A re-examination of pressure effects on enantioselectivity in asymmetric catalytic hydrogenation

Article abstract of DOI:10.1021/ja952988g

Marked shifts in enantioselectivity in the asymmetric hydrogenation of several prochiral substrates were observed as a function of the availability of hydrogen to the catalyst in both heterogeneous and homogeneous catalytic reactions. The key kinetic parameter affecting enantioselectivity was found to be concentration of molecular hydrogen in the liquid phase, [H₂], rather than hydrogen pressure in the gas phase, and it was observed that under typical reaction conditions, [H₂] could differ widely from its equilibrium saturation value. It was demonstrated that the reported pressure dependence on enantioselectivity may in fact be reproduced at constant pressure for several systems by varying the rate of gas-liquid mass transfer. The general significance of the conclusions suggest that considerations of hydrogen diffusion limitations might be important in other asymmetric hydrogenation studies reported in the literature. For systems where enantioselectivity depends positively on hydrogen pressure, the intrinsic ability of a catalyst to effect asymmetric hydrogenation may be masked in a reaction carried out under conditions where gas-liquid diffusion is the rate-limiting step.

Full text of DOI:10.1021/ja952988g

1348
J. Am. Chem. Soc. 1996, 118, 1348-1353
A Re-Examination of Pressure Effects on Enantioselectivity in
Asymmetric Catalytic Hydrogenation
Yongkui Sun, Ralph N. Landau,† Jian Wang, Carl LeBlond, and
Donna G. Blackmond*,‡
Contribution from the Merck & Co., Inc., P.O. Box 2000 RY55-228, Rahway, New Jersey 07065
ReceiVed August 29, 1995X
Abstract: Marked shifts in enantioselectivity in the asymmetric hydrogenation of several prochiral substrates were
observed as a function of the availability of hydrogen to the catalyst in both heterogeneous and homogeneous catalytic
reactions. The key kinetic parameter affecting enantioselectivity was found to be concentration of molecular hydrogen
in the liquid phase, [H2], rather than hydrogen pressure in the gas phase, and it was observed that under typical
reaction conditions, [H2] could differ widely from its equilibrium saturation value. It was demonstrated that the
reported pressure dependence on enantioselectivity may in fact be reproduced at constant pressure for several systems
by varying the rate of gas-liquid mass transfer. The general significance of the conclusions suggest that considerations
of hydrogen diffusion limitations might be important in other asymmetric hydrogenation studies reported in the
literature. For systems where enantioselectivity depends positively on hydrogen pressure, the intrinsic ability of a
catalyst to effect asymmetric hydrogenation may be masked in a reaction carried out under conditions where gas-
liquid diffusion is the rate-limiting step.
Introduction
and exhaustive detail of the kinetic work and because of the
striking conclusion that the major enantiomeric product resulted
from the minor intermediate species. In those studies, spec-
troscopic and analytical data were used to propose a mechanism
and develop rate laws for the (R)- and (S)- branches of the
catalytic cycle. The observed effect of hydrogen pressure on
enantioselectivity was then rationalized in terms of the different
dependence on hydrogen concentration for the rate of formation
of each product.
Recently, these data from Halpern’s laboratory were recast
by Boudart and Djega-Mariadassou12 in terms of an example
of kinetic coupling between elementary steps in a catalytic cycle,
which can occur when the assumption of quasi-equilibrium
between reactive intermediates and reactant or product molecules
does not hold. They demonstrated that for the special case of
two catalytic cycles occurring in parallel, as in the case of
enantioselective reactions, the product selectivity may be
affected by reaction conditions such as pressure if the elementary
steps in one of the cycles are coupled to one another more
strongly than are those in the other cycle.
The purpose of the present paper is to highlight another aspect
of the kinetics of two- and three-phase catalytic systems that
plays an important role in determining enantioselectivity but
has received little attention in the literature. This work focuses
on the relationship between gas-phase hydrogen pressure and
solution concentration of molecular hydrogen during a hydro-
genation reaction, and the importance of the latter in dictating
enantioselectivity. In all of the work cited above, the measured
variable of reaction pressure is used interchangeably with the
concentration of molecular hydrogen in solution, [H2], assumed
to equal the equilibrium solubility of hydrogen, [H2]sat, at the
temperature and pressure of the reaction. This assumption holds,
however, only when the maximum rate of gas-liquid mass
transfer under reaction conditions far exceeds the rate of
hydrogen consumption by the catalytic reaction. Hydrogen
pressure, which measures reactant concentration in a phase
In many chiral hydrogenation reactions, enantioselectivity has
been shown to exhibit a marked pressure dependence. Examples
include the homogeneously catalyzed hydrogenation of a wide
variety of conjugated prochiral olefins with transition metal
catalysts containing chiral phosphine ligands,1-6 the hydrogena-
tion of imines with soluble chiral titanocene catalysts,7,8 and
the heterogeneously catalyzed hydrogenation of R-keto esters
over Pt surfaces containing chiral modifiers.9 In addition, the
role of pressure in dictating ultimate diastereoselectivity has also
been noted in substrate-directed hydrogenation reactions of
chiral substrates with achiral catalysts.10 In most of these cases,
detailed kinetic data are limited, and, as Noyori has noted,1 the
origin of this pressure effect has yet to be rationalized.
One particular case, the hydrogenation of R-acylaminoacrylic
acid derivatives over [Rh(dipamp)]+ by Landis and Halpern3,4
has become a textbook example11 both because of the elegance
* Author to whom correspondence should be directed: Donna G.
Blackmond, Institut fu¨r Technische Chemie, Universita¨t Essen, D45117
Essen, Germany. TEL 49 201 183 3922, FAX 49 201 183 3144, email
donna.blackmond@uni-essen.de.
† Present address: Sandoz Pharmaceutical Corporation, 59 Route 10, East
Hanover, NJ 07936-1080.
‡ Present address: Institut fu¨r Technische Chemie, Universita¨t Essen,
D45117 Essen, Germany.
X Abstract published in AdVance ACS Abstracts, January 15, 1996.
(1) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley
Interscience, New York, 1994; Chapter 2.
(2) Takaya, H.; Ohta, T.; Inoue, S.-I.; Tokunaga, M.; Kitamura, M.;
Noyori, R. Org. Synth. 1993, 72, 74.
(3) Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746.
(4) Halpern, J. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1985; p 41.
(5) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106.
(6) Chan, A. S. C. Chemtech 1993, March, 46.
(7) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
8592.
(8) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
11703.
(9) Blaser, H. U.; Garland, M.; Jallet, H. P. J. Catal. 1993, 144, 569.
(10) Evans, D. A.; Morrissey, M. M. J. Am. Chem. Soc. 1984, 106, 3866.
(11) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. Principles
and Applications of Organotransition Metal Chemistry, 2nd ed.; University
Science Books: Mill Valley, CA, 1987; pp 538-541.
(12) Boudart, M.; Dje´ga-Mariadassou, G. Catal. Lett. 1994, 29, 7. It
should be pointed out for clarity that the designations of (R)- and (S)- in
the original Halpern work are transposed in ref 12.
0002-7863/96/1518-1348$12.00/0 © 1996 American Chemical Society

Pressure Effects on EnantioselectiVity
J. Am. Chem. Soc., Vol. 118, No. 6, 1996 1349
different from that in which the reaction occurs, is hence a less
meaningful kinetic parameter than true solution hydrogen
concentration.
A simplified description of the pathway followed by hydrogen
from the gas phase to its incorporation into the product is given
by the consecutive reaction network
the reaction depends on the relative magnitudes of these two
constants, and two extreme cases may be described. If the
hydrogen consumption rate of the reaction is very high, so that
the interfacial mass transfer rate is approached by that of the
reaction’s requirement for hydrogen, the solution becomes
starved for hydrogen and [H2] approaches zero. The maximum
observed rate is then dictated not by kinetics but by the driving
force for mass transfer, rmax
H2(g)kTLaH2(l)kTdissH* kkin8product
(1)
d[H2]
rmax
)
) kLa*([H2]sat)
(3)
where kLa, kdiss, and kkin represent forward rate constants for
each step, H2(g), and H2(l) represent gas and liquid-phase
hydrogen concentrations, and H* represents an intermediate
species associated with the catalyst. The relative rates of these
steps determine the relative concentrations of the species shown,
and it is only when kLa is very large compared to the other
constants that the first step in the sequence can be assumed to
be in equilibrium, and the solution concentration was assumed
to be [H2]sat. Thus an additional rate process, that of hydrogen
dissolution, must be considered in order to give an accurate
general description of the concentration of hydrogen available
for the catalytic reaction, which we will show has important
implications for enantioselectivity.
This paper describes two examples of asymmetric hydrogena-
tion studies from our laboratories, one heterogeneous and one
homogeneous catalytic reaction, in which marked changes in
enantioselectivity were observed for reactions carried out by
varying the solution concentration of hydrogen even while
maintaining the reaction vessel at constant hydrogen pressure.
Moreover, we demonstrate with the kinetic data from the classic
study of Landis and Halpern3 that it is possible to reproduce
their observed variation of enantioselectivity with pressure, while
holding hydrogen pressure constant and instead systematically
changing [H2] by varying the gas-liquid mass transfer rate. The
conclusion that the interplay of mass transfer and intrinsic kinetic
rate processes may have a profound effect on enantioselectivity
is of general significance for studies in this field, suggesting
that careful scrutiny of the results of other catalytic hydrogena-
tion reactions reported in the literature may be indicated.
dt
with the variables defined as in eq 2. This equation describes
the brief transient period which always occurs when hydrogen
is first introduced to a solution, and, in the case of poorly stirred
reactors, the condition of low [H2] may persist throughout the
course of the reaction. On the other hand, if the consumption
of hydrogen by the reaction is very slow, the input required to
maintain a steady high concentration of hydrogen is small, and
the solution concentration approaches its solubility limit, [H2]sat.
The rate of change of hydrogen concentration in the solution is
then dictated by the kinetics of the reaction. This case in fact
represents the implicit assumption made in the literature
discussed above.
Thus the solution concentration of hydrogen during reaction
depends on the relative magnitudes of the hydrogen input and
consumption terms, and both pressure ([H2]sat) and mass transfer
characteristics (kLa) as well as the intrinsic kinetic constant kkin
play a role in determining [H2]. The examples given in this
paper demonstrate how enantioselectivity may be influenced
by this interplay of mass transfer and kinetic rate processes,
even for reactions carried out at constant hydrogen.
Hydrogenation of Ethyl Pyruvate over Cinchonidine-
Modified Pt/Al2O3. Enantioselectivity in the hydrogenation of
R-keto esters to R-hydroxy esters over heterogeneous catalysts
has been reported to be affected by a number of variables
including hydrogen pressure, solvent, metal particle size and
structure, and type of support.9,13-17 In our studies of the
hydrogenation of ethyl pyruvate to (R)- and (S)-ethyl lactate
Results and Discussion
Gas-Liquid Mass Transfer. The mass balance for hydro-
gen in the liquid phase during a batch catalytic hydrogenation
reaction consists of a term for hydrogen input from the gas phase
and a term for consumption of hydrogen due to the reaction:
d[H2]
)
dt
kLa*([H2]sat - [H2]) - kkin*f{[H2];[catalyst];[substrate]}
accumulation ) input - consumption
(2)
we kept all of these variables constant, including hydrogen
pressure, and instead varied the effective solution hydrogen
concentration, [H2], by experimentally changing the gas-liquid
The hydrogen input term is equal to the rate of gas-liquid mass
transfer, a function of the mass transfer rate coefficient, kLa
(units of time-1), and a concentration driving force, which is
the difference between the equilibrium solubility of hydrogen
at reaction conditions, [H2]sat, and the actual solution concentra-
tion, [H2] (both with units of mol/volume). The hydrogen
consumption term is described by the kinetic rate law for the
reaction, which in the general case is a rate constant kkin (units
depend on the rate expression) multiplied by some function of
the catalyst, hydrogen, and substrate concentrations.
(13) Singh, U. K.; Landau, R. N.; Sun, Y.; LeBlond, C.; Blackmond, D.
G.; Tanielyan, S. K.; Augustine, R. L. J. Catal. 1995, 154, 91.
(14) (a) Wehrli, J. T.; Baiker, A.; Monti, D. M.; Blaser, H. U. J. Mol.
Catal. 1990, 61, 207. (b) Garland, M.; Jalett, H. P.; Blaser, H. U. In
Heterogeneous Catalysis and Fine Chemicals II; Guisnet et al., Eds.;
Elsevier: Amsterdam, 1991; p 177.
(15) Augustine, R. L.; Tanielyan, S. K.; Doyle, L. K. Tetr. Asymm. 1993,
4, 1803.
(16) Wang, G.; Heinz, T.; Pfaltz, A.; Minder, B.; Mallat, T.; Baiker, A.
J. Chem. Soc., Chem. Commun. 1994, 2047; Minder, B.; Mallat, T.; Baiker,
A.; Wang, G.; Heinz, T.; Pfaltz, A. J. Catal. 1995, 154, 371.
(17) (a) Sutherland, I. M.; Ibbotson, A.; Moyes, R. B.; Wells, P. B. J.
Catal. 1990, 125, 77. (b) Meheux, P. A.; Ibbotson, A.; Wells, P. B. J.
Catal. 1991, 128, 387.
While kkin is an intrinsic kinetic property of the catalytic
system, kLa is strongly affected by characteristics of the reactor
vessel, including agitation speed. The magnitude of [H2] during

1350 J. Am. Chem. Soc., Vol. 118, No. 6, 1996
Sun et al.
such as solvent, metal particle size, or modifier characteristics.
Further kinetic studies of this system will be published
separately.19
Hydrogenation of Geraniol over [RuCl2(S)-tolyl-binap]2‚-
NEt3. Enantioselective hydrogenation of allylic alcohols has
been extensively studied by Noyori1,2 using homogeneous Ru-
(binap) catalysts where the enantioselectivity has been found
to be strongly pressure dependent.
Figure 1. Enantioselectivity and solution hydrogen concentration at
50% conversion as a function of the gas-liquid mass transfer coefficient
in a series of hydrogenation reactions of ethyl pyruvate over modified
Pt/Al2O3 at constant pressure of 575 kPa and 303 K. [H2] was
calculated from inserting rate data from calorimetry measurements (see
Experimental Section) into eq 2.
For hydrogenation of geraniol,2 the enantioselectivity to (R)-
citronellol using a [Ru(OCOCH3)2--(S)-binap] catalyst increased
from 70 to 98% as the reaction pressure was increased from 4
to 100 atm (400-10 000 kPa). Hydrogenation of the Z-isomer,
nerol, with the Ru(binap) catalyst of opposite absolute stereo-
chemistry afforded a similar trend of pressure and enantiose-
lectivity. Our studies of this reaction provide a second example
of the sensitivity of enantioselectivity to actual solution hydrogen
concentration under constant pressure conditions. Table 2 shows
that the enantioselectivity in geraniol hydrogenation more than
doubled with an order of magnitude increase in the mass transfer
coefficient for reactions carried at 135 kPa. This increase in
kLa also doubled the solution hydrogen concentration, effectively
allowing it to reach its solubility limit, [H2]sat, at the temperature
and pressure of the reaction.
Comparison of the last two entries in Table 2 with the first
two demonstrates how kLa and [H2]sat may each under different
conditions be important in dictating enantioselectivity. When
the magnitude of kLa was great enough so that mass transfer
was no longer the limiting step, the enantioselectivity in geraniol
hydrogenation increased from 57 to 90 ee% with a fourfold
increase in pressure (and hence [H2]sat) for reactions carried out
at constant kLa. Hydrogenation of nerol under identical
conditions of rapid hydrogen mass transfer yielded 99 ee% (to
(S)-citronellol). Interestingly, these high enantioselectivities20
were observed under conditions close to the low pressure limit
of Noyori’s study,1,2 where they reported 70% ee in both
geraniol and nerol hydrogenation. This suggests that the lower
pressure reactions described in ref 2 may have been carried out
under conditions where the solution concentration of hydrogen
was considerably lower than [H2]sat. Detailed kinetic studies
of both experimental systems described in this paper will be
published elsewhere.21
mass transfer coefficient, kLa. For our reactor configuration,
kLa was found to increase by more than two orders of magnitude
by varying the agitation speed from 400-2000 rpm.
Figure 1 demonstrates that enantioselectivity and solution
hydrogen concentration18 varied as a function of the mass
transfer coefficient kLa in these constant pressure reactions. Over
a range of agitation speeds common in standard reaction
systems, we in fact observed the spectrum of conditions
encompassing the two extreme cases described earlier, with a
rise in [H2] from nearly zero to a value approaching its solubility
limit. Moreover, the enantioselectivity increased by almost a
factor of three concomitant with the rise in [H2]. This
profoundly sensitive relationship between [H2] and enantiose-
lectivity, even at constant hydrogen pressure, emphasizes the
importance of direct knowledge of [H2] for rational kinetic
interpretation of enantioselectivity.
When the rate of mass transfer became so high that [H2]
approached [H2]sat, further increases in kLa caused no additional
increase in the enantioselectivity. Pressure determines [H2]sat
(at a given temperature) and therefore may set the upper limit
on enantioselectivity in this reaction for a given catalyst system.
Under hydrogen-starved conditions, however, the rate-limiting
step becomes equal to the rate of input of hydrogen to the
solution, in which both the mass transfer coefficient, kLa, and
the solubility, [H2]sat, play a role. From eq 3, therefore, one
may predict conditions for obtaining identical rates, and hence
identical values for [H2], in two extreme cases: for a system
exhibiting high [H2]sat and low kLa (high pressure and poor gas-
liquid mass transfer) or alternatively for a system with low [H2]sat
and high kLa (low pressure and good gas-liquid mass transfer).
The results of two such experiments are shown in Table 1. Even
for very different experimental conditions, similar gas-liquid
mass transfer rates did indeed lead to similar [H2] concentrations
when that rate was the controlling step. In addition, the
enantioselectivities obtained under these very different pressures
were identical, underscoring the importance of the actual
solution concentration [H2] as the parameter dictating enanti-
oselectivity in this system. When consideration is given to the
variation in reactor configurations employed in studies of this
catalytic system found in the literature, with the concomitant
variation in kLa and hence [H2] values, one can begin to
rationalize the wide range of reported enantioselectivities for
this system.9,12-17 In fact, unless results for this system are
compared on the basis of [H2] rather than reaction pressure, it
is difficult to interpret the role of other experimental variables
Analytical Treatment of Kinetic Data from the Hydro-
genation of Methyl-(Z)-r-acetamidocinnamate with Rh-
(18) The solution concentration was calculated by integration of eq 2
with the experimental reaction rate profile obtained from reaction calorimetry
inserted in the hydrogen consumption term and experimentally determined
kLa and [H2]sat values inserted in the hydrogen input term (descriptions of
the calorimetric and mass transfer measurements are given in the Experi-
mental Section).
(19) Sun, Y.; LeBlond, C.; Wang, J.; Landau, R. N.; Blackmond, D. G.
J. Catal. Submitted for publication.
(20) This result was obtained both for geraniol hydrogenation with the
[RuCl2(S)-tolyl-binap]2‚NEt3 catalyst) described in this paper and with the
[Ru(OCOCH3)2(R)-binap] catalyst described in ref 2 (in this case with 87%
ee to the (S)-citronellol).
(21) We have recently observed that study of the hydrogenation of
geraniol using these chiral phosphine catalysts is complicated by a separate
kinetic consideration, the existence of a competitive isomerization reaction
which can influence the ultimate enantioselectivity achieved. Nerol, the
Z-isomer of geraniol, does not undergo this isomerization (Sun, Y.; LeBlond,
C.; Wang, J.; Blackmond, D. G.; Laquidara, J.; Sowa, J. R. J. Am. Chem.
Soc. 1995, 117, 12647.

Pressure Effects on EnantioselectiVity
J. Am. Chem. Soc., Vol. 118, No. 6, 1996 1351
a
Table 1. Hydrogenation of Ethyl Pyruvate over Pt/Al2O3
pressure
(kPa)
agitation
(rpm)
[H2]sat b
(102 M)
soln H concnc
mass transfer
gas-liquid mass
enantio-
[H2] (102 M)
coeffd kLa (102 s-1
)
transfer ratee (104 M s-1
)
selectivityf (ee %)
580
300
575
750
1.26
0.63
0.11
0.11
5.2
11.5
5.98
5.98
45
45
a 1 M ethyl pyruvate in propanol at 303 K. b Measured as described in the Experimental Section. c Calculated using eq 2 in the text. d Measured
as described in the Experimental Section. e Calculated from eq 3 in the text. f Measured at 50% conversion.
Table 2. Hydrogenation Allylic Alcohols over Ru(binap)a
pressure
(kPa)
agitation speed
(rpm)
[H2]sat b
(102 M)
soln H concnc
[H2] (102 M)
mass transfer
enantio-
substrate
coeffd kLa (s-1
)
selectivitye (ee %)
geraniol
geraniol
geraniol
nerol
135
135
525
525
200
1600
1600
1600
0.33
0.33
1.2
0.15
0.33
1.2
0.0077
1.1
1.1
21
57
90
99
1.2
1.2
1.1
a 0.19 M solution of geraniol or nerol in methanol at 283 K with [RuCl2(S)-tolyl-binap]2‚NEt3. b Measured as described in the Experimental
Section. c Calculated using eq 2 in the text. d Measured as described in the Experimental Section. e Measured at 30% conversion.
Table 3. Kinetic Constants from Ref 3 for the Hydrogenation of
Methyl-(Z)-R-acetamidocinnamate with Rh(dipamp)+
typical reaction conditions. This was accomplished by inserting
the above rate equations into the term for hydrogen consumption
in eq 2 and solving the mass balance for solution hydrogen
concentration.22 [H2] was determined in this manner for
reactions carried out at the arbitrarily chosen constant hydrogen
pressure of 1000 kPa.23 The mass transfer coefficient, kLa, was
varied over the range 0.001-0.2 s-1, similar to values found in
our laboratory measurements over a range of typical reactor
agitation speeds.24 These [H2] values were then used to calculate
the rates of (R)- and (S)- formation from eqs 4 and 5, and hence
enantioselectivity, as a function of kLa.
kinetic constants
from eqs 4 and 5
(this paper)
kinetic constants
as defined in
ref 3a
values at
298 K
from ref 3
ka
kb
1.1 M-1 s-1
59 M-1 s-1
km2 aj
km2 inKm1 in
Km1 aj
min
kc
197 M-1
k
2b
min
-1
k
Figure 2 confirms that a sensitive relationship between
enantioselectivity and actual solution concentration of hydrogen
also holds for this catalytic system. By varying the mass transfer
coefficient kLa at constant hydrogen pressure, we were able to
mimic the decrease in ee (95% to 75%) found by Landis and
Halpern3 when pressure was varied by an order of magnitude.
Moreover, the rate of production of (R)- and (S)- products as a
function of [H2] shown in Figure 3 looks strikingly similar to
Figure 6 in ref 3, but in the present case the rate dependence
was found at constant pressure, compared to the pressure
variation from 0.3-10 atm employed in that work. This
confirms that the “pressure effect” is more rigorously related
to the availability of hydrogen in solution, terms which are not
necessarily equivalent.
a Kinetic variables defined according to the mechanism in Figure 2
of ref 3 where the constants found in the cycle forming the major (S)-
product from the minor intermediate species is given the superscript
{min}, and those from the cycle forming the minor (R)-product from
the major intermediate species is given the superscript {maj}.
(dipamp)+. The hydrogenation of this R-amido prochiral olefin,
studied extensively by Halpern’s group3,4 as noted earlier, leads
to high selectivity to the (S)-enantiomer
Figure 2 suggests that the implicit assumption that the solution
was near [H2]sat made in ref 3 is valid at 1000 kPa provided
that the kLa value in that experimental system was 0.05 s-1 or
greater, values which are within the capabilities of most small
stirred autoclaves at moderately high agitation speeds; however,
achieving good gas-liquid mass transfer in systems such as
These authors developed expressions for the rates of production
of each enantiomer and determined kinetic constants for this
system
(22) The rate constants used in eqs 4 and 5 were those determined at
298 K in ref 3 (see Table 3). The reaction time chosen for the integration
limit of the hydrogen mass balance was 100 s, which corresponds to
conversions of between 30 and 60% over the pressure range studied in ref
3. Reaction time is arbitrary in the present case since in this kinetic model,
which is zero-order in substrate concentration, [H2] remains constant with
conversion of substrate. It should be noted, however, that reaction time
becomes an important consideration for nonzero order substrate kinetics,
in which case [H2] will vary with extent of reaction.
d[R]
dt
) ka[H2][Rh]tot
kb[H2][Rh]tot
(4)
(5)
d[S]
dt
(23) 1000 kPa is approximately the high pressure limit of the study in
)
ref 3, with a resultant [H2]sat value of 0.025 M.
1 + kc[H2]
(24) Comparison of results obtained from different experimental apparatus
on the basis of agitation speed alone is no more rigorous than, as discussed
in the text, comparison on the basis of pressure. The mass transfer
coefficient is a strong function of reactor characteristics (including reactor
size, shape, fill level, mode of gas introduction, and type of impeller, in
addition to agitation speed). These considerations render both pressure and
agitation speed as less meaningful parameters than actual solution concen-
tration of hydrogen in attempting to compare kinetic data from different
laboratories.
where [R] and [S] represent concentrations of the two product
enantiomers, [H2] is the solution concentration of hydrogen,
[Rh]tot is the catalyst concentration, and the ka, kb, and kc are
lumped constants from ref 3 as defined in Table 3.
These detailed kinetic results afford us the opportunity to
study the solution concentration of hydrogen under a range of

1352 J. Am. Chem. Soc., Vol. 118, No. 6, 1996
Sun et al.
enantioselectivity was favored by high [H2]. Not only may
enantioselectivity be altered under conditions of poor gas-liquid
mass transfer but also valid comparisons of different catalysts
are precluded if the true kinetic behavior is masked by a rate-
limiting diffusion step.
Conclusions
In this work we demonstrate that the interplay between mass
transfer and intrinsic kinetic rate processes has the potential to
effect marked shifts in enantioselectivity in the catalytic
hydrogenation of prochiral substrates. We found that the
pressure dependence of enantioselectivity cited in several
examples of both homogeneous and heterogeneous asymmetric
catalytic hydrogenations could in fact be mimicked at constant
pressure by varying the rate at which molecular hydrogen is
transferred from the gas into the liquid phase. This suggests
that hydrogen pressure is a valid kinetic parameter only when
efficient mixing allows the solution to approach its solubility
limit for hydrogen, a condition frequently not met in typical
laboratory apparatus. The solution concentration of hydrogen,
rather than pressure, is the rigorous kinetic variable which should
be considered in comparing studies carried out under different
gas-liquid mass transfer conditions. A re-evaluation of the
experimental conditions employed in studies reported in the
literature suggests that the true kinetics, and hence the potential
for high enantioselectivity, in a number of catalyst systems may
in some cases have been obscured to rate-limiting diffusion
processes.
Figure 2. Enantioselectivity and solution hydrogen concentration at
50% conversion of substrate, as a function of the gas-liquid mass
transfer coefficient at constant pressure, using kinetic data for
hydrogenation of methyl-(Z)-R-acetamidocinnamate with Rh(dipamp)+
as described in ref 3. [H2] was calculated from inserting rate
expressions from eqs 4 and 5 (see text and Table 3) into eq 2.
Experimental Section
The heterogeneous catalytic hydrogenation of 1 M ethyl pyruvate
(Aldrich, 98%) in n-propanol (Aldrich, 99%) was carried out over a 1
wt% Pt/Al2O3 catalyst (Precious Metals Corporation) with dihydrocin-
chonidine added as a surface modifier (prepared by hydrogenating
cinchonidine, Aldrich). The substrate/Pt and Pt/modifier mole ratios
employed were 1740 and 1.2 mol/mol, respectively. The homogeneous
catalytic reaction of 0.19 M geraniol and nerol (Alfa, 99%) in methanol
(Aldrich, 99.9%) was carried out over [RuCl2(S)-tolyl-binap]2‚NEt3
(Strem) using a substrate/Ru ratio of 1400 mol/mol.
Figure 3. Rate of production of [R] and [S] enantiomers vs solution
hydrogen concentration [H2] at constant pressure using kinetic data
reported for hydrogenation of methyl-(Z)-R-acetamidocinnamate with
Rh(dipamp)+ as described in ref 3. [H2] was calculated from inserting
rate expressions from eqs 4 and 5 (see text and Table 3) into eq 2.
Kinetic data taken from ref 3.
Hydrogenation reactions were carried out in a reaction calorimeter
(Mettler RC1) with agitation speeds of 200-1600 rpm. Reaction rates
were measured by monitoring the calibrated heat flow of the reaction
as described previously.12 Briefly, the technique involves completing
an energy balance around the reacting system. Equation 6 shows that
for an isothermal, batch reacting system, the heat flow is proportional
to the reaction rate
shaker reactors or unstirred NMR tubes is problematic.25 In
addition, it is important to note that in studies of the effect of
pressure on catalytic behavior, the rate-controlling process can
change from gas-liquid mass transfer to kinetics over the range
of pressures chosen for study, even without changing other
parameters. At lower pressures, where the saturation [H2]
concentration is lower, consumption of hydrogen by the reaction
may more readily deplete the solution of hydrogen, and higher
kLa values are generally required in this situation to ensure
operation outside of the gas-liquid mass transfer controlled
regime.26
An interesting point to note in this system is that high
selectivity to the (S)-product was favored by conditions in which
the system is starved for hydrogen, and hence working in a
diffusion limited regime could be beneficial in this case. In
contrast, for the two experimental examples given above, high
dCi
qr ) Vr
∆Hrxn,i
(6)
∑
( )
dt
i
where qr is the heat released or consumed by the reaction, Vr is the
volume of the reactor contents, (dCi/dt) is the reaction rate and ∆Hrxn,i
the heat of reaction of the ith reaction. Automated data acquisition at
6-s intervals with an accuracy of better than 0.1 W afforded an
extremely accurate measurement of reaction rate throughout the
reaction.
Gas-liquid mass transfer coefficients and hydrogen solubilities in
the reaction solutions were measured as described previously.12,27 The
substrate-solvent mixture in the absence of catalyst was charged to
the reactor and degassed, and the reactor was pressurized and isolated
under hydrogen (135-525 psi). Agitation was then commenced, and
the pressure drop in the reactor was measured at a rate of 10 Hz. The
mass transfer coefficient, kLa, is given as
(25) An especially important concern is to insure that reactions carried
out in apparatus for collecting spectroscopic data mimic the mass transfer
characteristics of the same reactions completed in other apparatus used for
collecting kinetic data.
(26) The ratio of mass transfer to kinetic rates may often be increased
by changing other conditions, for instance by lowering reaction temperature
or catalyst concentration, or, in systems which have a positive dependence
on substrate concentration, working at lower substrate molarity.
(27) Deimling, A.; Karandikar, B. M.; Shah, Y. T.; Carr, N. L. Chem.
Eng. J. 1984, 29, 140.

Pressure Effects on EnantioselectiVity
J. Am. Chem. Soc., Vol. 118, No. 6, 1996 1353
were used in the hydrogen input term of eq 2. In these two experimental
studies, product selectivity, reported as absolute enantiomeric excess,
was measured by GC on a Chiraldex B-TA chiral column
(Pf - Pe)
Pi - Pe
Pi - Pf
ln
) kLa*t
(7)
[
] [P - P
]
f
where Pe is the equilibrium vapor pressure of the mixture at the
temperature of the experiment, the initial and final pressures are Pi
and Pf, and the pressure at any time t is P.
|[R] - [S]|
ee(%) )
100
(8)
[R] + [S]
The total pressure decrease until equilibrium is established also yields
the solubility of hydrogen in the solution under the conditions of the
experiment. From these parameters the maximum rate of hydrogen
delivery from the gas to the liquid may be determined by eq 3 given
in the text where the [H2]sat value is the solubility of hydrogen at the
final pressure of the experiment.
The actual solution concentration of hydrogen, [H2], was determined
by solving eq 2, given in the text, over a range of values of kLa. For
the experimental studies of the hydrogenation of ethyl pyruvate and
geraniol, eq 2 was integrated to give [H2] at different conversion levels.
The reaction rate profiles determined from heat flow calorimetry were
inserted in the hydrogen consumption term, and the kLa and [H2]sat
values corresponding to those conditions, measured as described above,
In the example involving the hydrogenation of methyl-(Z)-R-
acetamidocinnamate, the rate expressions and kinetic constants from
ref 3 (given in eqs 4 and 5 and Table 3) were used in the hydrogen
consumption term in eq 2, which was solved numerically for [H2] using
[H2]sat ) 0.025 M and kLa values in the range of those determined
experimentally in our laboratories.
Acknowledgment. Stimulating discussions with Professor
John R. Sowa, Jr. from Seton Hall University are gratefully
acknowledged.
JA952988G