Continuous Enantioselective hydrogenation of ethyl pyruvate in "Supercritical" ethan: Relation between phase behavior and catalytic performance

Article abstract of DOI:10.1006/jcat.2001.3222

Continuous hydrogenation of an α-ketoester was studied in a fixed-bed reactor over cinchonidine-modified Pt/Al₂O₃ using "supercritical" ethane as solvent. Ethane as solvent offers good enantioselectivity and very fast conversion of ethyl pyruvate to ethyl lactate. The phase behavior at 15°-50°C and 140 bar was studied in a computer controlled view cell. Elimination of the liquid-gas phase boundary in the reaction system at higher fluid density led to a significant enhancement of reaction rate only at low hydrogen concentrations. Changes in the composition of the reaction mixture with conversion had little effect on the phase behavior in the system ethane, ethyl lactate, ethyl pyruvate, and H₂. The enantioselectivity dropped strongly in the experiments conducted at up to 140°C, while the reaction rate did not increase as expected from an Arrhenius-type behavior. The unambiguous interpretation of the striking changes in rate and selectivity of high-pressure reactions requires a careful analysis of the phase behavior under reaction conditions. The obvious limitations of describing multicomponent phase behavior with that of the pure solvent was shown in the results. The consideration of the phase behavior of a binary fluid system is an ideal guide for rationalizing the phase behavior-related phenomena typical of multicomponent high-pressure reaction systems.

Full text of DOI:10.1006/jcat.2001.3222

Journal of Catalysis 200, 377–388 (2000)
doi:10.1006/jcat.2001.3222, available online at http://www.idealibrary.com on
Continuous Enantioselective Hydrogenation of Ethyl Pyruvate
in “Supercritical” Ethane: Relation between Phase
Behavior and Catalytic Performance
R. Wandeler, N. Ku¨nzle, M. S. Schneider, T. Mallat, and A. Baiker1
Laboratory of Technical Chemistry, Swiss Federal Institute of Technology, ETH Zentrum, CH-8092 Zu¨rich, Switzerland
Received November 27, 2000; revised January 26, 2001; accepted February 26, 2001; published online May 15, 2001
Most “supercritical” reactions are conducted far from a
critical point (9); still, the special effects observed in rate
and selectivity are often traced to a “critical” phenomenon,
mostly a change from a two-phase to a one-phase sys-
tem. Although the importance of phase behavior in high-
pressure systems is generally accepted, the complexity of
high-pressure multicomponent systems is often underesti-
mated. Even if the number and nature of phases present in
a reaction mixture is investigated experimentally, assump-
tion of a phase behavior similar to that of a pure fluid is
quite common. Typical phenomena inherent to multicom-
ponent systems are, e.g., coexisting phases with different
composition, fluid–fluid immiscibilities, and related discon-
tinuities of critical lines (10). Disregarding these phenom-
ena maylead to a false interpretation ofthe observed effects
in high-pressure chemistry. Note that the widely used term
supercritical is deprived of any meaning in multicomponent
systems since phase separation is still possible at conditions
beyond the mixture critical point (“retrograde condensa-
tion” (10, 11)) or the critical points of the pure components
(“gas–gas immiscibility” (10)). For convenience, the term
“supercritical” (“sc”) is used here in quotes for a dense
fluid phase at temperatures exceeding its mixture critical
point, irrespective of further liquid phases present.
Continuous hydrogenation of an -ketoester has been studied
in a fixed-bed reactor over cinchonidine-modified Pt/Al2O3 using
“supercritical” ethane as a solvent. Application of ethane as a sol-
vent offers good enantioselectivity and very fast conversion of ethyl
1
pyruvate to ethyl lactate (average turnover frequency of 15 s
at ambient temperature). The phase behavior in the temperature
range 15–50 C and at pressures up to 140 bar has been investi-
gated in a computer-controlled view cell, equipped with on-line
video imaging and recording. The changes in reaction rate and
enantioselectivity with pressure (density), temperature, and hy-
drogen concentration are interpreted by considering the number
and nature of phases present under the conditions applied. The
results illustrate the obvious limitations of describing multicom-
ponent phase behavior with that of the pure solvent. We demon-
strate that consideration of the phase behavior of a binary fluid sys-
tem is an ideal guide for rationalizing the phase behavior-related
phenomena typical of multicomponent high-pressure reaction
c
systems.
2001 Academic Press
Key Words: enantioselectivity; hydrogenation; ethyl pyruvate;
-
ketoester; supercritical ethane; high-pressure reactions; binary mix-
ture; phase diagram; fluid equilibrium.
INTRODUCTION
Application of supercritical fluids (SCFs) as solvents and
reactants attracts growing interest in both homogeneous
(1–4) and heterogeneous (4–6) catalysis. Near the condi-
tions where two phases critically merge, fluids reveal strik-
ing phenomena: some physical properties exhibit major
tunability, with possible discontinuity or divergence, and
fluctuations in density or concentrations lead to critical
opalescence (7). At temperatures above the critical value,
however, supercritical fluids lose these almost magic “criti-
cal” properties; yet, they reveal a unique combination of
gas-like and liquid-like qualities due to their intermediate
molecular density, which renders them interesting media
for chemical processes (8).
Heterogeneously catalyzed continuous hydrogenations
in supercritical solvents have been reported for a variety of
substrates (4–6); however, only chemoselective hydrogena-
tions have been studied. We propose that enantioselective
hydrogenations are well-suited test reactions to explore the
interrelation between phase behavior and catalytic perfor-
mance due to their high sensitivity to the reaction medium.
Here we report the continuous enantioselective hydro-
genation of ethyl pyruvate (EP, Scheme 1) in “supercritical”
ethane (pc = 48 bar,Tc = 32 C). Ethyl pyruvate hydrogena-
tion over cinchonidine (CD)-modified Pt isthe most studied
example of -ketoester hydrogenation (12–22), affording
up to 97.5% enantioselectivity (ee) under carefully opti-
mized conditions (23, 24). Enantioselective hydrogenation
of EP in “supercritical” ethane and CO2 has already been
investigated in a batch reactor (25), and more recently in
1 To whom correspondence should be addressed. Fax: +41 1 632 11 63.
E-mail: baiker@tech.chem.ethz.ch.
377
0021-9517/01 $35.00
c
Copyright
2001 by Academic Press
All rights of reproduction in any form reserved.

378
WANDELER ET AL.
ton equipped with another sapphire window for illumina-
tion of the system. The cell is custom-designed starting from
a commercial screw-type manual pump (SITEC Sieber En-
gineering AG, Switzerland). The setup of the view cell al-
lows the observation of even minor volumes of gaseous
and liquid phases and thus facilitates reliable static mea-
surements of equilibria using the synthetic method (27).
The view cell is designed for experiments in the temper-
ature range 20 to 200 C and at pressures up to 200 bar.
The sapphire windows at the front and back of the cell are
sealed using a PTFE O-ring and a direct metal–sapphire
sealing, respectively. The moving piston is sealed with a
combination of a PTFE/carbon–PTFE Bridgman sealing
and a PTFE O-ring. The variable volume of the view cell
is measured with a displacement transducer (Genge &
Thoma HP 22 CP) monitoring the position of the mov-
ing piston. Temperature is controlled with an oil-containing
heating jacket and a combined thermo-/cryostat (Julabo
F25 HD). Temperature is measured with a Type J thermo-
couple with on-board cold-junction temperature compen-
sation. Pressure is measured with a pressure transmitter
with integrated amplifier for high temperature and pres-
sure (Dynisco MDT422H-1/2-2C-15/46) to allow reliable
pressure measurements over a broad temperature range
at low stagnant volume. The view cell is equipped with a
magnetic stirrer (Heidolph MR 2002) for mixing and a sys-
tem of automated valves (SITEC Sieber Engineering AG,
SCHEME 1. Enantioselective hydrogenation of ethyl pyruvate over
cinchonidine (CD)-modified Pt/Al2O3 to afford (R)-ethyl lactate.
a flow reactor (26) showing that “sc” ethane in a superior
reaction medium. This preliminary studies did not include
a detailed analysis of the phase behavior under reaction
conditions.
EXPERIMENTAL METHODS
Phase Behavior Studies
The phase behavior of the system under reaction con-
ditions was investigated in a computer-controlled high-
pressure view cell of variable volume (23–63 ml), equipped
with on-line digital video imaging and recording. A
flowchart of the view cell setup is given in Fig. 1.
The magneticallystirred cellconsistsofa horizontalcylin-
der equipped with a sapphire window covering the entire
diameter (26 mm) and an opposite, horizontally moving pis-
FIG. 1. Flowchart of the high-pressure view cell including the organization of process control and acquisition of data and images. PI, pressure
indicator; PT, pressure transducer; TI, temperature indicator; TIC, temperature controller; FI, flow indicator; LI, length indicator; WI, weight indicator;
RVx, high-pressure reduction valves; MVx, magnetic valves; NVx, needle valves; HVF/HVP, manual needle valves for cell filling and purge, respectively;
RMx, mass-flow meter; MM, magnetic mixer; DM, displacement transducer; KS, cryostat; TS, thermostat; CCD, 8-bit monochrome CCD camera.

ENANTIOSELECTIVE HYDROGENATION IN “SUPERCRITICAL” ETHANE
379
Switzerland), automated needle valves (Ka¨mmer Ventile, used as diluent to prevent full conversion of EP at the flow
Germany), manual needle valves (SITEC Sieber Engi- rates chosen; the catalytic studies thus aimed at clarifying
neering AG, Switzerland), and mass-flow meters (Rheonik the influence of the phase behavior on the rate and selec-
Messgera¨te GmbH, Germany) for adding fluids into the tivity, rather than optimal usage of the continuous reactor.
system as well as purging the reactor contents after an ex- The catalyst was pretreated at 400 C by flushing with 12 ml
1
periment. Filling of the view cell can be double-checked min N2 (99.995% ) for 30 min, followed by a reductive
with the help of a balance (Mettler Toledo SG32001), on treatment in H2 (99.999% ) for 90 min. After being cooled to
which the view cell is mounted self-supportingly.
room temperature in H2, the catalyst was immediately
The phase behavior has been monitored by on-line transferred to the reactor. It has been shown that high-
video imaging with a system developed in cooperation with temperature pretreatment of Pt/alumina in H2 can dou-
Videal AG, Switzerland. The view cell can be illuminated ble the ee, and exposure to ambient air after the reduc-
with visible light of variable wavelength and intensity. The tive treatment has no significant influence on the catalyst
light is supplied by a cold light source with correspond- performance (30).
ing filters via optical fibers and a sapphire window at the
The reaction was conducted at a molar ethane : EP : H2
back of the cell. The analogue video signal transmitted by a ratio of 200 :1 :k, where k was 2, 10, or 20. A flow of 1.0 ml
monochrome 8-bit CCD camera (Kappa CF 8/4) isrecorded min 1 EP (Fluka, 97% ) was mixed with ethane (99.5% ) and
digitally (Panasonic DVCPro AJ-D230). The very sensitive H2 (99.999% ) in a static mixer before entering the reactor.
camera shows turbulences and differences in phase densi- CD (Fluka, >98% ) was fed together with EP at a molar
ties that are hardly visible without optical aids, rendering CD : EP ratio of 1 : 2500. The corresponding solution was
the observation by on-line video imaging very accurate.
prepared immediately before the reaction and kept cool
The view cell is operated using a computer-based ap- and in the dark to minimize side reactions (31). EP/CD
proach for temperature control, data acquisition and pro- and ethane were continuously fed into the reactor with an
cessing, image acquisition, and mixing. Changes in the view HPLC pump (Gilson M305). Note that minor amounts of
cell’s volume as well as in dosing of components were in- chiral modifier have to be fed continuously into the reac-
duced manually. Analogue input and output signals, as well tor to maintain the good ee with time-on-stream (32). The
as digital I/O, are handled by two 16-bit, 20 kS/s AT and ethane flowwaskept constant bya two-step expansion valve
PCI data acquisition boards (NI AT/PCI-MIO-16XE-50) (NWA PE103) and monitored with a rotameter. H2 was
via corresponding connector boards with on-board cold- continuously fed into the reactor by a six-port valve.
junction temperature compensation for the thermocouple
Conversion and ee were determined without derivati-
and relays. Serial communication with the thermostat, bal- zation with an HP 5890A gas chromatograph and a chiral
ance, and digital video recorder is managed by an ISA four- capillary column (WCOT fused silica 25 m 0.25 mm, coat-
port board (NI AT-4-RS232). The analogue monochrome ing CP Chiralsil-Dex CB, Chrompack). Enantioselectivity
video signal is captured using a monochrome image acqui- is expressed as ee (% ) = R (% ) S (% ). The ca. 1% racemic
sition board (NI IMAQ PCI-1408).
ethyl lactate impurity in EP was taken into consideration.
Software for control of the view cell was developed us- Turnover frequency (TOF) is related to the number of sur-
ing National Instruments (NI) BridgeVIEW on a Windows face Pt sites; Pt dispersion after heat treatment was 0.27
NT-based 300-MHz Pentium II computer. The approach in (33). Chemoselectivity to ethyl lactate was always 100% .
design of the software solution is similar to that of a high-
pressure batch system for in situ monitoring of heteroge-
neously catalyzed reactions reported in detail elsewhere
(28, 29).
RESULTS
Phase Behavior
The phase behavior of the reaction mixture is character-
ized by the four basic isobaric phase equilibrium transitions
Catalytic Hydrogenation
Catalytic studies were carried out in a continuous shown in Fig. 2: (i) At 20 C and low H2 concentrations, the
stainless-steel tubular fixed-bed reactor of 12.5-mm inner system consisted of a liquid EP-rich phase in equilibrium
diameter, equipped with either an electric heating or a cool- with a gaseous ethane-rich phase at low pressures. With
ing jacket. The reaction temperature was monitored with increasing pressure the amount of liquid increased, result-
an adjustable thermocouple inside the catalyst bed. Con- ing in an equilibrium of a homogeneous liquid EP/ethane
stant pressure was maintained with a pressure controller phase with a gaseous ethane-rich phase at medium pres-
(NWA).
sures, and a liquid EP/ethane single phase with dissolved
A mechanical mixture of 100 mg 5 wt% Pt/Al2O3 H2 at higher pressures. At medium pressures and higher
(Engelhard 4759) and 900 mg Al2O3 as diluent was em- H2 concentrations, a gaseous H2-rich phase persisted in
ployed, resulting in a catalyst bed length of 15 mm. The equilibrium with the homogeneous liquid EP/ethane phase,
particle size of the catalyst was 25–250 m. Alumina was saturated with H2. (ii) At 30 C, the system consisted of a

380
WANDELER ET AL.
FIG. 2. Phase behavior in the system ethane : EP : H2 as a function of pressure and temperature for a molar ratio of 200 :1 :10. The phase transitions
in the shaded area are illustrated by snapshots A–F on the right. 20 C: liquid EP and ethane fully miscible, leading to a “conventional” transition from
a gaseous system at low pressures to a liquid system at high pressures by way of a two-phase region. 30 C: liquid EP and ethane only partially miscible;
condensation of an EP-rich liquid phase at low pressures and an additional ethane-rich liquid phase as pressure is increased, leading to a liquid–liquid–
vapor equilibrium; a further increase in pressure leads to a two-phase equilibrium of ethane-rich phases and, finally, to a single liquid phase. 40 C: same
behavior as at 30 C up to the liquid–liquid–vapor equilibrium; further increase in pressure leads to an equilibrium of the liquid EP-rich phase and a
dense ethane-rich phase, with either the gaseous ethane-rich phase disappearing or critically merging with the liquid ethane-rich phase (at temperatures
slightly above 40 C) as pressure is increased. 50 C: Condensation of an EP-rich liquid phase in equilibrium with a gas-like “sc” ethane-rich phase;
transition to a single-phase system with increasing pressure. The bright round spot at the opposite end of the cell is the sapphire window used for
illumination; the outer white circle is caused by reflection of light at the outer flange of the sapphire window; the vertical thermocouple and PTFE
magnetic stirrer at the bottom of the cell are visible.
liquid EP-rich phase in equilibrium with a gaseous ethane-
rich phase at low pressures. With increasing pressure the
system went through a three-phase LLV equilibrium (EP-
rich liquid, ethane-rich liquid, and ethane/H2-rich gaseous
phase) at around 50 bar, before changing to an equilibrium
of a homogeneous liquid EP/ethane phase in equilibrium
with a gaseous ethane/H2-rich phase. (iii) At 40 C, the sys-
tem consisted of a liquid EP-rich phase in equilibrium with
a gaseous ethane-rich phase at low pressures. With increas-
ing pressure, the system again went through a three-phase
LLV equilibrium (EP-rich liquid, ethane-rich liquid, and
ethane/H2-rich gaseous phase, see Fig. 3G) whereby the up-
per two ethane-rich phases critically merged in the vicinity
of 40 C and 70 bar in an upper critical endpoint (UCEP),
as shown in Figs. 2D and 3H. Further increase in pressure
FIG. 3. Interlaced video image of the view cell showing the phase
behavior of two ethane/EP/H2 mixtures at around 40 C. (G) Three-
phase liquid–liquid–vapor equilibrium at 55 bar. (H) Critical merging
led to an equilibrium of a liquid EP-rich phase and a “sc”
ethane-rich phase at first with decreasing amount of liquid
and finally to a single-phase system. (iv) At 50 C, i.e., be-
yond the upper critical endpoint of the coexistence of the
ethane-rich phases, the system exhibited a two-phase equi-
librium of a liquid EP-rich phase and a dense fluid (“sc”)
ethane-rich phase, continuously blending into one phase at
higher pressures.
of the upper two ethane-rich phases at 70 bar, leading to an equilib-
rium of a “supercritical” ethane-rich phase and a liquid EP-rich phase.
The bright round spot at the opposite end of the cell is the sapphire
window used for illumination; the outer white circle is caused by re-
flection of light at the outer flange of the sapphire window; the ver-
tical thermocouple and magnetic stirrer at the bottom of the cell are
visible.

ENANTIOSELECTIVE HYDROGENATION IN “SUPERCRITICAL” ETHANE
381
The number and nature of phases at a given tempera-
ture and pressure depended strongly on H2 concentration.
Accordingly, the pressure required for transition to a single-
phase system increased remarkably with temperature and
H2 concentration in the system, as illustrated in Fig. 4.
Measurements with different compositions (Fig. 5), cor-
responding to reaction mixtures at conversions of 0, 50,
and 100% , showed that the overall density (which is cru-
cial for phase behavior) does not change significantly with
FIG. 5. Comparison of three different compositions, corresponding
to reaction mixtures at conversions of 0% (line), 50% (open symbols),
and 100% (filled symbols) with a molar ratio of ethane : (EP + EL) :
H2 = 200 :1 :2 at various temperatures (30 C, 35 C, 40 C, 50 C from black
to light gray). Arrow indicates the density required to reach the one-phase
region.
conversion in the entire temperature and pressure ranges
investigated.
The CD concentration in the reaction mixture was more
than an order of magnitude lower than the impurity level of
EP. Hence we assumed that the effect of CD on the phase
behavior is negligible and that the system can be well rep-
resented by the ethane/EP/H2 mixture discussed above.
Catalytic Studies
At low and medium temperatures the conversion of EP
to ethyl lactate increased with pressure, as illustrated in
Fig. 6 for the reaction at 40 C. Interestingly, the conversion
FIG. 4. Influence of pressure and H2 concentration on the overall
density and phase behavior of the reaction mixture for 30, 40, and 50 C.
Ethane : EP : H2 molar ratio = 200 :1 :k, where (᭹) k = 2, (᭿) k = 10, (᭢)
k = 20. Phases: [1] gaseous, ethane/H2-rich phase; [2] dense fluid, ethane-
rich phase; [3] liquid, EP-rich phase. Arrow indicates the density required
to reach the one-phase region. Note the significant increase in pressure
required to reach this density with increasing temperature and H2 con-
centration. The hexagons mark and label the corresponding snapshots in
Figs. 2, 3, 11, and 13.
FIG. 6. Conversion of EP (top) and phase behavior of the reaction
mixture (bottom) at 40 C as a function of overall density at various H2
concentrations. Ethane : EP : H2 molar ratio = 200 :1 :k, where (᭹) k =
2, (᭿) k = 10, (᭢) k = 20. Phases: [1] gaseous, ethane/H2-rich phase; [2]
dense fluid, ethane-rich phase; [3] liquid, EP-rich phase. Arrow indicates
the density required to reach the one-phase region.

382
WANDELER ET AL.
changed continuously with density at higher H2 concentra-
tions, irrespective of changes in phase behavior. In contrast,
at low H2 concentration the appearance of one single phase
was accompanied by a pronounced rate enhancement.
Whereas the rate enhancement with increasing pressure
persisted at 50 C for low H2 concentration, high H2 concen-
trations resulted in a slightly falling tendency in EP conver-
sion. Figure 7a shows a comparison of EP conversion at
30 and 50 C for high H2 concentration, clearly exemplify-
ing the transition of a positive influence of pressure on the
reaction rate at lower temperature to a negative effect at
50 C.
FIG. 8. Influence of pressure and H2 concentration on the enantio-
selectivity at 30 C. Ethane : EP : H2 molar ratio = 200 :1 :k, where (᭹) k =
2, (᭿) k = 10, (᭢) k = 20.
At high pressures, conversions in the range 40–70% were
found for all temperatures and H2 concentrations (at the
mass-flow rates applied). The maximum conversion de-
creased slightly with increasing temperature. Interestingly,
at 50 C and pressures exceeding 70 bar, highest conversion
was obtained at a molar EP : H2 ratio of 1 : 10. Doubling the
H2 concentration resulted in a lower conversion by 20% .
Enantioselectivity to (R)-ethyl lactate was found to ex-
hibit rising, constant, and falling tendency with increasing
total pressure, depending on the temperature and H2 con-
centration. Some examples are collected in Fig. 8. Rising ee
with pressure was observed at low temperature and H2 con-
centration, shifting to a decreasing tendency with increasing
temperature and H2 concentration. For most conditions, the
ee varied smoothly, almost linearly, with pressure, despite
evident changes in the phase behavior (Fig. 4). Since in-
creasing pressure generally resulted in higher conversion,
the enantioselectivity exhibited similar trends with increas-
ing conversion and pressure (Fig. 9). Under certain condi-
tions, however, a change from a rising to a falling trend with
increasing conversion could be identified (Fig. 9, 50 C). An-
other intriguing observation is that at low temperature and
high H2 concentration the ee dropped by ca. 10% in a nar-
row conversion range of 20% (Fig. 9). For comparison, in
conventional organic solvents the variation of ee with con-
version is minor, except the tendency to rise in the initial
transient period when impurities are present (34).
Experiments carried out in the temperature range 35 to
140 C revealed an interesting behavior of reaction rate and
ee (Fig. 10). The decline in ee at higher temperature is
FIG. 7. Typical examples of the changes in enantioselectivity and con-
version with temperature and overall density or pressure. Ethane : EP : H2
molar ratio 200 :1 :20. (᭞) 30 C; (᭢) 50 C. (a) Influence of pressure on the
conversion of EP. (b) Enantioselectivity (top) and conversion of EP (bot-
tom) as a function of overall density. Arrow indicates the density required
to reach the one-phase region.
FIG. 9. Enantioselectivity as a function of EP conversion. Ethane :
EP :H2 molar ratio = 200 :1 :2, (᭺) 30 C, (᭹) 50 C; Ethane : EP : H2 molar
ratio = 200 :1 :20, (᭞) 30 C.

ENANTIOSELECTIVE HYDROGENATION IN “SUPERCRITICAL” ETHANE
383
(verified down to 15 C) at the molar ethane : EP ratio of
200 : 1 considered here. Figure 11 illustrates this change in
EP solubility in the region of coexistence of a liquid and
gaseous ethane-rich phase, i.e., separation of a liquid EP-
rich phase at higher temperature for a system with low H2
concentration.
The solubility of EP in the ethane-rich dense phase is ex-
pected to depend mainly on the density of this phase in the
temperature range investigated (37). In fact, complete sol-
vation of EP occurred at a density of around 300 kg m 3 for
all temperatures and H2 concentrations applied, resulting
in a saturated ethane-rich dense phase under these condi-
tions. Figure 4 shows that the higher the H2 concentration in
the system, the higher is the pressure required to achieve a
density of 300 kg m 3 and thus complete solubility of EP in
the dense ethane-rich phase. Note that this isochoric pres-
sure effect of H2 exceeds significantly the pressure increase
that can be expected assuming ideal gas behavior, inde-
pendent of the number of phases present. As illustrated
in Fig. 12, this deviation from ideal behavior became more
pronounced with increasing pressure, due to interaction of
H2 with the dense phase(s). Thisphenomenon is not surpris-
ing under the conditions applied. However, it questions the
common practice in high-pressure hydrogenations when in-
terpretingthe influence ofH2 “partialpressure” on the cata-
lyst performance.
The major influence of temperature and H2 concentra-
tion on the pressure required to obtain a single-phase sys-
tem is illustrated in Fig. 13. The matrix in temperature and
H2 concentration shows the condensation of a new EP-
rich liquid phase from the single-phase reaction mixture
via an isoplethic increase in temperature, or an isothermal
increase in H2 concentration, at temperatures and pressures
well above the critical values of the pure solvent (ethane,
Tc = 32.2 C, pc = 48.8 bar). This striking observation
FIG. 10. Influence of temperature on conversion and ee in the hydro-
genation of EP at 100 bar and molar ethane : EP : H2 ratios of 200 :1 :k.
Open symbols: k = 2, filled symbols: k = 20. Catalyst amount was 10 times
lower than under standard conditions.
probably due to a change in the adsorption mode of CD. As-
suming that the adsorption mode changes from adsorption
via the quinoline ring (parallel to the Pt surface) to tilted ad-
sorption (35), it can be inferred that at higher temperature
the modifier no longer adopts the appropriate adsorption
geometry for the enantio-discriminating interaction with
EP (21, 22).
The weak dependence of reaction rate on temperature
can be explained by the two counteracting factors: (i) en-
hancement of rate with increasing temperature, and (ii) loss
of ligand acceleration effect at higher temperature due to
inappropriate anchoring of the modifier. Another factor in-
fluencing the dependence of reaction rate and ee on temper-
ature could be partial hydrogenation of the quinoline moi-
ety which is expected to be more pronounced at higher H2
concentration (36). Although experiments were performed
at two different hydrogen concentrations the results cannot
give a conclusive answer to which of the factors discussed
is more important.
Finally, it should be stressed, that the continuous enan-
tioselective hydrogenation in “supercritical” ethane af-
forded remarkably fast reaction with good ee. At best, a
TOF of 15 s 1 at 70% conversion was obtained at 25 C. In
comparison, using toluene as a solvent at ambient tempera-
ture provided a TOF of 1.8 s 1 under otherwise comparable
conditions and optimal H2 concentration.
DISCUSSION
FIG. 11. Interlaced video image of the view cell showing the phase
behavior of an ethane : EP : H2 mixture with 200 :1 :2 molar ratio. (I) 15 C;
EP is completely soluble in the liquid ethane-rich phase. (J) 31 C, during
expansion; liquid EP and ethane are partially immiscible (three-phase
liquid–liquid–vapor equilibrium with a thin film of a liquid EP-rich phase
at the bottom of the cell); note the emerging gas bubbles (H2) in the liquid
ethane-rich phase during expansion. For an explanation, of the general
features of the snapshots cf. Fig. 3.
Phase Behavior of the Reaction System
The reaction system exhibited a diverse phase behavior
in the parameter range considered. Liquid ethane and EP
exhibited only partial miscibility at temperatures exceeding
ca. 25 C, while being fully miscible at lower temperatures

384
WANDELER ET AL.
In contrast to pure fluids, binary fluid–fluid phase equi-
libria exhibit most of the phenomena found in multicom-
ponent mixtures. The relatively simple binary fluid phase
equilibria therefore provide a practically useful basis for
generalization of phase equilibrium principles (38), and are
suitable for rationalizing the phase behavior-related phe-
nomena typical of multicomponent reaction systems. How-
ever, note that phase equilibria are not necessarily reached
in a flow reactor. Nevertheless such considerations are a
valuable guide for the interpretation of the role of phase
behavior in catalytic performance. Binary diagrams can be
described by three dimensions and correspondingly be de-
picted in, e.g., p,T, x diagrams (pressure, temperature, com-
position). In weighing model accuracy against complexity,
we propose to describe the phase behavior of reaction mix-
tures by binary fluid phase equilibria.
Even for binary fluid mixtures, phase diagrams reveal a
great variety (10). To comprehensively discuss the phenom-
ena encountered in such systems, it is of advantage to clas-
sify the various types of topologies. The classification used
here is that introduced by Scott and van Konynenburg (39,
40). They predicted qualitatively five types of binary fluid
phase diagrams by applying the empirical van der Waals
equation of state to binary mixtures and recognized a sixth
type empirically found in binary systems.
FIG. 12. Pressure increase induced by isochoric addition of H2 to a
mixture of ethane and EP at 40 C, leading to a mixture with a molar
ethane : EP : H2 ratio of 200 :1 :10 as a function of the overall density of the
ethane/EP mixture. Full line : H2-induced pressure increase as measured;
dashed line: pressure increase as expected from ideal gas behavior. Arrow
indicates the density required to reach the one-phase region.
demonstrates the danger of assuming that the phase be-
havior of a multicomponent system is similar to that of the
pure solvent—another practice often encountered in inter-
preting reactions in “supercritical” solvents.
Solubility of H2 in the liquid phases decreased with in-
creasing temperature and decreasing pressure. The pres-
sure effect on H2 solubility in the ethane-rich liquid phase
is illustrated in Fig. 11(J), where emerging gas bubbles on
expanding the system are clearly visible.
These observations illustrate the influence of temper-
ature, pressure, and H2 concentration not only on the
number and nature of phases present in the reaction
mixture, but also on their composition. Phase behavior,
comprising the composition of phases present in the sys-
tem, does inevitably vary with changes of the reaction
parameters. These variations should therefore be consid-
ered throughout the process for an unequivocal interpre-
tation of the differences in rate and selectivity of the
reaction.
Modeling Phase Behavior with a Binary Fluid Mixture
The fact that coexisting phases are in general of differ-
ent composition, and the possibility of fluid–fluid immis-
cibilities and related discontinuities of critical lines, ren-
der phase diagram topologies of multicomponent systems
rather complex. Since these phenomena do not occur with
pure fluids, multicomponent phase behavior cannot satis-
factorily be approximated by the simple topology of a pure
fluid phase diagram. On the other hand, a detailed con-
sideration of the real multicomponent system, in our case
ethane/H2/EP/ethyl lactate/CD, is of questionable value
in a discussion of high-pressure reactions when weighed
against the complexity thus introduced.
FIG. 13. Matrixofinterlaced video imagesofthe viewcellshowingthe
dependence of phase behavior on temperature and H2 concentration. The
reaction mixture consists of one phase at the conditions applied in (F), (K),
and (L). An increase in temperature from conditions (K) or an increase in
H
2 concentration from conditions (L) resulted in condensation of a new
liquid EP-rich phase in (M) well above the critical values of ethane. For
an explanation of the general features of the snapshots cf. Fig. 3.

ENANTIOSELECTIVE HYDROGENATION IN “SUPERCRITICAL” ETHANE
385
The phase behavior of our reaction system can be under- higher-temperature section of phase diagrams found in type
stood in terms of immiscibility of the EP-rich and ethane- IV and V binary mixtures. The isopleth at composition xm
rich dense phases at higher temperatures, interfering with in this diagram shows the same phase topology as found in
the gas–liquid critical line of the ethane-rich phases. It the hydrogenation reaction mixture—self-evidently, apart
can be approached in the parameter range considered us- from a higher degree of freedom for the three-phase equi-
ing a binary fluid phase diagram of type IV or V as a libria found in the five-component mixture examined. The
model. Binary mixtures conforming to types IV and V change in phase behavior with pressure in the temperature
reveal complete miscibility of liquid phases at intermedi- range 20–50 C (Fig. 2) may be well approximated by that of
ate temperatures with the presence of a region of liquid– the binary model, as illustrated in Fig. 15. The binary fluid
liquid immiscibility up to higher temperatures and thus model embeds the experimentally observed phase behav-
interference with the gas–liquid critical line and the ad- ior into a broader context. It ameliorates the qualitative un-
dition of a low-temperature liquid–liquid immiscibility in derstanding of the multicomponent phenomena observed,
type IV. Figure 14 shows qualitatively an axonometry of the such as the difference in phase behavior observed at 30
and 40 C (Fig. 2), or the critical merging of the ethane-rich
phases at around 40 C. Furthermore, it provides a feasi-
ble basis for extrapolation of the observed phase behavior
to other temperatures and pressures, a prerequisite for the
rational design of further experiments.
Interpretation of EP Hydrogenation on the Basis
of Phase Behavior
The number and nature of coexisting phases during EP
hydrogenation exhibited significant changes in the temper-
ature, pressure, and H2 concentration range examined. The
observed variations in reaction rate and ee (Figs. 4, 6–9)
may well be interpreted on the basis of this phase behavior
study.
A dramatic effect of H2 concentration on the reaction
rate has been achieved by varying the overall density
(Fig. 6). In the low-density region, where the EP-rich liq-
uid phase coexists with the ethane-rich gas phase, EP is
hydrogenated predominantly in the liquid phase. In con-
trast, at high overall density the reaction is confined to the
ethane-rich, liquid or “supercritical” single phase. The pre-
dominant locus of reaction thus changes from the liquid
EP-rich phase at low overall density to the dense (liquid or
“sc”) ethane-rich phase at high overall density. At high H2
concentrations, this transition apparently occurs smoothly
with increasing pressure (see Fig. 6). At low H2 concen-
tration, however, the hydrogenation of EP in the EP-rich
liquid phase is relatively slow due to H2 mass-transport lim-
itations in the EP-rich liquid phase. The shift of the hydro-
FIG. 14. Qualitative axonometry and corresponding intersections of
genation reaction to the ethane-rich dense phase with in-
creasing pressure eliminates the mass-transport limitation,
as reflected in the remarkable increase in EP conversion
where single-phase conditions are reached.
There is a generally observed trend that increasing pres-
sure (density) accelerates the reaction (see Fig. 6). This
correlation can be traced to a faster hydrogenation reac-
tion in the ethane-rich dense phase and/or an increase in
residence time in the catalyst bed. The almost constant
EP conversion, independent of pressure, at 50 C and high
H2 concentration (Fig. 7) can be attributed to another ef-
fect: with increasing H2 availability and temperature, an
the high-temperature section of a binary mixture showing type IV or type
V phase behavior. , Component of higher volatility; , component of
lower volatility; L, liquid phase; Li, liquid phase rich in component i; V,
gaseous (vapor) phase. Combinations of L, Li, and V denote equilibria of
mutually saturated phases and are emphasized by differing crosshatched
filling of the corresponding two-phase area. Full line (in intersections):
bubble-point line; dashed line (in intersections): dew-point line. (᭺) Crit-
ical point of the pure component; (᭹) mixture critical point (gas–liquid
or liquid–liquid); (M) upper critical endpoint (UCEP); (᭞) lower criti-
cal endpoint (LCEP); (᭜) parameters of phases in equilibrium in L L V
equilibrium shown in intersections. Note that the three-phase equilibrium
L L V appears as a plane perpendicular to the p, T plane in p, T, x space.
The isopleth at x = xm shows the same phase topology as found in the
reaction mixture in the parameter range observed (see Fig. 15 right).

386
WANDELER ET AL.
FIG. 15. Number and nature of phases in the hydrogenation reaction mixture (left), and the isopleth at composition xm in the binary fluid mixture
phase diagram used to model the phase behavior of the reaction (right; axonometry of the corresponding phase diagram is given in Fig. 14). Note
the similarity in the phase behavior of the binary model and reaction mixture, apart from the degree of freedom for the three-phase liquid–liquid
vapor equilibrium. , Component of higher volatility; , component of lower volatility; L, liquid phase; Li, liquid phase rich in component i; V, gaseous
(vapor) phase. Combinations of L, Li, and V denote equilibria of mutually saturated phases and are emphasized by differing crosshatched filling of the
corresponding two-phase area. The dewpoints for the reaction system (bottom left) have been estimated on basis of the vapor pressure of EP calculated
from a two-parameter corresponding state equation (46) using the ambient boiling point and the critical temperature and pressure (calculated in accord
using the Ambrose method as well as the Joback modification of Lyderson’s method (46)) as a reference.
acceleration of the competing hydrogenation of the aro-
As illustrated above, the changes in reaction rate and
matic ring system of CD is expected. This transformation ee during the enantioselective hydrogenation of EP can be
leads to weaker adsorption of the modifier on the Pt surface interpreted with the knowledge obtained in the study of
and, thus, to a loss of its enantio-differentiating ability (36, phase behavior of the ethane/H2/EP system.
41). Since CD not only provides the chiral information for
A comparison with the pertinent literature shows that
EP hydrogenation but also accelerates the reaction (42–44), the complexity of phase behavior—comprising the changes
consumption of the major part of CD should have a neg- in composition of the phases—is often not contemplated
ative effect on the hydrogenation rate. A similar negative sufficiently in the interpretation of high-pressure reac-
effect can also be caused by temperature-induced changes tions. Without investigation of the phase behavior, strik-
in the adsorption mode of CD, as discussed in the context ing changes in rate and selectivity are frequently attributed
of Fig. 10.
to an “expected” transition from two-phases to one-phase,
The variations of enantioselectivity as a function of den- i.e., the appearance of a single “sc” phase. Although in the
sity (and conversion) have to be attributed to several over- present literature the necessity of studying the phase be-
lapping effects. Higher enantioselectivity is expected in the havior of a multicomponent system is widely accepted, rel-
ethane-rich dense phase due to stabilization of a favor- atively little effort is made to experimentally confirm the
able conformation of CD in the strongly apolar medium phase behavior under reaction conditions. Description of
(45). Elimination of H2 transport limitation in the dense the system’s phase behavior with the phase behavior topol-
(“supercritical”) phase leads to higher actual surface hy- ogy of a pure fluid does not take into account the possible
drogen concentration, which in turn has a positive influ- changes in phase composition (and, correspondingly, sur-
ence on the ee (13, 34). Acceleration of the competing face concentration on a heterogeneous catalyst). It leads
hydrogenation of the aromatic ring system of CD is ex- to an unacceptable oversimplification of the system under
pected with increasing H2 availability and temperature. consideration. It has been shown that, in contrast to pure
Unfavorable adsorption of CD on Pt at higher temper- fluids, the phase diagram of binary systems is a very useful
ature also diminishes the ee. Superposition of these ef- and appropriate tool for rationalizing the phase behavior
fects leads to an increase in ee with increasing pressure of multicomponent systems.
at low H2 concentration and temperature, whereas the
From a technical point of view it is important that the
opposite trend is established at higher H2 concentration process in “supercritical” ethane facilitates an easy and
and temperature. These effects may lead to more complex complete separation of the solvent from the reactants and
variations as indicated by the bell-shaped ee conversion products by simple expansion of the reaction mixture at the
correlation in Fig. 9.
reactor outlet.

ENANTIOSELECTIVE HYDROGENATION IN “SUPERCRITICAL” ETHANE
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387
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We have shown the feasibility of heterogeneously cata-
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-
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and good enantioselectivity were achieved by continuous
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rate, whereas the effect on ee was less beneficial. Changes
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ethyl pyruvate, ethyl lactate, H2.
Experiments performed in the temperature range up
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The study confirms that unambiguous interpretation of
the sometimes striking changes in rate and selectivity of
high-pressure reactions requires a careful analysis of the
phase behavior under reaction conditions. The observed
effects in systems far from a critical point have to be in-
terpreted on the basis of this analysis, contemplating the
unique combination of liquid-like and gas-like qualities
for phases of intermediate density (“supercritical” phases).
The complex phenomena inherent to multicomponent sys-
tems are absent in pure fluids, which difference explains
why the solvent is an inappropriate model for the phase
behavior of a reaction mixture. The combined catalytic
and physicochemical study of EP hydrogenation demon-
strates that the phase behavior of binary systems is an ideal
guide for understanding high-pressure multicomponent
reactions, particularly when weighing model accuracy
against complexity.
19. Margitfalvi, J. L., Talas, E., and Hegedu¨s, M., Chem. Commun., 645
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ACKNOWLEDGMENTS
31. Ferri, D., Bu¨rgi, T., Borszeky, K., Mallat, T., and Baiker, A., J. Catal.
193, 139 (2000).
32. Ku¨nzle, N., Hess, R., Mallat, T., and Baiker, A., J. Catal. 186, 239
(1999).
Financial support by the Swiss National Science Foundation and the
Swiss Kommission fu¨r Technologie und Innovation (KTI) is gratefully
acknowledged.
33. Schu¨rch, M., Schwalm, O., Mallat, T., Weber, J., and Baiker, A., J. Catal.
169, 275 (1997).
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