Methods
Single-crystal structure analysis
Crystals for X-ray of 2d and 2e (polymorph 2) were obtained from a mixture of CH2Cl2/hexane, followed by slow evaporation in a refrigerator, while single crystals of compound 2e (polymorph 1) were prepared by recrystallization from CH3OH, which was allowed to slowly evaporate at room temperature. Single crystal diffraction data for compounds 2d and 2e (polymorph 1) were collected on a Nonius Kappa CCD diffractometer at room temperature with a MoKα radiation and graphite monochromator. The data were processed using the DENZO program. The data for compound 2e (polymorph 2) have been collected on a Agilent SuperNova dual source diffractometer with an Atlas detector at room temperature with MoKα radiation (0.71073 Å ) and processed using CrysAlis PRO software. All structures were solved with direct methods using SIR97. A full-matrix least-squares refinement on F2 was employed with anisotropic temperature displacement parameters for all non-hydrogen atoms for all compounds. The H atom from enol hydroxy groups and the H atom bonded to (C4) atom were located from difference Fourier map in all compounds. These hydrogen atoms were refined freely with their isotropic displacement parameters. In the case of 2e (polymorph 2) the paremeters of these H atoms were not refiened. The remaining H atoms of all three dimethoxy curcuminoid molecules were placed at idealized, calculated positions and treated as riding, with C–H = 0.93 for C(sp2) and 0.96 Å for methyl group and Uiso(H) = 1.2Ueq(C) or 1.5Ueq(C) for C(sp2) and methyl group, respectively. Crystals of compound 2e (polymorph 1) also contain solvent molecules (methanol), which were located in the channels, running parallel c axis. These methanol molecules are disordered and consequently their H atoms were not located. The SHELXL97 program was used for structure refinement and interpretation. Drawings of the structures were produced using the ORTEP-3, Platon and Mercury programs. Details of the crystal data, data collection, and refinement parameters are listed in Figures 2, 4 and 5. Structural and other crystallographic data have also been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 858801 (2d, Additional file 3) & 858802 (2e polymorph 1, Additional file 4) & 934715 (2e polymorph 2, Additional file 5). A copy of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
XRD measurements
X-ray powder diffraction data of solid 1, 2 and 3 were collected using a PANalytical X'Pert PRO (HTK) diffractometer with CuKα radiation. The room temperature reflection data were acquired from 2Θ angles of 5° to 30° in steps of 0.034°.
Solid-state NMR measurements
NMR spectra of solid samples were recorded on a Varian NMR System 600 MHz NMR spectrometer equipped with 3.2 mm NB Double Resonance HX MAS Solids Probe. Larmor frequencies of protons and carbon nuclei were 599.64 MHz and 150.79, respectively. The 1H MAS NMR spectra were externally referenced using adamantane. The 13C CPMAS NMR spectra were externally referenced using hexamethylbenzene (HMB). All samples were spun at the magic angle with 20 kHz during 1H measurement and 16 kHz during 13C measurements. Proton spectra were acquired using a spin echo sequence. The repetition delay in all experiments was 5 s. The number of scans was 16. The pulse sequence used for acquiring carbon spectra was a standard cross-polarization MAS pulse sequence with high-power proton decoupling during acquisition. The repetition delay in all experiments was 5 s and the number of scans was between 1000 and 1620. A 2D 1H-13C HETCOR NMR spectrum was acquired at 16 kHz MAS. Ramp CP transfer with duration of 500 μs was used.
Theoretical calculation
A theoretical investigation of all species were optimized at the density functional (DFT) level of theory employing the B3LYP/6-31G(d,p) model. Complete geometry optimization was performed for the ground-state structures in the gas phase and CH2Cl2 solutions of all the molecular systems considered. For the optimized geometries, the Mulliken, natural, and electrostatic atomic charges from the electrostatic potential were calculated. The Spartan'08 suite of quantum chemical programs was used to perform all the calculations, molecular orbital diagrams for HOMOs and LUMOs, the graphic display of the electrostatic potential maps (isovalue = 0.02; property colors range from -90 to 65 kJ/mol ). Theoretical UV–vis spectra were computed by TDDFT/B3LYP/6-31G(d,p) model and visualized using Gaussian function.
Characterization of compounds
Absorption spectra were recorded with a Lambda 750 UV–vis spectrophotometer from Perkin Elmer. NMR Spectra were recorded at 302 K with a Bruker Avance DPX 300 spectrometer operating at 300 MHz and 75 MHz for 1H and 13C, and Bruker Avance III 500 spectrometer operating at 500 MHz and 126 MHz for 1H and 13C, respectively. Proton and carbon spectra were referenced to TMS as the internal standard. Chemical shifts are given on the δ scale (ppm). Coupling constants (J) are given in Hz. Mass spectra and high-resolution mass spectra were obtained with a Q-TOP Premier instrument. Data are reported as m/z (relative intensity). Infrared spectra were recorded on a BIO-RAD Excalibur Series spectrophotometer using samples in potassium bromide disks. Elemental analyses were performed with a Perkin-Elmer 2400 Series II CHNS/O Analyzer. All spectral data obtained for new compounds are reported here. Melting points were measured with a Büchi 535.
General procedure for 1,7-bis(dimethoxyphenyl)-1,6-heptadiene-3,5-dione
Corresponding dimethoxy benzaldehyde (3.32 g, 20 mmol) was dissolved in ethyl acetate (10–20 mL) and tributylborate (5.94 mL, 22 mmol) was added. The reaction mixure was heated to 75°C. 2,4-Pentanedione (1.03 mL, 10 mmol) and powdery boric anhydride (0.52 g, 7.5 mmol) were mixed separately, carefully heated with stirring to obtain a paste, and added to the mixture of dimethoxybenzaldehyde and tributyl borate. The reaction mixture obtained was heated with stirring for 4.5 hours at 75°C, then cooled to room temperature; n-butylamine (0.25 mL, 2.5 mmol) in ethyl acetate (2.5 mL) was then slowly added. Stirring at room temperature continued during the night. The reaction mixture was quenched with the addition of 0.4N HCl (15 mL), heated for 1 hour at 60°C, then cooled on ice, and the solid residue filtered off and washed several times with methanol. The products obtained (2a, 2.06 g (52%); 2b, 2.45 g (62%); 2c, 2.53 g (64%); 2d, 2.77 g (70%); 2e, 1.70 g (43%); 2f, 1.66 g (42%)) were pure enough to yield satisfactory spectroscopic data (see Additional file 1) and elemental analysis; no additional purification by flash chromatography was necessary.
General procedure for halogenations
Compound 2 (396 mg, 1 mmol) was dissolved in CH3CN (40 mL), LiClO4 (64 mg, 0.6 mmol) was added, and the resulting mixture was stirred 10 min at room temperature. An acetonitrile solution of NCS (147 mg, 1.1 mmol) or NBS (196 mg, 1.1 mmol) was slowly added and stirring continued for the corresponding time, given in Figure 11, at room temperature. The product precipitate was filtered off. The filtrate was evaporated and dissolved in methanol. After being refrigerated overnight, an additional quantity of pure product was obtained (in some cases, additional crystallization from the mixture of CH2Cl2/hexane was done). Overall yields of pure products are given in Figure 11.
(1E,6E)-1,7-bis(2,3-dimethoxyphenyl)-4-chloro-1,6-heptadiene-3,5-dione (3a)
Yellow-orange solid, mp 167.1–167.7°C. 1H NMR (CDCl3, 500 MHz) δ ppm 16.41 (s, –OH), 8.09 (d, 2H, J = 15.9), 7.50 (d, 2H, J = 15.9), 7.28 (dd, 2H, J = 8.0, J = 1.0), 7.09 (dd, 2H, J = 8.0, J = 8.0), 6.97 (dd, 2H, J = 8.0, J = 1.0), 3.90 (s, 6H), 3.89 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ ppm 180.5, 153.2, 148.9, 138.1, 129.2, 124.2, 121.2, 119.7, 114.3, 108.5, 61.4, 55.9. IR (KBr) ν = 1617, 1578, 1482, 1428, 1271, 1071, 998, 980, 735 cm–1. CIMS (m/z) 433.1 (MH+ +2), 431.1 (MH+). CI-HRMS for C23H24ClO6+: calcd 431.1261, found 431.1258. EA for C23H23ClO6: calcd 64.11%C, 5.38%H; found 64.31%C, 5.39%H.
(1E,6E)-1,7-bis(2,4-dimethoxyphenyl)-4-chloro-1,6-heptadiene-3,5-dione (3b)
Orange solid, mp 169.9–170.8°C. 1H NMR (CDCl3, 500 MHz) δ ppm 16.78 (s, –OH), 8.04 (d, 2H, J = 15.8), 7.58 (d, 2H, J = 8.6), 7.40 (d, 2H, J = 15.8), 6.54 (dd, 2H, J = 8.6, J = 2.3), 6.46 (d, 2H, J = 2.3), 3.90 (s, 6H), 3.86 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ ppm 180.6, 163.1, 160.3, 138.2, 130.5, 117.8, 117.4, 107.7, 105.6, 98.3, 55.6, 55.5. IR (KBr) ν = 1596, 1507, 1462, 1298, 1276, 1248, 1212, 1104, 1031, 970, 819 cm–1. CIMS (m/z) 433.1 (MH+ +2), 431.1 (MH+). CI-HRMS for C23H24ClO6+: calcd 431.1261, found 431.1250. EA for C23H23ClO6: calcd 64.11%C, 5.38%H; found 63.80%C, 5.26%H.
(1E,6E)-1,7-bis(2,5-dimethoxyphenyl)-4-chloro-1,6-heptadiene-3,5-dione (3c)
Yellow-orange solid, mp 188.2–188.8°C. 1H NMR (CDCl3, 500 MHz) δ ppm 16.52 (s, –OH), 8.09 (d, 2H, J = 15.8), 7.47 (d, 2H, J = 15.8), 7.16 (d, 2H, J = 3.0), 6.94 (dd, 2H, J = 9.0, J = 3.0), 6.87 (d, 2H, J = 9.0), 3.87 (s, 6H), 3.83 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ ppm 180.5, 153.6, 153.3, 138.4, 124.7, 120.5, 117.4, 113.5, 112.5, 108.4, 56.2, 55.9. IR (KBr) ν = 1610, 1579, 1496, 1288, 1269, 1053, 1020, 974, 847, 801 cm–1. CIMS (m/z) 433.1 (MH+ +2), 431.1 (MH+). CI-HRMS for C23H24ClO6+: calcd 431.1261, found 431.1262. EA for C23H23ClO6: calcd 64.11%C, 5.38%H; found 63.94%C, 5.25%H.
(1E,6E)-1,7-bis(2,6-dimethoxyphenyl)-4-chloro-1,6-heptadiene-3,5-dione (3d)
Yellow-orange solid, mp 159.0–160.3°C. 1H NMR (CDCl3, 500 MHz) δ ppm 16.77 (s, –OH), 8.23 (d, 2H, J = 16.0), 7.91 (d, 2H, J = 16.0), 7.28 (dd, 2H, J = 8.4, J = 8.4), 6.57 (d, 4H, J = 8.4), 3.92 (s, 12H). 13C NMR (CDCl3, 75 MHz) δ ppm 181.6, 160.3, 133.8, 131.5, 122.8, 113.2, 108.5, 103.7, 55.9. IR (KBr) ν = 1603, 1582, 1478, 1258, 1210, 1109, 1035, 735 cm–1. CIMS (m/z) 433.1 (MH+ +2), 431.1 (MH+). CI-HRMS for C23H24ClO6+: calcd 431.1261, found 431.1254. EA for C23H23ClO6: calcd 64.11%C, 5.38%H; found 64.22%C, 5.49%H.
(1E,6E)-1,7-bis(3,4-dimethoxyphenyl)-4-chloro-1,6-heptadiene-3,5-dione (3e)
Orange solid, mp 173.8–174.6°C. 1H NMR (CDCl3, 500 MHz) δ ppm 16.62 (s, –OH), 7.73 (d, 2H, J = 15.6), 7.27 (d, 2H, J = 15.6), 7.23 (dd, 2H, J = 8.3, J = 1.8), 7.14 (d, 2H, J = 1.8), 6.90 (d, 2H, J = 8.3), 3.96 (s, 6H), 3.94 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ ppm 180.1, 151.5, 149.3, 143.3, 128.1, 123.4, 117.6, 111.2, 110.3, 107.8, 56.0. IR (KBr) ν = 1600, 1512, 1423, 1346, 1263, 1164, 1141, 1024, 969, 804 cm–1. CIMS (m/z) 433.1 (MH+ +2), 431.1 (MH+). CI-HRMS for C23H24ClO6+: calcd 431.1261, found 431.1270. EA for C23H23ClO6: calcd 64.11%C, 5.38%H; found 64.19%C, 5.35%H.
(1E,6E)-1,7-bis(3,5-dimethoxyphenyl)-4-chloro-1,6-heptadiene-3,5-dione (3f)
Yellow solid, mp 159.2–159.6°C. 1H NMR (CDCl3, 500 MHz) δ ppm 16.34 (s, –OH), 7.70 (d, 2H, J = 15.6), 7.37 (d, 2H, J = 15.6), 6.76 (d, 4H, J = 2.1), 6.53 (dd, 2H, J = 2.1, J = 2.1), 3.84 (s, 12H). 13C NMR (CDCl3, 75 MHz) δ ppm 180.1, 161.1, 143.5, 136.8, 120.2, 108.4, 106.5, 102.9, 55.5. IR (KBr) ν = 1624, 1596, 1455, 1352, 1290, 1207, 1159, 1062, 966, 835 cm–1. CIMS (m/z) 433.1 (MH+ +2), 431.1 (MH+). CI-HRMS for C23H24ClO6+: calcd 431.1261, found 431.1266. EA for C23H23ClO6: calcd 64.11%C, 5.38%H; found 63.72%C, 5.21%H.
(1E,6E)-1,7-bis(2,3-dimethoxyphenyl)-4-bromo-1,6-heptadiene-3,5-dione (4a)
Yellow solid, mp 155.5–155.7°C. 1H NMR (CDCl3, 500 MHz) δ ppm 16.86 (s, –OH), 8.06 (d, 2H, J = 15.8), 7.58 (d, 2H, J = 15.8), 7.28 (dd, 2H, J = 8.0, J = 1.0), 7.09 (dd, 2H, J = 8.0, J = 8.0), 6.97 (dd, 2H, J = 8.0, J = 1.0), 3.90 (s, 6H), 3.89 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ ppm 181.3, 153.2, 148.9, 138.5, 129.1, 124.2, 123.1, 119.8, 114.3, 98.3, 61.4, 55.9. IR (KBr) ν = 1614, 1576, 1482, 1272, 1075, 1000, 975, 742 cm–1. CIMS (m/z) 477.1 (MH+ +2), 475.1 (MH+). CI-HRMS for C23H24BrO6+: calcd 475.0756, found 475.0747. EA for C23H23BrO6: calcd 58.12%C, 4.88%H; found 57.95%C, 4.79%H.
(1E,6E)-1,7-bis(2,4-dimethoxyphenyl)-4-bromo-1,6-heptadiene-3,5-dione (4b)
Brown-orange solid, mp 143.1–145.6°C. 1H NMR (CDCl3, 300 MHz) δ ppm 17.21 (s, –OH), 8.01 (d, 2H, J = 15.7), 7.56 (d, 2H, J = 8.6), 7.48 (d, 2H, J = 15.7), 6.54 (dd, 2H, J = 8.6, J = 2.3), 6.46 (d, 2H, J = 2.3), 3.90 (s, 6H), 3.86 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ ppm 181.5, 163.1, 160.3, 138.7, 130.7, 119.8, 117.4, 105.6, 98.4, 97.7, 55.6, 55.5. IR (KBr) ν = 1595, 1506, 1464, 1298, 1277, 1252, 1212, 1030, 968, 822 cm–1. CIMS (m/z) 477.1 (MH+ +2), 475.1 (MH+). CI-HRMS for C23H24BrO6+: calcd 475.0756, found 475.0776. EA for C23H23BrO6: calcd 58.12%C, 4.88%H; found 57.73%C, 4.69%H.
(1E,6E)-1,7-bis(2,5-dimethoxyphenyl)-4-bromo-1,6-heptadiene-3,5-dione (4c)
Yellow solid, mp 162.9–163.4°C. 1H NMR (CDCl3, 500 MHz) δ ppm 16.96 (s, –OH), 8.06 (d, 2H, J = 15.8), 7.55 (d, 2H, J = 15.8), 7.15 (d, 2H, J = 3.0), 6.94 (dd, 2H, J = 9.0, J = 3.0), 6.87 (d, 2H, J = 9.0), 3.88 (s, 6H), 3.83 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ ppm 181.4, 153.5, 153.3, 138.7, 124.6, 122.5, 117.4, 113.7, 112.5, 98.2, 56.2, 55.9. IR (KBr) ν = 1610, 1578, 1497, 1289, 1268, 1053, 1018, 972, 799 cm–1. CIMS (m/z) 477.1 (MH+ +2), 475.1 (MH+). CI-HRMS for C23H24BrO6+: calcd 475.0756, found 475.0760. EA for C23H23BrO6: calcd 58.12%C, 4.88%H; found 57.90%C, 4.80%H.
(1E,6E)-1,7-bis(2,6 -dimethoxyphenyl)-4-bromo-1,6-heptadiene-3,5-dione (4d)
Yellow-orange solid, mp 126.7–127.4°C. 1H NMR (CDCl3, 500 MHz) δ ppm 17.19 (s, –OH), 8.21 (d, 2H, J = 15.9), 8.00 (d, 2H, J = 15.9), 7.28 (dd, 2H, J = 8.4, J = 8.4), 6.57 (d, 4H, J = 8.4), 3.92 (s, 12H). 13C NMR (CDCl3, 126 MHz) enol form δ ppm 182.4, 160.3, 134.1, 131.5, 124.6, 113.1, 103.7, 98.6, 55.9; diketone form δ ppm 190.2, 160.7, 136.9, 132.3, 124.2, 112.1, 103.6, 57.5, 55.8. IR (KBr) ν = 1603, 1580, 1477, 1397, 1257, 1207, 1110, 1036, 737cm–1. CIMS (m/z) 477.1 (MH+ +2), 475.1 (MH+). CI-HRMS for C23H24BrO6+: calcd 475.0756, found 475.0752. EA for C23H23BrO6: calcd 58.12%C, 4.88%H; found 58.21%C, 4.78%H.
(1E,6E)-1,7-bis(3,4-dimethoxyphenyl)-4-bromo-1,6-heptadiene-3,5-dione (4e)
Orange solid mp, 160.9–161.3°C. 1H NMR (CDCl3, 500 MHz) δ ppm 17.05 (s, –OH), 7.72 (d, 2H, J = 15.5), 7.34 (d, 2H, J = 15.5), 7.23 (dd, 2H, J = 8.3, J = 1.9), 7.13 (d, 2H, J = 1.9), 6.90 (d, 2H, J = 8.3), 3.96 (s, 6H), 3.94 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ ppm 181.0, 151.5, 149.3, 143.7, 128.0, 123.3, 119.4, 111.2, 110.3, 97.6, 56.0. IR (KBr) ν = 1599, 1512, 1422, 1343, 1261, 1236, 1163, 1140, 1025, 967, 806 cm–1. CIMS (m/z) 477.1 (MH+ +2), 475.1 (MH+). CI-HRMS for C23H24BrO6+: calcd 475.0756, found 475.0750. EA for C23H23BrO6: calcd 58.12%C, 4.88%H; found 58.31%C, 4.86%H.
(1E,6E)-1,7-bis(3,5-dimethoxyphenyl)-4-bromo-1,6-heptadiene-3,5-dione (4f)
Yellow solid, mp 154.7–154.9°C. 1H NMR (CDCl3, 500 MHz) δ ppm 16.79 (s, –OH), 7.68 (d, 2H, J = 15.6), 7.44 (d, 2H, J = 15.6), 6.76 (d, 4H, J = 2.2), 6.53 (dd, 2H, J = 2.2, J = 2.2), 3.84 (s, 12H). 13C NMR (CDCl3, 75 MHz) δ ppm 181.0, 161.1, 143.8, 136.8, 122.1, 106.5, 102.8, 98.1, 55.5. IR (KBr) ν = 1621, 1595, 1461, 1299, 1209, 1157, 1063, 967, 835 cm–1. CIMS (m/z) 477.1 (MH+ +2), 475.1 (MH+). CI-HRMS for C23H24BrO6+: calcd 475.0756, found 475.0752. EA for C23H23BrO6: calcd 58.12%C, 4.88%H; found 57.95%C, 4.66%H.