The 4,4,4-trifluoroacetoacetic acid keto-enol system in aqueous solution. Generation of the enol by hydration of trifluoroacetylketene

Article abstract of DOI:10.1021/ja991561x

Trifluoroacetylketene was generated in aqueous solution by flash photolysis of 2,2-dimethyl-6-trifluoromethyl-4H-1,3-dioxin-4-one and its spiro analogue, 4-trifluoromethyl-1,5-dioxaspiro[5.5]undec-3-en-2-one, and rates of hydration of the ketene to 4,4,4-trifluoroacetoacetic acid enol as well as subsequent ketonization of the enol were measured in this solvent across the acidity range [H⁺] = 10^-1-10^-12 M. Analysis of the rate profile produced by these data provides the acidity constants pQ_a,E = 1.85 for the carboxylic acid group of the enol and pQ^E_a = 9.95 for its enolic hydroxyl group, which make these groups 2 and 3 orders of magnitude more acidic, respectively, than the corresponding groups in the parent unfluorinated acetoacetic acid enol. Rates of enolization of the keto group of 4,4,4-trifluoroacetoacetic acid were also measured, by bromine scavenging, and these, together with a value of the equilibrium constant for hydration of the keto group to its gem-diol derivative based upon a free energy relationship, K_h = 2900, provide an estimate of the keto-enol equilibrium constant for this system: pK_E = 0.28. This is greater, by 2 orders of magnitude, than the keto-enol equilibrium constant for the unfluorinated acetoacetic acid.

Full text of DOI:10.1021/ja991561x

J. Am. Chem. Soc. 1999, 121, 8345-8351
8345
The 4,4,4-Trifluoroacetoacetic Acid Keto-Enol System in Aqueous
Solution. Generation of the Enol by Hydration of
Trifluoroacetylketene
Y. Chiang,† A. J. Kresge,*,† Q. Meng,† Y. Morita,‡ and Y. Yamamoto‡
Contribution from the Department of Chemistry, UniVersity of Toronto, Toronto, Ontario M5S 3H6,
Canada, and The Tohoku College of Pharmacy, Sendai 981, Japan
ReceiVed May 10, 1999. ReVised Manuscript ReceiVed July 6, 1999
Abstract: Trifluoroacetylketene was generated in aqueous solution by flash photolysis of 2,2-dimethyl-6-
trifluoromethyl-4H-1,3-dioxin-4-one and its spiro analogue, 4-trifluoromethyl-1,5-dioxaspiro[5.5]undec-3-en-
2-one, and rates of hydration of the ketene to 4,4,4-trifluoroacetoacetic acid enol as well as subsequent
ketonization of the enol were measured in this solvent across the acidity range [H+] ) 10-1-10-12 M. Analysis
of the rate profile produced by these data provides the acidity constants pQa,E ) 1.85 for the carboxylic acid
group of the enol and pQEa ) 9.95 for its enolic hydroxyl group, which make these groups 2 and 3 orders of
magnitude more acidic, respectively, than the corresponding groups in the parent unfluorinated acetoacetic
acid enol. Rates of enolization of the keto group of 4,4,4-trifluoroacetoacetic acid were also measured, by
bromine scavenging, and these, together with a value of the equilibrium constant for hydration of the keto
group to its gem-diol derivative based upon a free energy relationship, Kh ) 2900, provide an estimate of the
keto-enol equilibrium constant for this system: pKE ) 0.28. This is greater, by 2 orders of magnitude, than
the keto-enol equilibrium constant for the unfluorinated acetoacetic acid.
There is a large body of information on keto-enol tautom-
erism of â-ketoesters, gathered over the course of more than a
century.1 In striking contrast, few investigations of tautomerism
of â-ketoacids have been performed. We recently carried out
detailed studies of the acetoacetic acid (1)2 and the 2-oxocy-
clopentanecarboxylic acid (2)3 keto-enol systems, and we now
add to that an examination of the enol of 4,4,4-trifluoroaceto-
acetic acid (3).
acetoacetic acid exits as the ketone hydrate, 6, in aqueous
solution, the anhydrous acid tautomerizes to substantial amounts
of enol in organic solvents such as acetonitrile or tetrahydro-
furan; we consequently used such solutions as sources of the
enol as well.
Whereas our earlier work showed that rate and equilibrium
constants for interconversion of the various species involved
were much the same for the acetoacetic acid and 2-oxocyclo-
pentanecarboxylic acid systems, introduction of a trifluoromethyl
group has now provided some interesting differences. The rate
and equilibrium constants are summarized in Table 1.
We generated this enol, as we did the enol of acetoacetic
acid,2 by flash photolytic retro-[2 + 4]-cycloaddition of ap-
propriate dioxinones, using in this case 2,2-dimethyl-6-trifluo-
romethyl-4H-1,3-dioxin-4-one (4) and its spiro analogue, 4-tri-
fluoromethyl-1,5-dioxaspiro[5.5]undec-3-en-2-one (5) as the
photolysis substrates. Photocleavage of dioxinones is known to
produce acylketenes,4 which, in aqueous solution, are rapidly
hydrated to enols. We also found that, whereas 4,4,4-trifluoro-
Experimental Section
Materials. 4,4,4-Trifluoroacetoacetic acid was prepared by acid-
catalyzed hydrolysis of the ethyl ester;5 this produced the hydrate, which
was converted to anhydrous trifluroacetoacetic acid by sublimation
under reduced pressure. 2,2-Dimethyl-6-trifluoromethyl-4H-1,3-dioxin-
4-one was a sample prepared in a previous study,6 and 4-trifluoromethyl-
1,5-dioxaspiro[5.5]undec-3-en-2-one was made by an analogous method;
its properties were consistent with a literature description.7 All other
materials were best available commercial grades.
† University of Toronto.
‡ Tohoku College of Pharmacy.
(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 Chemsitry 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) Chiang, Y.; Kresge, A. J.; Nikolaev, V. A.; Popik, V. V. J. Am. Chem.
Soc. 1997, 119, 11183-11190.
(4) Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis 1994, 1219-
1248. Tidwell, T. T. Ketenes; John Wiley & Sons: New York, 1995; pp
125-128.
Kinetics. Flash photolytic rate measurements were made using
conventional flash lamp and laser systems (λexc ) 248 nm) that have
already been described.8 Substrate concentrations were of the order of
(5) Swarts, F. Bull. Sci. Acad. R. Belg. 1926, 12, 721-725.
(6) Morita, Y.; Kamakura, R.; Takeda, M.; Yamamoto, Y. J. Chem. Soc.,
Chem. Commun. 1997, 359-360.
(7) Iwaoka, T.; Murohashi, T.; Sato, M.; Kaneko, C. Synthesis 1992,
977-981.
10.1021/ja991561x CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/25/1999

8346 J. Am. Chem. Soc., Vol. 121, No. 36, 1999
Table 1. Summary of Rate and Equilibrium Constantsa
Chiang et al.
6 × 10-5 M, and reactions were monitored by following the rise and
decay of enol absorbance at λ ) 260-270 nm. Some reaction rates
were too slow to be determined well in even the conventional flash
photolysis system, and these measurements were consequently made
with a Cary 2200 spectrometer, using reaction mixtures in which
dioxinones had been activated by a single flash from the conventional
system, or reaction mixtures in which enol was supplied from a
tetrahydrofuran stock solution made using anhydrous trifluoroacetoace-
tic acid.
Rates of enolization of trifluoroacetoacetic acid were determined
using bromine to scavenge the enol as it formed. These measurements
were made in hydrobromic acid solutions, where bromine exists as the
tribromide ion, and reactions were followed by monitoring the
absorbance of this ion at λ ) 310 nm. Stoichiometric bromine
concentrations in the reaction mixtures were ca. 1 × 10-4 M, and
trifluoroacetoacetic acid concentrations were ca. 8 × 10-5 M.
The temperature of all reaction mixtures used for rate measurements
was controlled at 25.0 ( 0.05 °C. The rate data conformed to the first-
order rate law well, and observed rate constants were obtained by least-
squares fitting of exponential functions.
Results
Flash photolysis of the dioxinone substrates 4 and 5 in
aqueous solution produced a rapid, microsecond rise in absor-
bance at λ ) 260-270 nm, followed by a much slower decay.
These changes were assigned, on the basis of analogy with the
acetoacetic acid system where similar absorbance changes were
observed,2 to formation of trifluoroacetoacetic acid enol (8) by
hydration of trifluoroacetylketene (7), itself formed within the
time of the laser flash; this was then followed by subsequent
ketonization of the enol to trifluoroacetoacetic acid (9), eq 1.
This assignment is also supported by the response of these
absorbance changes to acid-base catalysis and to changes in
the isotopic composition of the solvent (vide infra).
Rates of decay of the enol were the same for this species
produced from the dimethyldioxinone 4 as for that produced
from the spirodioxinone 5. This is illustrated in Figure 1, where
rates of ketonization in perchloric acid solution are compared.
At these acidities, the enol exists in both un-ionized carboxylic
acid (8) and ionized carboxylate ion (10) forms, eq 2, but
ketonization occurs through the more reactive carboxylate form.
The rate law that applies to this reaction scheme is shown in
eq 3, where Qa,E is the ionization constant of the carboxylic
acid group and kKH is the rate constant for ketonization of the
+
carboxylate form catalyzed by the hydronium ion.
kobs ) kKH+Qa,E[H+]/(Qa,E + [H+])
(3)
Least-squares fitting of this expression gave kKH ) (7.42 (
+
0.16) × 102 M-1 s-1, Qa,E ) (1.46 ( 0.06) × 10-2 M 9 for
enol produced from the dimethyldioxinone and kKH+ ) (7.72 (
a Aqueous solution, 25 °C, ionic strength ) 0.10 M. Values in
(8) (a) Chiang, Y.; Hojatti, M.; Keefe, J. R.; Kresge, A. J.; Schepp, N.
P.; Wirz, J. J. Am. Chem. Soc. 1987, 109, 4000-4009. (b) Andraos, J.;
Chiang, Y.; Huang, C. G.; Kresge, A. J.; Scaiano, J. C. J. Am. Chem. Soc.
1993, 115, 10605-10610.
(9) This is a concentration ionization constant applicable at the ionic
strength (0.10 M) at which it was determined.
parentheses are estimates based upon hydration equilibrium constants,
Kh and K′, obtained using a free energy relationship; see text for
h
details. Acidity constants are concentration quotients at ionic strength
) 0.10 M. b Ratio of constant for 4,4,4-trifluoroacetoacetic acid system
to that for acetoacetic acid system.

The 4,4,4-Trifluoroacetoacetic Acid Keto-Enol System
J. Am. Chem. Soc., Vol. 121, No. 36, 1999 8347
Figure 3. Rate profiles for the hydration of trifluoroacetylketene (4)
and ketonization of 4,4,4-trifluoroacetoacetic acid enol (O).
Figure 1. Comparison of rates of ketonization of 4,4,4-trifluoro-
acetoacetic acid enol produced from dimethyldioxinone 4 (O and solid
line) and from spirodioxinone 5 (4 and broken line) in aqueous
perchloric acid solution at 25 °C.
M. This is characteristic of ketene hydration reactions, whose
rate profiles typically show extensive uncatalyzed regions: acid
catalysis is only rarely present, and base catalysis is usually
weak.2,3,8b,11 In the present case, the dioxinone substrates were
unstable in base and decomposed rapidly in sodium hydroxide
solutions more concentrated than ca. 0.01 M, further precluding
observation of base catalysis. Some measurements of ketene
hydration were also made in D2O solutions of perchloric acid
and in D2O with no acid or base added as well. These data are
summarized in Tables S1 and S3.10 The average value of the
rate constants so obtained, when combined with the H2O
counterpart, k ) (1.75 ( 0.30) × 106 s-1, gives the isotope
effect k(H2O)/k(D2O) ) 0.88 ( 0.02. Near-unity values of
isotope effects such as this are also characteristic of uncatalyzed
ketene hydrations,2,3,8b,11 as expected for a reaction that occurs
by nucleophilic attack of water on the ketene carbonyl carbon
atom in a process that involves no making or breaking of bonds
to hydrogen.12
Figure 2. Comparison of rates of ketonization of 4,4,4-trifluoro-
acetoacetic acid enol derived from dimethyldioxinone 4 (O and solid
line) and from the anhydrous acid (4 and broken line) in aqueous (CH2-
Enol Ketonization. Rates of ketonization of 4,4,4-trifluoro-
acetoacetic acid enol were measured in aqueous perchloric acid
and sodium hydroxide solutions. Acid and base concentrations
were varied, [HClO4] ) 0.001-0.1 M and [NaOH] ) 0.0006-
0.01 M, and replicate measurements were made at each
concentration; ionic strength was maintained constant at 0.10
M. The data so obtained are summarized in Tables S4 and S5.10
Rate measurements were also made in aqueous HCO2H, CH3-
+
OH)3CNH3 buffer solutions at 25 °C.
0.23) × 102 M-1 s-1, Qa,E ) (1.27 ( 0.09) × 10-2 M 9 for
enol produced from the spirodioxinone.
Rates of ketonization of enol produced by photolysis of the
dioxinones were also the same as those for enol obtained from
an equilibrated tetrahydrofuran stock solution made using
anhydrous trifluoroacetoacetic acid. This is illustrated in Figure
+
CO2H, H2PO4-, (CH2OH)3CNH3+, and NH4 buffers. Series
of buffer solutions of constant buffer ratio and constant ionic
strength (0.10 M) but varying total buffer concentration were
used. These data are summarized in Table S6.10
Strong buffer catalysis was found, with observed rate
constants increasing in the expected linear fashion with increas-
ing buffer concentration. The data were therefore analyzed by
least-squares fitting of eq 4. The zero-buffer-concentration
intercepts, ko, obtained in this way, together with rate constants
measured in perchloric acid and sodium hydroxide solutions,
+
2, where rates measured in (CH2OH)3CNH3 buffers are
compared. Linear least-squares analysis of these data gave kobs
/
s-1 ) (4.92 ( 0.68) × 10-3 + (3.82 ( 0.06)[buffer] for enol
from the dimethyldioxinone and kobs/s-1 ) (5.03 ( 0.85) ×10-3
+ (3.98 ( 0.08)[buffer] for enol from the acid.
Ketene Hydration. Rates of hydration of trifluoroacetylketene
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, [HClO4] ) 0.001-0.1 M
and [NaOH] ) 0.002-0.02 M, and replicate measurements were
made at each concentration. The ionic strength was held constant
at 0.10 M. The data so obtained are summarized in Tables S1-
S310 and are also displayed as the upper rate profile of Figure
3.
(11) (a) Allen, A. D.; Kresge, A. J.; Schepp, N. P.; Tidwell, T. T. Can.
J. Chem. 1987, 65, 1719. Allen, A. D.; Stevenson, A.; Tidwell, T. T. J.
Org. Chem. 1989, 54, 2843-2848. Tidwell, T. T. Acc. Chem. Res. 1990,
23, 273-279. Allen, A. D.; Baigre, L. M.; Gong, L.; Tidwell, T. T. Can.
J. Chem. 1991, 69, 138-145. (b) Andraos, J.; Kresge, A. J. J. Photochem.
Photobiol. A 1991, 57, 165-173. (c) Andraos, J.; Kresge, A. J.; Schepp,
N. P. Can. J. Chem. 1995, 75, 539-543. Chiang, Y.; Kresge, A. J.; Popik,
V. V. J. Am. Chem. Soc. 1995, 117, 9165-9171.
It may be seen that the rates measured remain constant
throughout the range of acidity examined, [H+] ) 10-1-10-12
(12) 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.
(10) Supporting Information; see paragraph at the end of this paper
regarding availability.

8348 J. Am. Chem. Soc., Vol. 121, No. 36, 1999
kobs ) ko + kbuff[buffer]
Chiang et al.
The two diagonal parts of this rate profile are connected by
another horizontal segment whose molecular interpretation is
less straightforward: this portion could be due to reaction of
the monoanion with H2O, or it could be caused by ionization
of the monoanion to dianion followed by reaction of that with
H+. An argument suggesting a choice between these possibilities
is presented below.
(4)
were used to construct the lower rate profile shown in Figure
3. Hydronium ion concentrations of 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.13
This rate profile is similar to those found for ketonization of
the enols of acetoacetic acid2 and 2-oxocyclopentanecarboxylic
acid,3 and it may be interpreted in the same way as those rate
profiles were, using the reaction scheme of eq 5. Downward
The rate law that applies to this reaction scheme is shown in
eq 6, in which kuc represents the mechanistically ambiguous
kKH+Qa,E[H+]
Qa,E + [H+]
k′Ko QEa
kobs
)
+ kuc
+
(6)
QEa + [H+]
middle portion of the rate profile and the other constants are as
defined by eq 5. Least-squares fitting of this expression produced
the following results: kKH+ ) (7.44 ( 0.20) × 102 M-1 s-1, kuc
) (2.12 ( 0.12) ×10-3 s-1, k′oK ) (3.20 ( 0.12) × 10-2 s-1
,
Qa,E ) (1.42 ( 0.08) × 10-2 M, pQa,E ) 1.85 ( 0.02,9 and QEa
) (1.13 ( 0.16) ×10-10 M, pQaE ) 9.95 ( 0.06.9
Interpretation of the horizontal middle portion of the rate
profile as representing ionization of monoanion to dianion
followed by reaction of the latter with H+ requires kuc to be
bends in rate profiles such as those found here at [H+] = 10-2
and [H+] = 10-10 M are commonly produced by ionization of
acidic groups in the substrate,14 and the present bends may be
attributed to ionization of the carboxylic acid and enolic
hydroxyl groups of the enol. Ketonization of enols is known to
occur by rate-determining protonation of the enol on its â-carbon
atom,15 and, since this profile represents reaction through
solvent-related species, protonation will take place by proton
transfer either from the hydronium ion, represented here by H+,
or from H2O. Moreover, since 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
forms. The short horizontal, “uncatalyzed” portion of this rate
profile at acidities above the first bend then represents keton-
ization through protonation on carbon by H+ of the ionized
carboxylate form of the substrate, when un-ionized carboxylic
acid is still the dominant substrate form: this reaction first
generates H+ in a fast equilibrium ionization and then uses it
up in the rate-determining step, producing an overall process
whose rate is independent of [H+]. At acidities below the first
bend, on the other hand, carboxylate ion is the principal substrate
form, and carbon protonation of this substance by H+ becomes
an acid-catalyzed process with rate proportional to [H+], which
produces a diagonal rate profile segment with slope ) -1.
At lower acidities, with [H+] < 10-8 M, the dianion becomes
the reactive form, but now [H+] is too low for H+ to be an
effective protonating agent, and H2O takes over the role of
proton donor. This produces a diagonal segment with slope )
+1 at acidities above the second bend, where the monoanion is
still the dominant substrate form: equilibrium ionization of the
second acidic (enolic) group to provide the reactive dianion
generates H+; this, however, is not used up in the rate-
determining step, and that gives an overall process whose rate
is inversely proportional to [H+], or directly proportional to
[HO-], producing an apparent hydroxide ion catalysis. At
acidities below the second bend, the dianion is the principal
substrate form, and reaction of this with H2O gives another
horizontal “uncatalyzed” profile segment.
equal to k′KH+ QE, and k′K can consequently be evaluated as
+
H
a
kuc/QE. In the case of acetoacetic acid enol, that gave the
a
improbably large rate constant k′KH ) 3 × 1011 M-1 s-1,2 and
+
this molecular interpretation was consequently rejected. The
present results, on the other hand, give the perfectly acceptable
value k′KH ) (1.88 ( 0.29) × 107 M-1 s-1, and a mechanistic
+
choice can therefore not be made here on the basis of the
magnitude of this rate constant. The alternative explanation,
however, i.e., carbon protonation of the monoanionic form of
the substrate by H2O with kuc ) kKo , leads to the improbably
low rate ratio, k′oK/kKo ) (3.20 × 10-2)/(2.12 × 10-3) ) 15.1,
for protonation of enolate ion and enol by H2O. In a number of
simple enol systems, ionization of the enol to enolate ion was
found to increase the rate of ketonization catalyzed by the same
acid by many orders of magnitude.16 For acetoacetic acid enol,
for example, this ratio is k′Ko /koK ) 5 × 104, and the reactivity-
selectivity principle leads to the expectation that this ratio should
be even greater for the present considerably less reactive system
(vide infra). Its small value thus suggests that this mechanistic
interpretation is not correct and that the other assignment, i.e.,
ionization of monoanion to dianion followed by protonation of
that by H+, is to be preferred. Such a stepwise mechanism has,
in fact, been assigned to this part of the rate profile for the
ketonization of simple enols on the basis of other evidence.16b
Additional support for the interpretation of the present rate
profile in terms of the ketonization reaction scheme of eq 5
comes from the form of buffer catalysis of these reactions. The
buffer catalytic coefficients, kbuff, of eq 4 can be separated into
their general acid, kHA, and general base, kB, components with
the aid of eq 7, in which fA is the fraction of buffer present in
the acid form. Application of this relationship gave kHA ) (3.53
kbuff ) kB + (kHA - kB)fA
(7)
( 0.60) × 10-1 M-1 s-1 and kB ) (1.20 ( 0.08) M-1 s-1 for
H2PO4- buffers and kHA ) (3.14 ( 4.95) × 10-1 M-1 s-1 and
+
kB ) (4.96 ( 0.29) M-1 s-1 for (CH2OH)3CNH3 buffers,
showing both general acid and general base catalysis in the more
acidic H2PO4- buffer solutions but only general base catalysis
(13) Bates, R. G. Determination of pH Theory and Practice; Wiley: New
York, 1973; p 49.
(14) Loudon, G. M. J. Chem. Educ. 1991, 68, 973-984.
(15) Keeffe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport,
Z., Ed.; Wiley: New York, 1990; Chapter 7.
(16) (a) Pruszynski, P.; Chiang, Y.; Kresge, A J.; Schepp, N. P.; Walsh,
P. A. J. Phys. Chem. 1986, 90, 3760-3766. (b) Chiang, Y.; Kresge, A. J.;
Santaballa, J. A.; Wirz, J. J. Am. Chem. Soc. 1988, 110, 5506-5510.

The 4,4,4-Trifluoroacetoacetic Acid Keto-Enol System
J. Am. Chem. Soc., Vol. 121, No. 36, 1999 8349
becomes an acid-catalyzed process with rate proportional to
[H+], giving a diagonal profile segment of slope ) -1.
Although enolization involves proton removal from the keto
isomer, it is unlikely that the initial state of the enolization
process is free ketoacid. Ketones with strongly electron-
withdrawing substituents, such as trifluoromethyl, are known
to form gem-diol hydrates,17 and trifluoroacetoacetic acid is a
deliquescent substance with a strong tendency to form a solid
hydrate.5 Ethyl trifluoroacetate exists mainly, and sometimes
even completely, as the hydrate in water-organic solvent
mixtures,18 and there is evidence that the hydration equilibrium
is set up rapidly relative to the rate of enolization.18a This
suggests that 4,4,4-trifluoroacetoacetic acid in aqueous solution
will exist in mobile equilibrium with its gem-diol hydrate and
that the latter will be the major species present. The enolization
process may, therefore, be formulated as shown in eq 8. The
Figure 4. Rate profile for the enolization of 4,4,4-trifluoroacetoacetic
acid in aqueous HBr solutions at 25 °C.
+
in the more basic (CH2OH)3CNH3 solutions. Ketonization,
rate law that applies to this reaction scheme is shown in eq 9.
being a reaction that occurs by rate-determining proton transfer
from catalyst to substrate, should, of course, show general acid
catalysis. In situations where the rate-determining step is
preceded by acid ionization of the substrate, however, such as
the present conversion of monoanionic to dianionic substrate
forms, the prior acid-base equilibrium will convert the general
acid catalysis of the rate-determining step into overall general
base catalysis. It is significant, therefore, that both general acid
and general base catalysis was observed in the more acidic
buffers, where our mechanistic interpretation has ketonization
occurring by rate-determining carbon protonation of the mono-
anion (general acid catalysis) plus ionization of that anion to
dianion, followed by rate-determining carbon protonation of that
species (general base catalysis), whereas only general base
catalysis was observed in the more basic buffers, where our
interpretation has only the latter mechanism operating.
Least-squares fitting of this expression gave kEo,h ) (1.91 (
0.06) × 10-3 s-1 and Qa,h ) (3.51 ( 0.28) × 10-4 M, pQa,h
)
3.45 ( 0.04.9
kobs ) kEo,h[H+]/(Qa,h + [H+])
(9)
Discussion
Equilibria. Keto-enol equilibrium constants can be evaluated
as ratios of enolization to ketonization rate constants: KE )
kE/kK, and we have employed this method to obtain values of
KE for the acetoacetic acid2 and 2-oxocyclopentanecarboxylic
acid3 systems. In the present case, because the rates of
enolization measured refer not to free ketone but rather to a
gem-diol hydrate initial state (vide supra), this technique leads
to hydrate-enol rather than keto-enol equilibrium constants.
Two such constants may be evaluated: KE,h for the equilibrium
involving un-ionized carboxylic acid groups shown in eq 10
and KE′ ,h for the equilibrium involving carboxylate ions shown
in eq 11. The first of these constants applies to the region of
Ketone Enolization. Rates of enolization of 4,4,4-trifluoro-
acetoacetic acid, monitored by bromine scavenging, were
measured in hydrobromic acid solutions over the concentration
range [HBr] ) 0.0001-0.01 M. A number of acid concentra-
tions were used, and replicate measurements were made at most
concentrations. The ionic strength of the reaction mixtures was
maintained at 0.10 M through the addition of NaBr. These data
are summarized in Table S710 and are displayed as the rate
profile of Figure 4.
This rate profile has a downward bend, which suggests that
the substrate is undergoing acid ionization in the range of acidity
used for these rate measurements. Since enolization, being a
proton removal process, puts negative charge on the substrate,
the ionized and already negatively charged form of the substrate
will be less reactive than the neutral un-ionized form. Enoliza-
tion, moreover, must be the microscopic reverse of ketonization,
which was assigned a mechanism in this range of acidity
consisting of rate-determining proton transfer from hydronium
ion to substrate, giving a water molecule as the conjugate base
reaction product; water will, therefore, be the proton removing
agent in the enolization process.
acidity represented by the first horizontal segments of the rate
profiles of Figures 3 and 4 and may be evaluated from data
obtained in this region as KE,h ) kEo,h/(kHK+Qa,E) ) (1.81 ( 0.09)
× 10-4, and the second applies to the region of acidity
represented by the diagonal segments immediately following
these horizontal portions and may be evaluated as K′
)
E,h
kEo,h/(Qa,hkK+) ) (7.31 ( 0.47) ×10-3
.
H
Both of these constants are small, and they indicate that enol
is only a minor species present to an extent of less than 1% in
aqueous solutions of 4,4,4-trifluoroacetoacetic acid. This may
appear to be at variance with reports that much greater amounts
of enol are found in equilibrated solutions of ethyl trifluoro-
At acidities above the bend in this rate profile, where the
substrate exists in its reactive un-ionized form, enolization will
consequently be a simple “uncatalyzed” reaction of substrate
with water, producing a horizontal profile segment. At acidities
below the bend, on the other hand, where the substrate is in its
less reactive ionized form, conversion of that to un-ionized acid
will first take place; this requires a proton, and the reaction thus
(17) Bell, R. P. AdV. Phys. Org. Chem. 1966, 4, 1-29.
(18) (a) Camps, F.; Coll, J.; Messeguer, A.; Roca, A. Tetrahedron 1977,
33, 1637-1640. (b) Fomin, A. N. J.; Saloutin, V. I.; Pashkevich, K. I.;
Bazhenov, D. V.; Grishin, Y. K.; Ustynyuk, Y. A. Bull. Acad. Sci. USSR
DiV. Chem. Sci. (Engl. Transl.) 1983, 32, 2361-2364.

8350 J. Am. Chem. Soc., Vol. 121, No. 36, 1999
Chiang et al.
acetoacetate in organic solvents.18a,19 These seemingly disparate
observations are reconcilable, however, if most of the system
in aqueous solution exists as hydrate, with both keto and enol
isomers only minor forms.
the present system, however, the trifluromethyl group is two
carbon atoms farther away from the carboxylic acid group than
it is in trifluoroacetic acid, and this will attenuate its acid-
strengthening influence on this group. The spatial relationship
of trifluoromethyl to enolic hydroxyl group, on the other hand,
is the same as it is to the hydroxyl group of trifluoroacetic acid,
but ionization of the enol puts negative charge into an already
negatively charged group, and that will oppose the acidifying
effect of trifluoromethyl and attenuate it once again.
Information regarding this question may be obtained by
converting the hydrate-enol equilibrium constants into keto-
enol equilibrium constants according to the relationships KE )
KE,hKh. The required hydration equilibrium constants, Kh, have
not been measured, but reliable estimates may be made using
the free energy relationship of eq 12,20 with values of σ* from
the compilation by Perrin, Dempsey, and Serjeant.21 This free
An acidity constant for the carboxylic acid group of the keto
form of trifluoroacetoacetic acid, Qa,K, may be obtained through
the thermodynamic cycle shown in eq 13, where Qa,K
)
Qa,hKh/K′h ) 3.04 × 10-2 M, pQa,K ) 1.52.9 This value is 75
pKh ) 2.81 - 1.70Σσ*
(12)
energy relationship, for example, predicts Kh ) 42 for 1,1,1-
trifluoroacetone, which agrees well with the measured value
Kh ) 35.22 Use of this relationship provides Kh ) 2900 for 4,4,4-
trifluoroacetoacteic acid and K′h ) 34 for its carboxylate ion,
and application of these results to the hydrate-enol equilibrium
constants gives KE ) 0.52 for the unionized acid and K′ )
E
0.25 for the carboxylate ion.
The near-unit values of these keto-enol equilibrium constants
indicate that the keto and enol isomers of 4,4,4-trifluoro-
acetoacetic acid are, indeed, of comparable stability in aqueous
solution, consistent with observations made for organic
solvents.18a,19 These results are also consistent with the fact that,
in the kinetics studies described above, we were able to make
stock solutions containing considerable amounts of enol by
dissolving the anhydrous acid in tetrahydrofuran.
Comparison of these results with those for the acetoacetic
acid system2 shows that the trifluoromethyl group increases enol
content appreciably, by a factor of 90 for the un-ionized acids
and by a factor of 200 for the carboxylate ions. These effects
are consistent with the strongly electron-withdrawing nature of
the trifluoromethyl groups, which will produce an unfavorable
interaction with the adjacent positive end of the carbonyl group
dipole of the keto isomer, destabilizing this form and thereby
bringing its energy closer to that of the enol isomer.
The trifluoromethyl substituent also has a strong effect on
the ionization of various acidic groups in the present system.
Comparison of the present results with those for the enol of
acetoacetic acid2 shows that trifluoromethyl increases the acidity
constant of the carboxylic acid group of the enol (Qa,E) by a
factor of 160 and that it increases the acidity constant of the
enolic hydroxyl group (QEa ) by a factor of 1700. Both of these
effects are in the expected direction, inasmuch as the electron-
withdrawing ability of trifluoromethyl will stabilize the anionic
products of these acid ioniziation reactions. Neither effect, on
the other hand, is as great as the factor of 37 000 provided by
comparison of the acidity constant of trifluoroacetic acid (11,
pKa ) 0.19)23 with that of acetic acid (12, pKa ) 4.76).24 In
times greater than Qa,K for acetoacetic acid,2 which is less than
the factor of 160 obtained above for the effect of trifluoromethyl
on the acidity of the carboxylic acid group of the enol (Qa,E).
This difference shows that the vinyl group separating trifluo-
romethyl and carboxyl in the enol is a better transmitter of
electrical effects than is the carbonyl plus methylene entity of
the keto form.
Kinetics. Acyl subsituents increase the reactivity of ketenes
markedly. For example, the uncatalyzed hydration of acetylketene
in aqueous solution is 42 000 times faster than the corresponding
reaction of ketene itself.2,11b This enhanced reactivity has been
explained in terms of a reaction mechanism involving nucleo-
philic attack of water on the carbon atom of the ketene carbonyl
group, which generates a negative charge on the substrate that
can be stabilized by an acyl substituent. This explanation,
however, is inconsistent with the present results for trifluoro-
acetylketene. A trifluoroacetyl group, because of the additional
electron-withdrawing effect of trifluoromethyl, should be sub-
stantially better than an acetyl group at stabilizing such negative
charge being generated on the substrate, but the present results
give a rate constant for reaction of trifluoroacetylketene with
water that is virtually the same as that for reaction of
acetylketene with water: ko(CF3COCdCdO)/ko(CH3COCdCd
O) ) 1.14.
The present results, on the other hand, may not be inconsistent
with another reaction mechanism, eq 14, involving a cyclic
transition state, in which proton transfer from water to the acyl
oxygen atom occurs at the same time as nucleophilic attack on
the ketene carbonyl atom is taking place. If proton transfer
CF3CO2H
CH3CO2H
11
12
(19) Filler, R.; Naqvi, S. M. J. Org. Chem. 1961, 26, 2571-2573. Burdett,
J. L.; Rogers, M. T. J. Am. Chem. Soc. 1964, 86, 2105-2109; J. Phys.
Chem. 1966, 70, 939-941.
(20) Greenzaid, P.; Luz, Z.; Samuel, D. J. Am. Chem. Soc. 1967, 89,
749-756.
offsets negative charge generation in such a transition state, then
trifluoroacetylketene and acetylketene might show similar
reaction rates. There is some additional evidence from theoretical
calculations,25 relative reactivities,26 and isotope effects2 to
(21) Perrin, D. D.; Dempsey, B.; Serjeant, E. P. pKa Predictions for
Organic Acids and Bases; Chapman and Hall: New York, 1981; pp 109-
126.
(22) Guthrie, J. P. Can. J. Chem. 1975, 53, 898-906.
(23) Milne, J. B.; Parker, T. J. J. Soln. Chem. 1981, 10, 479-487.
(24) Harned, H. S.; Ehlers, R. W. J. Am. Chem. Soc. 1933, 55, 652-
656.
(25) Birney, D. M.; Wagenseller, P. E. J. Am. Chem. Soc. 1994, 116,
6262-6270.

The 4,4,4-Trifluoroacetoacetic Acid Keto-Enol System
J. Am. Chem. Soc., Vol. 121, No. 36, 1999 8351
in its carboxylate form (kKH+ ratio) and by a factor of 28 000 for
proton transfer from a water molecule to â-carbon of the doubly
ionized enolate-carboxylate ion (k′Ko ratio); these rate retarda-
tions are also in keeping with the electron-withdrawing nature
of trifluorormethyl, which lowers the electron density of the
enolic vinyl group and makes it less susceptible to electrophilic
attack by acids.
support such a cyclic reaction mechanism. It is not clear,
however, that such a cyclic mechanism would give the weakly
inverse solvent isotope effect found for this reaction in this case
(vide supra).
In contrast to its negligible effect on the rate of ketene
hydration, trifluoromethyl does influence rates of enolization
and ketonization. The rate of enolization by proton transfer from
the keto form to a water molecule, kEo, is 86 times greater for
trifluoroacetoacetic acid than for acetoacetic acid, in keeping
with the electron-withdrawing and acid-strengthening effect of
trifluormethyl. Rates of ketonization, on the other hand, are
lowered by the trifluoromethyl group: by a factor of 170 for
proton transfer from the hydronium ion to â-carbon of the enol
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-S7 of rate
data (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(26) Leung-Toung, R.; Wentrup, C. Tetrahedron 1992, 36, 7641-7654.
Allen, A. D.; McAllister, M. A.; Tidwell, T. T. Tetrahedron Lett. 1993,
34, 1095-1096. Birney, D. M.; Xu, X.; Ham, S.; Huang, X. J. Org. Chem.
1997, 62, 7114-7120.
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