Aldol condensation of trifluoroacetophenone and acetone: Testing a prediction

Article abstract of DOI:10.1021/ja9808696

Rate and equilibrium constants have been determined for both stages of the aldol condensation of acetone with trifluoroacetophenone. The extensive hydration of trifluoroacetophenone and the acid dissociation of the hydrate complicated the kinetic analysis. Dehydration of the intermediate ketol leads to two enones which equilibrate in base more rapidly than they undergo hydration to the ketol. This is consistent with interconversion via the enolate of the ketol, which loses OH^- faster than it undergoes C-protonation. The rate constant determined for the aldol addition step is in satisfactory agreement with the value predicted from a Marcus correlation (J. Am. Chem. Sec. 1991, 113, 7249-7255).

Full text of DOI:10.1021/ja9808696

6698
J. Am. Chem. Soc. 1998, 120, 6698-6703
Aldol Condensation of Trifluoroacetophenone and Acetone: Testing a
Prediction
J. Peter Guthrie* and Jonathan A. Barker
Contribution from the Department of Chemistry, UniVersity of Western Ontario,
London, Ontario, Canada N6A 5B7
ReceiVed March 16, 1998
Abstract: Rate and equilibrium constants have been determined for both stages of the aldol condensation of
acetone with trifluoroacetophenone. The extensive hydration of trifluoroacetophenone and the acid dissociation
of the hydrate complicated the kinetic analysis. Dehydration of the intermediate ketol leads to two enones
which equilibrate in base more rapidly than they undergo hydration to the ketol. This is consistent with
interconversion via the enolate of the ketol, which loses OH- faster than it undergoes C-protonation. The rate
constant determined for the aldol addition step is in satisfactory agreement with the value predicted from a
Marcus correlation {J. Am. Chem. Soc. 1991, 113, 7249-7255}.
Introduction
Scheme 1. Aldol Condensation of Acetone with
Trifluoroacetophenone; Ketone Hydration/Dissociation and
Ketol Dissociation Shown
The aldol condensation is a very important synthetic reaction.
Despite this importance there have been relatively few kinetic
studies.1 We have reported that both stages of the aldol
condensation can be described in terms of the Marcus relation
with the approximation of a constant intrinsic barrier for each
stage.1a This allowed prediction of the rate constants for
unknown aldol additions, and in particular the rate constant for
the reaction of acetone with trifluoroacetophenone was predicted
to be 104 times faster than the reaction of acetone with
acetophenone. We now report a study of the kinetics of this
reaction, showing that the prediction is correct.
There have been relatively few studies of substituent effects
on the aldol addition reaction,2-9 and most of those have
addressed the effects of ring-substituted aromatic compounds.
The present study of the detailed kinetics and equilibria for the
acetone-trifluoroacetophenone system supplies a measure of
the importance of the effects of polar substituents on the alkyl
group of the ketone.
followed by separation of the mixture of isomers by low-
pressure column chromatography.
General Strategy. The reaction system that was subjected
to kinetics analysis is shown in Scheme 1. This system is
complicated by hydration and ionization equilibria. Because
of the complexity of this system we will first outline the strategy
used to study the kinetics.
Results
Because the aldol equilibria lie well to the side of starting
materials, the kinetics of the reactions are most easily studied
in the retroaldol sense, which results in much cleaner kinetics.
The kinetics were followed by either UV spectrophotometry or
HPLC analysis of quenched samples and fitted to single or
double exponential equations as appropriate. When HPLC
analysis was used, and the data supported it, simultaneous fitting
of peak integrations of multiple species from multiple experi-
ments was used to obtain the best fit to all of the available data.
In aqueous base, isomerization of enones was observable as
a kinetic phase faster than hydration. The isomerization
equilibrium constant could be determined by analysis of HPLC
data. It is a striking feature of the kinetics that isomerization
is fast relative to hydration. This requires that the ketol not be
an intermediate on the reaction path from E-enone to Z-enone.
This observation was also made in a study of the corresponding
condensation of acetone with acetophenone.11 The suggested
mechanism is shown in Scheme 2 where attack of hydroxide
on enone gives the enolate corresponding to the ketol. Most
The reactions studied are summarized in Scheme 1. Samples
of the ketol and enone products were prepared. (Z)-2-Phenyl-
1,1,1-trifluoro-2-penten-4-one (3) was prepared by the literature
method.10 1,1,1-Trifluoro-2-hydroxy-2-phenyl-4-pentanone (2)
was synthesized by a directed aldol reaction employing a
preformed lithium enolate. (E)-2-Phenyl-1,1,1-trifluoro-2-
penten-4-one (4) was prepared by photoisomerization of 3
(1) (a) Guthrie, J. P. J. Am. Chem. Soc. 1991, 113, 7249-7255. (b)
references contained in ref 1a.
(2) Das, G.; Thornton, E. R. J. Am. Chem. Soc. 1990, 112, 5360-5362.
(3) Das, G.; Thornton, E. R. Tetrahedron Lett. 1991, 32, 5239-5242.
(4) Das, G.; Thornton, E. R. J. Am. Chem. Soc. 1993, 115, 1302-1312.
(5) Noyce, D. S.; Reed, W. L. J. Am. Chem. Soc. 1958, 80, 5539-5542.
(6) Coombs, E.; Evans, D. P. J. Chem. Soc. 1940, 1295-1300.
(7) Walker, E. A.; Young, J. R. J. Chem. Soc. 1957, 2045-2049.
(8) Noyce, D. S.; Reed, W. L. J. Am. Chem. Soc. 1959, 81, 624-628.
(9) Kandlikar, S.; Sethuram, B.; Navaneeth Rao, T. Ind. J. Chem. 1978,
16B, 914-916.
(10) Dull, D. L.; Baxter, I.; Mosher, H. S. J. Org. Chem. 1967, 32, 1622-
1623.
S0002-7863(98)00869-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/26/1998

Aldol Condensation of Trifluoroacetophenone and Acetone
J. Am. Chem. Soc., Vol. 120, No. 27, 1998 6699
Table 1. Rate Constants for the Hydroxide-Catalyzed
Scheme 2. Base-Catalyzed Enone Hydration and Retroaldol
Mechanism
Isomerization of (E)-2-Phenyl-1,1,1-trifluoro-2-penten-4-one (4)a
103[OH-]
(M)
103λ
λ/[OH-]
R
â
(s-1
)
(M-1 s-1
)
99.6
99.6
9.91
9.91
9.91
9.96
9.96
9.96
9.96
1.17b
1.17b
1.17b
0.502 1.075 253.2 ( 3.3
0.041 0.165 180.4 ( 4.7
2.542 ( 0.033
1.811 ( 0.047
1.839 ( 0.001
1.818 ( 0.001
1.815 ( 0.001
1.842 ( 0.015
1.830 ( 0.004
1.861 ( 0.001
1.772 ( 0.003
2.135 ( 0.001
2.066 ( 0.001
2.069 ( 0.001
2.129 ( 0.002
2.140 ( 0.002
av 1.94 ( 0.04
0.580 0.792
0.579 0.637
0.566 0.777
0.408 1.042
0.529 0.693
0.512 0.671
0.495 0.643
0.522 0.721
0.512 0.712
0.520 0.714
18.23 ( 0.01
18.01 ( 0.01
17.98 ( 0.01
18.3 ( 0.1
18.23 ( 0.04
18.54 ( 0.01
17.65 ( 0.03
2.503 ( 0.001
2.421 ( 0.001
2.426 ( 0.001
0.2878 ( 0.0003
0.2893 ( 0.0003
0.1352b 0.526 0.744
0.1352b 0.510 0.725
a In aqueous solution at 25.0 °C, ionic strength 0.1 (KCl), followed
by UV spectrometry at 245 nm. [E-enone]i ) 91 µM. Data were fitted
to the following: A ) R + â exp(-λt). Standard deviations for the
parameters are calculated by the least-squares procedure. Average value
is the weighted mean. b [OH-] determined by measurement of buffer
pH; [OH-] ) 10(pH-14)
.
and following the appearance of the Z-enone chromophore by
UV spectrophotometry. Experiments starting with Z-enone were
unsuccessful because the equilibrium strongly favors the Z-enone
and as a consequence the resulting absorbance change was too
small for accurate kinetics. The observed rate constants are
then the sum of the forward and reverse rate constants for
isomerization and are summarized in Table 1. The isomerization
was considerably faster than hydration which was observable
as a second kinetic phase at longer times.
The kinetics were also followed in pH 10 borate buffers by
HPLC analysis of quenched samples, starting with both Z- and
E-isomers. The separation achieved by HPLC allowed isomer-
ization to be followed in both directions. HPLC peak integra-
tion-time data were fit simultaneously to the system
often this is followed by reversal: expulsion of hydroxide ion
to give one or the other enone. Protonation at carbon to give
ketol proceeds at a slower rate. A second, kinetically equivalent
isomerization mechanism with γ-proton removal followed by
isomerization was also considered.11 There is no γ-proton for
the aldol product of acetone with trifluoroacetophenone, which
rules out the second mechanism and suggests that the first
mechanism is likely to be the correct one in this and the earlier
studies.
Hydroxide-catalyzed retroaldol cleavage of the ketol was
studied by UV spectrophotometry or by HPLC analysis of
quenched samples. In no experiment was there an accumulation
of dehydration product. The reactions were always pseudo-
first order. For 2 the pKa was within the pH range of interest
so the pKa was determined from the pH rate profile for the
retroaldol reaction. This had the added benefit that the first-
order rate constant for the retroaldol cleavage of the ketolate
was determined.
HPLC analysis of equilibrated solutions of ketones in aqueous
buffer or hydroxide was used to determine the aldol formation
equilibrium constants. Except for some acetone self-aldol, the
condensation of acetone with trifluoroacetophenone cannot be
complicated by competing aldol reactions because trifluoro-
acetophenone lacks R-hydrogens. It was complicated by
extensive hydration of the trifluoroacetophenone and pKa’s of
the trifluoroacetophenone hydrate and product ketol within the
pH region of interest. The self-aldol condensation of acetone
has been studied previously12 and was not examined in this
work. It is known to proceed only to a minor extent under our
conditions.12
A h B
for reaction in both directions, allowing determination of both
the forward and reverse rate constants and hence the equilibrium
constant. The rate and equilibrium constants obtained from
these experiments are the following: k3-4[OH-] ) (8.22 ( 0.16)
× 10-6 s-1, k4-3[OH-] ) (3.22 ( 0.05) × 10-4 s-1, and K3-4
) (2.55 ( 0.07) × 10-2. The HPLC data obtained are plotted
in Figure 1 with the lines of best fit determined by the method
of least squares. The scale for the experiment starting with
Z-enone is expanded to improve readability.
An additional experiment used HPLC analysis of equilibrated
solutions of enones to determine the equilibrium constant. The
enones were rapidly equilibrated in 0.1 M aqueous sodium
hydroxide, quenched, and then analyzed. The results were the
same whether starting with the E-enone or Z-enone. The
equilibrium constant determined was K3-4 ) (3.08 ( 0.08) ×
10-2 with negligible hydration to ketol at short times. This
equilibrium constant is significantly different than that obtained
at pH 10. Because the enone peaks are not completely resolved
by HPLC, it was necessary to use PEAKFIT,13 a mathematical
curve-fitting program, to fit the peaks and thus to estimate the
peak areas. Since the Z-enone peak was much larger than the
E-enone peak, it is probable that studying only the equilibrated
solutions resulted in a systematic error in quantitation. The
Kinetics of Isomerization. Now we will turn to a detailed
examination of the kinetics, starting with the isomerization of
the enones. The kinetics of isomerization of the enones 3 and
4 were studied by injecting E-enone into dilute alkaline solution
(11) (a) Guthrie, J. P.; Wang, X. P. Can. J. Chem. 1992, 70, 1055-
1068. (b) This result seems counterintuitive but follows from the existence
of an intermediate common to the interconversion of 3 and 4 and the (slower)
conversion of either to 2. Therefore K3-4 ) k3-2/k4-2. There is of course
only one kobs for hydration of the equilibrating system, but it may be
expressed in terms of either k3-2 or k4-2
(12) Koelichen, K. Z. Phys. Chem. 1900, 33, 129-177.
.
(13) Jandel Scientific; now SPSS Inc., 444 North Michigan Avenue,
Chicago IL 60611.

6700 J. Am. Chem. Soc., Vol. 120, No. 27, 1998
Guthrie and Barker
Table 3. Rate Constants for the Hydroxide-Catalyzed Retroaldol
Cleavage of 1,1,1-Trifluoro-2-hydroxy-2-phenyl-4-pentanone (2)a
[OH-]b
(M)
[KETOL]ic
(mM)
106λ
R
â
(s-1
)
0.0983
0.0934
0.0483
0.0460
0.0244
0.0091
0.0047
0.0024
0.0012d
0.00020d
0.00014d
1.94
0.986
2.19
0.918
0.977
2.17
1.28
0.467
1.00
1.06
1.00
-0.00
0.02
0.07
-0.03
0.03
0.00
0.00
0.14
1.44
1.06
1.47
1.02
1.04
2.42
1.04
1.05
2.22
1.35
0.41
12.8 ( 0.2
13.0 ( 0.4
13.1 ( 0.6
10.8 ( 3.0
9.80 ( 0.18
5.24 ( 0.41
3.37 ( 0.03
2.60 ( 0.08
1.16 ( 0.03
0.25 ( 0.01
0.183 ( 0.003
-1.7E-06
-2.7E-07
-2.7E-07
a In aqueous solution at 25 °C, ionic strength 0.1 (KCl), followed
by HPLC analysis on quenched samples; disappearance of the peak
due to ketol, 3, was followed. Data were fitted to the following: [ketol]
) R + â exp(-λt) unless otherwise noted. b [OH-] determined by
titration, or from calculation of dilution with degassed water. c [ketol]
determined from the mass of ketol added. d [OH-] determined by
measurement of buffer pH; initial rate kinetics fit to [ketol] ) ú + ηt;
thence λ ) -η/ú (ú in mM).
Figure 1. E-Z isomerization of 2-phenyl-1,1,1-trifluoro-2-penten-4-
one in pH 10 borate buffer. Vertical axes are scaled for viewing
convenience. For reaction starting with E-enone, full scales are as
follows: E-enone 19.9 mM, Z-enone 50.3 mM. For reaction starting
with Z-enone, full scales are as follows: E-enone 1.0 mM, Z-enone
50.3 mM.
conditions by HPLC analysis of quenched samples. The
disappearance of the ketol peak in the HPLC showed first-order
kinetics and was followed for at least 3 half-lives for pH >11.
At pH 10 and 11, initial rate kinetics were used observing the
first 10% of reaction. The rate constants obtained (see Table
3) allow the construction of a pH rate profile (Figure 2).
Dehydration was not detected when starting with ketol, and
retroaldol cleavage was essentially complete and pseudo-first
order. Therefore, extracting the relevant portions from Scheme
1, the reaction can be considered as:
Table 2. Rate Constants for the Hydroxide-Catalyzed Hydration
of (Z)-2-Phenyl-1,1,1-trifluoro-2-penten-4-one (3)a
[OH-]b
(M)
105λ
104λ/[OH-]
R
â
(s-1
)
(M-1 s-1
)
0.100
0.100
0.100
0.100c
0.050
0.050
0.152
2.026
2.023
0.000
0.091
0.104
0.796
0.483
0.477
0.467
0.798
0.798
1.661 ( 0.001
1.739 ( 0.005
1.639 ( 0.002
1.614 ( 0.002
0.816 ( 0.003
0.846 ( 0.004
1.668 ( 0.001
1.746 ( 0.005
1.646 ( 0.002
1.621 ( 0.002
1.638 ( 0.007
1.698 ( 0.007
av 1.658 ( 0.012
OH
CF3
2
O
– O
O
a In aqueous solution at 25.0 °C, ionic strength 0.1 (KCl), followed
by UV spectrophotometry at 245 nm. Data were fitted to the following:
A ) R + â exp(-λt). Standard deviations for the parameters are
calculated by the least-squares procedure. Average value is the weighted
mean. b Determined by titration against standardized aqueous hydro-
chloric acid. c Hydration phase of E-Z isomerization/hydration starting
with E-enone.
k2-5
k5-3
k5-1
CH3
CH3
O
CF3
5
O
CF3
H3C
CH3
+
kinetics study at pH 10 where peaks of varying size are being
fit should be less susceptible to this systematic error. For this
reason the equilibrium constant determined from the HPLC data
at pH 10 is considered the most accurate.
1
Ketol deprotonation is a rapid equilibrium, so that kobs ) k5-1
/
(1 + K5-2/[OH-]). Fitting the data from Table 3 with weighted
It follows from Table 1 and K3-4 that the second-order rate
constants for the hydroxide-catalyzed isomerization of the
enones are as follows: k3-4 ) (4.83 ( 0.15) × 10-2 M-1 s-1
nonlinear least squares to this equation gives k5-1 ) (1.50 (
0.09) × 10-5 s-1, K5-2 ) Kw/Ka
) (1.4 ( 0.1) × 10-2 M,
ketol
ketol
and Ka
) (6.5 ( 0.5) × 10-13 M-1 (pKa ) 12.19 ( 0.04).
and k4-3 ) 1.89 ( 0.03 M-1s-1
.
Therefore, since k2-1 ) k5-1/K5-2 the second-order rate constant
for base-catalyzed retroaldol of the ketol is (9.7 ( 1.0) × 10-4
Kinetics of Enone Hydration. The kinetics of Z-enone
hydration were followed by UV spectrophotometry and were
found to be first order in hydroxide concentration. The data
are summarized in Table 2. E-enone isomerization experiments,
when followed for extended times, showed a second kinetic
phase with a rate consistent with enone hydration. Because the
hydration is the hydration of a mixture of E- and Z-enones, and
because the hydration of both proceeds through a common
intermediate, the hydration rates of each can be calculated. This
M-1 s-1
.
Kinetics and Equilibria for Ketol Formation and Dehy-
dration. Ketol and enone formation were followed in the
forward direction by mixing trifluoroacetophenone and acetone
in aqueous base or buffer and following the appearance of
products by HPLC. Trifluoroacetophenone was difficult to
quantify because of severe peak tailing in the HPLC. This is
presumably because of the ketone-hydrate equilibrium, and the
best separations are obtained at lower temperatures where this
equilibration is slowed. Elevated temperatures (to 40 °C)
resulted in more tail than peak while ice temperature gave a
tail that did not severely affect the quantitation of the ketol.
Early method development with methanol-water eluent with
stock solutions of ketone in either water or methanol showed
what appeared to be hemiacetal formation and breakdown on
is because it has been shown11 that kobs ) 2k3-2/(1 + K3-4
and similarly kobs ) 2k4-2/(1 + K4-3). The second-order rate
)
constants for hydroxide-catalyzed hydration are then k3-2
)
(8.09 ( 0.06) × 10-5 M-1 s-1 and k4-2 ) (2.1 ( 0.9) × 10-6
M-1 s-1
.
Retroaldol Cleavage. The retroaldol cleavage of ketol 2 was
studied under pseudo-first-order (excess base or buffered)

Aldol Condensation of Trifluoroacetophenone and Acetone
J. Am. Chem. Soc., Vol. 120, No. 27, 1998 6701
Figure 3. Apparent equilibrium constant as a function of pH for the
aldol reaction of acetone with trifluoroacetophenone.
Figure 2. pH dependence of apparent first-order rate constants for
retroaldol cleavage of 1,1,1-trifluoro-2-hydroxy-2-phenyl-4-pentanone
(2).
determined above. The results of the formation reactions are
summarized in Table 4. K1-2 was determined for each
experiment by correcting Kapp for hydration and pH effects, and
the column. The ratios of peaks and magnitude of absorbance
between the peaks were dependent on the composition of both
injection solvent and eluent. Acetonitrile-water mixtures
showed promise so that the earlier system was abandoned, but
its peculiarities support the hydration explanation for tailing.
It seemed imprudent to rely on the peak areas or peak heights
from trifluoroacetophenone because of peak tailing. The
equilibrium concentration of trifluoroacetophenone was taken
as its initial concentration, determined by mass used, minus the
concentration of ketol present, as determined by HPLC. This
undoubtedly introduces error, but that error can be estimated.
The trifluoroacetophenone peak was followed and agreed
approximately with the calculated concentration.Trifluoroac-
etophenone also undergoes slow haloform cleavage with a half-
life of 160 h in 0.1 M hydroxide solution.14 This effect is
ignored in these calculations. Acetone condenses with itself to
give diacetone alcohol and mesityl oxide. The HPLC showed
the presence of side products including acetone self-condensa-
tion products, identified by comparison to authentic samples,
which were ignored in the quantitation. Calculations of the
effect of self-aldol on the acetone concentration based on known
rates and equilibrium constants12,15 showed the effect would only
be a few percent. This effect is ignored in the calculations.
First-order growth of the ketol peak was observed and
followed for several half-lives. Nonlinear least squares was used
to determine both the apparent rate constants and the equilibrium
concentration of ketol. Only the equilibrium concentration is
of interest in this treatment. The apparent equilibrium constant,
defined as Kapp ) [ketol]total/([TFA]total[acetone]), is pH de-
pendent because the pKa’s of both the trifluoroacetophenone
hydrate and the ketol are in the pH range studied. Following
Scheme 1, the theoretical pH equilibrium profile should follow:
the weighted mean of the individual experiments is K1-2
)
(2.657 ( 0.003) × 103 M-1. Kapp as a function of pH is shown
in Figure 3, along with the theoretical line.
The point at the lowest pH in the aldol formation equilibrium
profile shows a very significant deviation from the line. The
HPLC data showed a possible decrease in the trifluoroacetophe-
none concentration that had not occurred in other runs. If the
TFA concentration estimated by inspection of the HPLC results
is used to calculate the observed equilibrium constant, the point
falls much closer to the line. To avoid inconsistency, this was
not done, but it seems likely that there are systematic errors for
this point.
The approach to equilibrium between ketol and enones is
expected to be slow except at high pH. At high pH, however,
the equilibrium is shifted in favor of the ketol by its conversion
to ketolate. As a result, detection of the enones was very
difficult, and our estimates of enone concentration at equilibrium
are correspondingly imprecise. The best compromise was a
hydroxide concentration near 0.05 M. HPLC analysis of
equilibrated solutions did not resolve the peaks from the two
enones so that a hybrid calibration constant calculated by using
the measured calibration constants for the two enones and the
isomerization equilibrium constant was used.
In this way the dehydration equilibrium constants were
determined: K2-3 ) (4.3 ( 0.4) × 10-3 and K2-4 ) (1.1 (
0.1) × 10-4. The rate and equilibrium constants determined
for the hydroxide-catalyzed reactions in the aldol condensation
of acetone with trifluoroacetophenone are summarized in Table
5.
Discussion
With the aldol condensation of acetone with trifluoroac-
etophenone fully characterized, the ability of the Marcus relation
to predict aldol reaction rates and substituent effects on the aldol
reaction can be assessed.
Kapp ) K1-2(1 + K5-2[OH-])/(1 + K1-6 + K1-7[OH-]) (1)
where K1-6 ) 77.6 and K1-7 ) 7.76 × 105 M-1 as determined
by Stewart,16,17 and K5-2 ) Kw/Ka ) (1.4 ( 0.1) × 10-2 M as
(16) Stewart, R.; Van Dyke, J. D. Can. J. Chem. 1970, 48, 3961-3963.
(17) Stewart, R.; Van der Linden, R. Can. J. Chem. 1960, 38, 399-
406.
(14) Guthrie, J. P.; Cossar, J. Can. J. Chem. 1990, 68, 1640-1642.
(15) French, C. C. J. Am. Chem. Soc. 1929, 51, 3215-3225.

6702 J. Am. Chem. Soc., Vol. 120, No. 27, 1998
Guthrie and Barker
Table 4. Apparent Aldol Formation Constants for the Reaction of Acetone with Trifluoroacetophenonea
102 [TFA]b
(M)
[OH-]b
(M)
102[TFA]ed
(M)
Kapp
(M-1
10-3 Kcalc
f
g
103[ketol]ec
[acetone]ed
pHe
)
(M-1
)
2.050 ( 0.002
1.007 ( 0.002
1.021 ( 0.002
1.020 ( 0.002
1.016 ( 0.002
0.528 ( 0.002
1.012 ( 0.002
1.020 ( 0.002
1.020 ( 0.002
1.011 ( 0.002
1.126 ( 0.002
1.013 ( 0.002
0.505 ( 0.002
0.510 ( 0.002
0.1
0.1
0.1
0.1
0.06
0.06
0.06
0.06
0.02
0.02
0.02
0.02
0.00113
0.00026
5.518 ( 0.039
2.320 ( 0.016
0.710 ( 0.009
0.257 ( 0.009
2.317 ( 0.024
0.602 ( 0.007
0.763 ( 0.011
0.268 ( 0.004
3.18 ( 0.01
1.498
0.775
0.950
0.994
0.784
0.467
0.936
0.993
0.702
0.645
1.000
0.962
0.169
0.157
1.076
0.998
0.291
0.098
0.998
0.490
0.291
0.099
0.997
0.996
0.289
0.091
0.538
0.537
12.87
12.94
12.95
12.95
12.68
12.73
12.69
12.70
11.90
11.89
11.91
11.98
11.05
10.41
0.342 ( 0.029
0.300 ( 0.019
0.256 ( 0.001
0.264 ( 0.000
0.296 ( 0.023
0.263 ( 0.004
0.281 ( 0.001
0.271 ( 0.000
0.453 ( 0.032
0.6 ( 1.7
3.40 ( 0.28
3.06 ( 0.19
2.62 ( 0.01
2.698 ( 0.003
2.69 ( 0.21
2.45 ( 0.04
2.56 ( 0.01
2.481 ( 0.001
1.88 ( 0.13
3.66 ( 0.69
2.32 ( 6.95
1.26 ( 0.05
0.434 ( 0.005
0.587 ( 0.000
3.70 ( 0.14
1.81 ( 0.02
0.515 ( 0.003
3.36 ( 0.13
2.728 ( 0.001
3.29 ( 0.23
3.53 ( 0.14
5.47 ( 0.06
1.484 ( 0.016
av 2.656 ( 0.034
a In aqueous hydroxide or buffer solution at 25.0 °C; ionic strength maintained at 0.1 M with KCl; analysis by HPLC. b Concentration as added
to reaction flask. c Equilibrium concentration of ketol determined by HPLC analysis. d Concentration corrected for formation of ketol. e pH calculated
g
from hydroxide concentration corrected for consumption by TFA hydrate and ketol. f [ketol]e/([TFA]e[acetone]e). K1-2 calculated from eq 2.
Table 5. Summary of Rate and Equilibrium Constants for the
Hydroxide-Catalyzed Aldol Condensation of Acetone with
Trifluoroacetophenone
Scheme 3. Thermodynamic Cycles Used To Derive the
Equilibirum Constant Needed for the Marcus Analysis of the
Aldol Addition of Acetone to Trifluoroacetophenone
constant
value
(2.66 ( 0.03) × 103 M-1
a
K1-2
k1-2
k2-1
K2-3
k2-3
k3-2
b
c
2.75 ( 0.25 M-2 s-1
(1.03 ( 0.09) × 10-3 M-1 s-1
(4.3 ( 0.4) × 10-3
d
(3.5 ( 0.3) × 10-7 M-1 s-1
(8.09 ( 0.06) × 10-5 M-1 s-1
(1.09 ( 0.10) × 10-4
e
f
d
K2-4
(2.3 ( 1.0) × 10-10 M-1 s-1
(2.1 ( 0.9) × 10-6 M-1 s-1
(2.55 ( 0.07) × 10-2
e
k2-4
k4-2
f
g
K3-4
k3-4
k4-3
(4.83 ( 0.15) × 10-2 M-1 s-1
h
h
(1.89 ( 0.03) M-1 s-1
(1.44 ( 0.11) × 10-2 M-1
i
K5-2
other constants
Kaketol j
(6.9 ( 0.5) × 10-13 M-1
The estimated K1-2 and ketol pKa values, as used in the
original predictions for the aldol reaction of acetone with
trifluoroacetophenone, were both significantly different from
those determined in this study. By using the experimentally
determined values, the prediction using the Marcus relation is
significantly closer to the observed rate constants: within 0.44
log units for the retroaldol rate. There is another significant
source of uncertainty in these calculations. The calculated K1-2
is very sensitive to the hydration equilibrium constant for TFA
and the pKa of the hydrate. Changing the values of either of
these constants results in significant changes in the calculated
K1-2. Therefore the uncertainty in K1-2 for this reaction is more
realistically about 0.5 log units. Despite these uncertainties,
both the revised and original estimates gave predictions which
were within approximately an order of magnitude.
(1.94 ( 0.03) M-1 s-1
k
k3-4 + k4-3
a Determined from aldol formation reactions. b Calculated from k1-2
) k2-1 × K1-2
c Determined from hydroxide-catalyzed retroaldol.
d Determined by equilibrium concentration in aldol formation. e Cal-
f Calculated from
.
culated from k2-3 ) k3-2 × K2-3; k2-4 ) k4-2 × K2-4
.
the observed hydration rate constant with k3-2 ) kobs/(2(1 + K3-4));
k4-2 ) kobs/(2(1 + K4-3)). g Determined from HPLC analysis of enone
equilibration. h Determined from UV and HPLC studies of isomeriza-
tion; values calculated by k3-4 ) kobs/(1 + 1/K3-4); k4-3 ) kobs/(1 +
K
3-4). i Determined from the ketol retroaldol pH rate profile. j Calcu-
lated from Ka ) Kw/K5-2.
k Observed second-order rate constant from
enone isomerizations.
Table 6 summarizes the predicted 1a and observed equilibrium
and rate constants for the aldol reaction studied, as well as
revised predicted rate constants. These were calculated in the
same way as the originally predicted1a rate constants but using
the experimentally determined instead of estimated equilibrium
constants. The detailed calculations are summarized in Table
S1, and were based on the analysis shown in Scheme 3.
K1-2 is very sensitive to substitution on the electrophile. With
acetone as nucleophile, an equilibrium enhancement of 6.14 log
units can be achieved by changing from acetophenone to
trifluoroacetophenone as electrophile. The rate constant for
Table 6. Comparison of Predicted and Measured Equilibrium and Hydroxide-Catalyzed Rate Constants for the Aldol Reactionsa
a
b
b
log(K1-2/M-1
)
log(k+/M-2 s-1
)
log(k-/M-1 s-1
revd
)
nuc
elec
pred
2.47
meas
3.42
predc
0.48
revd
meas
0.44
predc
meas
acetone
TFA
0.90
-1.99
-2.52
-2.99
a Equilibrium constant for the formation of neutral ketol from neutral ketone plus neutral ketone. b Observable macroscopic rate constant; Vforward
) k+[HO-][acetone][TFA]free.; Vreverse ) k-[HO-][ketol]neutral c Predicted value1a based on estimated equilibrium constants, and an average value
.
for the intrinsic barrier. d Revised predicted values are estimated rate constants based on the aldol formation constants determined in this work,
including the kinetic pKa for the ketol, and an average value for the intrinsic barrier.1a

Aldol Condensation of Trifluoroacetophenone and Acetone
J. Am. Chem. Soc., Vol. 120, No. 27, 1998 6703
dependent variables. Nonlinear fitting assumed that the independent
variable was free from error, but used weighted dependent variables.
Extensive modifications were made to the nonlinear least-squares
programs in the course of this work. Provision was made for the
imposition of constraints on any parameter(s). This allowed parameters
not well-defined by the data to be constrained to be close to
independently determined values so that a better fit to the other
parameters could be obtained. The method used is described by
Deming.24
The program used to simultaneously fit multiple species in multiple
experiments uses functions of the individual microscopic rate constants
to determine observable rate constants and preexponential terms for
the change in concentration/integration of each species. This allows
the determination of both rate constants in an equilibrium, for example,
where otherwise three separate calculations would be required: calcula-
tion of the observed rate constant, calculation of the equilibrium
constant, and the determination of the individual microscopic rate
constants from the observed rate and equilibrium constants. Simulta-
neous fitting is a particular advantage when considering a cyclic
equilibrium where the observable preexponentials and rate constants
are complicated functions of the individual rate constants. Simultaneous
fitting also allows each set of data to act as a constraint on the others,
which results in much better fits when some of the data are of poor
quality.
aldol addition is also very sensitive to substituents in the
carbonyl electrophile. The enhancement in log kmic on going
from acetophenone to trifluoroacetophenone is 3.90 log units.
Although trifluoroacetophenone is far more reactive in terms
of the microscopic rate constant, it is actually less reactive in
terms of the observable behavior under normal synthetic
conditions because so much of the total trifluoroacetophenone
is tied up as the carbonyl hydrate anion. In terms of the free
ketones the rate ratio is 2.75/(3.41 × 10-4) ) 8065; in terms of
the total concentration of ketone (free, hydrated, or as the hydrate
anion) at 0.1 M HO- the rate ratio is (2.96 × 10-6)/(3.41 ×
10-5) ) 0.0866. The calculation for total ketone concentration
used the apparent pseudo-second-order rate constants for 0.1
M HO-.
This work demonstrates that large substituent effects can be
found for the aldol reaction when the nature of the carbonyl
electrophile is changed. This is in accord with the normal
behavior of carbonyl compounds toward nucleophilic addition.20
We have also demonstrated that it is possible to predict the
rate constant for an unknown aldol addition, even when it differs
very considerably in reactivity from the model compounds. The
prediction was based on the rates and equilibrium constants for
the reactions of CH2O, CH3CHO, PhCHO, and CH3COCH3 as
electrophiles with CH3CHO, CH3COCH3, and PhCOCH3 as
nucleophiles, and represents a predicted rate enhancement of 4
orders of magnitude over the reaction of acetone with acetophe-
none. This is a further demonstration of the utility of the Marcus
relation for correlation and prediction of rate constants for
organic reactions, and in particular for synthetically useful
reactions such as the aldol condensation.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial support
of this work.
Supporting Information Available: Preparation and spec-
troscopic data for compounds 2, 3, and 4; general methods and
kinetics procedures; table of detailed Marcus relation calcula-
tions of rate constants for the aldol reactions (9 pages, print/
PDF). See any current masthead page for ordering information
and Web access instructions.
Tools for making organic chemistry a more predictive science
are now at hand, and further developments of these methods
should have significant benefits both to the science and to its
applications.
JA9808696
(18) On the basis of the reported rate constant for acetone plus
acetophenone,11 the pKa for acetone,19 and the rate constant for the reaction
of acetone plus trifluoroacetophenone, Table 5, log kmic ) log kobs + pKa-
(acetone) - 14.00.
(19) Chiang, Y.; Kresge, A. J.; Tang, Y. S.; Wirz, J. J. Am. Chem. Soc.
1984, 106, 460-462.
(20) Carroll, F. A. PerspectiVes on Structure and Mechanism in Organic
Chemistry; Brooks/Cole: Pacific Grove, CA, 1998; p 422.
(21) Bevington, P. R. Data reduction and error analysis for the physical
sciences; McGraw-Hill: New York, 1969; pp 204-246.
(22) Deming, W. E. Statistical adjustment of data; Dover: New York,
1964; pp 49-58.
Experimental Section
Materials. Solvents and salts were BDH reagent grade unless
otherwise noted. All other chemicals were from Aldrich. THF was
dried by refluxing over sodium, and distilling. Acetone was spectro-
photometric grade and was used without further purification.
Methods. Least-squares analysis was carried out with FORTRAN
programs developed in this lab using the methods of Bevington21 and
Deming.22 Linear fits used weighted values for both independent and