J . Am. Chem. SOC. 1991, 113, 3910-3919
3910
Solvolysis of K-Region Arene Oxides: Substituent Effects on Reactions of Benz[ alanthracene 5,6-0xide1 Nashaat T. Nashed,**tSuresh K. Balani,? Richard J. Loncharich,t Jane M. Sayer,? David Y. Shipley,s Ram S. Mohan,s Dale L. Whalen,g and Donald M. Jerinat Contribution from the Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, and Molecular Graphics and Simulation Laboratory, Division of Computer Research and Technology, The National Institutes of Health, Bethesda, Maryland 20892, and the Laboratory for Chemical Dynamics, Department of Chemistry, University of Maryland Baltimore County Campus, Baltimore, Maryland 21 228. Received September 28, I990
Abstract: The solvolytic reactivity and products formed from benz[a]anthracene 5,6-oxide (BA-0) on substitution of a methyl group at positions 1 (I-MBA-0), 4 (4-MBA-0), 7 (7-MBA-0), 11 (11-MBA-0), and 12 (I2-MBA-O), on 7,la-dimethyl substitution (7,12-DMBA-O), and on 7-bromo substitution in 1:9 dioxane-water and in methanol at 25 "C are reported. These substitutions result in > 150-fold differencesin their rates of acid-catalyzed solvolysis and cause marked changes in the distribution of solvent adducts and phenols resulting from isomerization. Optically pure BA-O,7-MBA-O, 12-MBA-0, and 7,12-DMBA-O as well as their optically pure trans dihydrodiols were utilized to determine the point of attack by water in the hydrolysis reactions. In general, the reactions in aqueous dioxane (0.1 M NaCIO,) obeyed the rate equation kOM = kH[H+]+ ko, where kH is the second-order rate constant for acid-catalyzed reaction and ko is the first-order rate constant for spontaneous reaction, to provide biphasic pH-rate profiles. When ionic strength was maintained with 0.5 M KCI, however, more complex pH-rate profiles were observed for some of the arene oxides due to attack of chloride on the neutral epoxide to produce steady-stateconcentrations of chlorohydrins. Rate enhancement on methyl substitution is largest (kH,ca. 5-fold) when the methyl group is present in the hindered bay region (C, or CI2)or adjacent to the epoxide at C7. The combined effect of two methyl groups (7,12-DMBA-0) and ab initio by GAUSSIAN 86 and 88 is additive (ca. 25-fold). Theoretical calculations (molecular mechanics by KMODEL-PI programs) of carbocation stability indicate the importance of steric factors in determining relative reactivity and types of products formed from substituted benz[a]anthracene 5,6-oxides.
Introduction
K-Region arene oxides are potent mutagenic metabolites of several polycyclic aromatic Detoxification of these metabolites involves enzymatic hydrolysis catalyzed by epoxide hydrolase as well as conjugation with glutathione catalyzed by glutathione S-transferases.z Since an understanding of these reactions depends on knowledge of the solution chemistry of the arene oxides, their hydrolysis reactions have been studied extensively in aqueous solutions.k-"10 The hydrolysis reactions of K-region arene oxides derived from b e n ~ o [ a ] p y r e n e ,phenan~*~ threne (Phe)6*7and several of its derivatives,8 benz[a]anthracene (BA),639 7,12-dimethylbenz[a]anthracene (7,l 2-DMBA),I0 diben~[a,h]anthracene,~ and 3-methylcholanthrene9 have been reported in water and mixed aqueous solvents. Phenanthrene 9,lO-oxide (Phe-0), for example, undergoes hydronium ion catalyzed hydrolysis at low pH, spontaneous hydrolysis at intermediate pH values (ca. 7-1 2), and hydroxide ion catalyzed hydrolysis at pH > ca. 1 2.6 The acid-catalyzed hydrolysis of Phe-0 in water yields mostly 9-phenanthrol (75-80%), in addition to cis and trans dihydrodiols (20-25%, 1:2 ratio, respectively). The spontaneous reaction, however, produces mostly trans dihydrodiol (ca. 66%) and a reduced but still significant yield of phenol (ca. 33%).7 Less than 1% of the cis dihydrodiol is formed from this reaction. In 1:l dioxane-water, the major products (ca. 75%) from the acidcatalyzed hydrolysis of 7,12-DMBA-O are the cis and trans dihydrodiols in a 1:7 ratio.1° Smaller amounts (ca. 25%) of the C5 and c6 ketones, precursors to the corresponding phenols, constitute the balance of the products. The reduced yields of ketones from 7,12-DMBA-O were attributed to a retarding of the N I H shift pathway, relative to trapping of the carbocations by water, because of the dihedral twist in the ions formed from acid-catalyzed opening of the epoxide. It was postulated1° that the effect of this twist may "inhibit full cyclic conjugation in the N I H shift transition state, or cause the reacting C-H bond to overlap less with the adjacent empty p orbital". 'Laboratory of Bioorganic Chemistry. *Molecular Graphics and Simulation Laboratory. 1 Laboratory for Chemical Dynamics.
0002-7863/91/1513-3910.$02.50/0
In order to understand more fully the effects of substituents on the acid-catalyzed hydrolysis reactions of K-region arene oxides of BA, we have carried out kinetic and product studies of the hydrolysis and methanolysis reactions of 1-methyl, 4-methy1, 7-methyl, 11-methyl, 12-methy1, and 7,12-dimethyl derivatives of BA 5,6-oxide as well as methanolysis of its 7-bromo derivative (Scheme I). Product studies of optically active arene oxides in aqueous media and racemic arene oxides in acidic methanol allow determination of the regiospecificities for these reactions. The results of molecular mechanics calculations are used to gain insights into the effects of specific methyl substitutions on the geometries and relative energies of the arene oxides and carbocations formed from their acid-catalyzed opening.
Results Kinetics. General Results. The observed pseuddirst-order rate constants for the reactions of 4-MBA-O,7-MBA-O, 12-MBA-0, and 7,12-DMBA-0 in 1:9 dioxane-water (v/v) solutions at 25 "c containing 0.1 M NaCIO,, accurately fit eq 1, where kH is the second-order rate constant for the hydronium ion catalyzed re(1) Dedicated to the memory of Professor Emil T. Kaiser. (2) (a) Boyd, D. R.;Jerina, D. M. In Small Ring Heterocycles; Hassner, A., Ed.; John Wiley and Sons, Inc.: New York, 1985; Vol. 42, Part 3, pp 197-282. (b) Thakker, D. R.; Levin, W.; Wood, A. W.; Conney, A. H.; Yagi,
H.; Jerina, D. M. In Drug Stereochemistry-Analytical Methods and Pharmacology; Wainer, I. W., Drayer, D. E., Eds.; Marcel Dekker, Inc.: New
York, 1988; pp 271-296. (3) Conney, A. H. Cancer Res. 1982, 42, 4875. (4) Bruice, T. C.; Bruice, P. Y. Ace. Chem. Res. 1976, 9, 378. (5) Hylorides, M. D.; Lyle, T. A,; Daub, G. H.; Jagt, D. L. V. J. Org. Chem. 1979, 44, 4652. (6) Bruice, P. Y.; Bruice, T. C.; Dansette, P. M.; Selander, H. G.; Yagi, H.; Jerina, D. M. J . Am. Chem. Soc. 1976, 98, 2965. (7) Whalen, D. L.; Ross, A. M.; Dansette, P. M.; Jerina, D. M. J . Am. Chem. Soc. 1977. 99. 5672. (8) Okamoto, T.; Shudo, K.; Miyata, N.; Kitahara, Y.; Nagata, S. Chem. Pharm. Bull. 1978, 26, 2014. (9) Keller, J. W.; Heidelberger, C. J . Am. Chem. Soc. 1976, 98, 2328. (10) Keller, J. W.; Kundu, N. G.; Heidelberger, C. J . Org. Chem. 1976, 41, 3487.
0 1991 American Chemical Society
J . Am. Chem. SOC.,Vol. 113, No. 10, 1991 3911
Solvolysis of K - Region Arene Oxides Scheme l a b
BAY REGDN
OR OH
"OR
OH
OH
OH
"ROH = methanol or water. bKey: BA 5.6-oxide (BA-0), 1-methyl (I-MBA-0), 4-methyl (4-MBA-0), 7-methyl (7-MBA-0), 11methyl ( I I-MBA-O), 12-methyl (12-MBA-U), /,lL-dimethyl (7,12- DMBA-0), 7-bromo (7-BrBA-0). Table I. Rate Constants for the Hydrolysis Reactions of BA-0 and its Methyl-Substituted Derivatives in 1:9 Dioxane-Water (25 "C)
Solutions Containinn 0.1 M NaCIOl
,
compd BA-0 I-MBA-0 4- M B A - 0 7-MBA-0 1 I-MBA-0 12-MBA-0 7,12-DMBA-0 Phe-0
10-'kH, M-l S-I 0.89 f 0.06 5.0 f 1.0 2.3 f 0.2 4.7 f 0.2 1.1 i 0.2 4.2 f 0.2 23 f 3.0 0.39 f 3'
105ko,S-I
kH
1.o
5.6 2.6 5.3 1.2 4.7 25.8
4.4 i 0.5 3.3 f 0.2 7.0 f 0.3 35 f 4.0
Solutions Containing 0.5 M KCI compd 10-2kH, M-l S-' 105ko, s-I 103k2, M-1 s-1 k-z&lk,, M 7-MBA-0 4.6 f 0.2 0.34 f 0.02 0.48 f 0.05 (2.9 f 0.7) X IO-* 12-MBA-0 4.3 f 0.4 5.7 f 0.6 7.12-DMBA-0 24 f 2.0 34 f 3.0 1.5 f 0.2 (1.4 f 0.81 X a For comparison, values of kH for Phe-0 in water at 30 O C were 100 M-' s-I in the presence of 1.0 M KCI (ref 6) and 115 M-I s-I in the presence of 0.1 M NaCIO, (ref 7). Table 11. Listing of the Partial Rate Constants k5 and k6,D Along with Relative Values Compared to those of BA-0,b for Acid-Catalyzed Methanolvsis of Arene Oxides (25 OC)
compd 10-'kH, M-' S-I k H (rel) IO-*k5, M-I s-I 10-2k6, M-I s-l k5 (re11 k6 (rel) BA-0 4.76 1.o 1.76 3.00 1.o 1.o 3.6 8.45 8.45 4.8 2.8 I-MBA-0 16.9 4-MBA-0 19.0 4.0 10.3 8.7 5.9 2.9 7-MBA-0 27.7 5.8 8.3 19.4 4.7 6.5 1 I-MBA-0 6.3 3.8 1.4 1.3 1.3 2.5 12-MBA-0 22.3 4.7 2.2 20.1 1.2 6.7 157.0 7,12-DMBA-O 33.0 19.0 138.0 10.8 46.0 7-BrBA-0 1.1 0.23 1.05 0.05 0.6 0.017 'Values of kS and k6 were calculated by multiplying kH (standard deviation 2-6% of reported values) times the fraction of product arising from the C5and c6 carbocations, respectively. 'Values of k5 (rel) and k6 (rel) for each compound are relative to those for BA-0. Thus, comparisons between columns for k5 (rel) and k6 (rel) cannot be made.
action and ko is the first-order rate constant for the spontaneous reaction. This rate law corresponds to a biphasic pH-rate profile
+
k o w = k,[H+] ko (1) in which kobsdis dependent on the hydronium ion concentration at low pH but becomes pH-independent near or above neutrality. Rate constants k H and ko for those arene oxides studied are given in Table 1. Rate data for the hydrolysis of BA-0, 1-MBA-0, and 11-MBA-0 did not follow good pseudo-first-order kinetics at pH > ca. 5, possibly due to instability of the phenolic products, and therefore complete pH-rate profiles for these compounds were not determined. Second-order rate constants for the acid-catalyzed reactions of the K-region arene oxides in methanol (Scheme I) were obtained as described in the Experimental Section. These rate constants, the partial rate constants for reaction at C5 and C6, and their relative values compared to those for B A - 0 are listed in Table 11.
Specific Chloride Ion Effects. The pH-rate profile for the hydrolysis of 12-MBA-0 in 0.5 M KCI is indistinguishable from
Scheme 11
$J
-
products
kdH'1
\\ \ products
&o-
-CI
[H'l/K,_
-CI
that in 0.1 M NaC104 solutions (Figure S-I, supplementary material). In contrast, the pH-rate profiles for the reaction of 7-MBA-0 and 7,12-DMBA-O are more complicated in 0.5 M KC1 than in 0.1 M NaC104 such that a plateau region is observed at pH ca. 6-10 in which koM is significantly larger than expected
Nashed et al.
3912 J. Am. Chem. SOC.,Vol. 113, No. 10, 1991 Table 111. Distribution of Products between Phenols and
Dihydrodiols on Acid-Catalyzed Hydrolysis of Benz[a]anthracene 5,6-0xides in 1:9 Dioxane-Water at 25 "C Containing 0.1 M NaCIO" ratio c6:c5 for trans phenols diols diols compd % 5-OH % 6-OH % cis % trans k, kn BA-0 42 21 18 19 62:38 51:49 I-MBA-0 18 17 37 28 4-MBA-0 ND 35 22 43 7-MBA-0 27 ND 33 40 37:63 73:27 1 I-MBA 38 20 21 21 12-MBA-0 11 3 15 71 90:lO 72:28 7.12-DMBA-0 ND ND 12 88 88:12 85:15 'Ratios of hydrolysis at C5versus c6 for the trans dihydrodiols were determined with chiral substrates. Percentages of phenols and dihydrcdiols from each arene oxide were determined from NMR spectra of the total reaction products by integration of selected peak areas. Ratios of cis to trans dihydrodiols were confirmed by HPLC. ND indicates the compound was not detected in the NMR spectrum of the product mixture. See Experimental Section for carbocation origin of trans dihydrodiols.
on the basis of kH and ko values measured at lower and higher pH values, respectively (Figure S-2, supplementary material). Similar specific chloride ion effects have been observed in the reaction of indene 1,2-oxide,11 1,3-~yclohexadiene1,2-oxide,I2and Phe-0' in KCI solutions. The mechanism shown in Scheme I1 has been proposed to account for this effect, which is observable only when k2[CI-] L ko. We attribute the kinetic behavior of 7-MBA-0 and 7,12-DMBA-0 in KCI solutions (k2[C1-]:koratios are 7.3 and 2.1, respectively) to this same specific effect of chloride ion. The rate expression for a reaction that proceeds by the mechanism outlined in Scheme I1 is given by eq 2. Summaries
of rate constants kH, k2, k-2Ka/k3, and ko for reactions of 7MBA-0 and 7,12-DMBA-O, as well as kH and ko for 12-MBA-0, in 0.5 M KCI solutions are provided in Table I. A basis for predicting which arene oxides will show a chloride effect is presently unavailable. Product Studies. Hydrolysis. Yields and ratios of trans and cis dihydrodiols and isomeric K-region phenols from the acidcatalyzed hydrolysis of BA-0 and its methyl-substituted derivatives in 1 :9dioxane-water are provided in Table 111. These products are readily rationalized by the mechanism outlined in Scheme I where protonated epoxide undergoes rate-determining C - O bond cleavage to yield C5 and c6 carbocation intermediates. These cations either react with water to yield cis and trans dihydrodiols (methyl ethers in methanol) or rearrange to phenols. To determine the regioselectivity of the trans hydration reaction, acid-catalyzed hydrolyses of chiral BA-O,7-MBA-O, 12-MBA-0, and 7,12-DMBA-O were carried out and the enantiomeric compositions of the trans dihydrodiol products were determined. For example, acid-catalyzed hydrolysis of (+)-(5S,6R)-BA-0 yielded 38% of the 5R,6R and 62% of the 5S,6S enantiomer. Thus, 62% of the trans dihydrodiol is formed from the c6 carbocation and the remaining 38% from the C5carbocation. Table 111summarizes the amounts of trans dihydrodiol formed from the C5 and c6 carbocations of each of the optically active arene oxides studied. Spontaneous reaction (pH > ca. 7 5 0 . 1 M NaC104) of BA-0, 7-MBA-0, 12-MBA-0, and 7,12-DMBA-O gave mainly or entirely dihydrodiols in which the trans to cis ratio was >98:2. In contrast to the results in NaCIO4 solutions, a significant amount (12-14%) of cis dihydrodiol is formed in addition to the trans dihydrodiol from the hydrolysis of 7,12-DMBA-0 at pH 8 in the (11) Whalen, D. L.; Ross, A. M. J . Am. Chem. SOC.1976, 98, 7859. (12) Ross, A. M.; Pohl, T. M.; Piazza, K.; Thomas, M.; Fox, B.; Whalen, D.L. J . Am. Chem. Soc. 1982, 104, 1658.
Table IV. Effects of Substitution on Product Distribution for the
Acid-Catalyzed Methanolysis of Benz[a]anthracene 5,6-0xidesa 5% product % trans % cis % from each compd carbocation addition addition phenol BA-0 c 5 37 23 6 8 c 6 63 38 9 16 1-MBA-0 C5 50 44 6 ND c6 50 40 IO ND 4-MBA-0 c554 24 15 15 c 6 46 44 2 ND 7-MBA-0 C5 30 28 2 ND c 6 70 36 22 12 1 I-MBA-0 C5 40 19 6 15 c 6 60 30 11 19 12-MBA-0 c510 10 trace ND c 6 90 85 5 ND 7.12-DMBA-0 C5 12 11 I ND C6 88 81 7 ND 7-BrBA-0 c, 95 94 1 ND c, 5 4 1 ND 'Distribution of products is based on integration of NMR spectra. The ratio of cis to trans methanol adducts obtained by integration of peak areas on HPLC matched that from integration of NMR peak areas. Note that a phenolic 6-hydroxyl group derives from a C5 carbocation. ND indicates that the product was not detected by either analytical method.
presence of chloride ion. Under these conditions, reaction occurs in part via an intermediate chlorohydrin (Scheme 11), whereas in 0.1 M NaCIO4 at the same pH the ko reaction predominates. As in the case of Phe-0, the cis diol presumably arises from the chlorohydrin via a hydroxy carbocation intermediate identical with that formed in the kH reaction, whereas the ko reaction gives exclusively trans dihydrodiol in the absence of chloride ion.' The pronounced chloride ion effect on the pH-rate profile and products of hydrolysis of some arene oxides but not others (e.g., 12-MBA-0) points out the necessity for caution in studying these reactions in solutions containing chloride or other nucleophilic ions. Methanolysis. Solvolysis in methanol has the advantage that the cis and trans methanolysis reactions each yield two positionally distinct monomethyl ether adducts (Scheme I), one derived from the C5 carbocation and the second from the C6 carbocation. As expected, the acid-catalyzed methanolysis produced cis and trans adducts from both K-region carbocations. When the monomethyl ethers and phenols are characterized, the total amount of product derived from the C5versus the c6 carbocations can be determined. Table IV summarizes the amounts of cis and trans dihydrodiol methyl ethers and phenols formed from the C5 and c6 carbocations from the studied arene oxides.
Discussion Solvent Effects. Comparison of acid-catalyzed reaction rates (kH) in 1:9 dioxane-water (Table I) versus methanol (Table 11) indicates that relative reactivity for several arene oxides is similar in both solvents. Absolute reaction rates in methanol are 3-fold (1-MBA-0) to 8-fold (4-MBA-0) higher than in 1:9 dioxanewater, perhaps due to the stronger acidity of CH30H2+compared to H,O+.I3 The other apparent difference between the reactions in methanol and in 1:9 dioxane-water is the change in gross distribution of products between total phenols and total solvent adducts (cf. Tables I11 and IV). Significantly more trans methanol adducts are formed compared to trans dihydrodiols. This occurs mainly at the expense of phenols since the cis methanol adducts are only slightly reduced compared to cis dihydrodiols. The more nucleophilic methanol probably intercepts the carbocation intermediate faster than water, thus competing more favorably with the hydride migration pathway to phenols. In the cases of BA-0, 7-MBA-0, 12-MBA-0, and 7,12DMBA-0, the regioselectivity of the trans addition of water can (13) Arnett. E. M. In Prowess in Phvsical Orpanic Chemistrv: Cohen. S .
G.;St;eitwieser; A,, Jr.; Taft, 'R. W., Eds:; Intersci&e Publishers: New York, 1963; Vol. 1, pp 223-403.
Solvolysis of K-Region Arene Oxides
be directly compared to that of methanol since optically active arene oxides were used in the aqueous reactions. For BA-0, 12-MBA-0, and 7,12-DMBA-0, the ratio of trans adduct derived from attack at c5versus c6 was unaffected by solvent (water versus methanol), and for 7-MBA-0 the effect of solvent on this ratio is small. If one assumes that the carbocation origin of the cis dihydrodiols is identical with that of the cis methanol adducts, then the estimated distribution of total products derived from the Cs and c6 carbocations in water is similar to that determined in methanol, at least in the cases of BA-0, 7-MBA-0, 12-MBA-0, and 7,12-DMBA-O. Product studies of the methanolysis of the BA oxides (Table IV) provide complete regiochemistries of carbocation formation. Although there are some differences between the reactions in methanol and in 1:9 dioxane-water as described above, the order of reactivity and regioselectivities in both solvents are very similar. Thus, the mechanisms of reaction in both solvent systems appear to be quite similar. Substituent Effects on the Rates and Regiochemistry of Ring Opening of BA Oxides. The reactivity of BA-0 is approximately twice that of Phe-0. For the acid-catalyzed reaction of BA-0 (Table I), the ratio of k6:k5 is 1.7:l in methanol and is estimated to be 2.1:l in 1:9 dioxane-water. These data are consistent with earlier results that show that the solvolytic rate constants for benzyl and 2-naphthylmethylene substrates are very ~imi1ar.I~The total kinetic effect of a methyl substituent at the 1-, 4-,7-, or 12-position on kH for hydrolysis or methanolysis is rather small (3-6-fold increase: see Tables I and 11). The rate effect of a methyl group at the 1I-position is even smaller (1.2). The combined rate effect of the two methyl groups of 7,12-DMBA-O (Table I) accounts for its 26-fold higher reactivity relative to that of BA-0 (5.3-fold for 7-MBA-0 times 4.7-fold for 12-MBA-0 = 24.9-fold relative to that for BA-0). Thus, the contribution of the methyl groups to the free energy of activation is additive. In order to assess the kinetic effects of substituents on the relative amounts of c5-oand c6-0 bond cleavage, the acidcatalyzed methanolysis reactions of BA oxides are viewed as two parallel reactions to form the c5and (26 carbocations (Scheme I). Thus, the observed rate constant kH (Table 11) is the sum of the partial rate constants (k, + k6), and the ratio of Cs products to c6 products is ks:k6. From the observed rate constants for methanolysis of the BA oxides and the yields of Cs and c6 products, values of kS and k6 for each arene oxide are calculated (Table 11). For comparison, a methyl substituent in the meta position usually enhances the rate of solvolysis of benzyl systems by a factor of 2 or less,I5 and p-methylstyrene oxide is 19 times more reactive toward acid-catalyzed hydrolysis than styrene oxide.I6 These factors can be used to estimate the expected electronic effect of a methyl group on kH in the acid-catalyzed solvolysis of the K-region arene oxides. For example, a 12-methyl group should behave like a meta substituent relative to the 6position in a substituted BA 5,6-oxide, whereas a 7-methyl group should have a much greater rate effect (analogous to an ortho or para substituent) because of the possibility of direct resonance interaction with a developing carbocation at this center. Since, in the present compounds, methyl substituents at the I-, 4-, 7-, or 12-position are either peri to the epoxide group or are at sterically hindered bay-region positions, the kinetic effect may result from both electronic and steric factors and thus may differ from prediction based on simple benzylic systems. Furthermore, the extended conjugation in the BA system may complicate the interpretation of electronic effects. The regiochemistry of epoxide ring opening of BA-0, like the overall rate, is relatively insensitive to the effect of methyl substituents at the 1-, 4-,7-, and 11-positions (cf. Tables 111 and IV). Thus, methyl substitution at one of these positions does not selectively favor ring opening at either C-0 bond. Rather, the kinetic effect must increase the rates of formation of both the Cs and c6 carbocations. For example, a methyl (14) Streitwieser, A,, Jr. Solvolytic Displacement Reactions; McGraw Hill: New York, 1962; p 176 and references therein. (15) Reference 14, p 41. (16) Blumenstein, J. J.; Whalen, D. L. Unpublished results.
J. Am. Chem. SOC., Vol. 113, No. 10, 1991 3913
substituent at the 7-position increases the rate of epoxide ring opening at both c6 and c5by approximately the same factor ( a . 5-6). The effect on c6 is smaller than that expected for a substituent in a direct conjugation with the carbocation center, on the basis of the ca. 20-fold acceleration predicted for the electronic effect of a para-methyl group (seepreceding discussion). A methyl substituent at the 4-position, another peri location, also increases the rate of epoxide ring opening at both the c5and c6 positions. In each case, the effect of the peri-methyl group is to increase the rate of ring opening at the adjacent epoxide position slightly more than at the more distant epoxide center. The small magnitude of the effect of a methyl group upon reactivity at the adjacent center may be a consequence of opposing steric and electronic effects. The steric effect could rise from unfavorable interaction between the hydrogen at the carbocation center and the peri-methyl group. A bromine substituent in the 7-position peri to the epoxide retards opening a t c6 by a factor of ca. 62, presumably due mainly to an electronic effect, and has a relatively small effect on epoxide opening at C5. Effect of a pen’-MethylCroup on Phenol Formation. Significant amounts of both isomeric K-region phenols are formed on the acid-catalyzed hydrolysis and methanolysis of B A - 0 and 11MBA-0 (Tables 111 and IV). The yields of phenols from both hydrolysis and methanolysis of the arene oxides with peri-methyl substitution (4-MBA-0 and 7-MBA-0) are significantly lower. A particularly interesting observation is that 4-MBA-0 yields only C, phenol and 7-MBA-0 yields only Cs phenol, whereas similar amounts of Cs and C, phenols areformed from both BA-0 and 11-MBA-0 in either solvent. The reduced yields of phenol product from 4-MBA-0 and 7-MBA-0 indicate that the perimethyl group in each case inhibits phenol formation at the adjacent K-region carbon center. This observation can be rationalized by the mechanism outlined in Scheme 111 for for the formation of the C5 phenol from BA-0. Assuming axial opening of the c6-0 bond of protonated BA-0, the initial carbocation must have a pseudoaxial hydroxyl group. In order for the C5 phenol to be formed, the C5 hydrogen must migrate to c6. It IS therefore reasonable to assume that, along the reaction coordinate for phenol formation, conformational reorganization of this cation must occur to a structure in which the C5 hydrogen is in a pseudoaxial position. Such a conformation would have the C-H bond periplanar to the empty p orbital which is favorable for hydride migration to C6.I7 In the corresponding mechanism for the acid-catalyzed reaction of 4-MBA-0, a methyl group rather than a hydrogen is at the C4 position. The additional steric strain caused by the peri interaction between the C4 methyl and C5 hydroxyl groups would make this conformational isomerization slower and/or less favorable thermodynamically than in the parent BA-0 system. Such an effect would also explain the absence of the c6 phenol among the products of the acid-catalyzed solvolysis of 7-MBA-0. Thus, these peri-methyl substituents retard formation of phenols at the adjacent epoxide center. Effect of a Bay-Region Methyl Group on Phenol Yields and Regioselectivity. Substitution of a methyl group at the bay-region 12-position of BA-0 increases the rate of acid-catalyzed epoxide ring opening at the 6-position by a factor of 6.7 and has little effect on the rate of ring opening at the 5-position (Table 11). The rate enhancement at c6 is larger than that expected from a purely electronic effect, since the 12-methyl is located in a meta position relative to c6, and the electronic effect of this group on kH should be about 2.15 The yield of phenols (Tables 111 and IV) is sensitive to methyl substitution at a bay-region position (C, and Clz). Acid-catalyzed hydrolysis of 1-MBA-0, 12-MBA-0, and 7,12DMBA-0 produced 35, 14, and 0%, respectively, of phenolic (17) Sayer, J. M.; Yagi, H.; Silverton, J. V.;Friedman, S.L.; Whalen, D. L.; Jenna, D. M. J. Am. Chem. SOC.1982, 104, 1972.
3914 J . Am. Chem. SOC.,Vol. 113, No. I O , 1991
Nashed et al.
Table V. Calculated Energies for Toluene, 2-Methylnaphthalene, Benzyl Cation, and 2-Naphthylmethylene Cation and Differences in Resonance Stabilization Energies between the Cations" computational -E, hartrees ARSE,b level C,H,+ CiiHin C,Hn CinHa" kcal/mol RHF/STO-3G -265.653 99 -417.271 70 -266.475 65 -416.464 85 9.3 RHF/3-21G -267.380 36 -420.037 26 -268.240 19 -419.1 89 50 7.6 RHF/6-31G* -268.88668 -422.392 83 -269.740 12 -421.552 11 8.0 "Bond lengths and angles at each level of calculation are given in the supplementary material. *Resonance stabilization energy for the isodesmic reaction of CIOH7CH3 + PhCH2+ CloH7CH2'+ PhCH3.
-
Scheme IV
I2.MBA-0-a
12.MBA.O-b
products. In contrast, ca 60% phenols were obtained from BA-0 and 1 I-MBA-0. In methanol, BA-0 and 11-MBA-0 produced 24 and 35% of phenolic products, respectively, whereas no phenolic products were obtained on the solvolysis of I-MBA-0, 12-MBA-0, and 7,12-DMBA-0. In order to assess rigorously the potential contribution of steric factors to the rates and product distributions upon solvolysis of K-region arene oxides with methyl substitution at the bay region, theoretical calculations of the preferred conformations and energy levels of several BA oxides as well as carbocation intermediates were undertaken. Specifically, minimum energy conformations for the ground states of selected BA oxides as well as the energies of the c5and c6 carbocations conformationally related to each of these ground states were calculated. Effect of Methyl Substitution in the Bay Region on the Conformation of BA Oxides. Molecular mechanics calculations by the PCMODEL-PI program18 indicate that 1-MBA-0 and 12MBA-0 can each exist in two conformations of approximately equal energy. The two conformations of 12-MBA-0, for example, are given by structures a and b in Scheme IV. Conformation a, in which the C,2-C12a-C12b-CIdihedral angle is -28O, is 0.4 kcal/mol more stable than conformation b, in which this dihedral angle is 29'. Designations a and b for structures signify negative or positive values of this angle, respectively. For 1-MBA-0, the conformation with a C12-C12a-C12b-CI dihedral angle of 28O is 0.3 kcal/mol more stable than a second conformation with a naphthyl-phenyl dihedral angle of -28'. The observed energy difference of 0.3 kcal/mol gives a ratio of 62:38 for the two conformations by a Boltzmann distribution calculation. Similar PCMODEL-PI calculations of 7,12-DMBA-0 provide one conformation similar to conformation a, with a naphthyl-phenyl dihedral angle of -29O and a second conformation that is 1.7 kcal/mol less stable with a dihedral angle of 31O. This energy difference corresponds to a ratio of 9 5 5 for these conformational isomers. From X-ray structure determination, 7,12-DMBA-0 has a cI2-c1&
