Transition State Effects in the Acid-Catalyzed Hydrolysis of 5

Jan 20, 2006 - 5-Methoxyacenaphthylene 1,2-oxide (5) was synthesized by the reaction of 5-methoxyacenaphthylene with dimethyldioxirane. The rates and ...
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Chem. Res. Toxicol. 2006, 19, 217-222

217

Transition State Effects in the Acid-Catalyzed Hydrolysis of 5-Methoxyacenaphthylene 1,2-Oxide: Implications for the Mechanism of Acid-Catalyzed Hydrolysis of Cyclopenta[cd]pyrene 3,4-Oxide Chumang Zhao and Dale L. Whalen* Department of Chemistry, UniVersity of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250 ReceiVed October 10, 2005

5-Methoxyacenaphthylene 1,2-oxide (5) was synthesized by the reaction of 5-methoxyacenaphthylene with dimethyldioxirane. The rates and products from the acid-catalyzed and pH-independent reactions of 5 in 50:50 dioxane/water have been determined. The half-life of the pH-independent reaction of this very reactive epoxide in 50:50 dioxane/water is only 22 s. Acid-catalyzed hydrolysis of 5 in 50:50 dioxane/ water yields 62% of cis diol 6, 37% of trans diol 7, and ∼1% of 5-methoxy-1,2-dihydroacenaphthylen1-one (8). The pH-independent reaction of 5 yields mostly ketone 8 (94%), along with minor amounts of cis and trans diols. The relative stabilities of cis and trans diols 6 and 7 were determined by treating either cis or trans diol with perchloric acid in water solutions and following the approach to an equilibrium cis/trans diol mixture as a function of time. At equilibrium, the ratio of cis and trans diols is 19:81, which establishes that trans diol 7 is more stable than cis diol 6. The acid-catalyzed hydrolysis of epoxide 5 therefore yields the less stable cis diol as the major product. It is concluded that transition state effects therefore selectively stabilize the transition state for attack of water on the intermediate carbocation leading to the less stable cis diol. These results suggest that transition state effects are also responsible for formation of the major cis diol in the acid-catalyzed hydrolysis of cyclopenta[cd]pyrene 3,4-oxide, which has a cyclopenta-fused ring similar to that in 5. Introduction Acid-catalyzed hydrolysis of epoxides generally leads to diols resulting from inversion and/or retention of configuration at carbon, and the inversion/retention ratio varies from exclusive inversion for the reactions of some epoxides to mostly retention for reactions of other epoxides. In the acid-catalyzed hydrolysis of simple alkyl-substituted epoxides, C-O bond breaking and solvent O-C bond making are concerted, and only diols from inversion of configuration at carbon are formed (1, 2). However, acid-catalyzed hydrolysis of epoxides containing aryl or other groups that stabilize positive charge often proceeds by a stepwise mechanism in which diol products are formed from attack of solvent on an intermediate carbocation, and diols from both retention and inversion at carbon are formed (3-10). For those epoxides that undergo acid-catalyzed hydrolysis to yield more diol resulting from retention than from inversion, both conformational effects and transition state effects contribute to the observed result (11). The acid-catalyzed hydrolyses of aryl-substituted cyclohexene oxides with electron-donating groups substituted in the aryl ring yield 75-80% of cis diol as the major product (7). In this system, the cis diol was determined to be more stable than the isomeric trans diol. It was therefore assumed that relative energies of the transition states leading to cis and trans diols simply reflect the relative energies of the diol products. However, the acid-catalyzed hydrolyses of methoxy-substituted tetrahydronaphthalene epoxides and indene oxides also yield more cis than trans diol products, and in each * To whom correspondence should be addressed. Tel: 410-455-2521. Fax: 410-455-1874. E-mail: [email protected].

of these systems, the trans diol is more stable than its isomeric cis diol (11). In the acid-catalyzed hydrolysis of 5-methoxyindene oxide, which proceeds via a carbocation with only one conformation, transition state effects selectively lower the transition state energy leading to cis diol (11). The acid-catalyzed hydrolysis of 1,2,3,4-tetrahydronaphthalene 1,2-epoxide yields 95% of trans diol and only 5% of cis diol (12), whereas the acid-catalyzed hydrolysis of 6-methoxy1,2,3,4-tetrahydronaphthalene 1,2-epoxide yields 80% of cis diol and only 20% of trans diol (10). Conformational factors affecting the stereochemistry of attack of solvent may be primarily responsible for these observations (10, 13). Conformational factors also play important roles in determining the cis/trans tetrol ratios from acid-catalyzed hydrolyses of benzo[a]pyrene 7,8-diol 9,10-epoxides (14, 15). Cyclopenta[cd]pyrene, an environmental pollutant, is metabolized to cyclopenta[cd]pyrene 3-4-oxide (1) (16), which undergoes acid-catalyzed hydrolysis to yield 60% of cis diol 2, 34% of trans diol 3, and ∼6% of ketone 4 (17). Arene oxide 1 also reacts with dG in DNA to yield primarily cis adducts (18). We considered the possibility that acid-catalyzed hydrolysis of 1 (Scheme 1) yields cis diol as the major product because it may be more stable than the isomeric trans diol and that those factors that contribute to the greater stability of the cis diol might also contribute to lowering the transition state energy leading to the cis diol (17). In an effort to determine the relative stabilities of 2 and 3, we treated each diol with 0.1 M HClO4 solution and monitored the reactions as functions of time to determine if any diol equilibration occurred. However, both 2 and 3 slowly reacted to form unidentifiable products, and no

10.1021/tx050281u CCC: $33.50 © 2006 American Chemical Society Published on Web 01/20/2006

218 Chem. Res. Toxicol., Vol. 19, No. 2, 2006 Scheme 1

interconversion could be detected by HPLC analyses of the reaction mixtures (19). Possibly diols 2 and 3 were converted to ketone 4, which decomposed under the reaction conditions. The relative stabilities of cis and trans diols 2 and 3 could therefore not be established by this method, and it could not be determined if transition state energies leading to cis and trans diols in the acid-catalzyed hydrolysis of 1 parallel the relative energies of cis and trans diols in their ground states. Because we were unable to establish the relative stabilities of diols 2 and 3, we synthesized 5-methoxyacenaphthylene 1,2oxide (5), which has a cyclopenta-fused ring with an epoxide group similar to that of 1, and in this paper, we report the rates and products from reaction of 5 in aqueous dioxane solutions as a function of pH. We have also observed that both cis diol 6 and trans diol 7 undergo acid-catalyzed equilibration in 0.1 M HClO4 solution to a mixture of cis and trans diols and that at a much slower rate these diols are converted to ketone 8. Thus, the relative stabilities of 6 and 7 are established, and it is possible to determine if the energies of the transition states leading to diols in the acid-catalyzed hydrolysis of 5 reflect the relative energies of the diol ground states.

Experimental Procedures Materials and Methods. Dioxane and THF were distilled from sodium prior to use. All other reagents were purchased from commercial sources. Quantum chemical calculations were performed with the molecular modeling program Spartan04 (Wavefunction, Inc.). The pH values given throughout are those measured by the glass electrode, and for 10:90 dioxane/water and 50:50 dioxane/water, they correspond to apparent pH values. The activity of hydrogen ion measured by the glass electrode was assumed to be equal to the concentration of hydrogen ion. Synthesis of 5-Methoxyacenaphthylene 1,2-Oxide (5). The synthesis of 5 from 1,2-dihydroacenaphthylene (9) was accomplished by the synthetic route outlined in Scheme 2. Nitration of 9 yielded 5-nitro-1,2-dihydroacenaphthylene (20), which was converted to 5-amino-1,2-dihydroacenaphthylene by catalytic hydrogenation (21). High-temperature hydrolysis of 5-amino-1,2dihydroacenaphthylene with aqueous sulfuric acid yielded 5-hydroxy1,2-dihydroacenaphthylene (10) (22), which was converted to Scheme 2

Zhao and Whalen 5-methoxy-1,2-dihydroacenaphthylene (11) by methylation with dimethyl sulfate (23). 5-Methoxyacenaphthylene (12). Compound 11 (100 mg) was dissolved in 6 mL of benzene, and 147 mg of dichlorodicyanobenzoquinone (DDQ) was added to the solution. The mixture was heated at reflux for 2 h. The reaction mixture was then cooled and filtered through alumina III (6% H2O). The solvent was removed by rotary evaporation to yield 65 mg (66%) of yellow crystals; mp 62-63 °C. 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J ) 8.2 Hz, 1H), 7.66 (d, J ) 6.9 Hz, 1H), 7.56 (d, J ) 7.3 Hz, 1H), 7.50 (dd, J1 ) 6.9 Hz, J2 ) 8.2 Hz, 1H), 6.99 (d, J ) 5.1 Hz, 1H), 6.93 (d, J ) 5.1 Hz, 1H), 6.75 (d, J ) 7.3 Hz, 1H), 3.94 (s, 3H). Anal. calcd for C13H12O: C, 85.69; H, 5.53. Found: C, 85.51; H, 5.49. MS (EI) m/z 182 (M+). 5-Methoxyacenaphthylene 1,2-Oxide (5). A solution of 5.0 mg of 12 in 0.25 mL of acetone-d6 was precooled in a dry ice/ethylene glycol bath, and a solution of dimethyldioxirane in 0.75 mL of acetone-d6 (24) was added. The reaction solution was kept in the dry ice/ethylene glycol bath for another 10 min, at which time the color of the solution turned from yellow to colorless. The 1H NMR spectrum (400 MHz, acetone-d6) of this solution was recorded as follows: δ 7.89 (d, J ) 8.2 Hz, 1H), 7.64 (d, J ) 6.9 Hz, 1H), 7.55 (d, J ) 7.3 Hz, 1H), 7.42 (dd, J1 ) 6.9 Hz, J2 ) 8.2 Hz, 1H), 6.82 (d, J ) 7.3 Hz, 1H), 4.85(d, J ) 2.7 Hz, 1H), 4.80 (d, J ) 2.7 Hz, 1H), 3.96 (s, 3H). HRMS (FAB) calcd for C13H11O2+ [M + H+] m/z 199.0759; found, 199.0778. This product was used for kinetic and product studies without further purification. 5-Methoxy-1,2-dihydroacenaphthylene-cis-1,2-diol (6). A solution of 100 mg of 12 and 140 mg of osmium tetroxide in 10 mL of pyridine was stirred at room temperature for 4 h. A water solution of 0.3 g of sodium bisulfite was added, and the reaction mixture was stirred overnight. The mixture was extracted twice with 25 mL of ethyl acetate. The ethyl acetate extracts were combined, and the combined ethyl acetate solution was washed with 15 mL of 2 M HCl and 30 mL of saturated sodium bicarbonate solution. The ethyl acetate solution was dried over calcium sulfate, and the solvent was removed to yield 117 mg of crude product. This material was sublimed at 120 °C (0.02 mmHg) to yield 40.6 mg (34%) of white solid, which was recrystallized from ethyl acetate/diethyl ether to yield 27 mg (23%) of 6; mp 172-173 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.81 (d, J ) 8.2 Hz, 1H), 7.50 (apparent t, J1 + J2 ) 15.1 Hz, 1H), 7.45 (d, J ) 6.8 Hz, 1H), 7.36 (d, J ) 7.8 Hz, 1H), 6.96 (d, J ) 7.8 Hz, 1H), 5.26-5.19 (3 H), 5.13 (d, J ) 6.8 Hz, 1H), 3.93 (s, 3H). Anal. calcd for C13H12O3: C, 72.21; H, 5.59. Found: C, 72.11; H, 5.47. 5-Methoxy-1,2-dihydroacenaphthylene-trans-1,2-diol (7). A solution of 139 mg of iodine in 2.5 mL of benzene was added to a mixture of 251 mg of silver benzoate in 2.5 mL of benzene. The mixture was stirred for 30 min. Compound 12 (100 mg) in 1.0 mL of benzene was added dropwise, and the reaction mixture was stirred for 4 h under nitrogen. The reaction mixture was filtered, and the solvent was removed to give 256 mg of crude dibenzoate diester. To this product was added a solution of 2.5 mL of 6.7 M KOH and 25 mL of methanol. The aqueous methanolic KOH reaction solution was heated at reflux for 1.5 h. The reaction solution was cooled, and most of the methanol was removed by rotary evaporation. Water (25 mL) was added, and the mixture was extracted twice with 20 mL of ethyl acetate. The combined ethyl acetate solution was dried over calcium sulfate, and the solvent was removed to yield 137 mg of a crude product containing both trans diol 7 and cis diol 6 (trans/cis ratio 70:30). The crude product mixture was sublimed at 110 °C (0.02 mmHg), and the sublimate was recrystallized from diethyl ether/ethyl acetate to yield 20 mg of a solid material that was still a mixture of ∼70% trans diol and ∼30% cis diol. A sample of 13 mg of pure trans diol 7 was isolated by preparative HPLC on a C18 column with 60% methanol/40% water as eluting solvent; mp 155-156 °C. 1H NMR (400 MHz, DMSOd6): δ 7.83 (d, J ) 8.2 Hz, 1H), 7.52 (apparent t, J1 + J2 ) 15.1 Hz, 1H), 7.44 (d, J ) 6.8 Hz, 1H), 7.34 (d, J ) 7.3 Hz, 1H), 6.98 (d, J ) 7.3 Hz, 1H), 5.81 (d, J ) 6.4 Hz, 1H), 5.70 (d, J ) 6.4 Hz, 1H), 5.15 (dd, J1 ) 6.4 Hz, 1H), 5.13 (dd, J ) 6.4 Hz, 1H), 3.95

Transition State Effects in Arene Oxide Hydrolysis

Figure 1. Plot of kobsd for reaction of 5 vs apparent pH, 50:50 dioxane/ water, 0.1 M NaClO4, 25.0 ( 0.2 °C.

(s, 3H). Anal. calcd for C13H12O3: C, 72.21; H, 5.59. Found: C, 72.12, H, 5.56. 5-Methoxy-1,2-dihydroacenaphthylen-1-one (8). Compound 5 (7.1 mg) was dissolved in 3 mL of 50:50 H2O/THF containing 2 mM EPPS [(N-2-hydroxyethyl)piperazine-N′-3-propanesulfonic acid] at pH 7.65. After 5 min, the THF was removed, and the product was extracted into ethyl acetate. The organic layer was dried over Na2SO4, and the solvent was removed to yield 4.9 mg (69%) of yellow crystals. The crude product was recrystallized from ethyl acetate/diethyl ether solution to yield 2.1 mg of product; mp 142-144 °C. 1H NMR (CDCl3, 400 MHz): δ 8.32 (d, J ) 8.2 Hz, 1H), 7.95 (d, J ) 7.3 Hz, 1H), 7.67 (apparent t, J1 + J2 ) 15.1 Hz, 1H), 7.34 (d, J ) 7.3 Hz, 1H), 6.86 (d, J ) 7.8 Hz, 1H), 4.03 (s, 3H), 3.74 (s, 2H). Anal. calcd for C13H10O2: C, 78.77; H, 5.09. Found: C, 78.66, H, 4.91. The structure of 8 was confirmed by 1H NOE and decoupling experiments. The absorption of H-7 occurs as a doublet of doublets at δ7.67. Saturation of this absorption resulted in the simplification of absorptions at δ7.95 and δ8.32 from doublets to singlets; therefore, these two absorptions can be assigned to H-6 and H-8. The absorptions at δ6.86 and δ7.34 can be assigned to H-4 and H-3, respectively, because of the shielding effect of the methoxyl group. Irradiation of the absorption at δ6.86 led to NOE enhancements of only the absorption at δ7.34 and the methoxyl hydrogen absorption at δ4.03; thus, the absorption at δ6.86 was assigned to H-4. Irradiation of the absorption at δ7.34 also led to NOE enhancements of the H-4 absorption at δ6.86 and the methoxyl hydrogen absorption at δ4.03 but in addition led to an NOE enhancement of the benzylic H-2 absorption at δ3.74. These NOE observations confirm that the methylene C-2 hydrogens are benzylic to the phenyl ring containing the methoxyl group. Procedure for Monitoring Rates of Reaction of 5-Methoxyacenaphthylene 1,2-Oxide. For each kinetic run, approximately 10-15 µL of a stock solution of 5 in dioxane (1 mg/mL) was added to 2.0 mL of water or dioxane/water solution in the thermostated cell compartment (25.0 ( 0.2 °C) of a UV-vis spectrophotometer. Reactions were monitored at 265 nm, and pseudo-first-order rate constants were calculated by nonlinear regression analysis of the absorbance vs time data (cf. Figure 1). Product Studies of the Hydrolysis of 5-Methoxyacenaphthylene 1,2-Oxide. 1. Acid-Catalyzed Reaction. A 25 µL aliquot of 5 in dioxane (1 mg/mL) was added to 2 mL of 0.1 M HClO4 in 50:50 dioxane/water, where >99% of the reaction is acid-catalyzed. The reaction solution was allowed to stand at room temperature for 1.5 min and was then neutralized to pH 5-8 with NaOH solution. The resulting solution was analyzed by reverse phase HPLC on a C18 column with 50:50 methanol/water as eluting solvent (1.2 mL/min), and products were monitored by UV detector at 265 nm. The retention times of cis diol 6, trans diol 7, and ketone 8 were 10.7, 6.3, and 38.3 min, respectively, and the relative yields were 62, 37, and ∼1%, respectively. 2. pH-Independent Reaction. A 25 µL aliquot of 5 in dioxane (1 mg/mL) was added to 2 mL of 50:50 dioxane/water containing 2 × 10-3 M EPPS in which the pH was preadjusted to 7.65. After the reaction solution was allowed to stand at room temperature for 2 min, the solution was analyzed by HPLC under the conditions outlined in part 1 above. The extinction coefficient of ketone 8 at

Chem. Res. Toxicol., Vol. 19, No. 2, 2006 219

Figure 2. Plots of percent cis diol 6 vs time in the equilibration reactions starting from either cis diol 6 (9) or trans diol 7 (b) in 0.1 M HClO4/water solution, 25.0 ( 0.2 °C.

265 nm was measured to be 3.1 times greater than the extinction coefficients of diols 6 and 7. After correction for differences in extinction coefficients of the products at 265 nm, the yields of 6, 7, and 8 were calculated to be 4, 2, and 94%, respectively. Acid-Catalyzed Equilibration of cis and trans Diols 6 and 7. A solution 1.2 mg of cis diol 6 in 2.5 mL of methanol was prepared. A portion of this solution (0.75 mL) was added to 25 mL of 0.1 M HClO4 in water maintained at 25.0 ( 0.2 °C. At various times, 2 mL of the solution was removed, neutralized by addition of 0.1 M NaOH, and analyzed by HPLC under the conditions noted above for product studies. The same procedure was followed with the trans diol 7 as the starting material. At very long reaction times (49 h), an HPLC peak (∼5%) with the same retention time as ketone 8 was observed. The isomerization results are summarized in Figure 2.

Results pH Rate Profile and Products from Hydrolysis of 5. The synthesis of 5 was accomplished by the reaction of dimethyldioxirane with 12 in acetone. This epoxide is too reactive in water or dioxane/water solutions containing mostly water for its rates to be determined by a simple mixing technique. In 50: 50 dioxane/water solutions, however, the rate of the pHindependent reaction of 5 is sufficiently slow to be conveniently measured (half-life 22 s). Its pH rate profile over the pH range 4-8 is given in Figure 1. In this solvent, acid-catalyzed hydrolysis occurs at pH < ∼5, and a pH-independent reaction occurs at pH > ∼5. Rate data were fit to the equation kobsd ) kH[H+] + ko, where kH is the second-order rate constant for acid-catalyzed hydrolysis and ko is the first-order rate constant for the pH-independent reaction. Values of kH and ko are calculated to be 1.26 × 103 M-1s-1 and 3.1 × 10-2 s-1, respectively. Products from reaction of 5 in 50:50 dioxane/water containing 0.1 M HClO4, where >99% of the reaction is acid-catalyzed, and in 50:50 dioxane/water at apparent pH 7.65, where >99% of the reaction is via the pH-independent route, were determined. The acid-catalyzed hydrolysis of 5 in 0.1 M HClO4 yields 62% of cis diol 6, 37% of trans diol 7, and ∼1% of ketone 8. The pH-independent reaction of 5 yields mainly ketone 8 (94%), along with minor amounts of cis diol 6 (4%) and trans diol 7 (2%). These product distributions are very similar to the product distributions from the acid-catalyzed and pH-independent reactions of cyclopenta[cd]pyrene oxide (1) (17). Acid-Catalyzed Equilibration of cis and trans Diols 6 and 7. The relative stereochemistries of diols 6 and 7 were established by comparison of their 1H NMR spectra and HPLC retention times with authentic synthetic samples of cis and trans diols. Cis diol 6 was synthesized by the reaction of 12 with OsO4, followed by reduction of the osmate ester. Trans Diol 7 was prepared by the reaction of 12 with silver benzoate to yield a mixture of cis and trans benzoate diesters, followed by

220 Chem. Res. Toxicol., Vol. 19, No. 2, 2006

Zhao and Whalen

hydrolysis of the diester mixture to a mixture of cis and trans diols. The trans diol 7 was separated from the cis diol 6 by preparative HPLC. The relative stabilities of cis and trans diols 6 and 7 were established by the acid-catalyzed conversion of each diol to an equilibrium mixture of isomers (eq 1). k1

cis diol (6) + H+ {\ } trans diol (7) + H+ k -1

Table 1. Summary of kH and ko Values for Reactions of Styrene Oxides, Indene Oxides, Acenaphthylene Oxides, and Cyclopenta[cd]pyrene Oxide in Water and Dioxane/Water Solutions at 25 °C

(1)

The approaches to an equilibrium mixture of cis and trans diols 6 and 7 in 0.1 M HClO4/water solutions at 25 °C, starting from pure 6 and from pure 7, were monitored by HPLC as functions of time. Plots of % cis diol vs time for the approaches to a cis:trans diol equilibrium mixture follow pseudo-first-order kinetics and are given in Figure 2. The observed pseudo-firstorder rate constant (kobsd) for approach to an equilibrium from either side of eq 1 is equal to the sum of the forward and reverse pseudo-first-order rate constants (k1[H+] + k-1[H+]) and are the same within experimental error. Dividing kobsd by [H+] gives the average second-order rate constant of 0.96 M-1 h-1 for the acid-catalyzed approach to equilibrium (k1 + k-1). Extrapolation of the percent composition vs time data in Figure 2 yields a calculated equilibrium mixture containing 81% of trans diol 7 and 19% of cis diol 6. At a much slower rate, the mixture of 6 and 7 reacts to form ketone 8.

Discussion Reactivities of 5-Methoxyacenaphthylene 1,2-Oxide in Acid-Catalyzed and pH-Independent Reactions. The apparent second-order rate constants for acid-catalyzed epoxide hydrolysis do not change significantly as a function of solvent composition in water/dioxane mixtures. For example, kH for acid-catalyzed hydrolysis of 5-methoxyindene oxide in 1:3 dioxane/water is only ∼14% smaller than in water. Approximate comparisons of second-order rate constants for acid-catalyzed hydrolysis of indene oxides, acenaphthylene 1,2-oxides, and cyclopenta[cd]pyrene oxide in dioxane/water solvents that are somewhat different can therefore be made. However, the pH-independent reaction of 5-methoxyindene oxide is 5.7 times slower in 1:3 dioxane/water than in water. An increase of the percent of dioxane in a dioxane/water mixture therefore results in a significant lowering of the rate of the pH-independent reaction. Table 1 summarizes the rate constants for acid-catalyzed and pH-independent reactions of styrene oxides, indene oxides, acenaphthylene oxides, and cyclopenta[cd]pyrene oxide. Data from this table show that the substitution of a p-methoxy group in place of hydrogen in styrene oxide results in an increase of kH in water by 4.1 × 102 and an increase in ko by 7.1 × 102. Substitution of a methoxy group for hydrogen in the 5-positions of indene oxide and acenaphthylene oxide results in an increase in kH by factors of ∼59 and ∼34, respectively. The reduced substituent effects for reactions of indene oxides and acenaphthylene oxides suggest “earlier” transition states for their acidcatalyzed hydrolysis as compared to that for the acid-catalyzed hydrolysis of styrene oxides. Compound 5 is somewhat less reactive than 5-methoxyindene oxide but somewhat more reactive than cyclopenta[cd]pyrene oxide 1 toward acidcatalyzed hydrolysis. The rate of the pH-independent reaction of 5 in 50:50 dioxane/water is only slightly faster than the rate of the pH-independent reaction of 1 in 25:75 dioxane/water but, with a correction for the difference in solvent, 5 is estimated to be approximately an order of magnitude more reactive than 1 in the same solvent. In terms of both structure and reactivity, 5 serves as an excellent model for cyclopenta[cd]pyrene oxide 1.

compd kH (M-1 s-1) 13aa 13ba 14ab 14bc

2.7 × 101 1.1 × 104 8.9 × 102 5.2 × 104

ko (s-1) 4.2 × 10-6 3.0 × 10-3 1.3 × 10-4 5.2 × 10-2

compd kH (M-1 s-1) 15d 5e 1f

3.7 × 101 1.3 × 103 1.8 × 102

ko (s-1) 3.9 × 10-4 3.1 × 10-2 2.5 × 10-2

a Ref 25 (water). b Ref 9 (water). c Ref 11 (25:75 dioxane/water). d Ref 17 (water). e This work (50:50 dioxane/water). f Ref 17 (25:75 dioxane/ water).

pH-Independent Reaction of 5. The pH-independent reactions of 5 and 1 lead to 94% yields of isomeric ketones 8 and 4, respectively, along with minor yields of cis and trans diols. The transition states for rearrangement of 5 to ketone 8 (17) and of 1 to ketone 4 must have considerable positive charge development on the benzylic carbons at the transition state, because the benzylic C-O bond that undergoes cleavage in each system is the one leading to the more stable carbocation. By analogy with the pH-independent reactions of naphthalene 1,2epoxide (26), p-methoxystyrene oxide (27), and 6-methoxy1,2,3,4-tetrahydronaphthalene-1,2-epoxide (28), this reaction most likely occurs with 1,2-hydrogen migration to the electrondeficient benzylic carbon, possibly via a concerted reaction. Comparison of cis/trans Diol Product Ratios from AcidCatalyzed Hydrolysis of 5 and Equilibrium cis/trans Diol Ratios. The acid-catalyzed hydrolysis of both 5 and of 1 yields 60-62% of cis diol and 34-37% of trans diol, in addition to very minor yields of ketone products. However, trans diol 7 is more stable than cis diol 6; therefore, acid-catalyzed hydrolysis of 5 yields the less stable cis diol as the major product. Acidcatalyzed hydrolyses of 4-methoxyphenyloxirane (4-methoxystyrene oxide) (25), trans-2-methyl-1-(4-methoxyphenyl)oxirane (29), and 5-methoxyindene oxide (14b) (11) occur with ratelimiting epoxide ring opening to form discrete carbocation intermediates that have sufficient lifetimes to react with external nucleophiles such as azide ion, and the product-forming steps of each of these reactions are attack of water on the intermediate carbocation. It is therefore reasonable to assume that the acidcatalyzed hydrolysis of 5 occurs via a similar mechanism in which the product-forming steps are attack of water on a discrete carbocation intermediate as shown in Scheme 3. Although the epoxide group in 5 may undergo ring opening to give two different benzylic carbocations, 16 and 17, the epoxide opening pathway shown in Scheme 3 leads to the more stable benzylic carbocation (17) that is better stabilized by the methoxyl group. Density functional calculations at the B3LYP/ 6-31G* level of theory indicate that carbocation 17 is 7.73 kcal/ mol more stable than 16 in the gas phase and that there is a single conformation for intermediate 17. Attack of water from one face of the carbocation yields cis diol, and attack of water from the opposite face of the carbocation yields trans diol. The relative transition state energies for cis and trans attack of water on 17 determine the cis/trans diol product ratio. The transition

Transition State Effects in Arene Oxide Hydrolysis

Chem. Res. Toxicol., Vol. 19, No. 2, 2006 221 Scheme 3

state for cis attack of water on carbocation 17 must be stabilized by effects that are not present in the transition state for trans attack of water on 17, even though cis attack of water leads to the less stable cis diol product. Energetically favored cis attack of solvent on the intermediate hydroxycarbocation formed in the acid-catalyzed hydrolysis of 5-methoxyindene oxide has been attributed in part to intramolecular hydrogen bonding between the attacking water molecule and the β-hydroxyl group that is more favorable than hydrogen bonding between the attacking water molecule and solvent in the transition state for trans attack (11). A transition structure for cis attack of water, calculated at the MP2/6-31G*//MP2/631G* level of theory, is given by 18. In this structure, the H- - -O hydrogen bond distance between the incoming water molecule and the adjacent hydroxyl oxygen atom is calculated to be 1.91Å, which is within normal hydrogen bonding distance (30). Intramolecular hydrogen bonding between the attacking water molecule and the adjacent hydroxyl group is not possible for trans attack. The solvating effects of other water molecules and possibly different transition state geometries may also contribute to the difference in transition state energies for cis and trans attack of water on 17, but the magnitudes of these effects are difficult to quantify.

Conclusions Acid-catalyzed hydrolysis of 5 yields 6 as the major diol product and trans diol 7 as a minor product. However, acidcatalyzed equilibration studies show that trans diol 7 is more stable than cis diol 6. The mechanism proposed for the acidcatalyzed reaction of 5 involves formation of an intermediate carbocation, followed by attack of water from either side of the electron deficient benzylic carbon of the carbocation. Transition state effects must selectively stabilize the transition state for attack of water on the intermediate carbocation leading to the less stable cis diol. Because trans diol 7 is more stable than its isomeric cis diol 6, it is reasonable to assume that trans diol 3 in the cyclopenta[cd]pyrene system is more stable than its isomeric cis diol 2. Therefore, transition state effects are also most likely responsible for the observation that acid-catalyzed hydrolysis of 1 yields cis diol 2 as the major product. It is interesting to note that the stereochemistry associated with acidcatalyzed hydrolysis of 1 is similar to that of its reaction with DNA (18), which yields more cis than trans adducts. Although it is not possible to extrapolate from solution chemistry to the

reactions of 1 with DNA, there are some important similarities. The benzylic C-O bond of the epoxide group in 1 leading to the more stable carbocation is cleaved in both the acid-catalyzed hydrolysis of 1 and in its reaction with DNA. Transition state effects may also play a role in determining the stereochemistry of the reactions of 1 with DNA. Acknowledgment. Acknowledgment is made to the Donors of the American Chemical Society Petroleum Research Fund for support of this research. Supporting Information Available: Calculated structures and Cartesian coordinates for carbocations 16 and 17 (B3LYP/6-31G*) and calculated transition structure for cis attack of water on carbocation 17 (structure 18) (MP2/6-31G*). This material is available free of charge via the Internet at http://pubs.acs.org.

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