Arene dioxides of substituted pyrenes: synthesis and X-ray structural studies
Robert W. Murray1,
Megh Singh and
Nigam P. Rath
Department of Chemistry, University of MissouriSt Louis, 8001 Natural Bridge Road, St Louis, MO 63121, USA
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Abstract
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The arene dioxides of five 1-substituted pyrenes have been synthesized using dimethyldioxirane. The diasteroisomeric distribution of the dioxides has been determined. X-ray crystallographic structures of the dioxides have also been obtained. These structures show that for the cis dioxides the molecular structures show a departure from planarity, the extent of which is dependent on the substituent.
Abbreviations: APT, attached proton test; CCD, Charge Coupled Device; DMD, dimethyldioxirane; mp, melting point; GLC, gas liquid chromatography; PAH, polycyclic aromatic hydrocarbon; TLC, thin-layer chromatography; TMS, tetramethylsilane.
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Introduction
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It is now well established that some polycyclic aromatic hydrocarbons (PAHs) are metabolized to genotoxic materials many of which are carcinogenic (1). Arene oxides are known to be critical to carcinogenic behavior because of their proclivity for binding to important biological substrates. In this binding the oxide functional group is a necessary, but not usually sufficient factor. In general, carcinogenic behavior is associated with further metabolites of the oxides (2). Many PAHs have structures suggesting that they could be metabolized at more than one site leading to the possibility of arene dioxide formation. Any such dioxides would be expected to be further metabolized to other materials, some of which could be carcinogenic. The literature contains only a few references to the synthesis of arene dioxides. Some of these are laborious multistep syntheses (310). More recently dioxiranes have been shown to be very useful for the synthesis of arene oxides and dioxides (1116). We have recently used dimethyldioxirane, for example, to synthesize the stereoisomeric arene dioxides of two PAHs (R.W.Murray et al., submitted for publication).
Herein, we report on the synthesis of arene dioxides from five 1-substituted pyrenes. The dioxides are obtained as the stereoisomeric cis and trans pyrene-4,5:9,10-dioxide pairs. The dioxide isomers have been separated and the stereoisomer distribution determined. In most cases X-ray crystallography has been used to obtain structures of the dioxides.
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Materials and methods
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Methods
1H and 13C NMR spectra were recorded on a Varian XL-300 (1H, 300 MHz; 13C, 75 MHz), a Varian UNITY-plus (1H, 300 MHz; 13C, 75.4 MHz) or a Bruker ARX-500 (1H, 500.13 MHz; 13C, 125.76 MHz) spectrometer in deuteriochloroform (CDCl3) with tetramethylsilane (TMS,
= 0.00 p.p.m.) as an internal reference. All NMR data are reported in p.p.m. or
-values downfield from TMS, and coupling constants, J, are reported in Hz. 13C NMR spectra were proton decoupled and recorded in CDCl3. The center peak of the solvent CDCl3 at 77.00 p.p.m. was used as an internal reference. The multiplicities of the 13C NMR signals were determined by the attached proton test (APT) pulse sequence. Where necessary, COSY and HETCOR experiments were performed on a Bruker ARX-500 spectrometer (1H, 500.13 MHz; 13C, 125.76 MHz). Electron impact and chemical ionization mass spectra were recorded, at 70 eV ionizing voltage, on a HewlettPackard 5988A twin EI and CI quadrupole mass spectrometer connected to a HewlettPackard 5890A gas chromatograph fitted with a HewlettPackard 12 mx0.2 mmx0.33 µm Ultra-1 (cross-linked methyl silicone) column. Chromatographic separations on the chromatotron were accomplished using 12 mm Kieselgel 60 PF254 gypsum coated plates. UV-VIS spectra were obtained on a Hitachi U-3110 UV-vis spectrophotometer. Infrared spectra were recorded as KBr pellets on a PerkinElmer Model 1600 FT-IR spectrometer. Melting points (mps) were determined on a Dynamic Optics AHT 713921 hot-stage apparatus and are uncorrected. Microanalyses were performed by Atlantic Microlab (Norcross, GA).
Materials and reagents
Sodium bicarbonate, neutral alumina (Brockman Activity 1, 80200 mesh) and potassium iodide-starch paper were obtained from Fisher Scientific (Pittsburgh, PA). Acetone (Fisher reagent grade) was fractionally distilled over anhydrous potassium carbonate. Methylene chloride and hexane were obtained from Fisher Scientific and distilled from calcium hydride before use. Oxone (Du Pont), 2KHSO5·KHSO4·K2SO4, was obtained from Aldrich (Milwaukee, WI) and used as such. The dimethyldioxirane solution in acetone was prepared according to the literature procedure (1719) and was assayed for dioxirane content using phenyl methyl sulfide and the GLC method (19) or concentration was determined using a calibration curve of concentration of the DMD versus UV absorbance at 335 nm. Analytical thin-layer chromatography (TLC) analyses were performed on EM silica gel plates, 60PF254. Visualization was accomplished with UV light, iodine, KMnO4 solution and/or vanillin/sulfuric acid solution.
Preparation and purification of substituted pyrene derivatives
1-Bromopyrene, 1-nitropyrene and 1-hydroxypyrene purchased from Aldrich were of the highest purity and were used as such after verifying their purity by TLC and 1H NMR. 1-Methylpyrene was obtained from TCI America (Portland, OR) and was used as such. The commercial sample of 1-acetyl pyrene (Aldrich) was purified by recrystallization from acetone/hexane. 1-Acetyloxypyrene was synthesized from 1-hydroxypyrene (Aldrich) by the standard acetylation procedure.
1-Acetyloxypyrene
A mixture of 1-hydroxypyrene (0.1110 g, 0.5085 mmol), acetyl chloride (5 ml) and 4-dimethylaminopyridine (0.02 g, 0.164 mmol) was heated under reflux for 5 h. After the usual work-up, a crude sample of 1-acetyloxypyrene was obtained as an orange-yellow solid (0.1367 g, 100%). The crude sample was purified by radial chromatography [silica gel plate, CH2Cl2/hexane (1:1) as eluent] to obtain an analytically pure sample of 1-acetyloxypyrene as a cream crystalline solid; mp 105106°C, lit (20) mp 102°C; 1H NMR (300 MHz, CDCl3):
2.56 (s, 3H), 7.79 (d, J = 8.30 Hz, 1H), 8.02 (dd or appt, J = 7.57, 1H), 8.06 (s, 2H), 8.09 (AB q, J = 9.20 Hz, 2H), 8.158.24 (m, 3H); 13C NMR (75.4 MHz, CDCl3):
21.10, 119.72, 120.19, 123.08, 124.56, 125.00, 125.21, 125.48, 125.58, 126.29, 127.07, 127.10, 128.14, 129.14, 129.33, 130.96, 131.13, 144.28, 169.80; MS (EI, 70 eV): m/z (relative intensity) 261 (M + 1,3), 260 (M+,14), 218 (100), 189 (42), 187 (11), 94 (3), 43 (3); calculated for C18H12O2: 260.28.
General procedure for the reaction of 1-substituted pyrenes with dimethyldioxirane
The reaction of an equivalent of a substituted pyrene with several equivalents of a solution of dimethyldioxirane in acetone and in the presence of sodium bicarbonate (0.0250.100 g) was performed. The reaction mixture was stirred at room temperature in the dark for several days. The stirring was continued and the progress of the reaction was monitored by 1H NMR, TLC analysis (CH2Cl2/silica gel) and KI/starch at regular intervals. When all of the dimethyldioxirane was consumed, the solvent was removed in vacuo. The residue was then redissolved in acetone and a fresh batch of dimethyldioxirane was added. The dimethydioxirane administration was continued until complete consumption of starting material and/or the intermediate monooxides. The solvent was removed on the rotovap and the residue was dissolved in methylene chloride, dried with anhydrous sodium sulfate and filtered. The filtrate was passed through a small column of neutral alumina (15 g). Evaporation of the solvent gave an analytically pure sample of a mixture of the cis/trans dioxides. The cis/trans isomer ratios were determined from the 1H NMR of the crude reaction residues as well as the purified reaction residues. The relative ratios of the cis:trans isomers determined by 1H NMR analysis on the crude reaction residues were identical with those of the purified reaction mixture. The separation of the diastereoisomeric cis- and trans-dioxides was accomplished by repeated fractional crystallization from acetone. The trans-dioxides have very low solubility in this solvent whereas the cis-dioxides were fairly soluble.
1-Methylpyrene-4,5:9,10-dioxides
Following the general procedure the reaction of 1-methylpyrene (0.110 g, 0.5085 mmol), sodium bicarbonate (0.110 g) and 70 ml of 0.063 M dimethyldioxirane solution in acetone, afforded a creamy yellow solid (0.0957 g, 70%). 1H NMR analysis of the solid indicated the presence of an analytically pure mixture of cis/trans dioxides in a 56:44 ratio (55 ± 1.4). Repeated fractional crystallization of the residue with acetone afforded trans-1-methylpyrene-4,5:9,10-dioxide as very fine colorless needles; mp 210°C (dec); IR (KBr) 1571 (w), 1458 (w), 1450 (w), 1389 (w), 1296 (w), 1247 (w), 1163 (m), 1061 (m), 945 (w), 877 (w), 834 (s), 808 (vs), 787 (vs), 744 (s), 621 (w) 567 (m) cm1; 1H NMR (300 MHz, CDCl3):
2.65 (s, 3H), 4.527 (d, J = 4.18 Hz, 1H), 4.537 (d, J = 4.05 Hz, 1H), 4.555 (d, J = 4.05 Hz, 1H), 4.75 (d, J = 4.18 Hz, 1H), 7.26 (dq, J = 7.81, 0.73 Hz, 1H), 7.424 (dd, J = 7.77, 7.30 Hz, 1H), 7.57 (d, J = 7.68 Hz, 1H), 7.68 (dd, J = 1.89, 1.45 Hz, 1H), 7.705 (dd or appt, J = 1.42 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
19.13, 52.70, 55.72, 55.81, 56.05, 126.42, 126.72, 127.91, 129.13, 129.56, 130.10, 130.98, 131.01, 131.49, 131.59, 140.00; MS (EI, 70 eV): m/z (relative intensity) 249 (M + 1,21), 248 (M+,100), 247 (51), 231 (7), 219 (7), 189 (14), 124 (12), 101 (15), 94 (13); calculated for C17H12O2: 248.28. Analysis calculated for C17H12O2: C, 82.24; H, 4.87; found: C, 81.72; H, 4.96. The filtrate from the above crystallization was concentrated, diluted with hexane and stored in a freezer to afford a pale yellow crystalline solid which was filtered, washed with hexane and dried in vacuo to give cis-1-methylpyrene-4,5:9,10-dioxide: mp 170172°C (dec); IR (KBr) 1570 (m), 1457 (ms), 1385 (w), 1296 (w), 1213 (m), 1158 (m), 1070 (m), 1055 (ms), 833 (m), 860 (m), 810 (vs), 781 (vs), 733 (m), 676 (m), 646 (s), 620 (w), 579 (m) cm1; 1H NMR (300 MHz, CDCl3):
2.68 (s, 3H), 4.607 (d, J = 4.10 Hz, 1H), 4.61 (s, 2H), 4.87 (d, J = 4.10 Hz, 1H), 7.32 (dq, J = 7.68, 0.64 Hz, 1H), 7.473 (dd, J = 7.86, 7.22 Hz, 1H), 7.61 (d, J = 7.67 Hz, 1H), 7.716 (s, 1H), 7.74 (s, 1H); 13C NMR (75.4 MHz, CDCl3):
19.29, 53.29, 56.50, 56.63, 56.76, 127.62, 127.83, 129.74, 129.92, 129.98, 130.17, 130.51, 130.68, 131.61, 132.17, 139.06; MS (EI, 70 eV): m/z (relative intensity) 249 (M + 1,18), 248 (M+, 100), 247 (49), 231 (9), 219 (9), 189 (15), 124 (11), 101 (12), 94 (14); calculated for C17H12O2: 248.28. Analysis calculated for C17H12O2: C, 82.24; H, 4.87; found: C, 81.55; H, 4.78. The single-crystal X-ray analysis unambiguously proved the suggested stereochemistry of the cis-1-methylpyrene-4,5:9,10-dioxide.
1-Acetyloxypyrene-4,5:9,10-dioxides
Following the general procedure the reaction of 1-acetyloxypyrene (0.064 g, 0.2458 mmol), sodium bicarbonate (0.065 g), and 75 ml of 0.063 M dimethyldioxirane solution in acetone after 37 h gave a creamy crystalline solid (0.04530, 63%). 1H NMR analysis of the solid indicated the presence of an analytically pure mixture of cis/trans dioxides in a 60:40 ratio (60 ± 0.0). Fractional crystallization of the residue with acetone afforded trans-1-acetyloxypyrene-4,5:9,10-dioxide as a colorless solid: mp 228230°C; IR (KBr) 1753 (vs), 1571 (m), 1466 (w), 1438 (m), 1396 (w), 1366 (m), 1228 (vs), 1154 (w), 1103 (w), 1068 (m), 926 (ms), 834 (ms), 818 (ms), 790 (s), 744 (w), 686 (w), 663 (w), 623 (m) cm1; 1H NMR (500.13 MHz, CDCl3):
2.426 (s, 3H), 4.53 (d, J = 4.05 Hz, 1H), 4.56 (s, 2H), 4.66 (d, J = 4.05 Hz, 1H), 7.23 (d, J = 8.24, 1H), 7.46 (dd or appt, J = 7.56, 1H), 7.69 (d, J = 8.24 Hz, 1H), 7.70 (dd or appt, J = 1.60 Hz, 1H), 7.72 (dd or appt, J =1.52 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
20.98, 50.25, 55.22, 55.53, 55.73, 121.89, 123.64, 125.95, 128.05, 128.51, 128.96, 131.11, 131.57, 131.66, 131.68, 131.84, 131.84, 151.85, 169.04. Analysis calculated for C18H12O4: C, 73.97; H, 4.14; found: C, 73.28; H, 4.21. The filtrate from the above crystallization was evaporated and the residue was recrystallized from methylene chloride/hexane to afford very pale yellow flakes, which were filtered off, washed with hexane and dried in vacuo to give cis-1-acetyloxypyrene-4,5:9,10-dioxide: mp 214216°C; IR(KBr) 1764 (vs), 1572 (m), 1466 (m), 1438 (m), 1368 (ms), 1206 (vs), 1162 (w), 1102 (w), 1067 (m), 926 (ms), 862 (s), 834 (m), 818 (m), 800 (m), 785 (vs), 736 (m), 690 (w), 670 (m) cm1; 1H NMR (300 MHz, CDCl3):
2.43 (s, 3H), 4.61 (d, J = 4.05 Hz, 1H), 4.63 (s, 2H), 4.75 (d, J = 4.05 Hz, 1H), 7.26 (d, J = 8.24 Hz, 1H), 7.51 (dd or appt J = 7.55 Hz, 1H), 7.734 (d, J = 8.24 Hz, 1H), 7.736 (dd, J = 3.00, 1.37 Hz, 1H), 7.76 (dd, J = 2.62, 1.37 Hz, 1H); 13C NMR (125.76 MHz, CDCl3):
20.96, 50.99, 56.24, 56.38, 56.54, 121.61, 124.14, 127.10, 128.46, 129.30, 129.60, 130.71, 130.80, 130.97, 131.73, 132.16, 151.25, 169.29. Analysis calculated for C18H12O4: C, 73.97; H, 4.14; found: C, 73.95; H, 4.15. The single-crystal X-ray analysis unambiguously proved the suggested stereochemistry of the cis-1-acetyloxypyrene-4,5:9,10-dioxide.
1-Acetylpyrene-4,5:9,10-dioxides
Following the general procedure the reaction of 1-acetylpyrene (0.130 g, 0.5321 mmol), sodium bicarbonate (0.130 g) and 150 ml of 0.045 M dimethyldioxirane solution in acetone after 520 h yielded a creamy solid (0.1188 g, 81%). 1H NMR analysis of the solid indicated the presence of an analytically pure mixture of cis/trans dioxides in a 57:43 ratio (59 ± 1.4). Fractional crystallization of the solid with acetone gave a colorless solid, which was identified as trans-1-acetylpyrene-4,5:9,10-dioxide; mp 195200°C (dec); IR (KBr) 1734 (w), 1680 (vs), 1425 (w), 1363 (w), 1295 (mw), 1256 (m), 1216 (m), 1170 (w), 1062 (m), 821 (s), 793 (vs), 754 (w), 640 (w) cm1; 1H NMR (300 MHz, CDCl3):
2.73 (s, 3H), 4.53 (d, J = 4.15 Hz, 1H), 4.58 (appt or dd, J = 4.15 Hz, 2H), 5.13 (d, J = 4.15 Hz, 1H), 7.47 (dd or appt, J = 7.57 Hz, 1H), 7.707 (dd, J = 3.67, 1.22 Hz, 1H), 7.713 (d, J = 7.81 Hz, 1H), 7.73 (dd, J = 3.67, 1.46 Hz, 1H), 7.76 (d, J = 7.81 Hz, 1H); 13C NMR (125.75 MHz, CDCl3):
30.23, 52.12, 55.61, 55.95, 56.13, 125.73, 127.72, 128.61, 130.44, 130.93, 131.48, 131.53, 131.59, 131.62, 134.41, 142.19, 201.48; MS (EI, 70 eV): m/z (relative intensity) 276 (M+, 100), 261 (79), 245 (47), 234 (33), 233 (28), 206 (21), 205 (41), 189 (41), 165 (20), 150 (18), 149 (18), 83(34); calculated for C18H12O3: 276.28. Analysis calculated for C18H12O3: C, 78.25; H, 4.38; found: C, 78.15; H, 4.49. The filtrate from the above crystallization was concentrated and stored in a freezer to afford a pale yellow crystalline solid, which was recrystallized from acetone and hexane to afford yellow rods, which were filtered, washed with hexane and dried in vacuo to give cis-1-acetylpyrene-4,5:9,10-dioxide; mp 165167°C (dec); IR (KBr) 1734 (w), 1686 (vs), 1420 (w), 1356 (w), 1256 (w), 1214 (ms), 1064 (s), 820 (m), 876 (m), 790 (vs), 722 (w), 680 (w), 645 (w) cm1; 1H NMR (300 MHz, CDCl3):
2.75 (s, 3H), 4.617 (d, J = 4.05 Hz, 1H), 4.65 (appt or dd, J = 4.05 Hz, 2H), 5.28 (d, J = 4.05 Hz, 1H), 7.523 (dd, J = 7.82, 7.33 Hz, 1H), 7.74 (d, J = 7.81 Hz, 1H), 7.745 (dd, J = 2.20, 1.34 Hz, 1H), 7.77 (dd or appt, J = 1.46 Hz, 1H), 7.79 (d, J = 7.93 Hz, 1H); 13C NMR (125.75 MHz, CDCl3):
30.45, 52.62, 56.52, 56.56, 56.86, 126.88, 127.37, 128.63, 129.03, 130.06, 130.61, 130.66, 130.92, 132.17, 134.93, 141.96, 202.05; MS (EI, 70 eV): m/z (relative intensity 276 (M+,38), 261 (86), 245 (100), 234 (32), 233 (46), 207 (12), 189 (36), 165 (12), 150 (18), 83 (23), 43 (39); calculated for C18H12O3: 276.28. Analysis calculated for C18H12O3: C, 78.25; H, 4.38; found: C, 77.97; H, 4.42. The single-crystal X-ray analysis unambiguously proved the suggested stereochemistry of the cis-1-acetylpyrene-4,5:9,10-dioxide.
1-Bromopyrene-4,5:9,10-dioxides
Following the general procedure the reaction of 1-bromopyrene (0.112 g, 0.3984 mmol), sodium bicarbonate (0.100 g), and 100 ml 0.069 M dimethyldioxirane solution in acetone after 330 h yielded a creamy yellow solid (0.1048, 84%). 1H NMR analysis of the solid indicated the presence of an analytically pure mixture of cis/trans dioxides in a 60:40 ratio (59.5 ± 0.5). Fractional crystallization of the residue (0.100 g) from acetone gave a colorless solid, which was identified as trans-1-bromopyrene-4,5:9,10-dioxide (0.0365 g); mp 135140°C (dec); IR (KBr) 1735 (m), 1560 (m), 1458 (w), 1429 (w), 1290 (m), 1247 (m), 1169 (w), 1144 (w), 1068 (m), 1020 (w), 942 (w), 838 (m), 812 (vs), 788 (vs), 744 (ms), 602 (w) cm1; 1H NMR (300 MHz, CDCl3):
4.53 (d, J = 3.91 Hz, 1H), 4.546 (d, J = 4.15 Hz, 1H), 4.564 (d, J = 3.91 Hz, 1H), 5.02 (d, J = 4.15 Hz, 1H), 7.47 (appt or dd, J = 7.57 Hz, 1H) 7.54 (d, J = 8.12 Hz, 1H), 7.66 (d, J = 8.12 Hz, 1H), 7.71 (dd, J = 3.05, 1.35 Hz, 1H), 7.73 (dd, J = 3.30, 1.35 Hz, 1H); 13C NMR (125.75 MHz, CDCl3):
55.47, 55.57, 55.75, 55.95, 125.87, 127.62, 128.61, 128.74, 130.56, 130.78, 131.30, 131.71, 131.75, 132.26, 132.33; MS (EI, 70 eV): m/z (relative intensity) 314 (81Br-M+, 13), 312 (79Br-M+, 8), 298 (75), 296 (50), 284 (18), 218 (37), 190 (24), 189 (47), 188 (18), 187 (56), 176 (14), 149 (17), 148 (16), 121 (18), 112 (12) 97 (26), 96 (16), 95 (57), 94 (30), 93 (29), 81 (99), 80 (100), 79 (64); calculated for C16H9BrO2: 313.15. Analysis calculated for C16H9BrO2: C, 61.37; H, 2.90; found: C, 60.81; H, 3.13. The filtrate from the above crystallization was concentrated and stored in a freezer to afford colorless cubes, which were filtered, washed with hexane, and dried in vacuo to give cis-1-bromopyrene-4,5:9,10-dioxide (0.052 g); mp 150°C (dec); IR (KBr) 1735 (m), 1558 (s), 1458 (m), 1424 (m), 1376 (m), 1290 (m), 1238 (m), 1213 (m), 1168 (m), 1144 (m), 1083 (m), 1059 (s), 1022 (m), 874 (s), 835 (m), 812 (vs), 781 (vs), 744 (m), 664 (m) cm1; 1H NMR (300 MHz, CDCl3):
4.61 (d, J = 4.00 Hz, 1H), 4.62 (d, J = 4.00 Hz, 1H), 4.63 (d, J = 4.00 Hz, 1H), 5.18 (d, J = 4.00 Hz, 1H), 7.52 (app t or dd, J = 7.51 Hz, 1H), 7.58 (d, J = 8.20 Hz, 1H), 7.71 (d, J = 8.20 Hz, 1H), 7.74 (dd, J = 2.38 and 1.40 Hz, 1H), 7.77 (app t or dd, J = 1.64 Hz, 1H); 13C NMR (125.75 MHz, CDCl3):
56.34, 56.37, 56.43, 56.78, 126.65, 126.86, 128.69, 129.75, 130.70, 130.85, 130.95, 131.40, 131.47, 131.96, 132.05, 132.32; MS (EI, 70 eV): m/z (relative intensity) 314 (81Br-M+, 81), 312 (79Br-M+, 51), 298 (43), 296 (57), 285 (27), 283 (27), 269 (28), 235 (89), 234 (62), 218 (63), 206 (70), 205 (60), 190 (32), 189 (100), 188 (46), 177 (56), 176 (81), 175 (28), 156 (57), 81 (75), 80 (61), 79 (90); calculated for C16H9BrO2: 313.15. Analysis calculated for C16H9BrO2: C, 61.37; H, 2.90; found: C, 61.11; H, 3.00. The single-crystal X-ray analysis unambiguously proved the suggested stereochemistry of the cis-1-bromopyrene-4,5:9,10-dioxide.
1-Nitropyrene-4,5:9,10-dioxides
Following the general procedure the reaction of 1-nitropyrene (0.160 g, 0.647 mmol), sodium bicarbonate (0.100 g), and several batches of dimethyldioxirane solution in acetone after several weeks gave a creamy yellow solid (0.152 g). 1H NMR analysis of the solid indicated the presence of a mixture of cis/trans dioxides as the major products as well as traces of 1-nitropyrene-4,5-oxide and 1-nitropyrene-9,10-oxide. Purification of the residue on the Chromatotron using CH2Cl2/hexane (80/20 to 100% CH2Cl2) as eluent gave an analytically pure mixture of cis/trans dioxides (0.1163 g, 65%) in a 65:35 (65 ± 0.0) ratio and a mixture of unreacted 1-nitropyrene-4,5-oxide and 1-nitropyrene-9,10-oxide (0.010 g). Repeated fractional crystallization of the residue from acetone gave a colorless solid which was identified as trans-1-nitropyrene-4,5:9,10-dioxide; mp 245250°C (dec); IR (KBr) 1740 (m), 1526 (vs), 1474 (w), 1458 (w), 1357 (s), 1296 (m), 1248 (m), 1076 (m), 886 (w), 836 (ms), 826 (ms), 793 (vs), 733 (m) cm1; 1H NMR (500.13 MHz, CDCl3):
4.55 (d, J = 3.98 Hz, 1H), 4.58 (d, J = 3.88 Hz, 1H), 4.59 (d, J = 3.88 Hz, 1H), 5.02 (d, J = 3.98 Hz, 1H), 7.52 (dd or app t, J = 7.56 Hz, 1H), 7.74 (dd, J = 4.82, 1.32 Hz, 1H), 7.76 (dd, J = 4.70, 1.32 Hz, 1H), 7.80 (d, J = 8.25 Hz, 1H), 7.93 (d, J = 8.25 Hz, 1H); 13C NMR (125.76 MHz, CDCl3):
50.62, 55.17, 55.60, 55.96, 123.40, 124.83, 125.84, 128.66, 129.38, 131.18, 131.65, 131.74, 131.82, 131.85, 136.06, 152.40. Analysis calculated for C16H9NO4: C, 68.82; H, 3.25; found: C, 68.63; H, 3.32. The filtrate from the above crystallization was concentrated and stored in a freezer to afford pale yellow cubes, which were filtered, washed with hexane, and dried in vacuo to give cis-1-nitropyrene-4,5:9,10-dioxide; mp 230°C (dec); IR (KBr) 1741 (mw), 1522 (vs), 1481 (mw), 1458 (w), 1345 (s), 1250 (w), 1175 (w), 1158 (m), 1068 (s), 888 (m), 874 (m), 842 (m), 826 (ms), 788 (s), 732 (m), 702 (mw), 666 (m), 637 (w) cm1; 1H NMR (300 MHz, CDCl3):
4.66 (d, J = 4.00 Hz, 1H), 4.69 (dd or appt, J = 4.00 Hz, 2H), 5.16 (d, J = 4.00 Hz, 1H), 7.594 (dd, J = 7.88, 7.25 Hz, 1H), 7.79 (unresolved dd or appt, 1H), 7.82 (dd or appt, J = 1.26 Hz, 1H), 7.86 (d, J = 8.25 Hz, 1H), 7.99 (d, J = 8.25 Hz, 1H); 13C NMR (125.76 MHz, CDCl3):
51.57, 56.11, 56.36, 56.52, 123.17, 125.93, 126.43, 129.45, 129.92, 130.79, 130.86, 130.93, 131.94, 132.43, 136.63, 152.23. Analysis calculated for C16H9NO4: C, 68.82; H, 3.25; found: C, 68.56; H,3.31. The single-crystal X-ray analyses unambiguously proved the suggested stereochemistry of the trans- and cis-1-nitropyrene-4,5:9,10-dioxides.
Crystal data
Single crystals of all five of the cis-dioxides and the trans-1-nitro dioxide were grown by recrystallization of the products from various solvent systems at low and room temperatures as shown in Table I
. Suitable crystals for X-ray analysis could not be obtained for the other trans dioxides.
Single crystal X-ray diffraction structure determinations
Crystals of appropriate dimensions were mounted on glass fibers in random orientation. Preliminary examination and data collection were performed using a Siemens SMART Charge Coupled Device (CCD) Detector system single crystal X-ray diffractometer using graphite monochromated Mo K
radiation (
= 0.71073 Å) equipped with a sealed tube X-ray source (40 kVx50 mA) at 50°C. Preliminary unit cell constants were determined with a set of 45 narrow frames (0.3° in
) scans. Typically, a total of 4028 frames of intensity data were collected with a frame width of 0.3° in
and counting time of 10 s/frame at a crystal to detector distance of 4.900 cm. The double pass method of scanning was used to exclude any noise. Data were collected at 50° C for a total time of 19.1 h. The collected frames were integrated using orientation matrices determined from the narrow frame scans. SMART and SAINT software packages (21) were used for data collection and frame integration, respectively. Analysis of the integrated data did not show any decay. Final cell constants were determined by global refinement of xyz centroids of 8192 strong reflections. Integrated intensity data were corrected for systematic errors using SADABS (22) based upon Laue symmetry. Crystal data and intensity data collection parameters are listed in Table II
.
Structure solution and refinement were carried out using the SHELXTL-PLUS software package (23). The structures were solved by direct methods and refined successfully in the reported space groups. Full matrix least-squares refinements were carried out by minimizing
w(Fo2 Fc2)2. The non-hydrogen atoms were refined anisotropically to convergence. The hydrogen atoms were treated using appropriate riding model (AFIX m3). The final residual values and relevant structure refinement parameters are listed in Table II
.
A complete list of crystal data, positional and isotropic displacement coefficients, geometrical parameters, anisotropic displacement coefficients, hydrogen atom parameters anisotropic displacement coefficients for the non-hydrogen atoms, calculated and observed structure factors, and projection views of the molecules with non-hydrogen atoms represented by 50% probability ellipsoids and showing the atom labeling are deposited with the Cambridge Crystallographic Database Center, Cambridge, UK.
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Results and discussion
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Using a recently described (R.W.Murray et al., submitted for publication) improved procedure we have synthesized the previously unknown arene dioxides of five 1-substituted pyrenes. The dioxides are obtained as diastereoisomeric pairs as shown in Figure 1
. The dioxides are obtained in good yield and are easily purified and the isomers separated by fractional crystallization from acetone. These results again demonstrate the value of dimethyldioxirane (DMD) for giving these types of compounds, which are otherwise synthesized only with great difficulty by multistep procedures. Arene dioxides are of some interest to metabolic studies. Many PAHs contain more than one site where metabolic oxidation could occur, as for example when there is more than one K-region as in the substrates studied here. Any arene dioxides produced in this manner would be expected to be further metabolized to other materials, which could be mutagenic. In this connection it is of interest that naphthalene has been converted to an arene dioxide in animal liver metabolism studies (24,25). In this case both oxides are formed in the same ring. In another case an arene dioxide has been invoked as a metabolic precursor of a tetraol in the metabolism of dibenz[a,h]anthracene (26).
We have obtained X-ray crystal structures on all five cis stereoisomers of the dioxides as well as the trans isomer of the 1-nitro dioxide. The structures of the cis dioxides are given in Figure 2
and that for the trans 1-nitro compound is given in Figure 3
. Two properties of the dioxides require comment. In Table III
are given the diastereoisomer distribution of the dioxides as a function of the substituent at position 1.
In general, understanding the factors responsible for this change in dioxide isomer distribution with structure when dimethyldioxirane is the oxidant is a difficult task. We believe, however, that several distinct factors contribute to the isomer ratios. The observed ratio is presumably the result of the relative importance of these factors in any given structure. One of these factors is a steric interaction. When the steric interaction of the second oxide group with the existing oxide group is high then the trans isomer would be favored. The best example of this interaction is in naphthalene where the isomer ratio is found to be 2:98 (cis:trans) (R.W.Murray et al., submitted for publication). If only the steric factor is considered then one might expect that the isomer ratio would approach unity as the oxidized sites are moved further apart in the molecule. An example of this effect may be seen in dibenz[a,h]-5,6:12,13-dioxide where a dioxide cis:trans ratio of 45:55 is observed (R.W.Murray et al., submitted for publication). A second factor influencing the observed isomer ratios is the influence of a substituent on the attacking dioxirane as it approaches the monooxide. Dimethyldioxirane is a highly polar molecule that is likely to interact with dipoles present in the substrate. The monooxide functional group itself would be expected to act as such a dipole. An attractive force between the existing oxide group and the incoming dioxirane would tend to favor cis epoxidation. This effect may explain the observed isomer distribution of 75:25 (cis:trans) in the dioxide formed in unsubstituted pyrene (R.W.Murray et al., submitted for publication). In this case one would have to argue that the attractive force is more controlling than any steric effect thus leading to the cis isomer being favored. When the substituent is other than an existing epoxide group as in the cases of the 1-substituted pyrenes studied here, then analyzing the effect of that substituent is more difficult. As seen in Table III
, in all cases the 1-substituted pyrenes give an oxide isomer distribution favoring the cis isomer although the maximum amount of cis (65%) in the nitro compound is less than that observed (75%) for the unsubstituted pyrene. One possible interpretation of these results is to say that in all cases the existing oxide group is operating as it does in the unsubstituted pyrene thus generally giving a dioxide isomer distribution favoring the cis. The substituents then operate to mitigate this effect so that the isomer distribution decreases from the 75:25 seen in the unsubstituted case.
According to this view, the substituents in Table III
have a decreasing tendency to interfere in the operation of the steering effect of the existing oxide group as one reads down the table from nitro to methyl, that is, the nitro compound gives an isomer distribution that is closest to that of the unsubstituted pyrene, etc. This ordering of the compounds also reflects a decreasing dipole associated with the substituent. It is tempting to explain the substituent effect as being due to the ability of the substituent dipole to interfere with the cis-steering influence of the monooxide group. The fact that the existing oxide group is above the plane of the substrate whereas the 1-substituents have varying placement with respect to this plane may be one reason the oxide group appears to have the major influence on the isomer distribution. More work on the effect of substituents on dioxide isomer distributions is required before anything more definitive can be said on this point. A further complicating factor is that the dioxides are produced in two different routes, one each from the 4,5-monooxide and the 9,10-monooxide. In this connection we have noted that in all cases the 4,5-monooxide is formed faster than the 9,10-monooxide.
The second general property of the dioxides requiring comment is the influence of the substituent on the degree of departure from molecular planarity in the cis isomers of the dioxides. This is best seen in the X-ray structures shown in Figure 2
. The dioxides are arranged in decreasing order of molecular curvature with the 1-methyl dioxide having the most curvature and the 1-nitro compound having the least curvature. In the latter compound it is likely that the effect of the nitro substituent is related to its resonance interaction with the ring, which would tend to move one end of the molecule back in the direction of planarity. The methyl compound, with the expected least resonance interaction with the ring, thus has the most departure from planarity. For the trans-1-nitro dioxide the molecule is roughly planar as shown in Figure 3
. We have determined the curvature of the dioxides (Table IV
) by calculating the deviation of carbon atoms 2, 10b, 10c and 7 from the pyrene plane. The deviations can be positive or negative and the results are given as displacement from the least square mean plane for each substituent.
The occurrence of a departure from planarity in these cis-1-substituted arene dioxides may be significant. Glusker et al. have suggested (2730) that molecular distortions in some PAHs may be related to their reactivity and may also be related to enhanced carcinogenicity. The dioxides studied here represent possible metabolites of the substituted PAH precursors and not the PAHs themselves so that a similar analysis may not be readily made. On the other hand, the pronounced curvature present in some of these molecules would certainly be expected to enhance their general reactivity and perhaps their metabolic reactivity as well. All of these dioxides are now being tested for biological activity by the National Cancer Institute.
A complete list of positional and isotropic displacement coefficients for hydrogen atoms, anisotropic displacement coefficients for the non-hydrogen atoms, and a complete list of geometrical parameters and calculated and observed structure factors are available.
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Notes
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1 To whom correspondence should be addressed Email: aidan{at}admiral.umsl.edu 
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Acknowledgments
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The work described here was supported by grant number ES01984 from the National Institute of Environmental Health Sciences, NIH. Its contents are solely the responsibility of the authors and do not necessarily reflect the official views of the NIEHS, NIH. The Varian NMR spectrometer and the CCD diffractometer (partial funding) was purchased with support from the National Science Foundation.
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References
|
---|
- Harvey,R.G. (1997) Polycyclic Aromatic Hydrocarbons. WileyVCH, New York, NY.
- Harvey,R.G. (1991) Polycyclic Aromatic Hydrocarbons. Chemistry and Carcinogenicity. Cambridge University Press, Cambridge, UK, Ch. 4.
- Moriarty,R.M., Dansette,P. and Jerina,D.M. (1975) Pyrene derivatives oxygenated at both K-regions. Synthesis of a bis-arene oxide. Tetrahedron Lett., 25572560.
- Agarwal,S.C. and Van Duuren,B.L. (1975) Synthesis of diepoxides and diphenol ethers of pyrene and dibenz[a,h]anthracene. J. Org. Chem., 40, 23072310.[ISI]
- Vogel,E., Klug,H.-H. and Schäfer-Ridder,M. (1976) syn- and anti-naphthalene 1,2;3,4-dioxide. Angew. Chem. Int. Ed. Engl., 15, 229230.[ISI]
- Ishikawa,K. and Griffin,G.W. (1977) A complementary route to anti-1,2:3,4-naphthalene dioxide; direct oxidation of arenes with m-chloroperbenzoic acid. Angew. Chem. Int. Ed. Engl., 16, 171172.[ISI]
- Tsang,W.-S., Griffin,G.W., Horning,M.G. and Stillwell,W.G. (1982) Chemistry of anti- and syn-1,2:3,4-naphthalene dioxides and their potential relevance as metabolic intermediates. J. Org. Chem., 47, 53395353.[ISI]
- Agarwal,S.K., Boyd,D.R. and Jennings,W.B. (1985) Synthesis of benzo[g]chrysene, benzo[g]chrysene-9,10-oxide and benzo[g]chrysene-1,2:9,10-dioxide. J. Chem. Soc. Perkin Trans., 1, 857860.
- Agarwal,S.K., Boyd,D.R., McGuckin,R.M., Jennings,W.B. and Howarth,O.W. (1990) Synthesis of diarene oxides of benz[a]anthracene, chrysene and benzo[c]phenanthrene. J. Chem. Soc. Perkin Trans., 1, 30733080.
- Agarwal,S.C. and Van Duuren,B.L. (1977) Synthesis of 4,5:11,12-diepoxy-4,5,11,12-tetrahydrobenzo[a]pyrene and related compounds. J. Org. Chem., 42, 27302734.[ISI]
- Jeyaraman,R. and Murray,R.W. (1984) Production of arene oxides by the caroate-acetone system (dimethyldioxirane). J. Am. Chem. Soc., 106, 24622463.[ISI]
- Murray,R.W. and Jeyaraman,R. (1985) Dioxiranes 3. Activation of polycyclic aromatic hydrocarbons by reaction with dimethyldioxirane. In Cooke,M.W. and Dennis,A.J. (eds) Polynuclear Aromatic Hydrocarbons: Tenth International Symposium on a Decade of Progress. Battelle Press, Columbus, OH, pp. 595607.
- Kumar,S. and Murray,R.W. (1984) Carbonyl oxide chemistry. The NIH shift. J. Am. Chem. Soc., 106, 10401045.
- Murray,R.W. and Banavali,R. (1983) Formation of a K-region arene oxide by intramolecular O atom transfer. Tetrahedron Lett., 22, 23272330.
- Agarwal,S.K., Boyd,D.R., Jennings,W.B., McGuckin,R.M. and O'Kane,G.A. (1989) General synthetic routes to diarene oxides of polycyclic aromatic hydrocarbons. Tetrahedron Lett., 30, 123126.[ISI]
- Mello,R., Ciminale,F., Fiorentino,M., Fusco,C., Prencipe,T. and Curci,R. (1990) Oxidations by methyl(trifluoromethyl)dioxirane-IV. Oxyfunctionalization of aromatic hydrocarbons. Tetrahedron Lett., 31, 60976100.
- Murray,R.W. and Jeyaraman,R. (1985) Dioxiranes: synthesis and reactions methyldioxiranes. J. Org. Chem., 50, 28472853.[ISI]
- Singh,M. and Murray,R.W. (1992) Chemistry of dioxiranes 21: thermal reactions of dioxiranes. J. Org. Chem., 57, 42634270.[ISI]
- Murray,R.W. and Singh,M. (1996) Synthesis of epoxides using dimethyldioxiranes: trans-stilbene oxide. Org. Synth., 74, 91100.
- Vollman,H., Becker,H., Correll,M. and Streeeck.,H. (1937) Beiträge zur kenntnis des pyrens und seiner derivate. Justus Liebigs Annalen der Chemie, 531, 1159.
- Siemens (1995) Siemens Analytical X-ray. Siemens Analytical X-ray Division, Madison, WI.
- Blessing,R.H. (1995) An empirical correction for absorption anisotropy. Acta Cryst., A51, 3338.
- Sheldrick,G.M. (1996) SHELXTL-plus Program for the solution and refinement of structures. Siemens's Analytical X-ray Division, Madison, WI.
- Stillwell,W.G., Bouwsma,O.J., Thenot,J.-P., Horning,M.G., Griffin,G.W., Ishikawa,K. and Takaku,M. (1978) Methylthio metabolites of naphthalene excreted by the rat. Res. Commun. Chem. Pathol. Pharmacol., 20, 509530.[ISI][Medline]
- Horning,M.G., Stillwell,W.G., Griffin,G.W. and Tsang,W.-S. (1980) Epoxide intermediates in the metabolism of naphthalene by the rat. Drug. Metab. Dispos., 8, 404414.[Abstract]
- Platt,K.L. and Reischmann,I. (1987) Regio- and stereoselective metabolism of dibenz[a,h]anthracene: identification of 12 new microsomal metabolites. Mol. Pharmacol., 32, 710722.[Abstract]
- Glusker,J.P. (1985) X-ray analyses of polycyclic hydrocarbon metabolite structures. In Harvey,R.G. (ed.) Polycyclic Hydrocarbons and Carcinogenesis. Am. Chem. Soc. Monograph 283. American Chemical Society, Washington, DC, pp. 125185.
- Prout,P., Smith,A.D., Daub,G., Zacharias,D.E. and Glusker,J.P. (1982) 11-Methylbenzo[a]pyrene: bay region distortions. Carcinogenesis, 13, 17751782.[Abstract]
- Afshar,C.E., Carrell,J.C., Carrell,H.L., Harvey,R.G., Kiselyov,A.S., Amin,S. and Glusker,J.P. (1996) Bay-region distortions in a methanol adduct of a bay-region diol epoxide of the carcinogen 5-methylchrysene. Carcinogenesis, 17, 25072511.[Abstract]
- Carrell,J.C., Carrell,T.G., Carrell,H.L., Prout,K. and Glusker,J.P. (1997) Benzo[a]pyrene and its analogues: structural studies of molecular strain. Carcinogenesis, 18, 415422.[Abstract]
Received May 26, 1998;
revised September 4, 1998;
accepted September 25, 1998.