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Hydrogenation in supercritical 1,1,1,2 tetrafluoroethane (HFC 134a)

Andrew P. Abbott,a Wayne Eltringham,a Eric G. Hope*a and Mazin Nicolab
Received 27th May 2005, Accepted 11th August 2005
First published as an Advance Article on the web 2nd September 2005
DOI: 10.1039/b507554h

Conventional, unmodified, transition metal catalysts, substrates and reagents have sufficient
solubility in sc HFC134a for organic synthesis. Reactivities (100% conversion in 2 h) and
enantioselectivities (ca. 90%), comparable to those achievable in conventional organic solvents,
are obtained in the asymmetric hydrogenation of a series of substrates in this alternative reaction
medium using a rhodium(I)/MonoPhos catalyst.

Introduction phosphinite, phosphite and phosphoramidite ligands, but the

results are, at best, modest.12
Supercritical fluids (SCFs) have received a huge amount of These studies suggest that, for asymmetric hydrogenation at
attention, in both academia and industry, as alternative least, the apolarity of scCO2 is a significant issue. However, we
reaction media for more environmentally friendly chemical have previously shown that some hydrofluorocarbon (HFC)
processes.1–4 The key advantages of SCFs arise from their fluids such as difluoromethane and 1,1,1,2 tetrafluoroethane
tuneable polarity, high mass transport rates and environmental (HFC 134a) are relatively polar solvents,13–15 even in the sc
compatibility. Most studies have concentrated on scCO2 state, and this allows them to be used as efficient extraction
because of the easily accessible critical constants, cost and solvents either on their own or in conjunction with CO2.16,17
low toxicity, exemplified by the recent launch of a scCO2-based Furthermore, these solvents are also readily available and non-
commercial hydrogenation process by Thomas Swan.5 Whilst toxic. They have easily accessible critical constants (HFC 134a
the range of reactions evaluated in SCFs is large, the number Tc 5 374.1 K; pc 5 40.6 bar and CH2F2 Tc 5 351.1 K;
of examples of asymmetric induction are few1–4 and these are pc 5 57.8 bar), gaseous dipole moments of about 2 D15
virtually all restricted to scCO2. Asymmetric hydrogenation of and very high densities in the sc state. HFCs have been
a,b-unsaturated carboxylic acids by [Ru(OAc)2(BINAP)] in proposed as useful solvents for synthesis in the sc state and we
scCO2 was reported to afford low conversions and low have recently shown the first examples of the use of CH2F2 for
enantioselectivities, although both the conversion and ee’s the radical polymerisation of methylmethacrylate,18 the
could be improved when the ligand was made more CO2-philic
Friedel Crafts alkylation of anisole19 and the esterification of
by saturating two of the naphthyl rings.6 Solubility in scCO2
benzoic acid.20 Here, we report our results using sc HFC 134a
can also be enhanced by the introduction of perfluoroalkyl
as a convenient, environmentally benign solvent, for enantio-
substituents, for example in the 6,69-positions of the BINAP
selective hydrogenation.
ligand.7,8 However, we observed poor reactivity and enantio-
selectivity in the hydrogenation of dimethyl itaconate in
scCO2, which we have ascribed to the apolarity of the solvent.8 Results and discussion
We,8 and others,6,9 have observed enhanced conversions and The study took two parts. Initially, Wilkinson’s catalyst was
improved enantioselectivities for such ruthenium-catalysed used for the homogeneous hydrogenation of styrene, as a test
asymmetric hydrogenations in scCO2 by the addition of polar reaction, to establish catalytic protocols and the viability of
additives, such as methanol. However, here we add a note of HFC 134a as a solvent for hydrogenation. Subsequently,
caution since, under carefully controlled conditions, in our enantioselective hydrogenation in HFC 134a was evaluated
work it appears that the reaction is essentially finished before using a rhodium/MonoPhos catalyst generated in situ.
the conditions for scCO2 had been reached.8 Asymmetric Wilkinson’s catalysts have often been used as model systems
hydrogenation of a-enamides with a cationic Rh-DuPHOS for the homogeneous hydrogenation of alkenes in liquid
catalyst has been made possible by using a highly fluorinated, solvents21–23 and hence it was initially used for the hydro-
CO2-philic anion,10 and a similar approach has been adopted genation of styrene in sc HFC 134a. Although the solubility of
for the enantioselective hydrogenation of an imine with a [RhCl(PPh3)3] in HFC 134a could not be measured quantita-
cationic iridium catalyst.11 We have also shown that the
tively, a visual inspection using the cell shown in Fig. 1 showed
addition of a highly fluorinated anion offers improvements
that fully homogeneous solutions of Wilkinson’s catalyst in
in both reactivity and asymmetric induction in the asymmetric
HFC 134a up to 3 6 1023 M, at 383 K in the pressure range of
hydrogenation of dimethylitaconate with cationic rhodium
50–280 bar, could be readily prepared. In marked contrast, a
complexes containing perfluoroalkylated monodentate
similar experiment using 1.3 6 1023 mol dm23 [RhCl(PPh3)3]
a
in CO2 at 313 K in the pressure range 50–120 bar did not show
Chemistry Department, University of Leicester, Leicester, UK any evidence of catalyst dissolution. This is a significant
LE1 7RH. E-mail: egh1@le.ac.uk; Fax: +44 116 252 3789
b
Advanced Phytonics Ltd, Olway Works, Healey Road, Ossett, observation indicating that HFCs can be used as reaction
West Yorkshire, UK WF5 8LT media for homogeneous catalysis without the need for

This journal is ß The Royal Society of Chemistry 2005 Green Chem., 2005, 7, 721–725 | 721
 Fig. 1 Schematic diagram of the high-pressure apparatus used in this work.

co-solvents or modification of catalytic species, such as the The pressure dependency of the hydrogenation of styrene at
addition of perfluoroalkyl-ponytails, which is often a require- 383 K was also investigated and the results are shown in Fig. 3.
ment for homogeneous catalytic reactions in scCO2.1 The results had a reproducibility of ¡3% and the change in
Firstly, the time dependency of the hydrogenation of dielectric constant with pressure for the pure HFC 134a
styrene (6.56 6 1023 mol dm23) in sc HFC 134a, using solvent at 383 K is also shown.15 Reactions were carried out at
2.20 6 1026 mol dm23 of [RhCl(PPh3)3] and 0.57 mol dm23 of constant mole fraction in order to observe the effect of
hydrogen at 383 K and 100 bar total pressure, was pressure on the % conversion and rule out the possibility of
investigated. The results are shown in Fig. 2. It can be seen dilution effects as pressure is increased. The mole fractions
that the reaction reached maximum conversion after 1.75 h used are the same as those used in the time dependency study
and, therefore, subsequent hydrogenation reactions were at 383 K and 100 bar (Fig. 2). It can be seen that the %
carried out for 2 h to ensure that the reaction had gone to conversion increases with increasing pressure and this is
completion. The time dependency results are generally the attributed to the higher dielectric constant of HFC 134a at
average of at least two determinations and a reproducibility of higher pressures. It was suggested by Wilkinson et al.21,22 that
¡3% was obtained. Analysis of the data in Fig. 2 yields a the rate determining step for the hydrogenation of olefins
reaction rate of 167 ¡ 5 mmol dm21 h21 which is comparable involves the formation of an activated complex, which has a
to that reported for the hydrogenation of styrene in toluene.23 greater dipole moment than the reacting species and that some
charge separation is occurring during the formation of the

Fig. 2 Time dependency of the hydrogenation of styrene in HFC

134 using 2.20 6 1026 mol dm23 of [RhCl(PPh3)3] and 0.57 mol dm23 Fig. 3 Pressure dependency of the hydrogenation of styrene using
of hydrogen at 383 K and 100 bar total pressure. [RhCl(PPh3)3] in HFC 134a at constant mole fraction and 383 K.

722 | Green Chem., 2005, 7, 721–725 This journal is ß The Royal Society of Chemistry 2005
activated intermediate. The formation of such an activated
complex is likely to be more favourable in more polar solvents
and is, therefore, more favourable in HFC 134a at higher
pressures (higher dielectric constant).
This initial study, the first to use HFC 134a as a reaction
medium, demonstrates that both catalytic species and
substrates have sufficient solubilities without modification
to afford homogeneous hydrogenation conditions, and that
reactions rates comparable to those in liquid solvents can be
obtained.
The asymmetric hydrogenation studies in sc HFC 134a were
performed using [Rh(COD)2BF4] {bis(1,5-cyclo-octadiene)-
rhodium(I) tetrafluoroborate} as the catalyst precursor and
the monodentate (R)-MonoPhos ligand in a 1 : 2 ratio.
MonoPhos, an air- and moisture-stable species, is easily
prepared from readily available starting materials and it has
been shown that it can facilitate highly enantioselective Fig. 4 Pressure dependency of % conversion for the asymmetric
rhodium-catalysed hydrogenations in conventional solvent hydrogenation of substrates 1a–3a in HFC 134a at 383 K.
systems,24,25 whilst BF4 electrolytes have been shown to be
highly soluble and extensively dissociated in HFC 134a,26,27
making such a rhodium/MonoPhos catalyst ideal for investi-
gating asymmetric hydrogenation in sc HFC 134a. Reactions
were carried out using itaconic acid, dimethyl itaconate and
(Z)-a-acetamido-cinnamic acid (1a, 2a and 3a respectively in
Scheme 1) as model substrates. Prior to the catalytic studies in
HFC 134a, we benchmarked the rhodium/(R)-MonoPhos
catalytic system and our methodology in the hydrogenation
of 1a–3a in conventional organic solvents, where conversions
and enantioselectivities very similar to those reported pre-
viously were obtained.28
In HFC 134a hydrogenations were carried out at 383 K
under a variety of pressures at constant mole fraction, so that
dilution effects could be ruled out and the results are shown in
Fig. 4 and 5. The results shown for the pressure dependency
had a reproducibility of ¡4% whereas those for the enantio-
selectivity have a larger error of ¡8%. It can be seen from Fig. 5 Pressure dependency of enantiomeric excess for products
Fig. 4 that the % conversion during the asymmetric hydro- 1b–3b in HFC 134a at 383 K.
genation reactions shows a similar dependence on pressure as
those seen for styrene using [RhCl(PPh3)3] in Fig. 3 and the conflicting influences acting during the reaction; a negative
same reasoning is offered to explain these trends. For steric effect and the positive effect of increasing dielectric
conversions less than 100% it can be seen that the trend constant. At lower pressures it is suggested that the reaction is
follows the order 1a . 2a . 3a for a given pressure. One under steric control and steric factors are hindering olefinic
possible hypothesis for these observations is that there are two binding to the rhodium metal centre. The steric hindrance
around the position of unsaturation for each substrate follows
the trend 1a , 2a , 3a. At higher pressures the dielectric
constant becomes the influencing factor and the % conversion
increases to its maximum value of 100%.
In contrast to our studies on asymmetric hydrogenation in
scCO2,8 the enantioselectivities for the hydrogenation of 1a–3a
in HFC 134a (Fig. 5) are comparable to some of those
obtained in liquid solvents, which suggests that HFCs are
promising alternative solvents for asymmetric hydrogenation
of olefinic substrates. Within experimental error the enantio-
selectivities at constant mole fraction show no dependency on
pressure and, therefore, no dependency on the dielectric
constant of HFC 134a. These results are consistent with those
of de Vries and co-workers28 who carried out solvent screening
studies with the rhodium/MonoPhos catalyst using the methyl
Scheme 1 Reactions studied for asymmetric hydrogenation. ester of (Z)-a-acetamido-cinnamic acid and found that % ee

This journal is ß The Royal Society of Chemistry 2005 Green Chem., 2005, 7, 721–725 | 723
varied from 70 (methanol) to 95 (DCM) It was concluded that develop an ideal supercritical fluid extraction process, for the
non-protic solvents lead to higher enantioselectivities than separation of reagents and products, using a counter-current
protic ones and that the effect of solvent polarity could be separating column.32 This, coupled with the high solubility
ruled out. of catalysts and reagents, suggests that HFC 134a is a
It is well known that the concentration of hydrogen can have useful alternative to CO2 as solvent for reactions in the
an effect on the enantioselectivity during asymmetric hydro- supercritical state.
genation.29 Here, it was found that the % ee remained roughly
constant at 89 ¡ 2%, in the hydrogenation of 1a at 383 K Experimental
and 100 bar total, by varying the initial hydrogen pressure
from 2 to 20 bar. These results complement those obtained (R-)MonoPhos was prepared by the literature route,33 and all
using conventional organic solvents employing rhodium/ other reagents/products were commercial samples and used as
MonoPhos24,25,28 and rhodium/MonoPhos-based30 catalysts received.
that have illustrated that the hydrogen pressure has no effect The high-pressure cells were constructed from 316 stainless
on enantioselectivity, and suggest that the mechanism of steel and were heated using 240 V, 250 W band heaters
rhodium/MonoPhos catalysis is the same in sc fluids as in supplied by Walton Ltd. The temperature was controlled and
liquid solvents. maintained (¡0.5 K) using CAL 9900 heater/controllers
A study by Poliakoff et al.31 showed that the critical fitted with an iron/constantan thermocouple, the tip of which
parameters of CO2 were reduced during the hydrogenation of was in contact with the solvent close to the centre of the cell.
propane as the ratios of reagents to products changed. Here, The high-pressure seals between the body of the cells and the
a-acetamido-cinnamic acid was used as the substrate in a cell tops were provided by Teflon1 supported, standard nitrile
qualitative set of experiments to investigate the phase o-rings. The cells had 3 cm thick walls, a maximum working
behaviour of the HFC 134a hydrogenation system. A wind- pressure of 1 kbar and were rated to 1.5 kbar. Each high-
owed vessel was loaded with the same concentration amounts pressure system was fitted with pressure relief valves set
of 3a and catalyst used for the asymmetric hydrogenation to 300 bar for safety. Pressure was applied using a Thar
reactions and the system was pressurised with HFC 134a. This Technologies P-Series piston pump filled with polytetrafluoro-
process was repeated twice more using the same concentration ethane (PTFE) composite seals in order to accommodate the
amount of catalytic material but with a 50/50 substrate/ use of hydrofluorocarbon (HFC) solvents.
product mixture and with product alone (emulating the The high-pressure system used for the hydrogenation work
reaction going to completion). It was found from these is shown schematically in Fig. 1. The catalyst-loading chamber
investigations that, at 383 K, the lowest pressure at which is a 3 6 0.3 cm length of stainless steel pipe sealed at each end
multi-phase behaviour was observed was around 35–38 bar, by a valve. V1 is a two-way needle valve and V2 is a two-way
which is a small reduction on the critical pressure of pure HFC ball valve with a polychlorotrifluoroethylene (PCTFE) seat.
134a (40.59 bar). Above 38 bar and throughout the pressure The substrate was placed into the reaction vessel and the
dependency studies (Fig. 4) the system was in a single catalyst was loaded into the catalyst-loading chamber. In the
homogeneous phase. case of air- and moisture-sensitive catalysts the chamber was
loaded in a glove box and sealed under nitrogen using V1 and
V2. The cell was heated to the desired temperature and
Conclusion
evacuated to ensure the reaction vessel was air- and moisture-
This work has shown the first example of a reaction in sc free. The vessel was charged with the required amount of
HFC 134a. It has been demonstrated that homogeneous hydrogen and then pressurised with the appropriate solvent
catalysts can be used for hydrogenation reactions without the using the P-Series piston pump. The solvent gas was passed
need for co-solvents or fluorous ponytails. The hydrogenation through the catalyst-loading chamber, which flushed the
of styrene with Wilkinson’s catalyst was used as a model catalyst into the reaction vessel, thus starting the reaction.
system and it was found that reaction rates comparable to, and When using HFC solvents, cooling was applied before the gas
in some cases higher than, those in liquid solvents were entered the pump because the pump is more efficient at
obtained. The high reaction rates are attributed to the higher pumping liquids. The reaction was left for the desired amount
diffusivity of gaseous hydrogen in the supercritical media of time and the products/unreacted starting materials were
when compared to that in liquid solvents and the percentage collected by depressurisation into the larger volume collection
conversion is dependent on the solvent dielectric constant, vessel. The products were analysed using NMR (DPX 300),
which can be tuned by manipulating the HFC 134a system GC-MS (Perkin Elmer) and GC (Perkin Elmer Autosystem
pressure. XL controlled by Turbochrom software). The enantiomeric
High conversions and enantioselectivities have been obtained excess values for the hydrogenation of dimethyl itaconate and
for the asymmetric hydrogenation of a range of substrates a-acetamido-cinnamic acid were determined by GC using a
using a rhodium-MonoPhos catalyst in HFC 134a, which Chiraldex B-DM column. The enantiomeric excess values
suggests that HFCs are promising alternatives as reaction for the hydrogenation of itaconic acid were determined
media for the industrially important asymmetric hydrogena- using polarimetry. Absolute configurations for the itaconic
tion process. We have recently shown that methylsuccinic acid and dimethyl itaconate hydrogenation products (methyl-
acid (1b) and itaconic acid (1a) have significantly different succinic acid and dimethyl succinate) were determined by
solubilities in HFC 134a and that this has been used to comparison with commercially available enantiomerically pure

724 | Green Chem., 2005, 7, 721–725 This journal is ß The Royal Society of Chemistry 2005
products and that for acetylalanine, was determined using GC 12 D. J. Adams, W. Chen, E. G. Hope, A. J. West, J. Xiao and
A. M. Stuart, Green Chem., 2003, 5, 118.
literature data.34 13 A. P. Abbott and C. A. Eardley, J. Phys. Chem B, 1998, 102, 8574.
The reagent amounts for the constant mole fraction 14 A. P. Abbott and C. A. Eardley, J. Phys. Chem, B, 1999, 103, 2504.
asymmetric hydrogenation studies were 8.25 6 1025 mol of 15 A. P. Abbott, C. A. Eardley and R. Tooth, J. Chem. Eng. Data,
1999, 44, 112.
substrate and MonoPhos, 4.13 6 1027 mol of Rh(COD)2BF4
16 A. P. Abbott, C. A. Eardley and J. E. Scheirer, J. Phys. Chem., B,
and 1.65 6 1024 mol of H2 gas for reactions conditions of 1999, 103, 8790.
100 bar and 383 K. All other reactions were based on these 17 A. P. Abbott, C. A. Eardley and J. E. Scheirer, Green Chem., 2000,
mole fraction values. 2, 63.
18 A. P. Abbott, P. W. Dyer, E. G. Hope, S. Lange and S. Vukusic,
In a typical catalytic evaluation, small quantities of reagents Green Chem., 2004, 6, 81.
were introduced into the cell by dissolving the solid in an 19 A. P. Abbott, N. E. Durling and E. G. Hope, Chem. Phys. Chem.,
appropriate organic solvent and transferring the solution using 2005, 6, 466.
20 A. P. Abbott, N. E. Durling and E. G. Hope, J. Phys. Chem. B,
a Gilson pipette. The air-sensitive catalyst was dissolved in
2004, 108, 4922.
dried and degassed solvents and transferred into the catalyst- 21 S. Montelatici, A. van der Ent, J. A. Osborn and G. Wilkinson,
loading chamber in a glove box. The number of moles of J. Chem. Soc. A, 1968, 1054.
hydrogen was converted to pressure values using data from the 22 G. Wilkinson, R. D. Gillard and J. A. McCleverty, Comprehensive
Coordination Chemistry, Pergamon Press, Oxford, 1987.
NIST Chemistry WebBook.35 23 E. G. Hope, D. W. Kemmit, D. R. Paige and A. M. Stuart,
J. Fluorine Chem., 1999, 99, 197.
24 X. Jia, R. Guo, X. Li, X. Yao and A. S. C. Chan, Tetrahedron
Acknowledgements Lett., 2002, 43, 5541.
25 A.-G. Hu, Y. Fu, J.-H. Xie, H. Zhou, L.-X. Wang and Q.-L. Zhou,
The authors would like to thank Advanced Phytonics Ltd and Angew. Chem. Int. Ed. Engl., 2002, 41, 2348.
EPSRC (GR/R 05802) for funding this work. 26 A. P. Abbott and C. A. Eardley, J. Phys. Chem. B, 2000, 104, 9351.
27 A. P. Abbott, C. A. Eardley, J. C. Harper and E. G. Hope,
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