = 1.116,(Δ/σ)max= 0.000, (Δρ)max= 0.319 and (Δρ)min=–0.280 e/?3. And the selected bond lengths and bond angles are given in Table 1. The hydrogen bond lengths and bond angles are listed in Table 2.

Table 1. Selected Bond Lengths (?)and Bond Angles (°)for Compounds 1 and 2

Table 2. Hydrogen Bond Lengths (?)and Bond Angles (°)for Compounds 1 and 2

2. 5 Antibacterial testing

Preliminary in vitro tests for antibacterial activity of all compounds have been carried out by disk diffusion method. The antibacterial activities of compounds 1 and 2 against Escherichia coli, Sta- phylococcus aureus and Bacillus subtilis have been investigated at the dosages of 1, 5, 10, 15, 20 and 25 mg/mL, respectively, with the solvent of DMF. The disks with the tested substances and the blank(solvent)were added onto Petri dishes inoculated with the tested bacterial strains. After cultivation at 37 ℃ for 24 h, the diameters of the zones of inhibition were determined and DMF was inactive under the applied conditions.

3 RESULTS AND DISCUSSION

3. 1 Crystal structure of compound 1

Compound 1 crystallizes in the monoclinic space group P21/c. The asymmetric unit of 1 only consists of one 2-[(4-pyridylmethylene)-amino]phenol molecule, as shown in Fig. 1. The dihedral angle between benzene and pyridine rings is 61.56(5)°. The bond length of C(7)–N(1)(1.263(2)?)is shorter than the length of normal C–N (1.47 ?)and very close to that of C=N (1.279(1)?)[24]and C=N (1.267(4)?)[25],which is indicative of the significant double bond character. Overall bond distances and angles were found to correspond well with those of related compounds[24,25]. There is one kind of intramo- lecular hydrogen bonding interaction (O(1)–H(1)··N(1))in compound 1 (Fig. 1 and Table 2), and 2-[(4-pyridylmethylene)-amino]phenol molecules are joined into a 1D chain through C(3)–H(3)··O(1)hydrogen bonds (Fig. 2a), which are interlinked to produce a 2D structure through O(1)–H(1)··N(2)hydrogen bonds, in which the left- and right-handed helical chains can be observed (Fig. 2b). The repeating unit can be described as (-O(1)–C(1)–C(2)–C(3)–H(3)··O(1)–C(1)–C(2)–C(3)–H(3)-)n, and the pitch of the helix running along the b axis is the same as its length (7.282(1)?). In addition, two kinds of π-π interactions were observed between the pyridine rings. One kind of π-π interactions with the centroidto-centroid distance of 3.7638(9)? exist in the same layer, and another kind of π-π interactions with the centroid-to-centroid distance of 3.9599(9)? link the adjacent layers to form a 3D supramolecular structure (Fig. 2c).

Fig. 1. Asymmetric unit of 1 with displacement e llipsoids drawn at 30% probability level

3. 2 Crystal structure of compound 2

Compound 2 crystallizes in the orthorhombic space group Fdd2. The asymmetric unit of 2 only consists of one N,N?-bis(3-(furan-2-yl)allylidene)benzene-1,4-diamin molecule and is shown in Fig. 3.The structure for diimine displays an inversion center within the central benzene ring. The molecule adopts a typical “zigzag” or trans conformation along the imine (C(7)–N(1), C(14)–N(2))bond.Likewise, the furanyl rings adopt trans conformation with respect to each other. The dihedral angle between furanyl rings I (C(1), C(2), C(3), C(4), O(1))and II (C(17), C(18), C(19), C(20), O(2))is 5.54(13)°. The benzene ring forms dihedral angles of 16.55(13)and 12.44(12)° with the furanyl rings I and II, respectively. The aromatic nature of the furanyl rings is evident, with the C(1)–C(2)and C(3)–C(4)double bond lengths at 1.330(7)and 1.349(5)?, respectively[26]. The greater single bond character for the C(2)–C(3), C(4)–C(5)and C(6)–C(7)bonds is also obvious, with bond lengths in 1.414(6), 1.432(4)and 1.436(4)?, respectively. The distance of C(5)–C(6)(1.324(5)?)is very close to that of normal C=C (1.32 ?), which is indicative of the significant double bond character. The bond length of C(7)–N(1)(1.281(4)?)is shorter than the value of normal C–N (1.47 ?)and very close to that of C=N (1.281(2)?)[27]. In compound 2, the molecules are linked into a 1D chain through C(1)–H(1)··N(1)hydrogen bonds (Fig. 4).

Fig. 2. (a)View of the 1D chain structure in compound 1 along the a axis. (b)View of left- and right-handed helical chains in the 2D structure of 1 along the a axis. (c)3D supramolecular structure of 1 along the b axis

Fig. 3. Asymmetric unit of 2 with displacement ellipsoids drawn at 30% probability level

Fig. 4. View of the 1D chain structure in compound 2 along the c axis

3. 3 Testing of the antibacterial activities

The inhibition zones were measured in cm and the data of antibacterial activities are summarized in Table 3, which indicate that the title compounds display excellent antibacterial activities against the tested bacteria and compound 1 was found to be more active against all the test bacteria probably due to the presence of hydroxyl group. The higher concentration of the test samples, the more active against the tested bacteria.

Table 3. Antibacterial Activity Data of Compounds 1 and 2

4 CONCLUSION

In this study, two heterocyclic Schiff bases were prepared and mainly structurally characterized by X-ray diffraction. The molecular structures and intramolecular hydrogen bonding interactions of the title compounds were studied. Antibacterial activity testing showed that the synthesized Schiff base compounds displayed excellent antibacterial activities to the three bacteria, and the antibacterial activities increased with the increase of concentration.

(1)Ashraf, M. A.; Mahmood, K.; Wajid, A. Synthesis, characterization and biological activity of Schiff bases. International Conference on Chemistry and Chemical Process 2011, 10, 1–7.

(2)Nair, R.; Shah, A.; Baluja, S.; Chanda, S. Synthesis and antibacterial activity of some Schiff base complexes. J. Serb. Chem. Soc. 2006, 71, 733–744.(3)Karamunge, K. G.; Vibhute, Y. B. Synthesis and antimicrobial activity of some new Schiff bases. Journal of Physics: Conference Series 2006, 423,1–5.

(4)Zhu, Y. C.; Liu, X. P.; He, D. H.; Wu, W. D. Synthesis, crystal structure and antibacterial activity of 4,4?-hydrazine-1,2-diylidenebis(methanylylidene)bis(2-ethoxyphenol). Chin. J. Struct. Chem. 2013, 32, 1245–1249.

(5)Zhang, L.; Li, K. L. Synthesis, crystal structure and antimicrobial property of 4-bromo-2-[(3-methypyridin-2-ylimino)methyl]phenol. Chin. J. Struct.Chem. 2008, 27, 230–232.

(6)Asiri, A. M.; Khan, S. A. Synthesis and anti-bacterial activities of some novel Schiff bases derived from aminophenazone. Molecules 2010, 15,6850–6858.

(7)Cerchiaro, G.; Ferreira, A. M. D. Oxindoles and copper complexes with oxindole-derivatives as potential pharmacological agents. Journal of the Brazilian Chemical Society 2006, 17, 1473–1485.

(8)Pandeya, S. N.; Smitha, S.; Jyoti, M.; Sridhar, S. K. Biological activites of isatin and its dervatives. Acta Pharm. 2005,55, 27–46.

(9)Bhat, M. A.; Imran, M.; Khan, S. A.; Siddiqui, N. Biological activities of sulfonamides. J. Pharm. Sci. 2005, 67, 151–159.

(10)Karthikeyan, M. S.; Prasad, D. J.; Poojary, B.; Bhat, K. S.; Holla, B. S.; Kumari, N. S. Synthesis and biological activity of Schiff and Mannich bases bearing 2,4-dichloro-5-fluorophenyl moiety. Bioorg. and Med. Chem. 2006, 14, 7482–7489.

(11)Prakash, C. R.; Raja, S.; Saravanan, G. Synthesis, characterization and anticonvulsant activity of novel Schiff base of isatin derivatives. International Journal of Pharmacy and Pharmaceutical 2010, 2, 177–181.

(12)Li, Y.; Yang, Z. S.; Zhang, H.; Cao, B. J.; Wang, F. D.; Zhang, Y.; Shi, Y. L.; Yang, J. D.; Wu, B. A. Artemisinin derivatives bearing Mannich base group: synthesis and antimalarial activity. Bioorg. and Med. Chem. 2003, 11, 4363–4368.

(13)Ren, S. J.; Wang, R. B.; Komatsu, K.; Bonaz-Krause, P.; Zyrianov, Y.; Mckenna, C. E.; Csipke, C.; Tokes, Z. A.; Lien, E. J. Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide as potential antitumor agents. J.Med. Chem. 2002, 45, 410–419.

(14)Shi, L.; Ge, H. M.; Tan, S. H.; Li, H. Q.; Song, Y. C.; Zhu, H. L.; Tan, R. X. Synthesis and antimicrobial activities of Schiff bases derived from 5-chloro-salicylaldehyde. Eur. J. Med. Chem. 2007, 42, 558–564.

(15)Al-Omar, M. A.; Amr, A. E. Synthesis of some new pyridine-2,6-carboxamide-derived Schiff bases as potential antimicrobial agents. Molecules 2010,15, 4711–4721.

(16)Kuz’min, V. E.; Lozitsky, V. P.; Kamalov, G. L.; Lozitskaya, R. N.; Zheltvay, A. I.; Fedtchouk, A. S.; Kryzhanovsky, D. N. Analysis of the structure-anticancer activity relationship in a set of Schiff bases of macrocyclic 2,6-bis(2- and 4-formylaryloxymethyl)pyridines. Acta Biochim.Polon. 2000, 47, 867–875.

(17)Mohamed, G. G.; Omar, M. M.; Hindy, A. M. Metal complexes of Schiff bases: preparation, characterization, and biological activity. Turk. J. Chem.2006, 30, 361–382.

(18)Rajendran, G.; Amritha, C. S.; Anto, R. J.; Cheriyan, V. T. Synthesis, thermal and antitumour studies of Th(IV)complexes with furan-2-carboxaldehyde4-phenyl-3-thiosemicarbazone. J. Serb. Chem. Soc. 2010, 75, 749–761.

(19)Liu, C. B.; Chen, Y.; Yan, L. S.; Huang, D. H.; Xiong, Z. Q. Syntheses, characterization, and antibacterial activities of four new Schiff base compounds derived from 1-phenyl-3-methyl-4-benzoyl-2-pyrazolin-5-one. Journal of Heterocyclic Chemistry 2012, 49, 839–844.

(20)Demir, H. ?.; Kaya, ?.; Sa?ak, M. The oxidative polycondensation of 2-[(4-pyridilmethylene)-imino]phenol by molecular O2in alkaline medium:synthesis and characterization. Polymer Bulletin 2008, 60, 37–48.

(21)Sheldrick, G. M. SADABS. Program for Empirical Absorption Correction of the Area Detector Data. University of G?ttingen, Germany 1997.

(22)Sheldrick, G. M. SHELXS-97. Program for Crystal Structure Solution. University of G?ttingen, Germany 1997.

(23)Sheldrick, G. M. SHELXL-97. Program for Crystal Structure Refinement. University of G?ttingen, Germany 1997.

(24)Doleck, T.; Attard, J.; Fronczek, F. R.; Moskun, A.; Isovitsch, R. Structure and photophysics of a Schiff base-bipyridine ligand and its rhenium(I)tricarbonylchloro complex. Inorg. Chim. Acta 2009, 362, 3872–3876.

(25)Maury, O.; Guégan, J. P.; Renouard, T.; Hilton, A.; Dupau, P.; Sandon, N.; Toupet, L.; Bozee, H. L. Design and synthesis of 4,4?-π-conjugated[2,2?]-bipyridines: a versatile class of tunable chromophores and fluorophores. New J. Chem. 2001, 25, 1553–1566.

(26)Wang, S. J.; Gu, Q.; Su, Q.; Chen, X. D.; Zhang, Y. M. 2,4,5-Tri-2-furyl-1H-imidazole. Acta Cryst. 2009, E65, o3194.

(27)Tice, N. C.; Armstrong, J. R.; Maddox, J. B.; Ward, S. A.; Snyder, C. A.; Young, J. O. E. Synthesis, structure, and theoretical calculations of a furan-based molecular wire, N-[4-(2-furanylmethyleneamino)benzylidene]furan-2-amine. Heterocycles 2012, 85, 821–834.