The 2-oxocyclopentanecarboxylic acid keto-enol system in aqueous solution: Generation of the enol by hydration of an acylketene

Article abstract of DOI:10.1021/ja9704390

Flash photolysis of 2-diazocyclohexane-1,3-dione in aqueous solution produced 2-ketocyclopentylideneketene, which hydrated to the enol of 2-oxocyclopentanecarboxylic acid, and the enol then isomerized to the keto form of the acid. This ketene proved to be

Full text of DOI:10.1021/ja9704390

J. Am. Chem. Soc. 1997, 119, 11183-11190
11183
The 2-Oxocyclopentanecarboxylic Acid Keto-Enol System in
Aqueous Solution: Generation of the Enol by Hydration of an
Acylketene
Y. Chiang,† A. J. Kresge,*,† V. A. Nikolaev,‡ and V. V. Popik†
Contribution fron the Department of Chemistry, UniVersity of Toronto,
Toronto, Ontario M5S 3H6, Canada, and St. Petersburg State UniVersity, St. Petersburg, Russia
ReceiVed February 10, 1997X
Abstract: Flash photolysis of 2-diazocyclohexane-1,3-dione in aqueous solution produced 2-ketocyclopentyl-
ideneketene, which hydrated to the enol of 2-oxocyclopentanecarboxylic acid, and the enol then isomerized to the
keto form of the acid. This ketene proved to be a remarkably reactive substance, with an uncatalyzed hydration rate
constant of k ) 1.4 × 106 s-1 and a hydroxide-ion-catalyzed rate constant of 7.5 × 107 M-1 s-1; no acid catalysis
of hydration was found. Ketonization of the enol was a slower process with rate constants in the millisecond to
second range. The reaction shows a complex rate profile that could be interpreted in terms of rate-determining
proton transfer to the â-carbon atom of successively ionized forms of the enol in successively more basic solutions.
In concentrated acid solutions, the carboxylic acid group of the enol also underwent equilibrium protonation of its
carbonyl group, with pKSH ) -3.86. Acidity constants of the carboxylic acid group of the enol, pQa,E ) 4.16, and
E
the hydroxyl group of the enol, pQa ) 12.41, were also determined. (These acidity constants are concentration
quotients applicable at an ionic strength of 0.10 M.) Rates of enolization of the keto form of the substrate were also
measured by bromine scavenging, and these, in combination with ketonization rates, gave the keto-enol equilibrium
constants pKE ) 2.51 for the system in the un-ionized carboxylic acid form and pK′E ) 3.00 for the ionized carboxylate
form. The acidity constant of the carboxylic acid group of the keto form was determined as well: pQa,K ) 3.67.
Although enols of â-keto esters have been investigated
extensively for more than a century,1 little attention has been
paid to keto-enol isomerism in the â-keto acids themselves.
We recently carried out a detailed study of the enol of aceto-
acetic acid, 1,2 and we now add to that a somewhat more exten-
sive examination of the enol of 2-oxocyclopentanecarboxylic
acid, 2.
â-Ketocarboxylic acids such as acetoacetic acid can, in
principle, enolize to form either ketone enols 1 or carboxylic
acid enols 6, eq 2. Recent high-level ab initio calculations have
shown the ketone enol to be the more stable of these two
isomers.4 This is consistent with the fact that the remaining
carbonyl group in the ketone enol has one direct and one
vinylogous interaction with a hydroxyl group, whereas the
carbonyl group in the acid enol has only two vinylogous
hydroxyl group interactions: direct interactions can be expected
to be stronger and therefore more stabilizing than vinylogous
ones.
We generated this enol in aqueous solution by flash photolysis
of 2-diazocyclohexane-1,3-dione, 3. It was already known that
irradiation of this substance gives a photo-Wolff reaction pro-
ducing the acylketene 2-ketocyclopentylideneketene, 4, which,
in the presence of water, undergoes hydration to 2-oxocyclo-
pentanecarboxylic acid, 5, through its enol 2, eq 1.3 We were
able in the present study to monitor both the ketene hydration
and the enol ketonization reactions.
Experimental Section
Materials. 2-Diazocyclohexane-1,3-dione was prepared from cy-
clohexane-1,3-dione by diazo transfer using p-acetoamidobenzene-
sulfonyl azide as the diazo transfer reagent5 and fluoride ion as the
base. A mixture of 3.5 g of anhydrous KF and 1.38 g of cyclohexane-
1,3-dione (Aldrich) dissolved in 50 mL of CH2Cl2 was stirred at room
temperature while a solution of 2.4 g of p-acetamidobenzenesulfonyl
azide (Aldrich) in 10 mL of CH2Cl2 was added dropwise. The reaction
mixture was then left at room temperature overnight, after which it
was cooled to -10 °C, filtered through 4 cm of silica gel, washed with
0.1 M aqueous NaOH (2 × 100 mL), and dried with MgSO4. Removal
of the solvent in Vacuo and recrystallization of the residue from diethyl
† University of Toronto.
‡ St. Petersburg State University.
X Abstract published in AdVance ACS Abstracts, October 1, 1997.
(1) For reviews of the early work, see: Ingold, C. K. Structure and
Mechanism in Organic Chemistry, 2nd ed.; Cornell University Press: Ithaca,
NY, 1969; pp 794-837. Wheland, G. W. AdVanced Organic Chemistry,
3rd ed.; John Wiley & Sons: New York, 1960; pp 663-703. For a
summary of more recent studies, see: Toullec, J. In The Chemistry of Enols;
Rappoport, Z., Ed.; John Wiley & Sons: New York, 1990; pp 353-378.
(2) Chiang, Y.; Guo, H.-X.; Kresge, A. J.; Tee, O. S. J. Am. Chem. Soc.
1996, 118, 3386-3391.
(3) Korobitsyna, I. K.; Nikolaev, V. A. J. Org. Chem. USSR (Engl.
Transl.) 1976, 12, 1245-1251.
(4) Hoz, S.; Kresge, A. J. J. Phys. Org. Chem. 1997, 10, 182-186.
(5) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709-1716.
S0002-7863(97)00439-3 CCC: $14.00 © 1997 American Chemical Society

11184 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Chiang et al.
ether gave 1.05 g of yellowish crystals, mp 48-49 °C (lit. mp 47-49
°C6) whose 1H and 13C NMR spectra agreed well with literature values.7
2-Oxocyclopentanecarboxylic Acid. This was prepared by hy-
drolysis of ethyl 2-oxocyclopentanecarboxylate (Aldrich). A solution
of 1.2 g of the ester in 30 mL of 0.5 M aqueous NaOH was allowed
to stand at room temperature for 3 days. The resulting yellow solution
was then washed with five 15-mL portions of diethyl ether and cooled
to 0 °C, and 3 mL of concentrated aqueous HCl was added. The
resulting solution was extracted with five 20-mL portions of diethyl
ether, and the combined ether extracts were dried over anhydrous
Na2SO4 and then concentrated to 15 mL. This produced 120 mg of a
colorless crystalline byproduct of unknown constitution, which was
removed by filtration. Cooling of the filtrate to -72 °C produced
additional traces of this byproduct, which was also removed by filtration.
Removal of the solvent from the filtrate gave 74 mg of 2-oxocyclo-
pentanecarboxylic acid as a yellow oil whose 1H NMR spectrum agreed
with literature reports.3,8,9
All other materials were best available commercial grades.
Figure 1. Rate profiles for the hydration of 2-ketocyclopentyl-
ideneketene (4) and the ketonization of 2-oxocyclopentanecarboxylic
acid enol (O) in aqueous solution at 25 °C.
Kinetics. Rates of hydration of 2-ketocyclopentylideneketene were
measured with an excimer-laser flash photolysis system operating at λ
) 248 nm that has already been described,10 and rates of ketonization
of 2-oxocyclopentanecarboxylic acid enol were measured with a
conventional flash photolysis system that has also been described.11
The temperature of the reaction solutions was maintained at 25.0 (
0.1 °C, and the ionic strength was held constant at 0.10 M.
Rates of enolization of 2-oxocyclopentanecarboxylic acid were
monitored by bromine scavenging under first-order reaction conditions
with an excess of bromine over substrate. Bromine concentrations were
in the range (4-40) × 10-5 M and substrate concentrations, (1-15) ×
10-5 M. The reaction mixtures also contained bromide ion, supplied
as the inert salt NaBr used to maintain the ionic strength at 0.10 M
and also as the mineral acid HBr. Under these conditions, Br2 is
complexed as Br3- and the reactions were followed by monitoring the
decrease in absorbance of this ion at λ ) 266 or 310 nm. In sodium
hydroxide solutions, Br2 is converted to BrO- and the reactions here
were followed by monitoring the decrease in absorbance of this ion at
λ ) 330 nm. Measurements were made using either a Cary 2200
spectrometer or a Hi-Tech SF-S1 stopped-flow system; in both cases
the temperature of reaction solutions was maintained at 25.0 ( 0.05
°C.
trimethyl-4H-1,3-dioxin-4-one, 7, where the absorbance rise was
identified as the hydration of acetylketene, 8, to the enol of
acetoacetic acid, 1, and the decay was identified as ketonization
of this enol to the acid 9, eq 4.2 This similarity suggests that
an analogous assignment can be made in the present case, i.e.,
that the rise in absorbance here can be attributed to the hydration
of 2-ketocyclopentylideneketene, 4, itself formed by photolysis
of the diazo compound during the flash photolysis pulse, and
that the absorbance decay can be attributed to ketonization of
the enol of 2-oxocyclopentanecarboxylic acid, 2, thus formed,
according to eq 1. This conclusion is reinforced by the
established photochemistry of 2-diazocyclohexane-1,3-dione,
which is known to proceed according to eq 1, and also by the
fact that the rate profiles produced by these absorbance changes
(Vide infra) are typical of ketene-hydration and enol-ketonization
reactions.
Ketene Hydration. Rates of hydration of 2-ketocyclopen-
tylideneketene were measured in aqueous perchloric acid and
sodium hydroxide solutions and also in water with no acid or
base added. Acid and base concentrations were varied, but ionic
strength was kept constant at 0.10 M. The data so obtained
are summarized in Tables S1-S312 and are displayed as the
upper rate profile of Figure 1.
pKa Determination. The acidity constant of 2-oxocyclopentane-
carboxylic acid was determined spectrophotometrically by using the
difference in absorbance of the undissociated acid and its carboxylate
anion at λ ) 210 nm. Absorbance measurements were made on
solutions containing a fixed stoichiometric concentration of substrate
(3.11 × 10-4 M) and varying hydrogen ion concentrations but fixed
ionic strengh (0.10 M). The data so obtained were analyzed by least-
squares fitting of eq 3,
A ) (AHA[H+] + AAQa)/(Qa + [H+])
(3)
in which Qa is the acid dissociation constant (concentration quotient at
ionic strength ) 0.10 M) of 2-oxocyclopentanecarboxylic acid, AHA is
the absorbance of un-ionized acid, and AA is that of its carboxylate
ion.
These results show that the hydration of this ketene is not
catalyzed by acids up to an acidity of [H+] ) 0.10 M but is
weakly catalyzed by hydroxide ion. Such behavior is charac-
teristic of ketene hydration reactions, whose rate profiles
commonly show large uncatalyzed regions with weak or
nonexistent acid catalysis and somewhat stronger but still weak
base catalysis.10,13
Results and Discussion
Flash photolysis of aqueous solutions of 2-diazocyclohexane-
1,3-dione produces a rapid rise in absorbance in the region λ )
250-300 nm followed by a much slower decay. These
absorbance changes are very similar to those found in the
generation of acetoacetic acid by flash photolysis of 2,2,6-
Least-squares analysis of the present data gives the following
rate constants: ko ) (1.40 ( 0.01) × 106 s-1 for the uncatalyzed
reaction and kHO ) (7.53 ( 0.10) × 107 M-1 s-1 for the
-
(6) Stetter, H.; Kiehs, K. Chem. Ber. 1965, 98, 1181-1187.
(7) Leung-Toung, R.; Wentrup, C. J. Org. Chem. 1992, 57, 4850-4858.
(8) Tirpack, R. E.; Olsen, R. S.; Rathke, M. W. J. Org. Chem. 1985, 50,
4877-4879.
hydroxide-ion-catalyzed process. These results are similar to
the rate constants found for the hydration of acetylketene (8;
eq 4): ko ) 1.54 × 106 s-1 and kHO ) 1.86 × 108 M-1 s-1 2
.
-
(9) 13C NMR spectrum of the present preparation: δ (CDCl3) ) 213.01,
174.85, 55.03, 38.55, 27.63, 21.26.
(12) Supporting Information; see paragraph at the end of this paper
regarding availability.
(13) (a) Allen, A. D.; Kresge, A. J.; Schepp, N. P.; Tidwell, T. T. Can.
J. Chem. 1987, 65, 1719-1723. (b) Andraos, J.; Kresge, A. J. J. Photochem.
Photobiol. A 1991, 57, 165-173.
(10) Andraos, J.; Chiang, Y.; Huang, C. G.; Kresge, A. J.; Scaiano, J.
C. J. Am. Chem. Soc. 1993, 115, 10605-10610.
(11) Chiang, Y.; Hojatti, M.; Keeffe, J. R.; Kresge, A. J.; Schepp, N. P.;
Wirz, J. J. Am. Chem. Soc. 1987, 109, 4000-4009.

Generation of Enol by Hydration of an Acylketene
J. Am. Chem. Soc., Vol. 119, No. 46, 1997 11185
They show that 2-ketocyclopentylideneketene, like acetylketene,
is a very reactive substance, orders of magnitude more labile
is the major substrate form. At lower acidities, the dianion
becomes the reacting form, but now [H+] is so low that solvent
water takes over the role of protonating species. This produces
a diagonal segment of slope ) +1, representing apparent
hydroxide ion catalysis, at acidities above the second bend where
monoanion is still the major substrate form, and a horizontal
uncatalyzed portion at acidities below the second bend where
dianion is the major substrate species.
than ketene itself, for which ko ) 36.5 s-1 13b
This is consistent
.
with the mechanism of these reactions, which is known to
involve nucleophilic attack of water or hydroxide ion on the
carbon atom of the ketene carbonyl group: such attack generates
a negative charge on the substrate that can be stabilized by
delocalization into the additional carbonyl group of these
acylketenes.
Enol Ketonization. Rates of ketonization of 2-oxocyclo-
pentanecarboxylic acid enol were measured in aqueous per-
chloric acid and sodium hydroxide solutions and in aqueous
formic acid, acetic acid, biphosphate ion, tris(hydroxymethyl)-
methylamine, and ammonia buffers. All measurements were
made at a constant ionic strength of 0.10 M, except those in
concentrated perchloric acid solutions where the ionic strength
was equal to acid concentration. The data so obtained are
summarized in Tables S4-S7.12
The rate law that corresponds to this reaction scheme is given
as eq 7, whose rate and equilibrium constants are defined by
k′H+Q [H+]
QaE + [H+]
k′′oQaE
QaE + [H+]
aE
kobs
)
+ k′o +
(7)
eq 6. (Primed symbols are used for reactions of the monoan-
ionic form of the substrate and double-primed symbols for the
dianionic form.) Least-squares fitting of this expression gave
5
the following results: k′H ) (2.41 ( 0.13) × 10 M-1 s-1, k′o
+
The measurements in buffers were carried out in series of
solutions of constant buffer ratio and therefore constant hydrogen
ion concentration. Strong buffer catalysis was observed, and
the data conformed to the expected linear rate law of eq 5,
) (2.57 ( 0.30) × 10-2 s-1, k′′o ) (4.84 ( 0.28) × 102 s-1
,
E
Qa,E ) (6.98 ( 0.47) × 10-5 M (pQa,E ) 4.16 ( 0.03),15 Qa
E
) (3.93 ( 0.30) × 10-13 M (pQa ) 12.41 ( 0.03).15
The reaction scheme of eq 6 interprets the narrow horizontal
region at the bottom of the rate profile as reaction of the
monoanionic form of the substrate with water as the proton
donor. An alternative interpretation is reaction of the dianionic
form of the substrate with hydrogen ion as the proton donor;
kobs ) ks + kbuff[buffer]
(5)
in which ks is the rate constant for reaction through catalysis
by solvent-related species and kbuff is that for reaction via buffer.
Least-squares fitting of the data using eq 5 gave values of ks,
which, together with rate constants determined in perchloric acid
and sodium hydroxide solutions, are displayed as the lower rate
profile of Figure 1. Values of [H+] in the buffer solutions
needed for this purpose were obtained by calculation, using
literature pKa’s of the buffer acids and activity coefficients
recommended by Bates.14
the portion of the rate law representing this segment of the rate
E
+
+
profile then becomes k′′H Qa , where k′′H is the rate constant
for â-carbon protonation of the substrate dianion. Such an
interpretation was rejected in the case of acetoacetic acid enol
because the data gave k′′H ) 2.7 × 1011 M-1 s-1, which was
+
regarded as improbably large. The present system gives the
lower but perhaps still too large value k′′H ) 6.5 × 1010 M-1
+
s-1
.
This rate profile is similar to that obtained for the ketonization
of the enol of acetoacetic acid2 and, like the latter, can be
interpreted in terms of ketonization through rate-determining
â-carbon protonation of the mono- and dianionic forms of the
Although the rate profile for ketonization of 2-oxocyclopen-
tanecarboxylic acid enol up to an acidity of [H+] ) 0.10 M
(Figure 1) shows no evidence of further acid catalysis corre-
sponding to rate-determining carbon protonation of the un-
ionized form of the substrate, eq 8, such catalysis was found in
enol, eq 6. The bend in this rate profile at [H+] = 10-4
M
then represents ionization of the carboxylic acid group of the
substrate, and that at [H+] = 10-12 M represents ionization of
its enolic hydroxyl group.
more concentrated acids. Rates of this further reaction were
measured in aqueous perchloric acid solutions over the con-
centration range 6.7-9.9 M; the data so obtained are sum-
marized in Table S7.12
Observed first-order constants obtained in these concentrated
acid solutions were found to increase with solution acidity more
rapidly than in direct proportion to acid concentration. This is
commonly the case for rate-determining carbon-protonation
reactions, and the situation is generally handled by using an
acidity function to correlate the data; the Cox-Yates Xo
function16 appears to be the best scale currently available for
this purpose.17 In the present case, allowance must be made
for the background “uncatalyzed” reaction shown at the high
acidity end of the rate profile of Figure 1, which actually
represents hydrogen-ion catalysis of the anionic form of the
substrate under conditions where the un-ionized form is the
Because ketonization is an electrophilic addition reaction,
successively ionized forms of the substrate will be more reactive
than their precursors, and reaction will take place through them
even when they are relatively minor substrate species. This
will produce a horizontal “uncatalyzed” segment of the rate
profile at acidities above the first bend, where reaction is through
the monoanion but un-ionized enol is the major form of the
substrate, and a diagonal segment of slope ) -1 signifying
acid catalysis at acidities below the first bend, where monoanion
(15) This is a concentration quotient applicable at ionic strength ) 0.10
M.
(16) Cox, R. A.; Yates, K. Can. J. Chem. 1981, 59, 2116-2124.
(17) Kresge, A. J.; Chen, H. J.; Capen, G. L.; Powell, M. F. Can. J.
Chem. 1983, 61, 249-256.
(14) Bates, R. G. Determination of pH Theory and Practice; Wiley: New
York, 1973; p 49.

11186 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Chiang et al.
and the carboxylic acid carbonyl group. The fairly large slope
parameter found for this protonation, m ) 0.87, suggests that
the nonproductive site is the carbonyl group, because m values
for hydroxyl group protonation are usually much lower, Viz. m
) 0.13 for the protonation of methanol and m ) 0.14 for that
of ethanol, whereas m ) 0.56 for the protonation of benzoic
acid.21 The carboxylic acid group, moreover, might be expected
to be the more basic site in the present substrate, for protonation
of its carbonyl group produces a cation whose positive charge
can be delocalized, as shown in eq 11, whereas protonation of
Figure 2. Correlation of rates of ketonization of 2-oxocyclopentan-
ecarboxylic acid enol in concentrated aqueous perchloric acid solution
at 25 °C. The line shown was drawn using parameters obtained by
least-squares fitting of eq 10.
the enolic hydroxyl group gives a cation with a localized positive
charge. This assignment of nonproductive protonation site is
also consistent with the fact that the presently determined acidity
constant, pKSH ) -3.86, makes the conjugate acid of the present
substrate somewhat less acidic than protonated benzoic acid,
for which pKSH ) -4.73:21 the extra delocalization of positive
charge into the enolic hydroxyl group shown in structure 10 of
eq 11 will make this substance more stable, and consequently
a weaker acid, than protonated benzoic acid.
These considerations thus indicate that the progressive
retardation of ketonization through carbon protonation of the
un-ionized form of 2-oxocyclopentanecarboxylic acid enol,
seen above [HClO4] ) 8.2 M and illustrated in Figure 2, is
caused by nonproductive protonation of the substrate’s car-
boxylic acid group.
reaction’s initial state; observed rate constants in this region
+
are consequently equal to k′H Qa,E
. The situation can be
accommodated by adding this term to the standard expres-
sion generally used to correlate rate data with Xo,18 as shown
in eq 9,
log{(kobs - k′H+Qa,E)/[H+]} ) log kH+ + mqX
(9)
o
q
+
where kH is the rate constant for the reaction of eq 8 and m is
a slope parameter for the kinetic process. Such an expression
has been used successfully to correlate rates of enol ketonization
before,19 and it did so here as well up to an acid concentration
of 8.2 M. Beyond this point, however, observed rate constants
were progressively smaller than required by this expression.
Such deviations have been found for carbon-protonation reac-
tions before and have been assigned to competitive protonation
at another site which converts the substrate into a nonreactive
form.20 The further modification of the standard Cox-Yates
expression that this nonproductive protonation requires is shown
as eq 10,
Further support for interpretation of the rate profile of Figure
1 in terms of the reaction scheme of eq 6 may be obtained from
the form of acid-base catalysis shown by the ketonization
reaction in buffer solutions. Buffer catalytic coefficients, kcat,
can be separated into their general acid, kHA, and general base,
kB, components through the use of eq 12, in which fA is the
kcat ) kB + (kHA - kB)fA
(12)
fraction of buffer present in the acid form. Application of eq
12 requires data at several different buffer ratios to supply
information at several different values of fA, and this was
available in the present case for acetic acid, biphosphate ion,
and ammonium ion buffers. In the last two systems, hydrogen
ion concentrations were such that the enol substrate was
essentially completely in its monoanionic form, and slopes of
buffer dilution plots, ∆kobs/∆[buffer], could be equated with kcat.
In the acetic acid buffers, however, the substrate was present
in both monoanionic and neutral forms, and ∆kobs/∆[buffer] had
to be converted, through the use of eq 13, into kcat for reaction
log{(kobs - k′H+Qa,E)/[H+]} )
KSH
+
log kH+ + mqX + log
(10)
o
KSH+ + [H+]10mX
o
(
)
where KSH is the acidity constant of the substrate proto-
nated at the nonproductive site and m is a slope parameter for
this equilibrium process. As Figure 2 shows, this expression
correlates the present experimental data well. Least-squares
+
fitting gave the results, kH ) (5.30 ( 0.79) × 10-3 M-1 s-1
,
∆kobs
[H+] + Qa,E
k′H Qa,E ) 17.4 ( 0.9 s-1, KSH ) (7.26 ( 1.84) × 103 M, pKSH
+
kcat
)
Qa,E
(13)
) -3.86 ( 0.11, mq ) 0.89 ( 0.02, and m ) 0.87 ( 0.02. The
(
)(
)
Qa,E
∆[buffer]
+
value of k′H Qa,E obtained in this way agrees very well with
that derived from least-squares fitting the rate profile of Figure
beginning with monoanion only as the initial state.
1: k′H Qa,E ) 16.8 ( 1.4 s-1
.
+
Catalysis in acetic acid buffers proved to be wholly of the
general acid type. This is evident from Figure 3, where the
ordinate at fA ) 0 represents general base catalysis and that at
fA ) 1, general acid catalysis, and also from least-squares
analysis of the data, which gave kHA ) (1.34 ( 0.03) × 103
M-1 s-1 and kB ) -(4.42 ( 2.44) × 101 M-1 s-1. This result
is consistent with the fact that the acetic acid buffers lie in a
region of the rate profile where the ketonization mechanism
There are two weakly basic sites in the present substrate
whose protonation in concentrated acids would be expected to
hinder ketonization and give rise to the observed nonproductive
equilibrium effect. These sites are the enolic hydroxyl group
(18) Cox, R. A.; Yates, K. Can. J. Chem. 1979, 57, 2944-2951.
(19) Chiang, Y.; Kresge, A. J.; Krogh, E. T. J. Am. Chem. Soc. 1988,
110, 2600-2607. Chiang, Y.; Kresge, A. J.; Pruszynski, P. J. Am. Chem.
Soc. 1992, 114, 3103-3107.
(20) Kresge, A. J.; Yin, Y. J. Phys. Org. Chem. 1989, 2, 43-50. Kresge,
A. J.; Leibovitch, M. J. Org. Chem. 1990, 55, 5234-5236.
(21) Bagno, G.; Scorrano, G.; More O’Ferrall, R. A. ReV. Chem.
Intermediates 1987, 7, 313-352.

Generation of Enol by Hydration of an Acylketene
J. Am. Chem. Soc., Vol. 119, No. 46, 1997 11187
Figure 3. Relationship between buffer catalytic coefficients and the
fraction of buffer present as acid for the ketonization of 2-oxocyclo-
pentanecarboxylic acid enol in aqueous acetic acid buffer solutions at
25 °C.
Figure 4. Relationship between buffer catalytic coefficients and the
fraction of buffer present as acid for the ketonization of 2-oxocyclo-
pentanecarboxylic acid enol in aqueous biphosphate ion buffer solutions
at 25 °C.
assigned consists of rate-determining carbon protonation of the
enol monoanion; such a reaction can be expected to show
general acid catalysis. In biphosphate buffers, on the other hand,
the reaction shows both general acid and general base catalysis
(Figure 4); least-squares analysis gives kHA ) (1.46 ( 0.04) ×
102 M-1 s-1 and kB ) (3.16 ( 0.49) × 101 M-1 s-1. This is
consistent with the fact that these buffers lie in a region where
rate-determining carbon protonation of the monoanion is begin-
ning to give way to further ionization of this ion to the dianion
followed by rate-determining carbon protonation of that species;
the latter reaction with monoanion as the initial state will show
an inverse rate dependence on hydrogen ion concentration for
its prior equilibrium ionization step followed by general acid
catalysis for the rate-determining carbon-protonation step, which
is equivalent to general base catalysis. The ammonium ion
buffers lie well into the region where ketonization occurs solely
through the dianion with monoanion as the initial state, and
consistent with this is the fact that only general base catalysis
is observed here (Figure 5); least-squares analysis gives
kHA ) -(9.08 ( 7.23) M-1 s-1 and kB ) (1.45 ( 0.07) × 102
Figure 5. Relationship between buffer catalytic coefficients and the
fraction of buffer present as acid for the ketonization of 2-oxocyclo-
pentanecarboxylic acid enol in aqueous ammonium ion buffer solutions
at 25 °C.
M-1 s-1
.
Table 1. Catalytic Coefficients for the Ketonization of
2-Oxocyclopentanecarboxylic Acid Enol in Aqueous Solution at 25
These general base catalytic coefficients are related to general
acid catalytic coefficients for carbon protonation of the dianion,
k′′HA, as shown in eq 14, where QaBH is the acidity constant of
°Ca
b
b
catalyst
H+
HCO2H
k′HA (M-1 s-1
)
k′′HA (M-1 s-1
)
2.41 × 105
6.86 × 103
1.34 × 103
1.46 × 102
kB ) k′′HAQaE/QaBH
(14)
CH3CO2H
-
H2PO4
NH4
1.34 × 107
1.89 × 105
the buffer acid. Values of k′′HA obtained through this relation-
ship, together with values of k′HA for carbon protonation of the
monoanion, are listed in Table 1. It may be seen that both kinds
of rate constants decrease with decreasing acidity of the catalyst,
as expected, and also that the dianion is several orders of
magnitude more reactive than the monoanion, again as expected
and also as found before in comparisons of rates of reaction of
enols and the corresponding enolate ions.22 It is significant,
however, that the increased reactivity of enolate over enol found
here, k′′HA/k′HA ) 9.2 × 104 for catalysis by H2PO4-, is several
orders of magnitude less than the factors of 106-108 obtained
before for simple enols without â-carboxylate groups,22 inas-
much as the enol reaction here will be accelerated because the
â-carboxylate group can act as an intramolecular general base
catalyst in ketonization of the enol but not of the enolate ion;
such intramolecular general base catalysis was noted before in
+
a Ionic strength ) 0.10 M. b Error limits are given in the text.
the acetoacetic acid system, where its rate acceleration was
estimated to be approximately 2 orders of magnitude.2
The general magnitude of the ketonization rate constants
obtained here is consistent with an earlier study which found
rates of ketonization of this enol to be too fast to be measured
by conventional techniques.23
pKa Determination. The acidity constant of 2-oxocyclo-
pentanecarboxylic acid was determined by measuring the ab-
sorbance of solutions of the acid at a constant concentration in
aqueous perchloric acid solutions and formic acid, acetic acid,
and biphosphate ion buffers, all at a constant ionic strength of
0.10 M. As Figure 6, shows, the data so obtained (summarized
(22) Pruszynski, P.; Chiang, Y.; Kresge, A. J.; Schepp, N. P.; Walsh, P.
A. J. Phys. Chem. 1986, 90, 3760-3766. Chiang, Y.; Kresge, A. J.;
Santabella, J. A.; Wirz, J. J. Am. Chem. Soc. 1988, 110, 5506-5510.
(23) Kirby, A. J.; Meyer, G. J. Chem. Soc., Perkin Trans. II 1972, 1446-
1451.

11188 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Chiang et al.
Table 2. Summary of Rate and Equilibrium Constants for the
2-Ketocyclopentylideneketene and 2-Oxocyclopentanecarboxylic
Acid Systemsa
Figure 6. Spectrophotometric titration curve for the acid ionization
of 2-oxocyclopentanecarboxylic acid in aqueous solution at 25 °C.
Figure 7. Rate profile of the enolization of 2-oxocyclopentanecar-
boxylic acid in aqueous acid solutions at 25 °C.
order rate constants for the initial phase could consequently be
obtained. In sodium hydroxide solutions, on the other hand,
the initial phase was only about 5 times faster than the
subsequent phase, and separation of the two changes was more
difficult; first-order rate constants for the initial phase obtained
in these solutions were therefore less accurate. Such consump-
tion of additional amounts of halogen in enolization reaction
studies has been observed before24 and has been attributed to
subsequent hydrolysis and oxidation reactions of the initial
halogenated products;24a in the case of â-keto acids, such as
the present substrate, decarboxylation followed by additional
rapid halogenation is also known to occur.25
The enolization rate measurements in buffers, just like the
ketonization rate measurements, were performed in series of
solutions of constant buffer ratio but varying buffer concentra-
tion. Strong buffer catalysis was again found, with observed
rate constants conforming well to the linear rate law of eq 5.
Least-squares analysis gave intercepts of buffer dilution plots,
ks, which, together with the rate constants measured in hy-
drobromic acid solutions, are displayed in the rate profile of
Figure 7.
This enolization reaction can be expected to be the micro-
scopic reverse of the ketonization of 2-oxocyclopentanecar-
boxylic acid enol, which was assigned a mechanism in the region
of acidity of these enolization measurements involving rate-
determining proton transfer from a hydronium ion to the
â-carbon atom of the carboxylate-ion form of the enol, giving
un-ionized 2-oxocyclopentanecarboxylic acid and a water
molecule as reaction products (Vide supra). Enolization will
a Aqueous solution, 25 °C, ionic strength ) 0.10 M. b Error limits
are given in the text. c Concentration quotient at 0.10 M ionic strength.
in Table S812) describe the expected sigmoid titration curve.
Least-squares fitting of eq 3 gave the acidity constant Qa,K
)
(2.37 ( 0.26) × 10-4 M, pQa,K ) 3.63 ( 0.05;15 this result
agrees well with the acidity constant, pQa,K ) 3.68 ( 0.03,
obtained from the rate profile of enolization of 2-oxocyclopen-
tanecarboxylic acid (Vide infra).
Enolization. Rates of enolization of 2-oxocyclopentanecar-
boxylic acid were determined by bromine scavenging of the
enol as it formed. Measurements were made in hydrobromic
acid and sodium hydroxide solutions and also in acetic acid
buffers; the data obtained are summarized in Tables S9-S11.12
In all cases, an initial consumption of 1 equiv of bromine was
followed by a slower uptake of more halogen. In acidic
solutions, the initial phase was faster than the subsequent one
by well over an order of magnitude, and the two changes could
be easily separated by fitting either a double-exponential
expression or a single-exponential plus a straight line; good first-
(24) (a) Guthrie, J. P.; Cossar, J. Can. J. Chem. 1990, 68, 397-408.
Guthrie, J. P.; Cossar, J.; Lu, J. Can. J. Chem. 1991, 69, 1904-1908. (b)
Bell, R. P.; Page, M. I. J. Chem. Soc., Perkin Trans. II 1973, 1681-1686.
(25) Corey, E. J. J. Am. Chem. Soc. 1953, 75, 3297-3299.

Generation of Enol by Hydration of an Acylketene
J. Am. Chem. Soc., Vol. 119, No. 46, 1997 11189
because the microscopic reverse of this reaction, ketonization
in acetic acid buffers, showed only general acid catalysis (Vide
supra). Least-squares analysis gave the results kE
) (1.02
OAc-
( 0.10) × 10-1 M-1 s-1 and kEHOAc ) -(1.94 ( 7.89) × 10-1
M-1 s-1
.
Several measurements of the rate of bromination of 2-oxo-
cyclopentanecarboxylic acid were also made in D2O solutions
of DBr at an acid concentration of 0.10 M. The results,
summarized in Table S9,12 when combined with rate constants
obtained in H2O at the same acid concentration, give the isotope
effect kH O/kD O ) 1.82 ( 0.04. This isotope effect refers to
2
2
an acid concentration where the substrate is in its undissociated
carboxylic acid form and reaction occurs through proton removal
by a water molecule. Such a process, eq 17, would be expected
Figure 8. Relationship between buffer catalytic coefficients and the
fraction of buffer present as acid for the enolization of 2-oxocyclo-
pentanecarboxylic acid in aqueous acetic acid buffer solutions at 25
°C.
to show a solvent isotope effect in the normal direction (kH/kD
> 1) as the hydrogens of the attacking water molecule are
converted to the more loosely bound hydrogens of a hydronium
ion,27 and this isotope effect consequently offers additional
support for the identification of this process as an enolization
reaction.
therefore occur by rate-determining reaction of un-ionized
2-oxocyclopentanecarboxylic acid with a water molecule, giving
the horizontal plateau seen at the high acidity end of the rate
profile of Figure 7. The un-ionized acid, however, will also be
in equilibrium with its carboxylate ion, as shown in eq 15, and
Still further support is provided by a measurement of the rate
of deuterium incorporation into the R-position of 2-oxocyclo-
pentanecarboxylic acid made in a D2O solution of 0.10 M
DClO4. Loss of protium at this position was monitored by 1H
NMR using the six protons of the nonexchanging methylene
groups of the substrate as an integration standard. The data so
obtained conformed to the first-order rate law well, and least-
squares fitting gave the rate constant k ) (2.23 ( 0.18) × 10-2
s-1. This result is consistent with the bromination rate constant
obtained in D2O solution at the same acid concentration, k )
(3.13 ( 0.02) × 10-2 s-1, as it should inasmuch as enol
formation will be the rate-controlling stage of both bromination
and deuterium incorporation.
The less accurate rates of enolization measured in sodium
hydroxide solutions showed this reaction to be catalyzed by
hydroxide ion with rate constants a simple linear function of
hydroxide ion concentration. This is the expected result on the
basis of the mechanism assigned to the ketonization reaction in
this region, which consists of carbon protonation of the dianionic
form of the enol by solvent water, eq 18; the microscopic reverse
the need to convert this ion to un-ionized acid before enolization
can take place will give the acid-catalyzed region seen at the
low acidity end of the profile of Figure 7. The bend in the
profile connecting these two regions, of course, corresponds to
the ionization constant of the substrate acid.
The rate law that applies to this reaction scheme is shown in
eq 16,
E
ko [H+]
Qa,K + [H+]
kobs
)
(16)
whose rate and equilibrium constants are defined in eq 15. Least-
squares analysis of the data using this equation gave koE ) (5.25
( 0.14) × 10-2 s-1 and Qa,K ) (2.07 ( 0.13) × 10-4 M, pQa,K
) 3.68 ( 0.03.15 These results are nicely consistent with
determinations recently made in another laboratory,26 and the
rate constants also agree well with k ) 5.2 × 10-2 s-1 reported
before for the enolization of 2-oxocyclopentanecarboxylic acid
on the basis of more limited measurements made in 0.1 and
0.01 M HCl.24b The equilibrium constant also agrees well with
the acidity constant of 2-oxocyclopentanecarboxylic acid de-
termined directly by spectrophotometric titration, pQa,K ) 3.63
( 0.05 (Vide supra); the weighted average of these two results
gives Qa,K ) (2.13 ( 0.12) × 10-4 M, pQa,K ) 3.67 ( 0.02,15
as the best value of this acidity constant.
The enolization rate measurements in acetic acid buffer
solutions were performed at acidities where the substrate existed
in both undissociated carboxylic-acid and dissociated carboxy-
late-ion forms, and slopes of buffer dilution plots were
consequently converted to buffer catalytic coefficients for the
undissociated carboxylic-acid form by applying the analog of
eq 13. As Figure 8 demonstrates, the values of kcat so obtained
represent general base catalysis alone, with no contribution from
general acid catalysis. This, of course, is the expected result
of this process is removal of a carbon-bound proton from the
carboxylate form of the keto substrate by hydroxide ion, a
process whose rate of reaction will be directly proportional to
hydroxide ion concentration. Least-squares analysis of the data
-
gave the hydroxide-ion catalytic coefficient kHO ) 6.28 ( 0.28
M-1 s-1
.
Keto-Enol Equilibria. The enolization and ketonization
rate constants determined here may be combined to provide
values of keto-enol equilibrium constants for 2-oxocyclopen-
tanecarboxylic acid. Because of the presence of the carboxylic
acid group in this system, two such equilibrium constants can
be defined, one, KE, relating keto and enol forms with the
(27) Kresge, A. J.; More O’Ferrall, R. A.; Powell, M. F. In Isotopes in
Organic Chemistry; Buncel, E., Lee, C. C., Eds.; Elsevier: Amsterdam,
1987; Vol. 7, pp 177-273.
(26) Tee, O. S. Unpublished work.

11190 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Chiang et al.
carboxylic acid group un-ionized and another, K′E, with this
group ionized.
The first of these equilibria may be formulated as shown in
eq 19, using hydronium ion and water as the catalysts to effect
(24)
K′E ) kE -Q /(k′′ QE )
(25)
HO
w
o
a
where Qw is the acid ionization constant of water, and use of
the relevant data gives K′E ) (5.24 ( 0.56) × 10-4, pK′E )
3.28 ( 0.05. This result is broadly consistent with the value
obtained from the thermodynamic cycle. The fact that it is a
factor of 2 less, however, reflects the difficulty of obtaining an
the keto-enol isomerization. The equilibrium constant for this
reaction may be expressed as shown in eq 20, and use of the
accurate value of kE
(Vide supra), and the result from the
thermodynamic cycle is consequently to be preferred.
KE ) kE /(k′H+Q
)
a,E
(20)
HO-
o
values of kE ,k′H , and Qa,E determined here gives KE ) (3.13
These keto-enol equilibrium constants are much greater than
those for most simple ketones without carboxylic acid or
carboxylate ion substituents; for example, pKE ) 7.94 for
cyclopentanone itself.28 The relatively high enol contents found
here are in fact typical of â-dicarbonyl compounds in general,
where their magnitude is usually attributed to stabilization of
the enol isomer by intramolecular hydrogen bonding. A similar
explanation may be applied here, but that cannot be the entire
story because such an intramolecular hydrogen bond should be
stronger and therefore more stabilizing in the carboxylate ion
11 than in the carboxylic acid 12, and yet the enol content of
+
o
( 0.28) × 10-3, pKE ) 2.51 ( 0.04. Another estimate of KE
may also be made using acetic acid and acetate ion to effect
the interconversion, as shown in eqs 21 and 22,
KE ) kE -Qa,HOAc/(k′HOAcQa,E
)
(22)
OAc
and use of the appropriate data gives KE ) (2.98 ( 0.36) ×
10-3, pKE ) 2.53 ( 0.05, in very good agreement with the
previous value. The weighted average of these two results gives
KE ) (3.07 ( 0.22) × 10-3, pKE ) 2.51 ( 0.03, as the best
value of this keto-enol equilibrium constant.
Since the acidity constants of the carboxylic acid groups of
the keto and enol isomers in this system have both been
determined here, the thermodynamic cycle shown in eq 23 can
the carboxylate ion (pK′E ) 3.00) is less than that of the
carboxylic acid (pKE ) 2.51). Some other effect must also be
operating. A likely candidate is conjugative stabilization of the
carboxylic acid enol by electron release from the hydroxyl group
as shown in resonance structure 13; the analogous structure in
the case of the carboxylate ion enol 14 will be less stabilizing
because it puts negative charge onto an already negatively
charged group.
Acknowledgment. We are grateful to Professor O. S. Tee
for communicating to us his unpublished data on the enolization
of 2-oxocyclopentanecarboxylic acid and to the Natural Sciences
and Engineering Research Council of Canada and the United
States National Institutes of Health for financial support of this
work.
be set up and the relationship pK′E ) pKE + pQa,E - pQa,K
may be used to give K′E ) (1.00 ( 0.11) × 10-3, pK′E ) 3.00
( 0.05. Another estimate of this constant may also be obtained
using kinetic data determined in basic solution where hydroxide
ion and water are the keto-enol-interconverting catalytic pair.
The equilibrium there may be formulated as shown in eqs 24
and 25,
Supporting Information Available: Tables S1-S11 of rate
and equilibrium data (16 pages). See any current masthead page
for ordering information and Internet access instructions.
JA9704390
(28) Keeffe, J. R.; Kresge, A. J.; Schepp. N. P. J. Am. Chem. Soc. 1990,
112, 4862-4868.