On the implications of hemiketal formation during ethyl pyruvate hydrogenation in alcohol solvents

Article abstract of DOI:10.1006/jcat.1998.2247

Hemiketal formation between alcohol solvents and α-keto esters is shown to be catalyzed not only by the basic cinchonidine modifier but also by the acidic Pt/Al₂O₃ catalyst. Theoretical considerations and experimental results demonstrate that reaction calorimetry is a valid and accurate measure of the hydrogenation reaction, provided that the substrate and its hemiketal remain in equilibrium over the course of the reaction. The rate of hemiketal formation and, thus, the probability that the preequilibrium step will remain unperturbed during the hydrogenation reaction, is sensitive to the acidic properties of the support.

Full text of DOI:10.1006/jcat.1998.2247

JOURNAL OF CATALYSIS 179, 335–338 (1998)
ARTICLE NO. CA982247
PRIORITY COMMUNICATION
On the Implications of Hemiketal Formation during Ethyl Pyruvate
Hydrogenation in Alcohol Solvents
Frank M. Bohnen,1 Agnes Gamez,2 and Donna G. Blackmond3
Max-Planck-Institut fu¨r Kohlenforschung, Mu¨lheim an der Ruhr D-45470, Germany
Received July 15, 1998; revised July 25, 1998; accepted August 8, 1998
action (5). The results presented here show that hemiketal
formation in n-propanol is catalyzed not only by the basic
cinchonidine modifier but also by the acidic Pt/Al2O3 cata-
lyst. Theoretical considerations and experimental results
demonstrate that reaction calorimetry is a valid and accu-
rate measure of reaction progress in the hydrogenation of
ꢀ-keto estersin alcoholsolvents, provided that the substrate
and its hemiketal remain in equilibrium over the course of
the reaction.
Hemiketal formation between alcohol solvents and ꢀ-keto esters
is shown to be catalyzed not only by the basic cinchonidine modifier
but also by the acidic Pt/Al2O3 catalyst. Theoretical considerations
and experimental results demonstrate that reaction calorimetry is
a valid and accurate measure of the hydrogenation reaction, pro-
vided that the substrate and its hemiketal remain in equilibrium
over the course of the reaction. The rate of hemiketal formation
and, thus, the probability that the preequilibrium step will remain
unperturbed during the hydrogenation reaction, is sensitive to the
c
acidic properties of the support.
ꢀ 1998 Academic Press
EXPERIMENTAL
Materials
INTRODUCTION
The two Pt/Al2O3 catalysts employed in these studies
were used as received. A 1 wt% Pt (Precious Metals Corpo-
ration, PMC) catalyst was the same lot number as that used
in much of our previous work on this reaction (6). A 5 wt%
Pt catalyst (Engelhard E4759) which has been used exten-
sively by other workers in this field was also used. Ethyl
pyruvate was distilled immediately prior to use to afford
99.9% purity. The solvent n-propanol was distilled prior to
use.
Relationships between catalytic behavior and solvent
parameters in the asymmetric hydrogenation of ꢀ-keto es-
ters (1) have been studied extensively (2,3). The formation
of a hemiketal species between alcohol solvents and the
substrate (Eq. [1]) has been noted (4), although it is gen-
erally agreed that this reaction does not contribute to the
asymmetric reaction pathway:
Reaction Conditions
[1]
The instantaneous heat of formation of the n-propyl
hemiketal of ethyl pyruvate was monitored by reaction
calorimetry (Mettler RC1) as a function of time at 283 K
under 1 bar Ar in the presence and absence of the Pt/Al2O3
catalysts and the chiral modifier cinchonidine. This system
affords accurate measurement of the reaction heat flow to
ꢁ0.1 W, corresponding to a reaction rate of approximately
1 ꢁmol/s for a reaction with 1Hrxn of 20 kcal/mol.
We have previously demonstrated excellent agreement be-
tween two independent methods of measuring reaction
rate, one of which detects hemiketal formation as well as hy-
drogenation, and one which accounts only for the actual hy-
drogenation reaction. More recently, however, questions
have been raised about the potential for hemiketal forma-
tion to complicate measurement of the hydrogenation re-
RESULTS AND DISCUSSION
1 Present address: CONDEA Chemie GmbH, 25541 Brunsbu¨ttel,
Germany.
Reaction Calorimetry as a Kinetic Tool
2 Present address: 67400 Illkirch-Graffenstaden, France.
3 Corresponding author. E-mail: blackmond@mpi-muelheim.mpg.de.
As shown in Eq. [2], reaction calorimetry measures the
total rate of all concurrent reactions (in the general case,
335
0021-9517/98 $25.00
c
Copyright ꢀ 1998 by Academic Press
All rights of reproduction in any form reserved.

336
BOHNEN, GAMEZ, AND BLACKMOND
The heat flow curve of Fig. 1 represents contributions
from the hydrogenation reaction, consuming hydrogen and
ethyl pyruvate with a heat of reaction 1Hrxn,H (7), and the
2
reversible reaction between n-propanol and ethyl pyruvate
(Eq. [1]), which involves ethyl pyruvate, but not hydrogen
with a heat of reaction 1Hrxn,HK. Under the conditions of
the experiment shown in Fig. 1, an equilibrium mixture of
ethyl pyruvate and hemiketal was formed before the hydro-
genation reaction began. This reversible reaction is driven
toward ethyl pyruvate as conversion increases. Thus, the to-
tal rate measured by heat flow calorimetry will be given by:
dn
dnHK
dt
H2
rate = q˙ = (1Hrxn,H
)
ꢂ (1Hrxn,HK
)
.
[4]
2
dt
It is clear from examination of the two curves in Fig. 1 that
the ratio of rates measured by the two methods is constant
over the course of the reaction, which means that the ratio
of Eq. [4] to Eq. [3] equals a constant. This constraint can be
satisfied only if the hydrogenation rate and the net hemike-
tal formation rate are equal. This may be rationalized by
assuming that the hemiketal formation is a fast preequi-
librium step (Curtin-Hammett limit (8)). If the hydrogen
addition step proceeds slowly by comparison, then the equi-
librium is not perturbed. The rate at which the hemiketal
reacts to form ethyl pyruvate is thus dictated by the rate
at which ethyl pyruvate is consumed in the hydrogenation
reaction:
FIG. 1. Reaction rate as a function of reaction time in the cin-
chonidine-modified Pt/Al2O3 catalyzed hydrogenation of ethyl pyruvate
in n-propanol at 283 K and 585 kPa hydrogen, as described in Ref. (6). The
solid line is the rate of hydrogen uptake (Eq. [3]). The discrete data points
give the heat flow q˙ (Eq. [4]) measured by reaction calorimetry. The figure
is redrawn from Ref. (6b).
z reactions involving y different reactants, where 1Hrxn,i, j
and dni, j /dt are respectively the heat and the rate of the ith
reaction of component j):
j=y
i=z
X X
dni, j
dt
rate = q˙ =
1Hrxn,i, j
.
[2]
i=1 j=1
Therefore, it is important to establish by independent
means that the measured heat flow in fact reflects the rate
of the reaction under study. This is done in Fig. 1 for the
constant pressure hydrogenation of ethyl pyruvate in n-
propanol using cinchonidine-modified Pt (6b), where the
reaction rate was measured by two methods, hydrogen up-
take and reaction calorimetry, which monitor independent
properties of the reacting system. The excellent agreement,
even for the intitial transient period during which the re-
action rate rises, establishes the validity of the calorimet-
ric measurement of the hydrogenation reaction rate in this
case. This is confirmed below by a mathematical description
of the two methods of reaction rate measurement.
[5]
These equations taken together provide the relationship
between the global heat flow and the hydrogen uptake rate:
dnH
2
q˙ = (1Hrxn,H ꢂ 1Hrxn,HK
)
.
[6]
2
dt
Equation [6] gives the mathematical confirmation of what
Fig. 1 demonstrated experimentally, which is that in this
case both hydrogen uptake and reaction calorimetry meth-
ods accurately reflect the rate of ethyl pyruvate hydrogena-
tion. The overall measured heat of reaction (determined
by measuring the total area under the heat flow curve) will
be lower than the thermodynamic value for ethyl pyruvate
hydrogenation by the amount of heat initially required to
establish this equilibrium and appears as the proportional-
ity constant between the heat flow and the hydrogen uptake
rate. In cases where such an equilibrium is not established, a
discrepancy between heat flow and hydrogen uptake could
be observed.
Measurement of the uptake of hydrogen accounts for any
and all reactions which consume hydrogen. If substrate hy-
drogenation is the only reaction consuming hydrogen, then
the 1 : 1 reaction stoichiometry means that hydrogen up-
take, dnH /dt, may be taken as a direct measure of the total
2
rate of appearance of the product, dnprod/dt, where nprod
and nH refer to the moles of the hydrogenation product
2
formed and the hydrogen consumed, respectively:
dnprod
dt
dnH
dt
2
rate =
=
.
[3]

IMPLICATIONS OF HEMIKETAL FORMATION
337
Reaction Calorimetric Monitoring of Hemiketal Formation
Observations of hemiketal formation using reaction
calorimetry help to shed light on the reasons for differ-
ences between our work and the suggestion of Baiker
and coworkers (5b) that the hemiketal equilibration in n-
propanol is slow. Specifically, we show below that the pres-
ence of the Pt/Al2O3 catalyst is important in achieving rapid
formation of the hemiketal in n-propanol, while their work
did not address the role of the catalyst itself in the hemiketal
reaction in this solvent.
The heat flow was monitored for experiments in which
either cinchonidine or the Pt/Al2O3 catalyst was added to
an ethyl pyruvate–n-propanol mixture. When similiar ex-
periments are carried out in toluene (which cannot form
a hemiketal), no heat flow is observed, suggesting that
the heat release cannot be due to adsorption of the sub-
strate on the catalyst or its solution interaction with cin-
chonidine. Different alcohol solvents give results similar to
n-propanol, with the total area under the heat flow curve
increasing in the order i-propanol < n-propanol < ethanol,
consistent with their increasing propensity for hemiketal
formation. For experiments carried out in the absence of
the catalyst, the heat flow curve is consistent in each case
with hemiketal formation as measured by UV spectroscopy
FIG. 3. Heat flow curves for the formation of hemiketal from ethyl
pyruvate in n-propanol at 283 K catalyzed by the addition of Pt/Al2O3
followed by cinchonidine. Top curve: 2.5 g of 1 wt% Pt (PMC) addition
followed by addition of 350 mg cinchonidine. Bottom curve: 0.5 g of 5 wt%
Pt (E4759) followed by addition of 350 mg cinchonidine.
Figure 2 shows that the formation of the hemiketal pro-
(4,5b,9). When ethyl pyruvate hydrogenation is carried out ceeded much more rapidly in the presence of the PMC cata-
following these mixing experiments, the total area under lyst (with no cinchonidine) than it did in the presence of
the heat flow curve gives overall heats of reaction which are cinchonidine in the absence of the catalyst. The half-life for
3–5 kcal/mol lower in alcohol solvents than those measured hemiketal equilibration was less than 2 min in the pres-
in toluene, as is expected from Eq. [6]. These observations ence of the catalyst, and the process was 95% complete in
confirm that the heat release observed in Figs. 2 and 3 may less than 10 min. Addition of the modifier after this equili-
be attributed to the formation of the hemiketal.
bration gave no further heat flow. When cinchonidine was
added in the absence of the catalyst, the equilibration half-
life increased by an order of magnitude and the total equi-
libration required more than 2 h.
Baiker and coworkers (4) noted that hemiketal forma-
tion is base-catalyzed and that N-bases such as cinchoni-
dine are effective for this transformation. Grunwald(10)
has shown, however, that hemiketal formation may be cata-
lyzed by bases and also by acids. In the case shown in
Fig. 2, the alumina support may serve as the acid catalyst
for hemiketal formation. This accelerating role of the cata-
lyst would not be noted in solvents such as ethanol where
the cinchonidine-catalyzed process is inherently faster.
If alumina serves as an acid catalyst in the formation of
hemiketal, it may be important to consider the properties of
the particular alumina employed. In Fig. 3, we compare the
heat flow trace of hemiketal formation rate of the 1 wt%
Pt/Al2O3 PMC catalyst to that (on an equal Pt basis) of the
5 wt% Engelhard 4759 Pt/Al2O3 catalyst which was used in
the hemiketal studies of Refs. (4) and (5b). Figure 3 shows
that the rate was much slower in the presence of E4759;
a greater than 10-fold difference in rate, compared to the
PMC catalyst, is larger than could be accounted for simply
bythe difference in totalamount ofalumina in the two cases.
FIG. 2. Heat flow curves of ethyl pyruvate hemiketal formation in
n-propanol at 283 K catalyzed by the addition of 2.5 g Pt/Al2O3 (1 wt%
PMC) catalyst followed by 50 mg cinchonidine (top) or by 50 mg cinchoni-
dine followed by 2.5 g Pt/Al2O3 (bottom).

338
BOHNEN, GAMEZ, AND BLACKMOND
Addition of cinchonidine (seven times more than used in substrate and its hemiketal is rapid on the time scale of the
the experiment shown in Fig. 2) afforded completion of hydrogenation reaction. In this case, the sum of the rates
the process of hemiketal formation for the E4759 sample. of (hemiketal formation + hydrogenation) is proportional
Thus, it may be concluded that under some conditions the to the hydrogenation rate. The equilibrium is established
hemiketal equilibrium may indeed be perturbed by the en- by both acid and base catalysis. This work points out the
suing hydrogenation step when the E4759 catalyst is used. advantages of using multiple independent measures of in-
stantaneous reaction rate as a means of deriving mechanis-
Combined Kinetic Measurements
tic information about reaction processes.
This work shows that the use of multiple kinetic tools
provides a powerful mechanistic approach to understand-
ing complex reactions. Because they rely on different phys-
ical measurements to assess the same reaction parameter
(reaction rate), the combination of hydrogen uptake and
reaction calorimetry teaches us more about the hydrogena-
tion reaction than either can alone. The agreement between
the two methods during the initial transient period suggests
that hemiketal formation plays no special role in the rising
initial rate which was observed. This agreement also sup-
ports the suggestion that hydrogen is consumed principally
in the main reaction and not in side reactions of impurities,
unless such side reactions coincidentally exhibit rates and
thermodynamic heats of reaction identical to the rate and
heat of reaction of ethyl pyruvate and are not detectable in
the product analysis.
ACKNOWLEDGMENTS
Donation ofa Pt/Al2O3 catalyst from PreciousMetals/Activated Metals
Corporation is gratefully acknowledged. We thank the Max-Planck-
Gesellschaft for financial support of this work and W. Ko¨nen for exper-
imental assistance. Helpful discussions with J. S. Bradley and A. Pfaltz
(MPI) and Y. Sun (Merck & Co. Inc.) are also gratefully acknowledged.
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It is demonstrated both theoretically and experimentally
that reaction calorimetryprovidesa valid and accurate mea-
sure of the rate of hydrogenation of ꢀ-keto esters in alcohol
solvents, provided that a preequilibrium step between the