The 2-oxocyclohexanecarboxylic acid keto-enol system in aqueous solution

Article abstract of DOI:10.1021/ja030054j

Flash photolysis of 2-diazocycloheptane-1,3-dione or 2,2-dimethyl-5,6,7,8-tetrahydrobenzo-4H-1,3-dioxin-4-one in aqueous solution produced 2-oxocyclohexylideneketene, which underwent hydration to the enol of 2-oxocyclohexanecarboxylic acid, and the enol then isomerized to the keto form of the acid. Isomerization of the enol to keto forms was also observed using solid enol, a substance heretofore commonly believed to be the keto acid. Rates of ketonization were measured in perchloric acid, sodium hydroxide, and buffer solutions, and a ketonization rate profile was constructed. Rates of enolization of the keto acid were also measured using bromine to scavenge the enol as it formed. Rates of enolization and ketonization were then combined to provide the keto - enol equilibrium constant pK_E = 1.27. This and some of the other results obtained are different from the corresponding quantities for the 2-oxocyclopentanecarboxylic acid keto - enol system. These differences are discussed.

Full text of DOI:10.1021/ja030054j

Published on Web 05/02/2003
The 2-Oxocyclohexanecarboxylic Acid Keto-Enol System in
Aqueous Solution
J. A. Chang,† A. J. Kresge,*,† V. A. Nikolaev,‡ and V. V. Popik†
Contribution from the Department of Chemistry, UniVersity of Toronto,
Toronto, Ontario M5S 3H6, Canada, and Institute of Chemistry, St. Petersburg State UniVersity,
St. Petersburg 198904, Russia
Received January 27, 2003; Revised Manuscript Received March 18, 2003; E-mail: akresge@chem.utoronto.ca
Abstract: Flash photolysis of 2-diazocycloheptane-1,3-dione or 2,2-dimethyl-5,6,7,8-tetrahydrobenzo-4H-
1,3-dioxin-4-one in aqueous solution produced 2-oxocyclohexylideneketene, which underwent hydration
to the enol of 2-oxocyclohexanecarboxylic acid, and the enol then isomerized to the keto form of the acid.
Isomerization of the enol to keto forms was also observed using solid enol, a substance heretofore commonly
believed to be the keto acid. Rates of ketonization were measured in perchloric acid, sodium hydroxide,
and buffer solutions, and a ketonization rate profile was constructed. Rates of enolization of the keto acid
were also measured using bromine to scavenge the enol as it formed. Rates of enolization and ketonization
were then combined to provide the keto-enol equilibrium constant pKE ) 1.27. This and some of the other
results obtained are different from the corresponding quantities for the 2-oxocyclopentanecarboxylic acid
keto-enol system. These differences are discussed.
In striking contrast to â-keto esters, whose keto-enol
tautomerism has been investigated over the course of more than
a century and about which there is consequently an impressively
large body of information,1 little attention has been paid to keto-
enol tautomerism of the parent â-keto acids themselves. We
have recently reported detailed studies of the acetoacetic acid
(1),2 2-oxocyclopentanecarboxylic acid (2),3 and 4,4,4-trifluo-
roacetoacetic acid (3)4 keto-enol systems, and we now add to
that an examination of the 2-oxocyclohexanecarboxylic acid (4)
system. Our previous work showed strong similarities between
We began the present study by generating the enol, 6, as we
had before,2-4 through hydration of the corresponding ketocar-
bene, 5, eq 1, itself produced either by a photo-Wolff reaction
of 2-diazocycloheptane-1,3-dione, 7, eq 2, or by a photolytic
keto-enol tautomerism of acetoacetic acid and 2-oxocyclopen-
tanecarboxylic acid, but we now find interesting differences
between those systems and that of 2-oxocyclohexanecarboxylic
acid.
retro-[2+4]-cycloaddition reaction of 2,2-dimethyl-5,6,7,8-tet-
rahydrobenzo-4H-1,3-dioxin-4-one, 8, eq 3. Our initial work,
† University of Toronto.
‡ St. Petersburg State University.
(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.
however, raised the possibility that the solid material commonly
believed to be 2-oxocyclohexanecarboxylic acid is actually the
enol isomer. We therefore performed an X-ray diffraction
(3) Chiang, Y.; Kresge, A. J.; Nikolaev, V. A.; Popik, V. V. J. Am. Chem.
Soc. 1997, 119, 11183-11190.
(4) Chiang, Y.; Kresge, A. J.; Meng, Q.; Morita, Y.; Yamamoto, Y. J. Am.
Chem. Soc. 1999, 121, 8345-8351.
9
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J. AM. CHEM. SOC. 2003, 125, 6478-6484
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The 2-Oxocyclohexanecarboxylic Acid Keto−Enol System
A R T I C L E S
analysis on the solid and found that it is in fact the enol.5 We
consequently used this material directly for most of our
subsequent work.
Results and Discussion
Reaction Identification. Flash photolysis of aqueous solu-
tions of 2-diazocycloheptane-1,3-dione (7) or 2,2-dimethyl-
5,6,7,8-tetrahydrobenzo-4H-1,3-dioxin-4-one (8) produced a
rapid rise in absorbance in the region λ ) 270-290 nm followed
by a much slower decay. These absorbance changes are similar
to those found in our previous studies of â-oxocarboxylic keto-
enol systems2-4 and, by analogy with the previous work, may
be assigned to hydration of 2-oxocyclohexylideneketene (5),
giving the enol of 2-oxocyclohexanecarboxylic acid (6), fol-
lowed by ketonization of this enol to the acid itself, 4, eq 4.
Experimental Section
Materials. 2-Diazocycloheptane-1,3-dione (7) was prepared by diazo
group transfer from tosyl azide to cycloheptane-1,3-dione.6 A material
at first believed to be 2-oxocyclohexanecarboxylic acid (4) was prepared
by base-catalyzed hydrolysis of ethyl 2-oxocyclohexanecarboxylate;
this produced a solid, mp 82-83°, whose X-ray analysis showed it to
be the enol isomer (6) of 2-oxocyclohexanecarboxylic acid.5 2,2-
Dimethyl-5,6,7,8-tetrahydrobenzo-4H-1,3-dion-4-one (8) was prepared
from this enol plus acetone.7 All other materials were best available
commercial grades.
pKa Determination. The acidity constant of 2-oxocyclohexanecar-
boxylate ion ionizing further as a carbon acid was determined by
monitoring the reversible absorbance change at λ ) 276 nm that took
place as this reaction occurred. Absorbance measurements were made
using a Carey 2200 spectrometer whose cell compartment was
thermostated at 25.0 ( 0.05 °C.
This assignment is supported by the response of these absor-
bance changes to acid-base catalysis (vide infra).
Kinetics. Rates of hydration of 2-oxocyclohexylideneketene (5) were
measured using a nanosecond excimer laser flash photolysis system
operating at λ ) 248 nm that has already been described,8 and rates of
ketonization of the 2-oxocyclohexanecarboxylic acid enol (6) thus
produced were measured with a conventional microsecond (flash lamp)
flash photolysis system that has also already been described.9 The
temperature of the reacting solutions was maintained at 25.0 ( 0.05
°C, and photolysis substrate concentrations were of the order of 3 ×
10-5 M. Reactions were followed by monitoring absorbance changes
at λ ) 270-290 nm, and observed first-order rate constants were
calculated for the most part by least-squares fitting of an expontential
function. In some of the slower runs, however, instability of the
monitoring light source produced an absorbance drift, and a linear term
was consequently added to the exponential function. Rates of the very
slow reactions were measured by first generating the enol with a single
pulse from the conventional flash system and then quickly transferring
the ketonizing solution to a Cary 2200 spectrometer for reaction
monitoring with that instrument. Once again, the temperature of reacting
solutions was maintained at 25.0 ( 0.0 °C.
Ketene Hydration. Rates of hydration of 2-oxocyclohexy-
lideneketene, 5, were measured in dilute aqueous perchloric acid
and sodium hydroxide solutions and in biphosphate ion, tris-
(hydroxymethyl)methylammonium ion, and ammonium ion
buffers. The ionic strength of these solutions was maintained
at 0.10 M through addition of sodium perchlorate as required.
The ketene was generated by photo-Wolff reaction of diazo
compound 7 in the perchloric acid and buffer solutions. This
substrate, however, was unstable in sodium hydroxide solutions,
undergoing base-catalyzed ring cleavage,10 and dioxinone 8 was
therefore used as the flash photolytic substrate here instead.
Concordant results were obtained with the two substrates. The
data are summarized in Tables S1-S3.11
The rate measurements in buffers were performed in series
of solutions of constant buffer ratio and, because the ionic
strength was constant, also constant hydronium ion concentra-
tion, but varying buffer concentration. Observed first-order rate
constants proved to be linearly proportional to buffer concentra-
tion, and the data were therefore analyzed by linear least-squares
fitting of the buffer dilution expression shown as eq 5. The zero-
buffer-concentration intercepts, kint, obtained in this way,
Rates of ketonization in solutions prepared using solid enol were
also measured using the Cary spectrometer. Stock solutions of enol in
acetonitrile were prepared, and ketonizations were then initiated by
injecting a few microliters of these stock solutions into 3.0 mL of wholly
aqueous reaction mixtures. Some ketonization took place slowly in these
acetonitrile stock solutions, but useful amounts of enol still remained
even 1 day after preparation.
kobs ) kint + kbuff[buffer]
(5)
Rates of enolization were measured by bromine scavenging of the
enol as it formed. Bromine concentrations were in the range (4-100)
× 10-5 M, and substrate concentrations were in the range (3.5-12) ×
10-5 M, with bromine always in excess. The ionic strength of these
solutions was maintained at 0.10 M through the addition of sodium
bromide, and reactions were followed by monitoring the absorbance
change of tribromide ion at λ ) 310 nm. The temperature of reacting
solutions was again maintained at 25.0 ( 0.05 °C, and observed first-
order rate constants were calculated by least-squares fitting of an
exponential function.
together with the rate constants determined in perchloric acid
and sodium hydroxide solutions, are displayed as the upper
rate profile shown in Figure 1. Hydronium ion concentra-
tions of the buffer solutions needed for this purpose were
obtained by calculation using literature values of the buffer acid
acidity constants and activity coefficients recommended by
Bates.12
This rate profile shows no acid catalysis, a long uncatalyzed
portion, and weak hydroxide-ion catalysis. Such behavior is
typical of ketene hydration reactions, which commonly show
(5) Lough, A. J.; Kresge, A. J.; Zhu, Y. Acta Crystallogr. 2003, E59, σ344-
σ346.
(6) Cossy, J.; Belotti, D.; Thellend, A.; Pete, J. P. Synthesis 1988, 720-721.
Regitz, M.; Maas, G. Diazo Compounds Properties and Synthesis;
Academic Press: New York, 1986; Chapter 13.
(10) Regitz, M.; Maas, G. Diazo Compounds Properties and Synthesis; Academic
Press: New York, 1986; pp 511-512. Chiang, Y.; Kresge, A. J.; Zhu, Y.
ARKIVOC 2001, 2, 108-115.
(7) Sato, M.; Ogasawara, H.; Oi, K.; Kato, T. Chem. Pharm. Bull. 1983, 31,
1896-1901.
(8) Andraos, J.; Chiang, Y.; Huang, C. G.; Kresge, A. J.; Scaiano, J. C. J. Am.
Chem. Soc. 1993, 115, 10605-10610.
(11) Supporting Information; see paragraph at the end of this paper regarding
availability.
(9) Chiang, Y.; Hojatti, M.; Keeffe, J. R.; Kresge, A. J.; Schepp, N. P.; Wirz,
J. J. Am. Chem. Soc. 1987, 109, 4000-4009.
(12) Bates, R. G. Determination of pH Theory and Practice; Wiley: New York,
1973; p 49.
9
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A R T I C L E S
Chang et al.
solutions, are displayed as the lower rate profile of Figure 1.
Hydronium ion concentrations needed for this purpose were
again obtained by calculation using buffer acid acidity constants
from the literature and activity coefficients recommended by
Bates.12
This rate profile, like those for the ketonization of enols of
other â-oxocarboxylic acids,2-4 can be interpreted in terms of
the accepted reaction mechanism for enol ketonization involving
rate-determining protonation of the substrate on its â-carbon
atom.15 Because this profile refers to reaction through solvent-
related species, protonation will be either by the hydronium
ion, written here as H+, or by a water molecule, and, over the
acidity range represented by this profile, the enol will react
through either its monoanionic or its dianionic form, as shown
in eq 7.
Figure 1. Rate profiles for the hydration of 2-oxocyclohexylideneketene
(4) and the ketonization of 2-oxocyclohexanecarboxylic acid enol (O) in
aqueous solution at 25 °C.
large uncatalyzed regions with weak or nonexistent hydronium-
ion catalysis and somewhat stronger but still weak hydroxide-
ion catalysis.13 The present rate profile is similar to those found
before for ketenes whose hydrations produced the enols of
acetoacetic acid2 and 2-oxocyclopentanecarboxylic acid.3
Least-squares analysis using the simple rate law shown in
Because ketonization is an electrophilic addition reaction,
successively ionized forms of the enol will be more reactive
than their precursors, and ketonization will take place through
them even when they are relatively minor substrate species. This
produces a horizontal “uncatalyzed” rate profile segment at the
high acid end where reaction is through carbon protonation of
the enol carboxylate ion by H+, while un-ionized enol is still
the major substrate species. Such a reaction produces H+ in a
rapidly established preequilibrium and then uses it up in the
rate-determining step, giving an overall process independent of
H+ concentration.
eq 6 gave ko ) (3.45 ( 0.15) × 104 s-1 and kHO ) (1.08 (
-
kobs ) ko + kHO-[HO-]
(6)
0.03) × 107 M-1 s-1. These results show that the present ketene
is a rather reactive substance, consistent with the nucleophilic
nature of this reaction14 and the ability of the ketene’s â-carbonyl
group to stabilize the negative charge being generated on the
substrate in the reaction’s transition state.
As the acidity is lowered, this uncatalyzed ketonization gives
way to a reaction where H+ is still the protonating agent but
now the enol exists principally in its carboxylate ion form. This
produces a downward bend in the profile, corresponding to the
acid ionization constant Qa,E and leading to a diagonal acid-
catalyzed segment of slope ) -1. At sufficiently low acidity,
this acid catalysis gives way to a narrow second horizontal
plateau, whose origin, discussed below, is uncertain. Beyond
this plateau, ketonization takes place through the dianionic form
of the enol while its monoanion is still the dominant substrate
form, with water as the carbon-protonating agent. This gives a
preequilibrium which produces H+ that is now not used up in
the rate-determining step, giving a process whose rate is
inversely proportional to H+ concentration and having the
appearance of hydroxide-ion catalysis.
Enol Ketonization. Rates of decay of 2-oxocyclohexane-
carboxylic acid enol, 6, were measured in dilute aqueous
perchloric acid and sodium hydroxide solutions and in acetic
acid, biphosphate ion, tert-butylhydrogenphosphonate ion,
tris-(hydroxymethyl)methylammonium ion, ammonium ion,
and hydrogencarbonate ion buffers. The measurements in
perchloric acid were made using diazo compound and enol as
the substrate, those in sodium hydroxide using dioxinone and
enol as the substrate, and those in buffer using all three
substrates. Concordant results were once again obtained with
different substrates. The ionic strength of all solutions was
maintained at 0.10 M through the addition of sodium perchlorate
as required. The data thus obtained are summarized in Tables
S4-S6.11
The measurements in buffers were performed in series of
solutions of constant buffer ratio, and therefore constant
hydronium ion concentration, but varying total buffer concentra-
tion. Observed first-order rate constants were again linearly
dependent on buffer concentration, and the data were therefore
again analyzed by least-squares fitting of eq 5. The zero-buffer-
concentration intercepts obtained in this way, together with the
rate constants measured in perchloric acid and sodium hydroxide
In the rate profiles for ketonization of the enols of the previous
â-oxocarboxylic acids that we investigated, this apparent
hydroxide-ion catalysis became saturated and gave way to a
third horizontal plateau as the fully ionized enol became the
dominant substrate species.2-4 This did not happen in the present
E
case because the acidity constant of this enol, pQa ) 14.53
(vide infra) is well beyond the rate profile limit, p[H+] ) 12.80,
imposed by the requirement to keep ionic strength constant at
0.10 M.
(13) See, for example: Chiang, Y.; Kresge, A. J.; Popik, V. V. J. Am. Chem.
Soc. 1995, 117, 9165-9171.
(14) Tidwell, T. T. Acc. Chem. Res. 1990, 23, 273-279. Tidwell, T. T. Ketenes;
Wiley: New York, 1995; pp 576-585. Andraos, J.; Kresge, A. J. Can. J.
Chem. 2000, 78, 508-515.
(15) Keeffe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport, Z., Ed.;
Wiley: New York, 1990; Chapter 7.
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The 2-Oxocyclohexanecarboxylic Acid Keto−Enol System
A R T I C L E S
The rate law that corresponds to the reaction scheme of eq 7
is given as eq 8, with kuc as the rate constant for the process of
k′ +Qa,E[H+]
Qa,E + [H+]
H
kobs
)
+ k′ + k′ -[HO-]
(8)
uc
HO
uncertain origin responsible for the horizontal plateau at the
-
HO
center of the rate profile, k′
as the rate constant for the
apparent hydroxide-ion catalysis, and the other constants defined
by eq 7. Least-squares fitting of this expression gave k′H+
)
(1.35 ( 0.08) × 104 M-1 s-1, Qa,E ) (5.55 ( 0.39) × 10-5 M,
pQa,E ) 4.26 ( 0.03,16 kuc ) (2.32 ( 0.60) × 10-5 s-1, and
-
kH′ O (3.31 ( 0.07) M-1 s-1
.
It was pointed out above that the origin of the rate profile
plateau with rate constant kuc is uncertain. This is because it
could be due to ketonization of the monoanionic form of the
enol through carbon protonation by a water molecule or to
equilibrium ionization of the monoanion to dianion followed
by carbon protonation of that by H+. In the latter case, kuc
would be equal to k′′+ Q′E, and it is sometimes possible to
Figure 2. Rate profile for the enolization of 2-oxocyclohexanecarboxylic
acid in aqueous solution at 25 °C.
acid before enolization can take place will give the acid-
catalyzed profile region seen at the lower acidity end of the
profile of Figure 2. The bend in the profile connecting these
two regions, of course, corresponds to the ionization constant
of the substrate acid.
H
a
rule out this interpretation because the value of kH′′+ required
by this relationship is impossibly large. That, however, is
not the case here, for use of the estimate pQ′E ) 14.53 (vide
a
infra) leads to k′H′+ ) 7.9 × 109 M-1 s-1. This is a large rate
constant, but its value does not exceed the encounter-controlled
limit.
The rate law that fits this reaction scheme is shown in eq 10,
whose rate and equilibrium constants are defined in eq 9. Least-
kobs ) kEo[H+]/([H+] + Qa,K
)
(10)
Enolization. Rates of enolization of 2-oxocylcohexanecar-
boxylic acid were measured by bromine scavenging in aqueous
hydrobromic acid solutions and in acetic acid buffers. The ionic
strength of all solutions was maintained at 0.10 M through the
addition of sodium bromide as required. The data thus obtained
are summarized in Tables S7 and S8.11
The measurements in buffers were again made in series of
solutions of constant buffer ratio, and therefore constant H+
concentration, and observed first-order rate constants were found
to be linearly dependent upon buffer concentration. The data
were therefore analyzed by least-squares fitting of eq 5. The
buffer-independent rate constants, kint, thus obtained, together
with the rate constants measured in hydrobromic acid solution,
are displayed as the rate profile shown in Figure 2.
This enolization reaction is the microscopic reverse of the
ketonization of 2-oxocyclohexanecarboxylic acid enol, which
was assigned a reaction mechansim in the region of acidity of
these enolization rate measurements involving rate-determining
carbon protonation of the carboxylate-ion form of the enol by
H+, giving un-ionized 2-oxocyclohexanecarboxylic acid and a
water molecule as reaction products (vide supra). Enolization
will therefore occur by the rate-determining reaction of un-
ionized 2-oxoclohexanecarboxylic acid with a water molecule,
giving the horizontal “uncatalyzed” region seen at the high
acidity end of the rate profile of Figure 2. The un-ionized acid,
however, will also be in equilibrium with its carboxylate ion,
as shown in eq 9, and the need to convert this ion to un-ionized
squares analysis of the data using this expression gave kEo )
(3.79 ( 0.10) × 10-2 s-1 and Qa,K ) (2.91 ( 0.20) × 10-4 M,
pQa,K ) 3.54 ( 0.03.16 This rate constant is consistent with koE
) 1.34 × 10-2 M-1 s-1 reported for this reaction at 10 °C,17
and the acidity constant is in reasonable agreement with the
estimate pQa,K ) 3.24 that can be made using a σ-F correla-
tion.18
Keto-Enol Equilibria. The enolization and ketonization rate
constants determined here can be combined to provide keto-
enol equilibrium constants for the 2-oxocyclohexanecarboxylic
acid system (Table 1). Two such equilibrium constants may be
defined: one, KE, relating keto and enol isomers with the
carboxylic acid group in its un-ionized form and another, K′E,
with this group in its carboxylate ion form.
The first of these equilibria can be formulated as the ratio of
enolization to ketonization rate constants, as shown in eq 11,
using rate constants that refer to enolization in the “uncatalyzed”
K
KE ) kEo/ko
(11)
reaction region of the rate profile shown in Figure 2 and
ketonization in the corresponding region of the rate profile of
Figure 1. The rate profile of Figure 1, however, was constructed
using rates of decay of enol, which, because ketonization is
slightly reversible (KE ) 0.05; vide infra), are actually rates of
approach to equilibrium and contain a small (5%) enolization
component. The quantity k′ + Qa,E that represents the acid-
H
region plateau of the profile in Figure 1 must therefore be
(17) Cox, B. G.; Hutchinson, R. E. J. J. Chem. Soc., Perkin Trans. 2 1974,
613-616.
(18) Perrin, D. D.; Dempsey, B.; Serjeant, E. P. pKa Predictions for Organic
Acids and Bases; Chapman and Hall: New York, 1981; p 127.
(16) This is a concentration dissociation constant, applicable at ionic strength
) 0.10 M.
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A R T I C L E S
Chang et al.
Table 1. Summary of Rate and Equilibrium Constantsa
KEQa,E/Qa,K, with values of Qa,E and Qa,K obtained from rate
profile fittings, then leads to KE′ ) (1.02 ( 0.11) × 10-2, pK′
E
) 1.99 ( 0.05.
pKa Determination. The acidity constant of 2-oxocyclohex-
anecarboxylate ion ionizing further as a carbon acid, eq 13, was
determined spectrophotometrically by monitoring the reversible
UV absorbance change that accompanies this reaction. Measure-
ments were made in concentrated potassium hydroxide solutions
over the concentration range 1.5-17.3 M. The data thus
obtained are summarized in Table S9.11
These data were transformed into values of I ()[basic form]/
[acidic form]), and the fit of log I to different basicity functions
was examined. Three functions were tried: an H- scale based
on neutral indole indicators,19 an H) scale based on indoles
bearing carboxylate groups,19 and an H) scale based on aromatic
amines bearing carboxylate and sulfonate groups.20 The H- scale
based on indoles proved to be the most appropriate: it gave a
plot of log I versus H- whose slope was unity (0.96 ( 0.04),
whereas the other basicity functions produced slopes signifi-
cantly different from unity (0.85 ( 0.04 and 0.86 ( 0.04). The
data were therefore analyzed using the H- scale with the titration
curve expression of eq 14, in which 10(-H ) serves as a measure
-
of the basic strength of the solutions employed. Figure 3 shows
A ) (AAH10(-H ) + ABK′K)/(10(-H ) + K′K)
(14)
-
-
a
a
that the data conformed to this relationship well. Least-squares
analysis produced the result Ka′K ) (1.15 ( 0.08) × 10-17
,
pKa′K ) 16.94 ( 0.03.
Basicity functions such as the H- scale used here are anchored
to an infinitely dilute standard state, and the acidity constant
determined here is therefore a thermodynamic value applicable
at zero ionic strength. It may be converted into a concentration
dissociation constant appropriate to the ionic strength, 0.10 M,
used for the other measurements made here by application of
activity coefficients. Employment of f ) 0.8312 for the hydrogen
ion plus the acetate (f ) 0.775)12 and hydrogencitrate (f )
0.36)12 values as surrogates for the mono- and dianions of eq
13 then gives Q′K ) (2.98 ( 0.21) × 10-17, pQ′K ) 16.53 (
a Aqueous solution, 25 °C, ionic strength ) 0.10 M.
corrected by subtracting kEo to convert it into a pure ketoniza-
tion rate constant: kKo ) kH′ + Qa,E - kEo. Rates of enolization,
of course, require no correction because they were determined
by bromine scavenging under nonreversible conditions. The
rate and equilibrium constants determined here applied in this
way then lead to KE ) (5.34 ( 0.23) × 10-2, pKE ) 1.27 (
0.02.
a
a
0.03.16
The second keto-enol equilibrium constant, K′E, involving
carboxylate ion species, can be derived from KE using the
(19) Yagil, G. J. Phys. Chem. 1967, 71, 1034-1044.
(20) Halle, J.-C.; Terrier, F.; Schall, R. Bull. Soc. Chim. Fr. 1969, 4569-
thermodynamic cycle shown in eq 12. The relationship K′ )
4575.
E
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The 2-Oxocyclohexanecarboxylic Acid Keto−Enol System
A R T I C L E S
incompatibility of making measurements in this profile region
while maintaining an ionic strength of 0.10 M.
Comparison of Cyclohexyl and Cyclopentyl Systems. The
rates of hydration of 2-oxocyclohexylideneketene measured here
show this reaction to be significantly slower than hydration of
2-oxocyclopentylideneketene, by a factor of 41 for the uncata-
lyzed reaction and by a factor of 7 for the hydroxide-ion-
catalyzed process. This difference is consistent with the
nucleophilic character of these reactions, which occur by attack
of the nucleophile on the ketene carbonyl-group carbon atom
through approach in the ketene molecular plane:14 such an
approach is hindered in the cyclohexyl system but less so in
the cyclopentyl case. Cyclic ketenes can be expected to be
structurally similar to cyclic ketones, inasmuch as both have
exocyclic double bonds. In the most stable, chair conformation
of cyclohexanone, this double bond is eclipsed on both sides
by immediately adjacent carbon-hydrogen bonds,21 which
interfere with the in-plane approach of an external reagent to
the analogous ketene. In the favored half-chair conformation
of cyclopentanone, on the other hand, this eclipsing interaction
gives way to a more staggered arrangement,22 and an in-plane
approach to the analogous ketene is facilitated. It is significant,
moreover, that the difference between the cyclohexyl and
cyclopentyl system is greater for the slower uncatalyzed
hydration than for the faster hydroxide-ion-catalyzed process,
in keeping with the reactivity-selectivity principle.
Figure 3. Spectrophotometric titration curve for the carbon-acid ionization
of 2-oxocyclohexanecarboxylate ion in aqueous solution at 25 °C.
pQ′K and k′′ Determination. The thermodynamic cycle
a
o
given in eq 15 shows that Q′K ) K′ Q′E. This relationship then
a
E
a
The present results also show the keto-enol equilibrium
constants for the 2-oxocyclohexanecarboxylic acid system to
be greater than those for 2-oxocyclopentanecarboxylic acid, by
a factor of 17 for the reaction with the carboxylic acid groups
in their un-ionized form and by a factor of 10 for these groups
in their ionized carboxylate form. The direction of this difference
is the same as for the simple, uncarboxylated keto-enol systems,
where KE for cyclohexanone is 36 times that for cyclopen-
tanone.23 A ring-size effect in the same direction has also been
found for the keto-enol equilibria of 2-carbomethoxycycloal-
kanones.24
allows the enol acidity constant Qa′E to be determined from the
now known values of K′E and Q′K: Q′E ) Q′K/K′ ) (2.92 (
a
a
a
E
0.38) × 10-15 M, pQ′E ) 14.53 ( 0.06.16
a
It was pointed out above that values of this enol acidity
constant were obtained for other â-oxocarboxylic acid systems
from bends at the low acidity ends of their rate profiles. The
very low value of this acidity constant determined here for the
present system shows why such a rate-profile-derived determi-
nation could not be made in this case: the relevant bend would
have come well beyond the lowest acidity available, [H+] )
10-13 M, consistent with maintaining an ionic strength of 0.10
M.
Another interesting comparison for the 2-oxocyclohexan-
ecarboxylic acid and 2-oxocyclopentanecarboxylic acid systems
is provided by the acidity constants of the enol hydroxy groups
of the carboxylate ion forms of the substance, eq 17. These
This presently determined value of Q′E for the 2-oxocyclo-
a
hexanecarboxylic acid system can in turn be used to obtain a
value of the rate constant ko′′ for ketonization by the “uncata-
lyzed” route beyond the unobserved rate profile bend, that is,
through carbon protonation of the enol dianion by a water
molecule, as shown in eq 16. This rate constant is related to
acidity constants, with pQ′E ) 12.41 for n ) 33 and pQa′E
)
a
14.53 for n ) 4, differ by more than two pQ units. Both acids
are also considerably weaker than enols of simple monofunc-
tional aldehydes and ketenes, whose acidity constants tend to
lie in the range pQEa ) 10-11.25 This acid weakness may be
attributed to formation of a good hydrogen bond between the
hydroxyl and carboxylate groups in the initial state of the
(21) Eliel, E. L.; Wilen, S H. Stereochemistry of Organic Compounds; Wiley:
New York, 1994; p 733.
HO-
HO-
)
the hydroxide-ion catalytic coefficient of eq 8, k′ : k′
ko′′Q′E/Qw, and insertion of the known values of Q′E and the
(22) Giese, H. J.; Mijlhoff, F. C. Recl. TraV. Chim. Pays-Bas 1971, 90, 577-
a
a
583.
autoprotolysis constant of water, Qw, gives k′′ ) (1.80 ( 0.23)
o
(23) Keeffe, J. R.; Kresge, A. J.; Schepp, N. P. J. Am. Chem. Soc. 1990, 112,
4862-4868,
× 101 s-1. This result is considerably above the largest rate
constant measured at the low acidity end of the rate profile of
Figure 1, kobs ) 5 × 10-1 s-1, which again points to the
(24) Schwarzenbach, G.; Zimmerman, M.; Prelog, V. HelV. Chim. Acta 1951,
34, 1954-1957.
(25) Kresge, A. J. Acc. Chem. Res. 1990, 23, 43-48.
9
J. AM. CHEM. SOC. VOL. 125, NO. 21, 2003 6483

A R T I C L E S
Chang et al.
ionization reaction and electrostatic repulsion between the two
negative charges in the final state of this reaction; these effects
will stabilize the initial state and destabilize the final state,
increasing the energy difference between them and making the
acid weaker. The fact that the cyclohexyl enol is a weaker acid
than the cyclopentyl enol means that these effects must be
stronger in the cyclohexyl system than in the cyclopentyl system.
This is consistent with the fact that the exocyclic olefinic bonds
in cyclohexene26 are somewhat less splayed out than are the
corresponding bonds in cyclopentene.27 As a result, the hydrogen
bonding groups and the electrostatically repelling groups are
somewhat closer in the cyclohexyl system than in the cyclo-
pentyl system, giving cyclohexyl more initial state stabilization
and also more final state destabilization. The result is a
considerably less acidic cyclohexyl enol, as was observed.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for financial
support of this work.
Supporting Information Available: Tables S1-S9 of rate
and equilibrium data (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(26) Chiang, J. F.; Bauer, S. H. J. Am. Chem. Soc. 1969, 91, 1898-1901.
(27) Allen, W. D.; Csaszar, A. G.; Horner, D. A. J. Am. Chem. Soc. 1992, 114,
6834-6849.
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