Spontaneous Hydrolysis Reactions of cis- and trans-β-Methyl-4-methoxystyrene Oxides (Anethole Oxides): Buildup of frans-Anethole Oxide as an Intermediate in the Spontaneous Reaction of cis-Anethole Oxide

Article abstract of DOI:10.1021/jo991521b

Rates and products of the reactions of trans- and cis-β-methyl-4-methoxystyrene oxides (1 and 2) (anethole oxides) and β,β-dimethyl-4-methoxystyrene oxide (3) in water solutions in the pH range 4-12 have been determined. In the pH range ca. 8-12, each of these epoxides reacts by a spontaneous reaction. The spontaneous reaction of trans-anethole oxide (1) yields ca. 40% of (4-methoxyphenyl)acetone and 60% of 1-(4-methoxyphenyl)-1,2-propanediols (erythro:threo ratio ca. 3:1). The spontaneous reaction of cis-anethole oxide is more complicated. The yields of diol and ketone products vary with pH in the pH range 8-11, even though there is not a corresponding change in rate. These results are interpreted by a mechanism in which 2 undergoes isomerization in part to the more reactive trans-anethole oxide (1), which subsequently reacts by acid-catalyzed and/or spontaneous reactions, depending on the pH, to yield diol and ketone products. The buildup of the intermediate trans-anethole oxide in the spontaneous reaction of cis-anethole oxide was detected by ¹H NMR analysis of the reaction mixture. Other primary products of the spontaneous reaction of 2 are (4-methoxyphenyl)acetone (73%) and theo-1-(4-methoxyphenyl)-1,2-propanediol (ca. 3%). The rates and products of the spontaneous reaction of 2 and its β-deuterium-labeled derivative were determined, and the lack of significant kinetic and partitioning deuterium isotope effects indicates that the isomerization of 2 to ketone and to trans-anethole oxide must occur primarily by nonintersecting reaction pathways.

Full text of DOI:10.1021/jo991521b

J . Org. Chem. 2000, 65, 1407-1413
1407
Sp on ta n eou s Hyd r olysis Rea ction s of cis- a n d
tr a n s-â-Meth yl-4-m eth oxystyr en e Oxid es (An eth ole Oxid es):
Bu ild u p of tr a n s-An eth ole Oxid e a s a n In ter m ed ia te in th e
Sp on ta n eou s Rea ction of cis-An eth ole Oxid e
Ram S. Mohan,† Kostas Gavardinas,† Sampson Kyere,‡ and Dale L. Whalen*,‡
Department of Chemistry, Illinois Wesleyan University, Bloomington, Illinois 61701, and Department of
Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, Maryland 21250
Received September 27, 1999
Rates and products of the reactions of trans- and cis-â-methyl-4-methoxystyrene oxides (1 and 2)
(anethole oxides) and â,â-dimethyl-4-methoxystyrene oxide (3) in water solutions in the pH range
4-12 have been determined. In the pH range ca. 8-12, each of these epoxides reacts by a
spontaneous reaction. The spontaneous reaction of trans-anethole oxide (1) yields ca. 40% of (4-
methoxyphenyl)acetone and 60% of 1-(4-methoxyphenyl)-1,2-propanediols (erythro:threo ratio ca.
3:1). The spontaneous reaction of cis-anethole oxide is more complicated. The yields of diol and
ketone products vary with pH in the pH range 8-11, even though there is not a corresponding
change in rate. These results are interpreted by a mechanism in which 2 undergoes isomerization
in part to the more reactive trans-anethole oxide (1), which subsequently reacts by acid-catalyzed
and/or spontaneous reactions, depending on the pH, to yield diol and ketone products. The buildup
of the intermediate trans-anethole oxide in the spontaneous reaction of cis-anethole oxide was
1
detected by H NMR analysis of the reaction mixture. Other primary products of the spontaneous
reaction of 2 are (4-methoxyphenyl)acetone (73%) and threo-1-(4-methoxyphenyl)-1,2-propanediol
(ca. 3%). The rates and products of the spontaneous reaction of 2 and its â-deuterium-labeled
derivative were determined, and the lack of significant kinetic and partitioning deuterium isotope
effects indicates that the isomerization of 2 to ketone and to trans-anethole oxide must occur
primarily by nonintersecting reaction pathways.
In tr od u ction
Compounds in which the epoxide group is conjugated
with an aryl or vinyl group are greatly activated toward
both hydronium ion-catalyzed and spontaneous hydroly-
ses. The hydronium ion-catalyzed hydrolyses of aryl and
vinyl epoxides generally occur via a mechanism involving
an intermediate allylic or benzylic carbocation. Hydroly-
sis of (+)-styrene oxide, for example, yields styrene glycol
that is mostly racemic,4 suggesting the intermediacy of
a carbocation that collapses with solvent from both faces
of an electron-deficient carbon center. In contrast, acid-
catalyzed hydrolyses of simple, unactivated epoxides
occurs with inversion at the reaction center.5 An A2
mechanism with nucleophilic attack of solvent on the
protonated epoxide, thus bypassing an unstable primary
or secondary carbocation intermediate, has been pro-
posed.
Products from the spontaneous reaction of epoxides are
usually diols or carbonyl compounds. The mechanism of
the spontaneous reaction is dependent on the structure
of the epoxide. The spontaneous reaction of (+)-styrene
oxide, for example, yields only styrene glycol resulting
from inversion of configuration at the benzylic carbon,4b
suggesting that water acts as a nucleophile in attacking
this position. The spontaneous reactions of 1,3-cyclohexa-
diene oxide3c and 1,2,3,4-tetrahydronaphthalene 1,2-
oxide6 also yield only trans-1,2-diol products,6 suggesting
It has been observed that epoxides generally undergo
acid-catalyzed hydrolysis1,2 and that at intermediate pH
some epoxides undergo uncatalyzed, or “spontaneous”,
hydrolysis.2,3 At higher pH, epoxide ring opening by
attack of hydroxide ion may occur. The rate expression
for reactions of epoxides that undergo hydrolyses by all
three kinetically distinct mechanisms is therefore given
by eq 1, where kH is the specific second-order rate
kobsd ) kH[H+] + ko + kOH[HO-]
(1)
constant for the hydronium ion-catalyzed hydrolysis, ko
is the first-order rate constant for the spontaneous
hydrolysis, and kOH is the second-order rate constant for
the hydroxide ion-catalyzed hydrolysis.
† Illinois Wesleyan University.
‡ University of Maryland, Baltimore County.
(1) (a) Biggs, J .; Chapman, N. B.; Finch, A. F.; Wray, V. J . Chem.
Soc. B 1971, 55-63. (b) Biggs, J .; Chapman, N. B.; Wray, V. J . Chem.
Soc. B 1971, 63-65. (c) Biggs, J .; Chapman, N. B.; Wray, V. J . Chem.
Soc. B 1971, 66-71. (d) Biggs, J .; Chapman, N. B.; Wray, V. J . Chem.
Soc. B 1971, 71-74. (e) Pritchard, J . G.; Siddiqui, I. A. J . Chem. Soc.,
Perkin Trans. 2 1973, 452-457. (f) Parker, R. E.; Isaacs, N. S. Chem.
Rev. 1959, 59, 737-799.
(2) (a) Bronsted, J . J .; Kilpatrick, M.; Kilpatrick, M. J . Am. Chem.
Soc. 1929, 51, 428-461. (b) Pritchard, J . G.; Long, F. A. J . Am. Chem.
Soc. 1956, 78, 2663-2667. (c) Pritchard, J . G.; Long, F. A. J . Am. Chem.
Soc. 1956, 78, 6008-6013.
(3) (a) Kasperek, G. J .; Bruice, T. C. J . Am. Chem. Soc. 1972, 94,
198-202. (b) Blumenstein, J . J .; Ukachukwu, V. C.; Mohan, R. S.;
Whalen, D. L. J . Org. Chem. 1993, 58, 924-932. (c) Ross, A. M.; Pohl,
T. M.; Piazza, K.; Thomas, M.; Fox, B.; Whalen, D. L. J . Am. Chem.
Soc. 1982, 104, 1658-1665.
(4) (a) Berti, G.; Bottari, F.; Ferrarini, P. L.; Macchia, B. J . Org.
Chem. 1965, 30, 4091-4096. (b) Lin, B.; Whalen, D. L. J . Org. Chem.
1994, 59, 1638-1641.
(5) Wohl, R. A. Chimia 1974, 28, 1.
(6) Becker, A. R.; J anusy, J . M.; Bruice, T. C. J . Am. Chem. Soc.
1979, 101, 5679-5687.
10.1021/jo991521b CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/16/2000

1408 J . Org. Chem., Vol. 65, No. 5, 2000
Mohan et al.
Sch em e 1
F igu r e 1. Plots of log kobsd versus pH for reaction of 1-3 in
o
water solutions containing 0.1 M NaClO4, 25.0 ( 0.2 C. The
solid lines are theoretical, based on eq 1 and the rate constants
listed in Table 1.
a mechanism similar to that for the spontaneous reaction
of styrene oxide. 6-Methoxy-1,2,3,4-tetrahydronaphtha-
lene 1,2-oxide, in contrast, yields 76% of ketone product,
17% of cis-diol and 7% of trans-diol product.7 The
introduction of a group that stabilizes positive charge at
the benzylic position, therefore, significantly changes the
mechanism and products of the spontaneous reaction.
Evidence for rate-limiting hydrogen migration on the
ketone-forming component of the spontaneous reaction
of 6-methoxy-1,2,3,4-tetrahydronaphthalene 1,2-oxide
has been presented.8
trans-Anethole is metabolized to trans-anethole oxide
in rat, and the hydrolysis of this epoxide to anethole diols
is catalyzed by epoxide hydrolase.9 The stereoisomers of
anethole diols have been characterized.10 trans-Anethole
oxide (1) and its geometric isomer, cis-anethole oxide (2),
Ta ble 1. Ra te Con sta n ts for th e Rea ction s of 1 a n d 2 in
Wa ter Solu tion (25.0 ( 0.2 °C; 0.1 M Na ClO4)
a
compd
kH (M-1 s-1
)
ko (s-1
)
kOH (M-1 s-1
)
1
2
3
(1.51 ( 0.05) × 104 (4.12 ( 0.13) × 10-5 (1.69 ( 0.09) × 10-4
(1.58 ( 0.23) × 102 (1.78 ( 0.64) × 10-6
(3.17 ( 0.21) × 102 (3.42 ( 0.24) × 10-5
a
Values of kH for 1 and 2 are taken from ref 11.
however, the product mixture from the spontaneous
reaction of 2 is significantly different from that formed
in the spontaneous reaction of 1. Also, the ratio of
products from reaction of 2 in the pH region 7.5-9.5
changes, indicating a change of mechanism, although
there is not a corresponding change in rate constant.
Evidence for a buildup of trans-anethole oxide (1) as an
intermediate in the spontaneous reaction of cis-anethole
oxide (2) is presented, and mechanisms for the spontane-
ous reactions of 1 and 2 are discussed. For comparison,
the rate versus pH profile for the reaction of â,â-dimethyl-
4-methoxystyrene oxide (3) has also been determined.
Resu lts a n d Discu ssion
Ra te-p H P r ofiles. Plots of log kobsd for reaction of
1-3 in water solutions vs pH are shown in Figure 1. The
rate profile for reaction of 1 shows a region at pH < ca.
9 where acid-catalyzed hydrolysis predominates, a pla-
teau at pH ca. 9.5-12.5 where the spontaneous reaction
predominates, and a region at [HO-] > ca. 0.1 M where
the reaction becomes dependent on hydroxide ion con-
centration. The rate profiles for reaction of 2 and 3 also
show regions for acid-catalyzed hydrolysis at pH < ca. 7
and rate plateaus at intermediate pH due to the spon-
taneous reaction. Rate data for the reaction of 2 at pH >
12 do not conform to good first-order kinetics, presumably
due to some instability of the major ketone product from
the spontaneous reaction, and therefore, the rate profile
in Figure 1 for reaction of 2 does not include data above
this pH.
are quite reactive toward acid-catalyzed hydrolysis and
yield the same mixture of erythro and threo diol prod-
ucts.11 Identical diol product mixtures from acid-catalyzed
hydrolysis of 1 and 2 suggest that there is a common
benzylic carbocation intermediate and common product-
forming steps (Scheme 1).
We have also measured the rates and determined the
products of reaction of 1 and 2 at higher pH. At pH >
∼9 for 1 and > ∼7 for 2, the rates of reaction of these
epoxides become independent of pH, indicating that the
spontaneous reactions predominate in these pH ranges.
In contrast to the acid-catalyzed hydrolysis of 1 and 2,
(7) Gillilan, R. E.; Pohl, T. M.; Whalen, D. L. J . Am. Chem. Soc.
1982, 104, 4481-4482.
(8) Gillilan, R. E.; Pohl, T. M.; Whalen, D. L. J . Am. Chem. Soc.
1982, 104, 4482-4484.
(9) Marshall, A. D.; Caldwell, J . Food Chem. Toxicol. 1992, 30, 467.
(10) Ishida, T.; Bounds, S. V. J .; Caldwell, J .; Drake, A.; Takeshita,
M. Tetrahedron: Asymmetry 1996, 7, 3113-3118.
(11) Mohan, R. S.; Whalen, D. L. J . Org. Chem. 1993, 58, 2663-
2669.
Rate data for reaction of 1 are fit to eq 1, and rate data
for reactions of 2 and 3 are fit to the equation kobsd
)
kH[H+] + ko. Values of the rate constants for reactions of
1-3 are summarized in Table 1. Whereas the rate
constant for acid-catalyzed hydrolysis of trans-anethole
oxide (1) is ca. 50 times larger than that of its cis isomer

Hydrolysis Reactions of Anethole Oxides
J . Org. Chem., Vol. 65, No. 5, 2000 1409
Sch em e 2
2, the spontaneous rate constant for reaction of 1 is only
slightly greater (ca. 30-50%) than that for reaction of 2.
The lower reactivity of 2 toward acid-catalyzed hydrolysis
compared to 1 has been attributed to differences in strain
energy between reactants and transition states and not
to a destabilization of the transition state for reaction of
2 by steric inhibition of resonance.11 It is also noteworthy
that the rate of the spontaneous rate for reaction of 3 is
significantly slower than that for reaction of 2, although
the rates of acid-catalyzed hydrolyses of 2 and 3 are quite
similar.
The reactions of both 1 and 2 at sufficiently low pH
where they react > 99% by the acid-catalyzed route yield
identical product mixtures within experimental error,
consisting of 20% of erythro-1-(4-methoxyphenyl)-1,2-
propanediol (5) and 80% of threo-1-(4-methoxyphenyl)-
1,2-propanediol (6).11 This observation has been inter-
preted in terms of a mechanism in which 1 and 2 react
with H+ to yield the same, discrete carbocation interme-
diate 4, which undergoes CR-Câ bond rotation at a rate
faster than attack by solvent at the electron-deficient
benzylic carbon of the carbocation (Scheme 1).
P r od u cts of th e Sp on ta n eou s Rea ction of 1. At pH
> ca. 9, the rate profile for reaction of 1 levels out into a
plateau, indicating a change in mechanism from acid-
catalyzed hydrolysis to spontaneous reaction of 1 with
the solvent. The ratio of products from reaction of 1
changes gradually with increase in pH from 20% erythro-
diol/80% threo-diol at pH < 5.7 to ca. 46% erythro-diol,
14% threo-diol and 40% ketone at pH 9.5-10.5 (Scheme
2). The pH at the midpoint for the changeover in
mechanism is 8.5. The hydronium acid-catalyzed hy-
drolysis of 1 therefore results in mostly syn hydration,
whereas, in the spontaneous hydrolysis of 1, anti hydra-
tion is favored.
P r od u cts of th e Sp on ta n eou s Rea ction of 2. The
mechanism of reaction of 2 changes from acid-catalyzed
hydrolysis at low pH to spontaneous reaction at inter-
mediate pH, with a pH of 7.0 at the midpoint for
changeover in mechanism. The ratio of products from
reaction of 2 changes from 20% erythro-diol/ 80% threo-
diol at pH 3.8 to 7% erythro-diol, 23% threo-diol, and 70%
ketone at pH 7.95, where > 90% of the reaction of 2
proceeds via the spontaneous reaction. The product
mixture from the spontaneous reaction of 2 contrasts
with that from the spontaneous reaction of 1 in several
ways. First, considerably more ketone (ca. 80% vs 40%)
is formed from the spontaneous reaction of 2. Second,
whereas the ratio of erythro- and threo-diol products from
the spontaneous reaction of 1 (46% erythro/14% threo)
is considerably different than that from the acid-
catalyzed hydrolysis of 1 (20% erythro/80% threo), the
reactions of 2 at pH < 5, where acid-catalyzed hydrolysis
occurs, and at pH 8.0, where the spontaneous reaction
predominates, yield diol products in approximately the
same ratio (20% erythro/80% threo).
F igu r e 2. Plots of percent yield of (4-methoxyphenyl)acetone
product formed from reaction of 2 in water solutions (0.1 M
NaClO4) versus pH and percent erythro-diol in the diol product
mixture from reaction of 2 [(%erythro × 100)/(%erythro + %threo)]
versus pH. The line through the data for percent yield of
ketone is theoretical, based on eq 2 and the product data from
reaction of 2 at pH < 8. The line through the percent erythro-
diol product data is theoretical, based on the partitioning
expected from Scheme 3 and the rate constants of Table 1.
mechanism, then the relative yields of diol and ketone
products should remain constant. However, there is a
gradual change in products within this pH-rate plateau
until, at pH 11.0-11.5, the reaction of 2 yields 84% of
ketone 7, 10% of erythro-diol 5, and 6% of threo-diol 6.
Thus, the yield of ketone from reaction of 2 at pH 11.2 is
slightly more than expected from rate-product studies
at lower pH, and the ratio of erythro- and threo-diol
products changes from ca. 20:80 at pH 7.95 to ca. 65:35
at pH > 11. These results suggest that there is a further
change in mechanism for product formation from 2 in the
pH plateau extending from pH 8-12, even though there
is no change in the rate of reaction of 2 in this pH range.
Insight into the mechanisms of reaction of 2 is obtained
from plots of the percent yield of ketone product vs pH
and of the ratio of erythro- and threo-diol products vs pH
(Figure 2). At pH < 4, where > 99% of the reaction of 2
is acid-catalzyed, only diol products are detected from the
reaction of 2. Reaction of 2 at higher pH, however, yields
ketone product. The yield of ketone product increases
with increase in pH, with an inflection point at ap-
proximately pH 7. This corresponds to the pH for
changeover in mechanism from acid-catalyzed to spon-
taneous. A reasonable rate-product correlation exists,
indicating that the spontaneous reaction of 2 yields >
70% ketone. However, the yield of ketone appears to
increase significantly more in the pH range 8-10, where
the rate of reaction of 2 is relatively constant.
Figure 2 also shows a plot of the percent of erythro-
diol in the diol product mixture ((%erythro × 100)/(%erythro
+ %threo) from reaction of 2 as a function of pH. There is
no detectable change in this diol product ratio from
reaction of 2 between pH 3.5 and pH 8. At pH slightly
less than 9, however, this ratio begins to increase with
increasing pH until at pH 11.2 the yield of erythro-diol
exceeds that of the threo isomer. Whereas Figure 2 shows
that the change in ketone yield from reaction of 2
correlates with the change in rate constant, with a
midpoint for change at approximately 7, the change in
diol product ratio from reaction of 2 does not occur until
Product studies of the spontaneous reaction of 2 at pH
8.5-11.2 were also carried out. A rate plateau is present
in this pH region, and if there is no change in reaction

1410 J . Org. Chem., Vol. 65, No. 5, 2000
Mohan et al.
Sch em e 3
total amount of ketone formed directly from 2 in its
spontaneous reaction. Ketone product is not detected
from the acid-catalyzed reaction of 2. Fitting of the
product yield data from reaction of 2 vs pH for those pH
values < pH 8 to eq 2 yields a value of 73% for (%
ketone)max. The remaining 27% of product formed from
the spontaneous reaction of 2 are trans-anethole oxide
(1), formed as a reactive intermediate, and diols. Our
complete product studies fit a model in which the
spontaneous reaction of 2 yields 73% of ketone 7, ca. 24%
of trans-anethole oxide (1), and ca. 3% of threo-diol 6 as
primary products. trans-Anethole oxide formed as an
intermediate undergoes further reaction to form products
from acid-catalyzed and/or spontaneous hydrolysis, de-
pending upon the pH of the solution. If the pH of the
solution is sufficiently high (>ca. 9.5) such that trans-
anethole oxide reacts completely by the spontaneous
reaction, then 40% of trans-anethole oxide formed as a
reactive intermediate from reaction of 2 will react to yield
ketone 7. Thus, the total yield of ketone from reaction of
2 at pH 11 is 83% (73% formed directly from 2 and 10%
formed from the secondary reaction of the intermediate
trans-anethole oxide).
the pH is > 8. This lack of a product-rate correlation
for diol formation is not consistent with a mechanism in
which most of the diol products arise directly from
reaction of 2. If this were the case, then the diol ratio is
expected to undergo change at pH 6-8, with a midpoint
for changeover at pH 7. Instead, the diol product ratio
from reaction of 2 does not undergo a change until the
pH is significantly higher, above pH 8.0. The change in
diol product ratio from reaction of 2 does occur in the
pH range where there is a change in mechanism for
reaction of trans-anethole oxide (1) from acid-catalyzed
hydrolysis to spontaneous hydrolysis, where the midpoint
for the change in mechanism is at pH 8.5. The observed
results are readily explained by the mechanism shown in
Scheme 3, in which the diol products from reaction of 2
are mostly derived from trans-anethole oxide (1), formed
as a reactive intermediate in the spontaneous reaction of
2. Thus, the spontaneous reaction of 2 proceeds in part
by isomerization to its trans isomer 1, which is more
reactive than 2 in both acid-catalyzed and spontaneous
hydrolyses. Scrambling of deuterium between the trans
and cis â positions during the spontaneous reaction of
trans-â-deutereo-4-methoxystyrene oxide provides a pre-
cedent for a mechanism in which epoxide isomerization
occurs during its spontaneous reaction.12
If the pH of the spontaneous reaction of 2 is < ca. 8,
the trans isomer 1 that is formed as an intermediate
reacts mostly by an acid-catalyzed reaction to yield only
erythro- and threo-diols 5 and 6 in an 20:80 ratio, the
same as that from the acid-catalzyed reaction of 2.
Therefore, there is no significant change in the erythro/
threo diol ratio in the pH 5-8 region, even though there
is a change in mechanism for reaction of 2. However, if
the pH of the spontaneous reaction of 2 is > ca. 8, then
the trans isomer 1 that is formed as an intermediate
reacts increasingly by the spontaneous reaction with
increase in pH. Whereas the intermediate trans-epoxide
formed in the hydrolysis of 2 at pH < 8.0 does not react
to form ketone product, it does react at pH > 9.0 by the
spontaneous reaction to yield 40% of ketone product. This
mechanism therefore provides a rationale for both the
change in erythro/threo diol ratio and the small ad-
ditional increase in yield of ketone from reaction of 2 that
occur at pH > ca. 8.5, even though there is no change in
the rate of reaction of 2 above this pH.
Detection of tr a n s-An eth ole Oxid e a s a n In ter -
m ed ia te in th e Sp on ta n eou s Rea ction of cis-An e-
th ole Oxid e. In a simulation of the concentration of
trans-anethole oxide that would build up in the sponta-
neous reaction of cis-anethole oxide by the mechanism
outlined in Scheme 3, the values of ko given in Table 1
for 1 and 2, and the assumption that the spontaneous
reaction of 2 yields 24% of trans-anethole oxide, it is
calculated that the concentration of 1 should build up to
maximum of ca. 8% of the initial concentration of 2 at
approximately 1 half-life for reaction of 2 (see Supporting
Information). The spontaneous reaction of 2 at pH 10.5
1
in 5:95 dioxane-water was therefore monitored by H
NMR to detect the buildup of this intermediate. In Figure
1
3A are shown the H NMR absorptions of the Câ-epoxide
hydrogens of cis-anethole oxide (2) (δ 3.28) and trans-
anethole oxide (1) (δ 3.02). In Figure 3B is shown the
NMR spectrum of the reaction mixture from the spon-
taneous reaction of 2 after 8.5 h at room temperature,
slightly more than 1 half-life for its reaction. The absorp-
tion at δ 3.02 of the â-epoxide hydrogen of trans-anethole
oxide in the mixture from the spontaneous reaction of 2
builds up over time to ca. 7% of the epoxide mixture after
reaction of 2 for 8-12 h. This absorption diminishes at
longer reaction times and is not detected in the NMR
spectrum of the product mixture taken after 31 h. These
observations are consistent with the mechanism given
in Scheme 3, in which the spontaneous reaction of 2
proceeds in part to form trans-anethole oxide 1.
Deu ter iu m Isotop e Effects in th e Sp on ta n eou s
Rea ction of cis-An eth ole Oxid e-â-d (2d ). To gain
information on the nature of the rate-limiting step in the
spontaneous reaction of 2, we prepared cis-anethole oxide
labeled at the â-epoxide position with deuterium (2d ) and
compared the rates and products of its spontaneous
reaction with those of 2. The major products of the
spontaneous reaction of 2 are ketone 7, resulting from
hydrogen migration from the â-position to the R-position,
and trans-anethole oxide (1). A mechanism for formation
of these products from 2 is given in Scheme 4. The
reaction of 2 yielding ketone may occur in a single step
involving concerted C-O bond breaking and hydrogen
migration (path a) or via an intermediate species such
The percent of ketone product from the reaction of 2
as a function of pH is determined by the fraction of the
reaction that proceeds by the spontaneous route and is
given by eq 2. In this equation, % ketone is the amount
ko
% ketone
(% ketone)max
)
(2)
ko + kH[H+]
of ketone formed at a given pH and (% ketone)max is the
(12) a) Ukachukwu, V. C.; Blumenstein, J . J .; Whalen, D. L. J . Am.
Chem. Soc. 1986, 108, 5039-5040. (b) Ukachukwu, V. C.; Whalen, D.
L. Tetrahedron Lett. 1988, 29, 293-396.

Hydrolysis Reactions of Anethole Oxides
J . Org. Chem., Vol. 65, No. 5, 2000 1411
close to unity for the hydrogen migration step to be rate-
limiting if the hydrogen atom is substantially migrated
at the transition state. This small kinetic isotope effect
is consistent with a mechanism in which hydrogen
migration occurs after a rate-limiting step such as
formation of the zwitterion 8a /b (path b). Since hydrogen
migration occurs after the rate-limiting step in this
pathway, only a small secondary isotope effect due to the
step forming the intermediate will be observed. However,
if there is a substantial normal isotope effect on the
ketone-forming step for reaction of this intermediate (8a
f 7), then a partitioning isotope effect will still be
observed in which the yield of ketone from the spontane-
ous reaction of 2d is reduced compared to the yield ketone
from the spontaneous reaction of 2. However, we have
observed that the relative yields of ketone product from
reaction of 2d over the pH range 5-12 are identical
within experimental error to the relative yields of ketone
from 2. Thus, there is neither a significant primary kinetic
deuterium isotope effect nor partitioning deuterium iso-
tope effect on product formation in the spontaneous
reaction of 2d . Therefore, ketone and trans-epoxide
cannot both be formed from a common zwitterion inter-
mediate but must be formed from nonintersecting reaction
pathways. In the spontaneous reaction of precocene I
oxide, it is proposed that ketone and diol products are
formed from separate pathways that do not cross.14
Mech a n ism of th e Sp on ta n eou s Rea ction of cis-
An eth ole Oxid e (2). A possible mechanism for the
spontaneous reaction of 2 that does not involve a common
intermediate leading to formation of both ketone and
trans-epoxide is given in Scheme 5. In this mechanism,
benzylic C-O bond breaking occurs, coupled with rota-
tion of the CR-Câ bond either in clockwise or anticlock-
wise directions. The dipolar structures shown in Scheme
5 represent rotational structures along the reaction
coordinates between reactants and products and are not
meant to imply the existence of energy minima or the
lack of hydrogen bonding to solvent. If CR-Câ bond
rotation occurs much faster than the dipolar species
collapse to products, then a partitioning isotope effect
should be observed. However, if bond rotation in one
direction leads to one set of products and bond rotation
in the other direction leads to a second set of products,
then neither kinetic nor partitioning deuterium isotope
effects on the reaction of 2d will be observed.
F igu r e 3. 1H NMR absorptions of the Câ-epoxide hydrogens
of cis- and trans-anethole oxides (A) and of the reaction
mixture from the spontaneous reaction of cis-anethole oxide
after reaction in 5:95 dioxane-water at pH 10.5 for 8.5 h at
room temperature (B).
Sch em e 4
as zwitterion 8a /b. If hydrogen migration occurs in the
rate-limiting step, then there should be a normal kinetic
deuterium isotope effect of ca. 2-3 on the ketone-forming
step.13 Since ketone 7 is the major product (∼73%) from
the spontaneous reaction of 2, then the observed isotope
effect (koH/koD) of this reaction should be ∼2. Isomeriza-
tion of 2 to the trans isomer 1, however, does not involve
C-H bond breaking, and therefore, the isotope effect on
the isomerization reaction should be near unity. Thus, if
hydrogen migration in the ketone-forming pathway of the
spontaneous reaction of 2 is rate-limiting, then the rate
of the spontaneous reaction of 2d should be approxi-
mately half that of 2, and the relative yield of ketone
product from the spontaneous reaction of 2d should be
substantially lowered. From six measurements of the rate
constant ratio for reaction of 2 and 2d in the pH range
Cleavage of the benzyl C-O bond coupled with rotation
of the epoxide oxygen toward the aryl group (anticlock-
wise rotation) yields structures 9 and 10. Cleavage of the
benzylic C-O bond coupled with rotation of the epoxide
oxygen away from the aryl group (clockwise rotation)
yields structures 12 and 13. The reaction coordinate for
isomerization from cis-epoxide 2 to trans-epoxide 1 must
include one structure, either 10 or 12, with the Câ-H
bond located favorably for hydrogen migration. Hydrogen
migration from structure 10 leads to transition state 11,
in which the aryl and methyl groups are located in an
energetically favorable trans relationship. However, hy-
drogen migration from structure 12 leads to transition
state 14, in which the aryl and methyl groups are located
in a sterically unfavorable cis relationship. If transition
state 14 is sufficiently high in energy, then 12 will
undergo further bond rotation and epoxide ring closure
D
10.3-10.9, the kinetic deuterium isotope effect koH/ko
was calculated to be 1.06 ( 0.02. This value is much too
(13) Collins, C. J .; Rainey, W. T.; Smith, W. B.; Kaye, I. A. J . Am.
Chem. Soc. 1959, 81, 460. (b) Winstein, S.; Takahashi, J . Tetrahedron
1958, 2, 316.
(14) Sayer, J . M.; Grossman, S. J .; Adusei-Poku, K. S.; J erina, D.
M. J . Am. Chem. Soc. 1988, 110, 5068-5074.

1412 J . Org. Chem., Vol. 65, No. 5, 2000
Mohan et al.
Sch em e 5
via structure 13 to trans-epoxide 1 faster than it will go
to ketone product via the transition structure 14. A
mechanism that is consistent with our results involves
epoxide ring opening and bond rotation partially in a
clockwise direction about the CR-Câ bond to form mostly
isomeric epoxide 1 and partially in an anticlockwise
direction about the CR-Câ bond to form mostly ketone
product via the lower energy transition state 11 for
hydrogen migration. However, epoxide ring opening in a
particular direction must be committed to lead to a
particular product mixture. The hydrogen migration step
will thus not be rate-limiting. These rearrangement
pathways for conversion of 2 to isomeric epoxide and
ketone products may be examples of “asynchronous
concerted” reactions,15 in which epoxide ring opening is
essentially complete before bond rotation or hydrogen
migration occurs.
Mech a n ism of Diol F or m a tion in th e Sp on ta n e-
ou s Rea ction of tr a n s-An eth ole Oxid e (1). Whereas
the spontaneous reaction of cis-anethole oxide (2) yields
very little (∼3%) diol product as primary product, the
spontaneous reaction of the trans epoxide yields sub-
stantial (∼60%) diol product, in addition to ketone 7. The
ratio of erythro:threo diol products from this reaction (∼3:
1) is substantially different than the erythro:threo diol
ratio from the acid-catalyzed hydrolysis of 1 (∼20:80).
One possible mechanism for diol formation in the spon-
taneous reaction of an epoxide involves general acid-
catalyzed epoxide ring opening by water to yield a
solvationally equilibrated carbocation, which reacts with
water to yield the same diol mixture as that formed from
reaction of the epoxide with hydronium ion.16 If all of the
threo-diol from the spontaneous reaction of 1 were formed
from reaction of water with carbocation 4, then ∼14% of
threo-diol and ∼3-4% of erythro-diol would arise from
this pathway. This mechanism, if operative, would ac-
count for approximately 30% of the diol product from the
spontaneous reaction of 1. The remaining 70% of diol
product (erythro-diol) would have to be formed via
another reaction pathway.
is consistent with a mechanism in which some of the
threo-diol is formed from general acid-catalyzed epoxide
ring opening by water to yield carbocation 4, which at
higher pH reacts with hydroxide ion to re-form 1 faster
than it reacts with water to form mostly threo-diol.
However, concerted reactions for formation of both
erythro- and threo-diols cannot be ruled out. The major
erythro-diol product is that expected from anti addition
of solvent to the benzylic carbon of 1. Most of this diol
might therefore be formed by nucleophilic addition of
water to 1, concerted with epoxide ring opening.
p H-Ra te P r ofile for Rea ction of â,â-Dim eth yl-4-
m eth oxystyr en e Oxid e (3). Both acid-catalyzed and
spontaneous reactions of 3 in 0.1 M NaClO4 solution yield
1-(4-methoxyphenyl)-1,2-dihydroxy-2-methylpropane. The
value of kH for acid-catalyzed hydrolysis of 3 is much
closer to that for acid-catalyzed hydrolysis of 2 than to
that of 1, suggesting that the steric and electronic factors
of a cis-â-methyl group for these two reactions are very
similar. trans-â-Methyl-4-methoxystyrene oxide (kH ) 1.5
× 104 s-1) is only slightly more reactive than 4-methoxy-
styrene oxide (kH ) 1.1 × 104 s-1),12a and therefore, the
introduction of a trans-â-methyl group has little effect
on the reactivity of the epoxide group toward acid-
catalyzed hydrolysis. The rate of the spontaneous reac-
tion for 3, however, is much less than that for reaction
of 2. The significantly lower reactivity of 3 toward
spontaneous hydrolysis can be attributed in part to the
fact that methyl migration to form ketone is not favor-
able. Greater torsional strain introduced by the two
â-methyl groups upon going to the transition state will
also contribute toward reduction of the reaction rate.
Su m m a r y
The spontaneous reaction of trans-anethole oxide yields
40% of 1-(4-methoxyphenyl)-2-propanone (7), in addition
to 60% of a mixture of erythro- and threo-diols 5 and 6 in
a 3:1 ratio. Thus, spontaneous hydrolysis of 1 gives
mainly anti-hydration of the epoxide group. The two
major primary products of the spontaneous reaction of
cis-anethole oxide are ketone 7 and trans-anethole oxide,
formed in a ratio of ca. 3:1. trans-Anethole oxide, however,
is formed only as a reactive intermediate and reacts
further to form diol and ketone products by acid-catalyzed
and/ or spontaneous reactions, depending on the pH of
the solution. Thus, the spontaneous reaction of cis-
anethole oxide involves partial isomerization to the trans
isomer. Kinetic and product deuterium isotope effects in
the spontaneous reaction of 2 are best explained by a
The detailed mechanisms of diol formation in the
spontaneous reaction of 1 remain uncertain. The percent
of erythro isomer in the diol product mixture is observed
to increase slightly from ∼70% at pH 10.5 to ∼80% at
pH 11.8, although the rate of the reaction of 1 does not
appear to change significantly (Figure 1). The slightly
lower yield of threo-diol from reaction of 1 at higher pH
(15) Coxon, J . M.; Maclagan, R. G. A. R.; Rauk, A.; Thorpe, A.;
Whalen, D. J . Am. Chem. Soc. 1997, 119, 4712-4718.
(16) Islam, N. B.; Gupta. S. C.; Yagi, H.; J erina, D. M.; Whalen, D.
L. J . Am. Chem. Soc. 1990, 112, 6363-6369.

Hydrolysis Reactions of Anethole Oxides
J . Org. Chem., Vol. 65, No. 5, 2000 1413
for 60 h after which time it was saturated with sodium chloride
and extracted with ethyl acetate (3 × 20 mL). The organic layer
was washed with brine solution (4 × 20 mL) and dried (Na2-
SO4), and the solvent was removed on a rotary evaporator to
mechanism in which ketone product 7 and trans-epoxide
product 1 arise primarily from nonintersecting reaction
pathways.
1
yield 18 mg of an oil. The H NMR spectrum of this oil showed
Exp er im en ta l Section
that it was a mixture of p-methoxyphenylacetone and the
erythro- and threo-diols 5 and 6, respectively. The ketone:diols
ratio was determined by comparing the relative intensities of
the integrals of the methyl absorption of the ketone with the
methyl absorptions of the diols and was found to be 41:59,
respectively. The erythro:threo diol ratio was calculated from
the integrals of the peaks due to the hydrogens attached to
the benzylic carbon atoms and was found to be 77:23, respec-
tively. These results agreed well with product ratios deter-
mined by HPLC analysis of the reaction solutions.
Gen er a l Meth od s. NMR spectra were recorded at 80 MHz
except for the experiment in which trans-anethole oxide was
detected by 1H NMR as an intermediate in the spontaneous
reaction of cis-anethole oxide. For this experiment, spectra
were recorded at 270 MHz.
Ma ter ia ls. Benzene and dioxane were distilled from sodium
benzophenone ketyl. Pyridine was dried over and distilled from
potassium hydroxide pellets. Sodium perchlorate was dried at
120 °C for 12 h. trans-Anethole oxide (1) and cis-anethole oxide
(2) were prepared by published procedures.11 â,â-Dimethyl-4-
methoxystyrene oxide (3) was prepared by epoxidation of â,â-
dimethyl-4-methoxystyrene.17
Sp on ta n eou s Rea ction of cis-An eth ole Oxid e a t p H
10.6. A solution of 2 (16 mg) in 0.2 mL of dioxane was added
to 20 mL of 5:95 dioxane-H2O at pH 10.6 buffered with 2 ×
10-3 M CAPS. The resulting solution was allowed to stir at
room temperature for 60 h, after which time it was saturated
with sodium chloride and extracted with ethyl acetate (5 ×
20 mL). The organic layer was washed with water (4 × 20 mL)
and dried (Na2SO4), and the solvent was removed on a rotary
Kin etics P r oced u r es. For each kinetic run, approximately
10 µL of a stock solution of epoxide in dioxane (ca. 1 mg/mL)
was added to 2.0 mL of reaction solution in the thermostated
cell compartment (25.0 ( 0.2 °C) of a UV-vis spectrophotom-
eter. Reactions were monitored at 231-232 nm, and pseudo-
first-order rate constants were calculated by nonlinear regres-
sion analysis of the absorbance versus time data. For kinetic
runs at intermediate pH, approximately 2 × 10-3 M acetic acid,
pH 4.1-5.5; MES (2-[N-morpholino]ethanesulfonic acid), pH
5.5-6.3; MOPSO (3-[N-morpholino]-2-hydroxypropanesulfonic
acid, pH 6.3-7.3; HEPES (N-(2-hydroxyethyl)piperazine-N′-
2-ethanesulfonic acid), pH 7.3-8.0; EPPS (N-2-(hydroxyethyl)-
piperazine-N′-3-propanesulfonic acid, pH 8.0-8.7; CHES (2-
[N-cyclohexylamino]ethanesulfonic acid), pH 8.7-9.8; and
CAPS (3-[cyclohexylamino]-1-propanesulfonic acid, pH 9.8-
11.0, buffers were used for pH control. The contribution of
buffer catalysis to kobsd is generally < 3%.
P r od u ct Stu d ies for Rea ction of tr a n s-An eth ole Oxid e
(1) a n d cis-An eth ole Oxid e (2). Aliquots of a solution of 1
or 2 in dioxane were added to 3.0 mL of 0.1 M NaClO4 solutions
whose pH had been preadjusted by addition of 0.1 M HClO4
or 0.1 M NaOH solutions. For reactions of 1 at pH ca. 5-10,
approximately 10-3 M buffer was used, as outlined in the
previous section for kinetic studies, to maintain pH. For
reactions of 2 at pH > 9, no buffer was added for pH control.
For these reaction solutions, the pH generally changed from
0.1 to 0.3 pH units during the course of the reaction. Even
small rate enhancements from the buffer acid, which would
catalyze the formation of diols, would affect the diol ratio
significantly, since diols are minor products from the reaction
of 2 above pH 9. Reaction solutions were allowed to stand at
room temperature for > 8 half-lives. The pH was of the
solutions was then adjusted to 5-8, and they were analyzed
by reverse phase HPLC on a C18 column with 1:1 methanol-
water as eluent, 1.5 mL/min. Products were monitored by UV
detection at 232 nm, where the extinction coefficients of diol
and ketone products were determined to be very similar.
Retention times of erythro-diol 5, threo-diol 6, and ketone 7
were 3.3, 4.1, and 7.1 min, respectively.
1
evaporator to yield 11 mg of an oil. The H NMR spectrum of
this oil showed that the major product of the reaction was (p-
methoxyphenyl)acetone. The ketone:diol ratio was obtained by
comparing the integrals of the absorption of the methyl group
in the 1H NMR of the ketone with the absorptions of the methyl
groups of the diols and found to be 84:16. The IR spectrum of
the crude oil closely resembled that of a commercial sample
of (p-methoxyphenyl)acetone.
Detection of tr a n s-An eth ole Oxid e a s a n In ter m ed ia te
in th e Sp on ta n eou s Rea ction of cis-An eth ole Oxid e. The
pH of 100 mL of 5:95 dioxane-water containing 2 × 10-3
M
CAPS buffer was adjusted to 10.5, and the solution was
degassed by bubbling nitrogen through it. A solution of 70 mg
of cis-anethole oxide in 0.5 mL dioxane was added to the
dioxane-water solution. A turbidity resulted, and therefore
an additional 1.0 mL of dioxane was added. Nitrogen was
slowly bubbled through the reaction solution. At time intervals
of 6.0, 8.5, 11.5, 24.5, and 31 h, a 15 mL aliquot of the reaction
solution was extracted with diethyl ether (3 × 20 mL). The
combined ethereal extracts was washed with water (3 × 20
mL) and saturated sodium chloride solution (20 mL) and dried
over anhydrous sodium sulfate. Solvent was removed to yield
an oil (10-15 mg) that was dissolved in CDCl3 and analyzed
1
by H NMR at 270 MHz.
Ack n ow led gm en t . This investigation was sup-
ported, in part, by the National Institutes of Health,
National Research Service Award GM 08663 from the
Minority Access to Research Careers Undergraduate
Student Training in Academic Research (MARC U*
STAR) Program at UMBC, and in part by Illinois
Wesleyan University.
Su p p or tin g In for m a tion Ava ila ble: Text and schemes
describing experimental procedures for the synthesis of â-deu-
terio-cis-anethole oxide (2d ) and â,â-dimethyl-4-methoxysty-
rene oxide (3) and the equation and graph of simulated buildup
of trans-anethole oxide in the spontaneous reaction of cis-
anethole oxide. This material is available free of charge via
the Internet at HTTP://pubs.acs.org.
Sp on ta n eou s Rea ction of tr a n s-An eth ole Oxid e (1) a t
p H 10.6. A solution of 1 (28.0 mg) in 0.2 mL of dioxane was
added to 20 mL of 0.1 M NaClO4 (5:95 dioxane-H2O, v/v) at
pH 10.6 (buffered with 2 × 10-3 M CAPS) in a vial. The
resulting solution was allowed to stand at room temperature
(17) Tiffeneau, M.; Le´vy, J . Bull. Soc. Chim. Fr. 1926, 763-782.
J O991521B