Jordan Journal of Chemistry Vol. 9 No.3, 2014, pp. 170-186 JJC Green Synthesis, Crystal Structure and Bioactivity of C-(p- substituted phenyl)calix[4]resorcinarenes-DMSO Inclusion Complexes Solhe F. Alshahateeta, Salah A. Al-Trawneha, Wael A. Al-Zereinib, Saad S. Al-Sarhana aDepartment of Chemistry, Mutah University, P.O. BOX 7, Mutah 61710, Alkarak, Jordan bDepartment of Biological Sciences, Mutah University, P.O. BOX 7, Mutah 61710, Alkarak, Jordan Received on April 24, 2014 Accepted on Jun. 26, 2014 Abstract Green synthesis of calix[4]resorcinarene hosts with p-substituted phenyl group at their methine carbons was achieved. Fluorine, chlorine and bromine atoms, as well as methoxy group, were selected as substituents at the para position of the benzaldehyde which was condensed with resorcinol in presence of solid p-toluenesulfonic acid. The solid state structures of the newly prepared C-(p-fluorophenyl)calix[4]resorcinarene-DMSO and C-(p-chlorophenyl)- calix[4]resorcinarene-DMSO inclusion complexes were determined by single-crystal X-ray diffraction and found to form different structural conformations; chair (C2h) and boat (C2v), respectively. In addition, both crystal structures adopted several intermolecular noncovalent supramolecular interactions which were carefully investigated and presented in terms of crystal engineering and supramolecular chemistry. The synthesized C-(p-substitutedphenyl)calix[4]- resorcinarene hosts inhibited the growth of Gram-positive bacteria with the C-(p-bromophenyl)- calix[4]resorcinarene derivative being the most potent agent (MIC=15.6-125 μg/ml). Keywords: C-(p-substituted phenyl)calix[4]resorcinarenes-DMSO inclusion complex; Boat conformation; Chair conformation; Crystal structure; Bioactivity; Non-covalent interactions. Introduction Non-covalent intermolecular interactions of multicomponent crystalline compounds are of great interest to chemists due to their wide-range uses and application areas such as energy storage, drug delivery and separation technology.[1] Calix[4]resorcinarenes represent a class of macrocyclic molecules used as potential lattice hosts for different guests.[2] In crystal engineering and supramolecular chemistry, understanding the intermolecular interactions between molecules is very important and crucial to understanding many biological processes.[3-11] Through this understanding, chemists hope to predict both the industrial applications and the properties of any given crystalline solid material. Research work on different calix[4]resorcinarenes and proposing new efficient and green methods for their Corresponding author: e-mail: [email protected] 170 preparation is worldwide conducted.[12-21] Design and preparation of different types of lattice host molecules and investigating their ability to form different forms of crystalline materials with different potential applications are, therefore, of our main interest.[22-38] Compounds 6-9 were reported in literature to be prepared in alcoholic acid catalyzed solutions as a mixture of two conformers; chair and boat were formed.[13,15-20] In this work, the selective solvent-free formation of one isomeric product and the bioactivity of C-(p-substituted phenyl)calix[4]resorcinarenes hosts 6-9 (Scheme 1) is reported. In addition, the new 6·(DMSO)8 and 8·(DMSO)8 lattice inclusion complexes were prepared and their crystal structures were determined using X-ray crystallography. The intermolecular interactions were carefully discussed and presented in terms of supramolecular chemistry. R R c HO d OH O H b a OH HO OH + OH R HO OH HO OH 1 R = Cl R R 2 R = Br 3 R = F 5 6-9 4 R = OCH3 Scheme 1: Synthetic route for C-(p-substitutedphenyl)calix[4]resorcinarene 6-9.[36] Experimental Materials and physical measurements All solvents were purchased as analytical reagent grade. Melting points were measured on a Stuart scientific melting point apparatus in open capillary tubes. The infrared spectra were recorded over the range of 4000-500 cm-1 on a Maltson 5000 FTIR spectrometer. 1H-NMR and 13C-NMR measurements were conducted on a Bruker 500 MHz. Chemical shifts were referenced to TMS as the internal standard and deuterated dimethylsulfoxide (DMSO-d6) as the solvent. In all of the compounds reported, the internal aromatic proton in the cavity could not be observed by NMR in the indicated solvent; this might be attributed to ring current effects. Similar findings were observed in our previous related work.[38] X-ray single crystal structure determination was accomplished using a Bruker SMART APEX-1000 diffractometer. General procedure for the synthesis of compounds 6-9 171 A solvent-free procedure was applied to synthesize compounds 6-9 in very good yields.[36] Equimolar amounts of resorcinol (1 mol) and p-substituted benzaldehyde (1 mol) 1-4 were ground in the presence of solid p-toluenesulfonic acid (0.05 mol) as a catalyst using a mortar and pestle. The reactants melted on grinding but thereafter the contents solidified. The reaction mixture was ground again, washed with water, filtered and dried to give compounds 6-9 in excellent yields (90-95 %). The products obtained were identical with those obtained through reactions in acidic solutions.[13,15-20] Preparation of C-(4-chlorophenyl)calix[4]resorcinarene 6 4-Chlorobenzaldehyde and resorcinol (1:1) were mixed together in presence of a catalytic amount of p-toluenesulfonic acid (0.05 mol) and processed as described above. Spectral data were: IR (KBr), cm-1: 3435, 2912, 1620, 1510, 1489, 1429, 1209, 1 3 1078, 1014, 552; H-NMR (500 MHz, DMSO-d6), (ppm) 8.69 (br, 8H, OH), 7.05(d, J 3 = 8.5 Hz, 8H, Ha), 6.63 (d, J = 8.5 Hz, 8H, Hb), 6.19 (br, 4H, Hd), 5.62 (s, 4H, H- 13 benzylic).; C-NMR (125 MHz, DMSO-d6), δ (ppm): 41.4, 102.5, 120.3, 127.5, 129.9, 130.4, 145.3, 155.3. Elem. Anal. Calcd for C52H36Cl4O8: C, 67.11; H, 3.90. Found: C, 67.34; H, 3.92. Direct crystallization of compound 6 from fresh DMSO yielded crystals of the lattice inclusion compound that were suitable for single-crystal X-ray study. Preparation of C-(4-bromophenyl)calix[4]resorcinarene 7 4-Bromobenzaldehyde and resorcinol (1:1) were mixed together in presence of a catalytic amount of p-toluenesulfonic acid (0.05 mol) and processed as described above. Spectral data were: IR (KBr), cm-1: 3441, 2901, 1618, 1508, 1485, 1429, 1402, 1 1240, 1209, 1078, 1011, 550m; H-NMR (500 MHz, DMSO-d6), (ppm) 8.70 (s, 8H, 3 3 OH), 7.19 (d, J = 8.5 Hz, 8H, Ha), 6.58 (d, J = 8.5 Hz, 8H, Hb), 6.18 (br, 4H, Hd), 5.61 13 (s, 4H, H-benzylic); C-NMR (125 MHz, DMSO-d6), δ (ppm): 41.4, 102.6, 118.3, 120.2, 128.6, 130.5, 130.9, 145.8, 153.7. Elem. Anal. Calcd for C52H36Br4O8: C, 56.34; H, 3.27. Found: C, 56.17; H, 3.28. Preparation of C-(4-fluorophenyl)calix[4]resorcinarene 8 4-Fluorobenzaldehyde and resorcinol (1:1) were mixed together in presence of a catalytic amount of p-toluenesulfonic acid (0.05 mol) and processed as described above. Spectral data were: IR (KBr), cm-1: 3412, 2930, 1605, 1508, 1431, 1213, 1159, 1 3 1076, 553; H-NMR (500 MHz, DMSO-d6), (ppm) 8.63 (s, 8H, OH), 6.80 (t, JH-H = 8.4 3 3 Hz, 8H, Ha), 6.65 (dd, JH-F = 8.5 Hz, JH-H = 8.4 Hz, 8H, Hb), 6.17 (br, 4H, Hd), 5.63 (s, 13 2 4H, H-benzylic).; C-NMR (125 MHz, DMSO-d6), δ (ppm): 41.3, 102.6, 114.1 (d, JC-F 3 1 = 21 Hz), 120.8, 130.3 (d, JC-F = 8 Hz), 142.3, 153.2, 160.5 (d, JC-F = 239 Hz). Elem. Anal. Calcd for C52H36F4O8: C, 72.22; H, 4.20. Found: C, 72.50; H, 4.23. Direct crystallization of compound 8 from fresh DMSO yielded crystals of the lattice inclusion compound that were suitable for single-crystal X-ray study. Preparation of C-(4-methoxyphenyl)calix[4]resorcinarene 9 172 4-Methoxybenzaldehyde and resorcinol (1:1) were mixed together in presence of a catalytic amount of p-toluenesulfonic acid (0.05 mol) and processed as described above. Spectral data were: IR (KBr), cm-1: 3408, 2891, 1609, 1510, 1429, 1246, 1208, 1 1180,1147, 1076, 1032; H-NMR (500 MHz, DMSO-d6), (ppm) 8.42 (s, 8H, OH), 7.19 3 3 (d, J = 8.4 Hz, 8H, Ha), 6.58 (d, J = 8.4 Hz, 8H, Hb), 6.24 (br, 4H, Hd), 5.61 (s, 4H, H- 13 benzylic); 3.72 (s, 3H, -OCH3); C-NMR (125 MHz, DMSO-d6), δ (ppm): 41.7, 55.1, 102.5, 113.0, 122.0, 129.9, 139.1, 153.8, 157.9. Elem. Anal. Calcd for C56H48O12: C, 73.67; H, 5.30. Found: C, 74.00; H, 5.32. Solution and refinement of the crystal structures Reflection data were measured at 223(2) K on a Bruker SMART APEX-1000 diffractometer equipped with a CCD detector and Mo-Kα sealed tube. SMART was used for collecting frame data, indexing reflection, determination of lattice parameters, integration of intensity of reflections and scaling. SADABS was used for absorption correction and SHELXTL for space group, structure determination, and least-square refinements on F2.[39-41] All non-hydrogen atoms were assigned anisotropic displacement parameters in the refinement. All hydrogen atoms were added at calculated positions and refined using a riding model. Supplementary data Crystallographic data for the structural analysis reported in this paper have been deposited in the Cambridge Structural Data Centre, CCDC, Numbers (915290- 915291). Copies of the information may be obtained free of charge from Director, CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033; email: [email protected].