Ketonization of (Z)-2-methoxy-1,2-diphenylvinyl alcohol. Quantitative evaluation of the remarkable kinetic stability of this enol

Article abstract of DOI:10.1139/v98-163

Rates of ketonization of (Z)-2-methoxy-1,2-diphenylvinyl alcohol were measured in aqueous perchloric acid and sodium hydroxide solutions as well as in formic acid and ammonium ion buffers, and the results were used to construct a rate profile for this reaction. These data show this substance to be a remarkably stable enol with a lifetime of 3.6 h at the bottom of its rate profile and a hydrogen ion catalytic coefficient 660 000 times less than that for the enol of acetophenone. Comparison with simple models allows partition of this rate factor into a 440-fold retardation for the β-phenyl substituent and a 1500-fold retardation for the β-methoxy substituent. A global rate of enolization of the keto isomer producing both Z and E enol isomers was also measured, and this leads to pK(E) > 5.4-as the lower limit of the ketoenol equilibrium constant for the Z enol. This result could be dissected into an enol-content enhancing effect of δ pK(E) = 3.2 for the β- phenyl group and a surprising enol-content diminishing effect of δ pK(E) > 0.6 for the β-methoxy group.

Full text of DOI:10.1139/v98-163

1284
Ketonization of (Z)-2-methoxy-1,2-diphenylvinyl
alcohol. Quantitative evaluation of the
remarkable kinetic stability of this enol
E.A. Jefferson, A.J. Kresge, L. Matthew, and Z. Wu
Abstract: Rates of ketonization of (Z)-2-methoxy-1,2-diphenylvinyl alcohol were measured in aqueous perchloric acid
and sodium hydroxide solutions as well as in formic acid and ammonium ion buffers, and the results were used to
construct a rate profile for this reaction. These data show this substance to be a remarkably stable enol with a lifetime
of 3.6 h at the bottom of its rate profile and a hydrogen ion catalytic coefficient 660 000 times less than that for the
enol of acetophenone. Comparison with simple models allows partition of this rate factor into a 440-fold retardation
for the β-phenyl substituent and a 1500-fold retardation for the β-methoxy substituent. A global rate of enolization of
the keto isomer producing both Z and E enol isomers was also measured, and this leads to pKE > 5.4 as the lower
limit of the keto–enol equilibrium constant for the Z enol. This result could be dissected into an enol-content
enhancing effect of δ pKE = 3.2 for the β-phenyl group and a surprising enol-content diminishing effect of δ pKE > 0.6
for the β-methoxy group.
Key words: enol ketonization, enol stability, keto–enol equilibrium, β-phenyl and β-methoxy substituent effects in keto–
enol systems.
Résumé : Opérant en solutions aqueuses d’acide perchlorique et d’hydroxyde de sodium ainsi que dans l’acide
formique et des tampons d’ion ammonium, on a mesuré les vitesses de cétonisation de l’alcool (Z)-2-méthoxy-1,2-
diphénylvinylique et on a utilisé les résultats pour édifier un profil de vitesses de cette réaction. Ces données montrent
que cette substance est un énol remarquablement stable dont le temps de vie est de 3,6 h au fond de son profil de
vitesse et pour lequel le coefficient catalytique de l’ion hydrogène est 660 000 fois plus faible que dans le cas de
l’énol de l’acétophénone. Une comparaison avec des modèles simples permet de diviser ce facteur de vitesse en un
facteur retardant de 440 attribuable au substituant phényle en β et un facteur retardant de 1500 pour le substituant β-
méthoxy. On a aussi mesuré une vitesse globale d’énolisation de l’isomère cétonique conduisant aux isomères E et Z
de l’énol; elle permet d’établir à 5,4 la valeur inférieure limite du pKE de la constante d’équilibre céto–énolique de
l’énol Z. On peut disséquer ce résultat en un effet, δ pKE > 0,6 du groupe β-méthoxy, qui d’une façon surprenant
diminue le contenu en énol.
Mots clés : cétonisation d’un énol, stabilité d’un énol, équilibre céto–énolique, effets des substituants β-phényle et β-
méthoxy sur les systèmes céto–énoliques.
[Traduit par la Rédaction] Jefferson et al. 1288
OH
O
Most thermodynamically unstable enols are also unstable
kinetically and cannot be isolated, let alone characterized by
standard methods commonly used for stable substances. A
notable exception is (Z)-2-methoxy-1,2-diphenylvinyl alco-
hol, 1, which reverts to its more stable keto isomer, 2-
methoxy-1,2-diphenylethanone, 2, eq. [1], so slowly that its
structure could even be determined by X-ray crystallography
(1).
This enol was prepared (1) by treating 1,2-diphenyldi-
azoethanone, 3, with sulfuric acid in methanol solution. Un-
der these conditions, solvolysis of the diazo compound
occurred through rapid pre-equilibrium protonation on
[1]
OMe
OMe
Ph
Ph
Ph
Ph
1
2
carbonyl oxygen followed by rate-determining loss of nitro-
gen, eq. [2]; this generated a vinyl cation, 4, which was cap-
tured by solvent on its less hindered side to give the
methoxy enol, 1, eq. [3].
Received May 12, 1998.
E.A. Jefferson, A.J. Kresge,1 L. Matthew, and Z. Wu. Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6,
Canada.
1Author to whom correspondence may be addressed. Telephone: (416) 978–7259. Fax: (416) 978–7259. E-mail:
akresge@chem.utoronto.ca
Can. J. Chem. 76: 1284–1288 (1998)
© 1998 NRC Canada

Jefferson et al.
1285
OH
O
HO
Ph
H+
+
•
Ph
Ph
-N2
[2]
[3]
Ph
Ph
Ph
+
2
N
N
2
3
4
OH
by adding sodium perchlorate as required. The kinetic data
fit the first-order rate law well, and observed first-order rate
constants were obtained by least-squares fitting of an expo-
nential function.
HO
Ph
+
•
OMe
MeOH
Ph
Ph
+
-
H
Ph
Kinetics, enolization
1
4
Rates of enolization of 2-methoxy-1,2-diphenylethanone
were measured in aqueous sodium hydroxide solutions by
using bromine to scavenge the enol as it formed. In basic so-
lutions, bromine reacts with hydroxide ion according to
eq. [4] and consequently exists as hypobromite ion; reac-
tions were therefore followed by monitoring the absorbance
of this ion at λ = 330 nm.
Cooling the reaction mixture caused the enol to separate in
crystalline form, and this solid was then characterized by its
spectra and reactions in the usual way, and its cis-phenyl ge-
ometry was established by X-ray diffraction.2
To provide a quantitative assessment of the remarkable
stability of this enol we have measured rates of its keto-
nization in aqueous solution and have used the results to
construct a reaction rate profile. We have also measured
rates of enolization of the keto isomer, 2, in order to obtain
an estimate of the keto–enol equilibrium constant for this
system.
[4]
Br2 + 2HO− → BrO− + H2O + Br−
Measurements were made with a Cary 2200 spectrometer
whose cell compartment was thermostatted at 25.0 ± 0.05°C.
In a typical experiment, 20 ␮L of saturated aqueous bromine
solution was added to 10 mL of sodium hydroxide solution,
whose ionic strength had been adjusted to 0.10 M by adding
sodium bromide as required. Each of two 3.0 mL quartz
cuvettes was then filled with this solution, and the absor-
bance of one was recorded at λ = 330 nm; this reading was
later employed to calculate the hypobromite ion concentra-
tion, using ε330 = 300 M–1 cm–1 (4), in order to convert
stoichiometric into actual sodium hydroxide concentrations
according to the relationship of eq. [4]. The second cuvette
was then placed in the reference compartment of the spec-
trometer and bromination was initiated by adding 5 ␮L of an
acetonitrile stock solution of ketone to the first cuvette. Such
double-beam operation minimized base-line drifting, which
was prevalent without the use of a reference sample. Ketone
concentrations in the reaction solutions were 4 × 10–4 M,
and hypobromite concentrations were 1 × 10–3 M. The ki-
netic data conformed to the first-order rate law well, and ob-
served first-order rate constants were obtained by least-
squares fitting of an exponential function.
Materials
1,2-Diphenyldiazoethanone was prepared by mercuric ox-
ide oxidation of benzil hydrazone (3). All other materials
were best available commercial grades.
Kinetics, ketonization
Rates of ketonization of (Z)-2-methoxy-1,2-diphenylvinyl
alcohol were measured by monitoring the increase in prod-
uct ketone absorbance at λ = 250 nm using a Cary 2200
spectrometer with sample compartment thermostatted at 25.0
± 0.05°C. Reactions were initiated by adding aliquots of
methanol stock solution of enol to reaction media that had
come to temperature equilibrium with the spectrometer cell
compartment. The enol stock solutions were made just be-
fore use by allowing 1,2-diphenyldiazoethanone to solvolyze
at room temperature in methanol containing 0.1 M per-
chloric acid. It was found that 12 min was the optimum time
for this solvolysis to take place: enol formation was nearly
complete but subsequent ketonization of the enol, which was
ca. 20 times slower under these conditions, had not yet oc-
curred to any appreciable extent. Five ␮L aliquots of these
freshly prepared enol stock solutions were then added to
3.0 mL portions of reaction media; final concentrations of
enol in the solutions upon which the kinetic measurements
were made were ca. 3 × 10–5 M. The enol is easily oxidized
by atmospheric oxygen (1), and all solutions were therefore
purged with argon. Ionic strength was maintained at 0.10 M
Ketonization
Rates of ketonization of 2-methoxy-1,2-diphenylvinyl al-
cohol were measured in aqueous perchloric acid solutions at
10 different concentrations over the range [HClO4] = 0.001–
0.1 M and in aqueous sodium hydroxide solutions at seven
different concentrations over the range [NaOH] = 0.0005–
0.05 M. Replicate measurements were made at each concen-
tration. The data so obtained have been deposited and are
summarized in Tables S1 and S2.3
2 Sterically hindered enols for which access to the vinyl group is inhibited by bulky substituents are also remarkably stable (2).
3 Tables S1–S4 may be purchased from: The Depository of Unpublished Data, Document Delivery, CISTI, National Research Council of
Canada, Ottawa, Canada, K1A 0S2.
© 1998 NRC Canada

1286
Can. J. Chem. Vol. 76, 1998
Fig. 1. Rate profile for the ketonization of 2-methoxy-1,2-
diphenylvinyl alcohol in aqueous solution at 25°C.
Fig. 2. Relationship between hydroxide ion concentration and
observed rate constants for the enolization of 2-methoxy-1,2-
diphenylethanone in aqueous solution at 25°C.
Rates of ketonization of 2-methoxy-1,2-diphenylvinyl al-
cohol were also measured in formic acid and ammonium ion
buffers. Series of buffer solutions of constant buffer ratio
and constant ionic strength (0.10 M), and therefore constant
hydrogen ion concentration, but different buffer concentra-
tions were used. Buffer concentrations were varied by a fac-
tor of five, and replicate measurements were made at each
concentration. The data so obtained are summarized in Ta-
ble S3 of the depository.3
Observed first-order rate constants measured in these
buffer solutions proved to be accurately proportional to
buffer concentration, and the data were therefore analyzed
by least-squares fitting of eq. [5].
and the uncatalyzed portion adjoining that represents either
protonation of enol by solvent water or ionization of enol to
the much more reactive enolate ion followed by carbon
protonation of that by hydrogen ion. Following this
uncatalyzed region is a segment of apparent hydroxide ion
catalysis produced by ionization of enol to enolate followed
by carbon protonation of that by water, and saturation of this
catalysis, which occurs when the position of the ionization
equilibrium shifts from enol to enolate, gives the second
uncatalyzed region at the very right of the profile.
The rate law that describes this reaction scheme is shown
in eq. [7],
[7]
Kobs = kH+ [H+] + k + k′o QaE͞(QaE + [H+])
UC
[5]
kobs = ko + kcat[buffer]
whose symbols are defined by eq. [5] with kUC = either ko or
k′H+ QaE . Least-squares fitting of this expression gave the
The zero-buffer-concentration intercepts, ko, obtained in this
way were then used, together with the rate constants mea-
sured in perchloric acid and sodium hydroxide solutions, to
construct the rate profile shown in Fig. 1. Hydrogen ion con-
centrations of the buffer solutions needed for this purpose
were obtained by calculation, using literature values of the
buffer acid dissociation constants and activity coefficients
recommended by Bates (5).
Rate profiles such as that of Fig. 1 are a characteristic fea-
ture of enol ketonization reactions (6). They reflect a reac-
tion mechanism consisting of rate-determining protonation
on β-carbon of either the enol or the enolate ion, as shown in
eq. [6].
following results: kH+ = (1.89 ± 0.06) × 10–3 M–1 s–1, kUEC
=
=
(7.71 ± 0.13) × 10–5 s–1, k′o = (4.99 ± 0.10) s–1, and Qa
(4.22 ± 0.34) × 10–11 M, pQa = 10.38 ± 0.04.4
E
Enolization
Rates of enolization of 2-methoxy-1,2-diphenylethanone
were measured in aqueous sodium hydroxide solutions at six
different concentrations over the range [NaOH] = 0.02–0.08
M. Replicate measurements were made at each concentra-
tion. The data so obtained are summarized in Table S4 of the
depository.3
Observed first-order rate constants determined in these so-
lutions proved to be accurately proportional to sodium hy-
droxide concentration (see Fig. 2), and linear least-squares
analysis gave kHO− = (5.59 ± 0.12) × 10–2 as the hydroxide
ion catalytic coefficient for the enolization reaction.
-
OH
O
QaE
OMe
OMe
Ph
Ph
+ H+
Ph
Ph
[6]
+
H+
kH
'
H+ kH
+
Reaction identification
2-Methoxy-1,2-diphenylvinyl alcohol is a vinyl ether as
well as an enol, and, in view of the fact that vinyl ethers are
subject to facile acid-catalyzed hydrolysis (7), this substance
might have undergone that reaction, as shown in eq. [8],
rather than the intended ketonization. It is known, however,
that acid-catalyzed ketonization of enols is at least an order
'
H2O
k
o
H2O ko
The acid-catalyzed portion at the extreme left of the profile
represents carbon protonation of the enol by hydrogen ion,
4 This acidity constant is a concentration quotient applicable at ionic strength equal to 0.10 M.
© 1998 NRC Canada

Jefferson et al.
1287
OH
OH
OH
+
OMe
H2O
O
H+
OMe
[8]
[9]
Ph
Ph
Ph
+
MeOH
Ph
Ph
OH
Ph
OMe
O
O
Ph
gl
OMe
OMe
Br
kE
Ph
Br2
Ph
+
Ph
OH
Ph
Ph
Ph
Ph
gl
OMe
-
O
OH
O
OMe
OMe
OMe
Q w
fkE
+ HO-
+ H2O
[10]
+ HO-
Ph
Ph
Ph
E
k'o
Qa
Ph
Ph
Ph
of magnitude more rapid than the hydrolysis of the corre-
sponding methyl vinyl ethers (6). The ketonization of enols,
moreover, is strongly catalyzed by bases as well as by acids,
whereas the hydrolysis of vinyl ethers is catalyzed only by
acids. This, plus the fact that 2-methoxy-1,2-diphenyl-
ethanone, 2, is the only product formed (1), would appear to
make it safe to conclude that the process under observation
here is in fact the intended ketonization reaction.
difference in free energy of activation of δ∆G‡ = 7.9 kcal
mol−1.
This rate factor may be separated into effects of β-phenyl
and β-methoxy by using rates of ketonization of the trans-
enol of phenylacetaldehyde, 6, kH+ = 7.45 × 10–2 M–1 s–1
(10), and of vinyl alcohol, 7, kH+ = 3.30 × 101 M–1 s–1 (11),
to estimate retardation by a β-phenyl group. The result, a
factor of 440, then leaves 1500 as the β-methoxy group ef-
fect. Similarly large rate retardations by β-phenyl and β-
methoxy groups occur in vinyl ether hyrolysis; for example,
kH+ for trans-β-methoxystyrene (12), 8, is 1100 times less
than that for methyl vinyl ether (13), 9, and kH+ for cis-1,2-
dimethoxyethene (14), 10, is 13 000 times less than that for
methyl vinyl ether. These retardations in rates of vinyl ether
hydrolysis are believed to be the result of initial-state free-
energy lowering by the well-known double-bond stabilizing
effects of phenyl and methoxyl groups (15), which are par-
tially lost in the reactions’ transition states. A similar expla-
nation can be advanced for the effect of these groups on enol
ketonization reactions, and the greater velocities of the
ketonizations over the vinyl ether hydrolyses, and their con-
sequent earlier and more reactant-like transition states, can
be invoked to rationalize the somewhat smaller size of the
effects in ketonization than in vinyl ether hydrolysis.
OH
OH
OH
OH
OMe
Ph
Ph
Ph
Ph
1
5
6
7
Reactivity
The lifetime of 2-methoxy-1,2-diphenylvinyl alcohol, 1, at
the bottom of its rate profile (Fig. 1) is τ = 3.6 h. This con-
trasts sharply with the lifetime of the enol of acetophenone,
5, in the corresponding region, τ = 6 s (8), and shows that
the additional β-methoxy and β-phenyl substituents in 1 have
a very strong stabilizing effect.
Because the ketonization of enols at the bottom of their
rate profiles can occur by either of two mechanisms (vide
supra), a better assessment of the β-methoxy and β-phenyl
group effects may be made using rate constants from a dif-
ferent region of the profile. Use of the acid-catalyzed region,
moreover, allows comparison with vinyl ether hydrolysis;
this is useful because acid catalysis of both ketonization and
vinyl ether hydrolysis occurs by the same reaction mecha-
nism, i.e., simple rate-determining proton transfer to the sub-
strates’s β-carbon atom. Combination of kH+ = 1.25 × 103
M–1 s–1 for acetophenone enol (9) with the presently deter-
mined value for 2-methoxy-1,2-diphenylvinyl alcohol then
gives a rate factor of 660 000, which is equivalent to a
MeO
MeO
MeO
OMe
Ph
8
9
10
Keto–enol equilibrium
Keto–enol equilibrium constants have traditionally been
determined by the halogen titration method invented nearly
© 1998 NRC Canada

1288
Can. J. Chem. Vol. 76, 1998
a century ago (16). This method, unfortunately, fails when
enol contents are as low as is commonly the case for simple
aldehydes and ketones (17), and in that situation it is useful
to employ a kinetic method where the keto–enol equilibrium
constant is determined as the ratio of enolization to keto-
nization rate constants: KE = kE͞kK.
effect on rates of enol ketonization (vide supra). It is possi-
ble, however, that the various comparisons made leading to
this result are not entirely valid, inasmuch as they were
made using models containing only single phenyl substitu-
ents in which steric crowding interfered little, if at all, with
substituent-functional group interaction. The enol investi-
gated, 2-methoxy-1,2-diphenylvinyl alcohol, on the other
hand, is a sterically congested molecule, as shown by the
fact that its phenyl groups are twisted out of the vinyl plane
by some 47° (1).
The presently determined ketonization rate constants, of
course, refer only to the Z enol isomer, but the enolization
rate constants are global values referring to the production
of both Z and E enols, as shown in eq. [9]. Simply taking the
ratio of the enolization to ketonization rate constants deter-
mined here will therefore not produce a proper keto–enol
equilibrium constant: the global rate constants should be
separated into values for production of the individual iso-
mers, but that cannot be done because the method of analy-
sis used, bromination, does not distinguish between the
isomers. A simple ratio of presently determined rate con-
stants does, however, provide an upper limit to KE for the Z
isomer, and that is enough to produce an interesting result.
The keto–enol equilibrium involving the Z isomer pro-
moted by hydroxide ion may be represented as shown in
eq. [10], and the equilibrium constant for this representation
is given by eq. [11].
We are grateful to the Natural Sciences and Engineering
Research Council of Canada for financial support of this
work.
1. J.F. McGarrity, A. Cretton, A.A. Pinkerton, D.
Schwarzenbazch, and H.D. Flack. Angew. Chem. Int. Ed.
Engl. 22, 405 (1983); Angew. Chem. Suppl. 551 (1983).
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3. C.D. Nenitzescu and E. Solomonica. Org. Synth. Coll. Vol. 2,
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4. J.R. Jones. Trans. Faraday Soc. 61, 95 (1965).
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Wiley and Sons, New York. 1973. p. 49.
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by Z. Rappoport. John Wiley & Sons, New York. 1990.
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7. A.J. Kresge. Acc. Chem. Res. 20, 364 (1987).
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Chem. Soc. 110, 5506 (1988).
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6392 (1984).
10. Y. Chiang, A.J. Kresge, P.A. Walsh, and Y. Yin. J. Chem. Soc.
Chem. Commun. 869 (1989).
gl
fkE
Qw
QaE
[11] KE
=
k′o
In the latter expression, f is the (unknown) fraction of the
global enolization rate constant, kEgl, that refers to produc-
tion of the Z isomer only, Qw is the autoprotolysis constant
of water, and the remaining symbols are as defined by
eq. [6]. Insertion of numerical values into this expression
then leads to KE = (f) (4.22 × 10–6). Since f is a fraction less
than one, KE must be less than 4.22 × 10–6 with pKE > 5.38
as a lower limit.
Comparison of this result with pKE = 7.96 for aceto-
phenone (18) shows that β-phenyl and β-methoxy substitu-
ents introduced together increase enol content, and since
pKE = 5.38 is a lower limit, the combined effect of these
groups can be no greater than 7.96 – 5.38 = 2.58 pK units.
The effect of a β-phenyl substituent introduced alone may be
estimated as δ∆pKE = 3.16, by comparing pKE = 3.07 for the
trans-enol of phenylacetaldehyde, (10), 6, with pKE = 6.23
for acetaldehyde (11), 7. This difference is greater than the
upper limit of 2.58 pK units estimated above for the com-
bined effect of β-phenyl and β-methoxy substituents, which
means that the effect of β-methoxy alone must be in the op-
posite direction, i.e., the effect of this group must be to
lower rather than to raise enol content, and its magnitude
must be greater than 3.16 – 2.58 = 0.58 pK units.
11. Y. Chiang, M. Hojatti, J.R. Keeffe, A.J. Kresge, N.P. Schepp,
and J. Wirz. J. Am. Chem. Soc. 109, 4000 (1987).
12. Y. Chiang, A.J. Kresge, and C.I. Young. Can. J. Chem. 56, 461
(1978).
13. A.J. Kresge, D.S. Sagatys, and H.L. Chen. J. Am. Chem. Soc.
99, 7228 (1977).
14. A.J. Kresge and M. Leibovitch. J. Org. Chem. 55, 5234
(1990).
15. J. Hine. Structural effects on equilibria in organic chemistry.
John Wiley & Sons, New York. 1975. pp. 270–276.
16. K. Meyer. Justus Liebigs Ann. Chem. 380, 212 (1911).
17. J.R. Keeffe, A.J. Kresge, and N.P. Schepp. J. Am. Chem. Soc.
112, 4862 (1990).
This is a surprising result. It implies that β-methoxy sub-
stituents destabilize enols thermodynamically,5 in contrast to
the kinetic stabilization shown by their marked retarding
18. J.R. Keeffe, A.J. Kresge, and J. Toullec. Can. J. Chem. 64,
1224 (1986).
5 It is likely that β-substituents influence the position of keto–enol equilibria largely by altering the energy of the enol rather than that of the
keto isomer, because in the enol the substituent is placed directly on the functional group, whereas in the keto isomer it is insulated from the
functional group by a saturated carbon atom.
© 1998 NRC Canada