2,4,6-Thrimethylthioacetophenone and its enol. The first quantitative characterization of a simple thiocarbonyl system in aqueous solution [18]

Full text of DOI:10.1021/ja9826993

11830
J. Am. Chem. Soc. 1998, 120, 11830-11831
Treatment of an equilibrated aqueous solution of this mixture
with Ellman’s reagent, a substance commonly used for quantita-
tive estimation of thiol groups,6 gave an instantaneous uptake of
some reagent followed by a slower consumption of an additional
amount, with the slower consumption reaching a limiting value
in an exponential fashion. The initial fast uptake may be attributed
to reaction of thioenol already present in the solution at equilib-
rium, and the subsequent slower consumption may be assigned
to formation of additional enol by isomerization of the keto form.
This shows that significant amounts of enol exist in equilibruim
with the keto isomer in aqueous solution. The amplitude of the
initial uptake, moreover, increased at the expense of the amplitude
of the slower consumption with increasing basicity of the medium.
This indicates further that more enol species (enol + enolate)
exist at equilibruium in the more basic solutions, and that the
keto isomer is undergoing appreciable ionization as a carbon acid
in the pH range investigated (pH 6-8).
2,4,6-Trimethylthioacetophenone and Its Enol. The
First Quantitative Characterization of a Simple
Thiocarbonyl System in Aqueous Solution
A. J. Kresge* and Q. Meng
Department of Chemistry, UniVersity of Toronto
Toronto, Ontario M5S 3H6, Canada
ReceiVed July 30, 1998
It is known that thiocarbonyl compounds have a much stronger
tendency to undergo tautomeric change to their enol isomers, eq
1, X ) S, than is the case in the corresponding oxygen systems,
This interpretation of these phenomena leads to eq 2 in which
eq 1, X ) O,1 and since thiols are stronger acids than alcohols,
thioenols are also expected to be more acidic than their oxygen
analogues. However, little quantitative information concerning
such differences for simple carbonyl systems is available.2 We
wish to report that we have now determined keto-enol equilib-
rium and acid dissociation constants, as well as rate constants
for interconversion of the various species, for 2,4,6-trimethyl-
thioacetophenone, 1, in aqueous solution. This is the first
[EH] + [E-]
amplitude of initial uptake
amplitude of subsequent uptake
) R )
(2)
[KH]
EH, E-, and KH represent enol, enolate, and keto forms,
respectively. Introducing definitions of the keto-enol equilibrium
constant, KE ) [EH]/[KH], and the ionization constant of the keto
form as a carbon acid, QaK ) [E-][H+]/[KH], then gives eq 3,
R ) KE + QaK/[H+]
(3)
which predicts that R should be a linear function of 1/[H+]. The
data obtained conformed to this relationship well, and least-
squares analysis produced the following results: KE ) (1.15 (
0.05) × 10-1, pKE ) 0.94 ( 0.02, and QaK ) (1.19 ( 0.05) ×
10-8 M, pQaK ) 7.93 ( 0.02.7 Use of the further relationship
QaE ) KE/QaK, in which QaE is the ionization constant of the enol
quantitative characterization of a simple thiocarbonyl system in
this solvent, and together with published information on the
oxygen analogue 2,4,6-trimethylacetophenone, 2,3 it provides the
first quantitative comparison of oxygen and sulfur carbonyls in
the same medium.
We initially sought to examine tert-butyl methyl thioketone,
3, but we soon discovered that this substance undergoes facile
hydrolysis in aqueous solution at rates comparable to those of
keto-enol interconversion. Since hydrolysis probably occurs
through nucleophilic attack of water at the thiocarbonyl carbon,
we reasoned that this complication might be removed by
introducing steric hindrance to such attack in a substrate such as
1 and that this substance would consequently be more amenable
to detailed study. That proved to be the case.
ionizing as a sulfur acid, also gives the additional result QaE
(1.03 ( 0.06) × 107 M, pQaE ) 6.99 ( 0.02.7
)
The UV spectrum of an equilibrated acidic aqueous solution
of the present ketone plus enol consists of end absorption with a
shoulder at λ = 225 nm, which shifts to λ = 250 nm when the
solution is made basic. This change may be attributed to
ionization of the enol. Absorbances measured at a constant total
substrate concentration in solutions of different acidity gave a
smooth titration curve governed by an apparent acid ionization
constant, Qaeq ) [E-][H+]/([E] + [K]), and the data obtained
produced the result Qaeq ) (8.98 ( 1.15) × 10-9 M, pQaeq
)
8.05 ( 0.06.7 This equilibrium constant may also be expressed
in terms of KE and QaK as Qaeq ) QaK/(1 + KE), and use of the
values of these constants obtained in the experiments described
above employing Ellman’s reagent gives Qaeq ) (1.07 ( 0.04)
× 10-8 M, pQaeq ) 7.97 ( 0.02.7 These two independent
determinations of Qaeq agree with one another very well, and that
lends confidence to our interpretation of the phenomena observed.
We also performed kinetic measurements of the rate of
approach to keto-enol equilibrium in the present system, using
perchloric acid, sodium hydroxide, and buffer solutions. The
experiments in buffers were done by using series of solutions
of constant buffer ratio but varying total buffer concentration,
and extrapolation of these data to zero buffer gave intercepts,
We prepared 2,4,6-trimethylthioacetophenone by treating the
oxygen ketone, 2, with Lawesson’s reagent.4 The product
obtained proved to be a mixture of keto and enol tautomers whose
1H NMR spectrum in CDCl3 solution indicated a keto-enol ratio
of 5:1.5
(1) See, for example: Duus, F. In ComprehensiVe Organic Chemistry;
Barton, D., Ollis, W. D., Eds.; Pergamon Press: New York, 1979; Vol. 3, pp
385-388.
(2) Some recent studies providing limited information are described in:
(a) Selzer, T.; Rappoport, Z. J. Org. Chem. 1996, 61, 5462-5467. (b) Chiang,
Y.; Kresge, A. J.; Schepp, N. P.; Popik, V. V.; Rappoport, Z.; Selzer, T. Can.
J. Chem. 1998, 76, 657-661.
(3) Kresge, A. J.; Schepp, N. P. J. Chem. Soc., Chem. Commun. 1989,
1548-1549.
(6) Ellman, G. L. Arch. Biochem. Biophys. 1959, 82, 70-77. Riddles, P.
W.; Blakeley, R. L.; Zerner, B. In Methods in Enzymology; Hirs, C. H. W.,
Timasheff, S. N., Eds.; Academic Press: New York, 1983; Vol, 91, pp 49-
60.
(7) This is a concentration equilibrium constant applicable at the ionic
strength of the present measurements, 0.10 M.
(4) Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-O. Bull.
Soc. Chim. Belg. 1978, 87, 223-228. Cava, M. P.; Levinson, M. I. Tetrahedron
1985, 41, 5061-5087.
(5) Satisfactory 13C NMR and high-resolution mass spectra were also
obtained.
10.1021/ja9826993 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/03/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 45, 1998 11831
Table 1. Comparison of 2,4,6-Trimethylacetophenone and
2,4,6-Trimethylthioacetophenone Keto-Enol Systems
2,4,6-trimethyl-
acetophenonea
2,4,6-trimethylthio-
acetophenone
pKE
6.92
10.69
17.61
0.94
6.99
7.93
pQaE b
pQaK b
a Reference 3. b Reference 7.
Further support for interpretation of the rate profile in terms
of the individual reactions shown in eqs 4 and 5 is provided by
isotope effects. The breakdown of observed rate constants into
contributions from enolization and ketonization presented in
Figure 1 indicates that enolization dominates in the basic region,
and consideration of the relative values of kE and kE [HO-]
o
HO-
shows that this reaction will occur through hydroxide-ion catalysis
in dilute sodium hydroxide solutions. The solvent isotope effect
on such a process can be expected to be inverse (kH/kD < 1) since
a solvated hydroxide ion is consumed and the hydrogen-oxygen
bonds of the solvent water molecules thus liberated are strength-
ened.9 Comparison of rates of reaction in H2O and D2O gave
Figure 1. Rate profile for keto-enol interconversion in the 2,4,6-
trimethylthioacetophenone system; (circles and solid line) rate of approach
to equilibrium, (dashed line) rate of enolization, and (dotted line) rate of
ketonization.
kE /kE
HO-
) 0.83 ( 0.01, consistent with this expectation. The
DO-
substrate isotope effect, on the other hand, should be in the normal
direction (kH/kD > 1) and probably of considerable magnitude,
and the measured value, kH/kD ) 5.89 ( 0.04, is again consistent
with expectation.
which, together with the perchloric acid and sodium hydroxide
results, provide the rate profile shown in Figure 1. Analysis of
this profile in terms of enolization effected by proton transfer
from ketone to hydroxide ion (kE ) and water (kE ), eq 4, and
HO-
o
The presently determined keto-enol equilibrium and acid
dissociation constants are compared with their counterparts for
the corresponding oxygen system in Table 1. It may be seen
that KE for the sulfur ketone is very much greater than that for
its oxygen analogue, by 6 orders of magnitude; this difference is
nicely consistent with the prediction KE(S)/KE(O) g 106 made
recently for a different oxygen-sulfur simple ketone pair.2a The
greater enol content of thioketones has been attributed to the
relative weakness of the sulfur-oxygen π-bond.2a The data of
Table 1 also show the sulfur enol to be a considerably stronger
acid than its oxygen analogue. This is consistent with the greater
acidity of thiophenol (pKa ) 6.49)10 over phenol (pKa ) 10.00),11
and it agrees as well with the only other comparison of acid
strengths of sulfur and oxygen enols, in which triphenylethene-
thiol, pQaE ) 8.49, was found to be a stronger acid than its oxygen
analogue by ∆pQaE ) 2.88.2b These differences in KE and QaE
combine to make 2,4,6-trimethylthioacetophenone a stronger
carbon acid than its oxygen counterpart by a remarkably large
10 orders of magnitude.
ketonization effected by protonation of enolate ion by hydronium
ion (kK ) and water (kK ), eq 5, leads to the following results:
H+
o
kE
) (4.00 ( 0.10) × 101 M-1 s-1, kE ) (1.82 ( 0.08) ×
HO-
o
10-4 s-1, kK ) (1.33 ( 0.32) × 104 M-1 s-1, kK ) (5.97 (
H+
o
0.24) × 10-5 s-1, and QaE ) (1.20 ( 0.32) × 10-7 M, pQaE
)
6.92 ( 0.11.7 The latter value agrees well with other determina-
tions of this quantity described above. These rate constants were
used to construct the various lines shown in Figure 1.
Buffer catalysis was strong in all of the buffer solutions
examined, and analysis of results obtained at different buffer ratios
showed the form of catalysis to be both general acid and general
base. This is as expected, for the rate constants measured were
specific rates of approach to equilibrium, which are sums of
enolization plus ketonization rate constants; enolization will be a
general base-catalyzed reaction and ketonization will be a general
acid-catalyzed process.8
Acknowledgment. We are grateful to the Natural Sciences and
Engineering Research Council of Canada for financial support of this
work.
JA9826993
(9) 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) Biggs, A. I. Trans. Faraday Soc. 1956, 52, 35-39.
(11) Liotta, C. L.; Perdue, E. M.; Hopkins, H. P., Jr. J. Am. Chem. Soc.
1974, 96, 7981-7985.
(8) Keeffe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport, Z.,
Ed.; Wiley-Interscience: New York, 1990; pp 390-480.