Hydrolysis of a Benzo[a]pyrene cis-9,10-Chlorohydrin
SCHEME 4
on this carbocation will yield the major cis tetrol that is
observed. The minor trans tetrol (4) formed in the
hydrolyses of DE-1 and cis-chlorohydrin 9 may also result
from attack of solvent on 2a, although some tetrol from
reaction of the less stable carbocation conformation 2b
cannot be ruled out.
The observation that DE-1 and its cis-chlorohydrin 9
both yield the same ratio of cis to trans tetrols (89% cis:
1
1% trans in 10:90 dioxane-water), both in the absence
of and in the presence of chloride ion, is intriguing. In
contrast, DE-2 undergoes acid-catalyzed hydrolysis to a
5
:95 ratio of cis and trans tetrols whereas its trans-
8
in 50:50 dioxane-water solutions, k-1/k
s
was calculated
-
1 11
chlorohydrin 8 hydrolyzes to a 21:79 ratio of cis and trans
tetrols when chloride ion is absent.11 However, at high
chloride ion concentrations DE-2 and its trans-chlorohy-
drin 8 both give a 35:65 ratio of cis to trans tetrols. One
possible explanation for the observation that both DE-1
and chlorohydrin 9 hydrolyze to the same ratio of tetrols
is that the “common intermediate” for these reactions
to be 23 M . The k-1/k
s
value for reaction of cis-
-
1
chlorohydrin 9 in 70:30 dioxane-water (41 M ) is
therefore only slightly larger than that for reaction of
trans-chlorohydrin 8 in 50:50 dioxane-water. The esti-
mated rate constants (k
and 2 with 10:90 dioxane-water solvent are estimated
s
) for reactions of carbocations 5
7
7
-1 -1
15,16
to be 2.0 × 10 and 1.6 × 10 M s , respectively,
so
(
Scheme 4) is the more stable equatorial carbocation con-
they have approximately the same reactivity with water
and would be expected to have about the same reactivity
formation 2a, and that this conformation undergoes
attack by water to give a major cis tetrol and a minor
trans tetrol. Conformation 2a might be formed directly
from the reaction of H with DE-1 and from ionization
of 9a and need not be in equilibrium with conformation
2
2
s
with chloride ion. The slightly greater k-1/k value for
reaction of cis-chlorohydrin 9 compared to that for
reaction of trans-chlorohydrin 8 may partly be due to the
fact that the reaction of 8 was carried out in 50:50
dioxane-water and the reaction of 9 was carried out in
+
b. A second possibility is that carbocation conformations
a and 2b undergo conformational interconversion faster
7
0:30 dioxane-water.
than they react with solvent and that a minor yield of
tetrols is formed from conformation 2b. In contrast, DE-2
and its trans-chlorohydrin hydrolyze via two distinct
carbocation conformations that do not rapidly intercon-
vert in the absence of chloride ion but do equilibrate
faster than they react with solvent at high chloride ion
concentrations.11 If it is assumed that carbocation cap-
ture by solvent occurs at approximately the same rate
for both conformations, then the product ratio at high
chloride ion concentrations will reflect their equilibrium
distribution.
Chloride ion is clearly a very reactive nucleophile
toward carbocations 2 and 5. The rate constant for
reaction of carbocation 5 with chloride ion (k-1) in 10:90
8
-1 -1 10
dioxane-water is estimated to be >2 × 10 M s , and
the reactivity of carbocation 2 with chloride ion is
comparable. This reactivity is within 1 or 2 orders of
magnitute of the diffusional limit.
Comparison of the Hydrolyses of DE-1 and cis-
Chlorohydrin 9. The hydrolysis of chlorohydrin 9 yields
the same ratio of cis and trans tetrols as the acid-
catalyzed hydrolysis of DE-1, both in the absence of
added chloride ion and in the presence of added chloride
ion. These results are consistent with the mechanism
outlined in Scheme 4, in which acid-catalyzed hydrolysis
of DE-1 and solvolysis of chlorohydrin 9 proceed via a
common carbocation intermediate 2. However, carbo-
cation 2 can exist in two conformations (Figure 4), one
in which all three hydroxyl groups occupy equatorial
positions (2a) and a second in which all three hydroxyl
groups occupy axial positions (2b). It has been suggested
that the principal cis tetrol product formed in the acid-
catalyzed hydrolysis of DE-1 is derived from axial attack
The present observations on the hydrolyses of DE-1
and DE-2 provide mechanistic insights into related
reactions of these DEs with nucleoside derivatives. We
recently reported the reactions of DE-1 and DE-2 with
2
6
the exocyclic N -amino group of O -allyl-3′,5′-di-tert-
6
butyldimethylsilyl-2′-deoxyguanosine (O -allyl di-TBDMS
dG) in trifluroethanol (TFE),17 a polar solvent that is
considerably more acidic as well as less nucleophilic than
6
water. Interestingly, DE-1 reacts with O -allyl di-TBDMS
2
dG to give the N adducts at C(10) in an 85:15 cis/trans
ratio, which is very close to the ratio of cis/trans tetrols
formed on acid-catalyzed hydrolysis of DE-1. This result
suggests that the same conformation of the carbocation
5
,6
of solvent on 2a.
To gain insight on the nature of the intermediate, we
have calculated structures of carbocation conformations
a and 2b at the B3LYP/6-31G* level of theory. Confor-
mation 2a with the hydroxyl groups in equatorial posi-
tions is calculated to be 3.7 kcal/mol more stable than
the triaxial conformation 2b in the gas phase. Ionization
of chlorohydrin 9 from conformation 9a is expected to
yield the more stable carbocation conformation 2a di-
rectly, and energetically favorable axial attack of solvent
6
intermediate from DE-1 is trapped by O -allyl di-TBDMS
2
dG in TFE and by solvent water in the present study.
2
DE-2 gives the N adducts in a 40:60 cis/trans ratio,
which is very similar to the cis/trans tetrol ratio (35:65)
formed from its acid-catalyzed hydrolysis at high chloride
ion concentration, where the carbocation conformations
10
are in rapid equilibrium. This observation is consistent
with the suggestion that the carbocation from DE-2
undergoes conformational equilibration in TFE faster
(
15) Lin, B.; Islam, N.; Friedman, S.; Yagi, H.; Jerina, D. M.; Whalen,
D. L. J. Am. Chem. Soc. 1998, 120, 4327-4333.
16) Islam, N. B.; Gupta, S. C.; Yagi, H.; Jerina, D. M.; Whalen, D.
L. J. Am. Chem. Soc, 1990, 112, 6363-6369.
(
(17) Ramesha, A. R.; Kroth, H.; Jerina, D. M. Tetrahedron Lett.
2001, 42, 1003-1005.
J. Org. Chem, Vol. 69, No. 23, 2004 8015