Long term continuous chemoenzymatic dynamic kinetic resolution of rac-1-phenylethanol using ionic liquids and supercritical carbon dioxide

Article abstract of DOI:10.1039/b821623a

The long term continuous dynamic kinetic resolution (DKR) of rac-phenylethanol in IL/scCO₂ biphasic systems was carried out by simultaneously using immobilized lipase (Novozym 435) and acidic zeolite catalysts at 50 °C and 100 bar, providing go

Full text of DOI:10.1039/b821623a

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PAPER
www.rsc.org/greenchem | Green Chemistry
Long term continuous chemoenzymatic dynamic kinetic resolution of
rac-1-phenylethanol using ionic liquids and supercritical carbon dioxide
Pedro Lozano,*a Teresa De Diego,a Corina Mira,a Kimberley Montague,a Michel Vaultierb and
Jose´ L. Iborra*a
Received 2nd December 2008, Accepted 19th January 2009
First published as an Advance Article on the web 13th February 2009
DOI: 10.1039/b821623a
The long term continuous dynamic kinetic resolution (DKR) of rac-phenylethanol in IL/scCO2
biphasic systems was carried out by simultaneously using immobilized lipase (Novozym 435) and
acidic zeolite catalysts at 50 ◦C and 100 bar, providing good yields (up to 98.0%) for R-phenylethyl
propionate with excellent enantioselectivity (up to 97.3% ee) and without any activity loss during
14 days of operation.
beta zeolite/Novozym-catalyzed DKR of benzylic alcohols in
1. Introduction
organic/fluorous biphasic system lead to no clear improvement
The preparation of chiral drugs as single enantiomers is one
in the process (95% yield, 75% ee).3d
of the most pressing goals in pharmaceutical science because
Water-immiscible ionic liquids (ILs) have recently emerged
of the different types of biological activity exhibited by each
as exceptionally interesting green non-aqueous reaction media
enantiomer. Kinetic resolution (KR) with enzymes is the most
for biotransformations, because of the high level of activity,4a
widely used method for separating the two enantiomers of a
stereoselectivity4b and stability5 displayed by enzymes in chem-
racemic mixture. However, the main drawback of this method
is that the chemical yield is limited to 50% and, it is necessary
to incorporate a further separation step (e.g. distillation, liquid–
ical transformations. The use of ILs as suitable reaction media
for the DKR of sec-alcohols catalyzed by lipase/ruthenium
complex has been described, leading to good yields (up to 95%)
after 2–6 days of reaction.6
liquid extraction, membrane process, etc) to isolate the desired
enantiomer.1 These limitations can be overcome by combining
kinetic resolution with in situ racemisation of the undesired
enantiomer, using so-called dynamic kinetic resolution (DKR).
Classically, transition metal (e.g. Ru2+) complexes2 and, more
recently, solid acids3 (e.g. zeolites) have been described as suitable
catalysts for the racemisation of sec-alcohols via hydrogen
transfer processes. DKR based on lipases combined with
metal catalysis has been assayed in anhydrous organic solvents
(e.g. toluene) under argon atmosphere and in a discontinuous
way, providing high yields (up to 99% and ee > 99.9%) of
the enantiomerically pure ester product in 1–6 days. DKR
approaches based on lipases combined with acidic zeolite
catalysts have also been described using water/organic sol-
vent biphasic media in a discontinuous way.3b,3c The potential
value of H-beta zeolites as heterogeneous alcohol-racemisation
catalysts for benzylic alcohols in aqueous phase has been
demonstrated, while the enzymatic KR step occurred in the
organic phase, leading to a corresponding R-ester with 78%
yield and 98% ee. The use of a perfluorous acyl donor (20,20,20-
trifluoroethanol 1H,1H,2H, 2H-perfluoundecanoate) in the Zr-
Biphasic systems based on ILs and supercritical carbon
dioxide (scCO2) for enzyme catalysis have been put forward
as the first approach to developing integral green biopro-
cesses in non-aqueous media, where both the biotransfor-
mations and extraction steps are coupled in efficient reac-
tion/separation processes.7 In this context, DKR processes of
rac-1-phenylethanol (1, see Fig. 1A) in IL/scCO2 systems have
been carried out combining immobilized Candida antarctica
lipase B (CALB) with silica modified with benzenosulfonic acid
groups as catalysts in a packed bed reactor at 50 ◦C and 100
bar.8 However, the use of both catalysts as a simple mixture
resulted in a complete loss of activity, probably due to the
acid environment around enzyme particles that could produce
deactivation. Consequently, it was necessary to pack catalyst
particles in three different layers (immobilized enzyme-acid
catalyst-immobilized enzyme) physically separated by glass wool
to obtain moderate results for the R-ester product (70% yield,
92% ee).
This paper describes for the first time the continuous DKR of
1 in IL/scCO2 systems by using a combination of immobilized
R
CALB (Novozym 435ꢀ) and acid zeolite catalysts packed
as a heterogeneous particle mixture (Fig. 1). The reactor
operated as a catalytic unit able to continuously transform
rac-1 in R-2, combining the advantages of ionic liquids to
stabilize enzymes in supercritical fluids, as a non-aqueous
“green” reaction/extraction system, with the advantages of a
continuous flow process for easy product separation and catalyst
reuse.
aDepartamento de Bioqu´ımica y Biolog´ıa Molecular B e Inmunolog´ıa,
Facultad de Qu´ımica, Universidad de Murcia, P.O. Box 4021, E-30100,
Murcia, Spain. E-mail: plozanor@um.es, jliborra@um.es;
Fax: 34.968.36.41.48; Tel: 34.968.36.73.92
bLaboratoire de Chimie et Photonique Mole´culaire, UMR CNRS 6510,
Universite´ de Rennes-1, Campus de Beaulieu, Av. Ge´ne´ral Leclerc,
F-35042, Rennes, France. E-mail: Michel.Vaultier@univ-rennes1.fr;
Fax: 33.2.99.28.69.55; Tel: 33.2.99.28.62.74
538 | Green Chem., 2009, 11, 538–542
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Racemization reactions
Standard reactions were carried out in 1-mL screw-capped vials
with teflon-lined septa, containing 0.6 M S-1 and 0.6 M 3 in
hexane (0.5 mL overall volume). Reactions were started by
adding zeolite catalyst previously coated with IL [Btma][NTf2]
(5 mg) and run at 50 ◦C in a glycerol bath for 3 h. At regular time
intervals, 20 mL aliquots were taken and suspended in 480 mL
hexane, and the biphasic mixture was strongly shaken for 3 min
to extract all substrates and product into the hexane phase. Then,
400 mL of hexane phase were collected and mixed with 100 mL of
150 mM butyl butyrate (internal standard) solution in hexane,
and finally analyzed by GC. All experiment were carried out in
duplicate.
DKR of rac-1 in scCO2
Both Novozym-IL (1 g) and zeolite-IL (0.5 g) catalysts were
added to a 10-mL test tube, and the resulting mixture was
strongly shaken for 5 min at room temperature to obtain an
homogenous distribution of particles. The final mixture was
placed in the cartridge of an ISCO 220SX (Teledyne Isco, Inc,
Lincoln, NE, USA) high pressure extraction apparatus of 10 mL
total capacity. The apparatus is equipped with a syringe pump
(ISCO model 100DX, 100 mL overall volume), needle valves
and devices for pressure, temperature and flow rate control. The
ISCO system was started by the continuous pumping of scCO2
at 100 bar and 50 ◦C, which automatically opens the exit valve,
bubbling continuously the CO2 through a calibrated heated
Fig. 1 A. DKR of rac-1-phenylethanol (rac-1) catalyzed by the
combined action of zeolite and immobilized Candida antarctica lipase
B (Novozym 435). B. Experimental set-up of the continuous packed
bed reactor containing both Novozym 435 and zeolite coated with ILs,
including GC chromatograms of the substrate inlet and product exit.
2. Experimental
◦
restrictor (1 mL/min, 70 C). Synthetic processes were carried
R
Immobilized Candida antarctica lipase B (Novozym 435ꢀ, EC
out for 6 h by continuously pumping a 3:rac-1 (2:1 mol:mol)
mixture into the scCO2 inlet flow at 6 mmol/min mass-flow rate,
by using a HPLC pump (model LC-10AT, Shimadzu Europe,
Duisburg, Germany) (see Fig. 1B). Substrates and products were
transported by the scCO2 flow through the catalytic cartridge,
and then recovered by depressurizing through the calibrated
heated restrictor by 30 minutes steps in a controlled amount of
hexane placed on an ice-bath. Samples were analyzed by GC. In
all cases, substrate and product mass-balances from the outlet
were consistent with the substrate mass-flow inlet.
3.1.1.3) was a gift from Novozymes S.A. (Spain). Zeolite Beta
CP811E-150 (Si:Al molar ratio = 75), and, zeolites HY CBV400
(Si:Al = 2.5) and HY CBV720 (Si:Al = 15) were obtained from
Zeolysts International (PA, USA). Substrates, solvents and other
chemicals were purchased from Sigma-Aldrich-Fluka (Madrid,
Spain), and were of the highest purity available. The ILs 1-butyl-
3-methylimidazolium hexafluorophosphate ([Bmim][PF6], 99%
purity) and 1-butyl-2,3-dimethylimidazolium hexafluoropho-
sphate ([Bdmim] [PF6], 99% purity) were from Solvent Innova-
tion Inc. (Germany); 1-octadecyl-3-methylimidazolium bis((tri-
fluoromethyl)sulfonyl)amide ([Odmim][NTf2], 99% purity) was
obtained from IoLiTec GmbH (Germany); trioctylmethyl-
ammonium bis((trifluoromethyl)sulfonyl)amide, [Toma][NTf2],
and butyltrimethylammonium bis((trifluoromethyl)sulfonyl)-
amide, [Btma][NTf2], were synthesized as described previously.5
GC analysis
Analysis were performed with a Shimadzu GC-2010 (Shimadzu
Europe, Duisburg, Germany) equipped with FID detector.
Samples were analyzed on a Beta DEX-120 column (30 m ¥
0.25 mm ¥ 0.25 mm, Supelco) and a FID detector in the following
conditions: carrier gas (He) at 1 MPa (105 mL/min total flow);
temperature programme: 60 ◦C, 10 ◦C/min, 130 ◦C; split ratio,
100:1; detector, 300 ◦C. The retention times of compounds
were as follows: 2 (3.1 min; propionic acid (PrA, 5.6 min),
butyl butyrate (internal standard, 7.1 min), R-1 (14.4 min), S-1
(14.9 min), S-2 (18.9 min) and R-2 (19.3 min).
Adsorption of IL onto catalyst particles
In a 10-mL capacity test tube, 1 mL of IL ([Bmim][PF6],
[Bdmim][PF6], [Odmim][NTf2], [Toma][NTf2], or [Btma][NTf2])
were dissolved in 3 mL acetonitrile. Then, 1 g of catalyst
(Novozym 435 or zeolite) was added, and the mixture was
gently stirred for 30 min at room temperature. Finally, the
acetonitrile was eliminated by continuous bubbling of N2 for
30 min at room temperature. The resulting catalyst-IL particles
were equilibrated to 0.11 water activity by over saturated LiCl
solutions in closed containers at 25 ◦C for one week prior to
use.9
3. Results and discussion
To know the activity of zeolites catalyzing racemization of S-1 in
DKR conditions, these catalysts were tested in a hexane medium
containing both S-1 and 3 substrates at the same concentration.
As shown in Fig. 2, the H-Beta CP811E zeolite was a suitable
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(see Table 1). These results agreed with previous works,3b,3c,11,12
where de-aluminated zeolites resulted in fast racemization of
1: the fastest reaction rates were always observed with H-Beta
zeolites.
The ability of Novozym coated with IL to catalyze the KR of
rac-1 in continuous operation with scCO2 at 50◦C and 100 bar
has been reported to increase the yield of R-2 product by only
up to 50% with an excellent enantioselectivity (ee > 99.9).8
The suitability of acid zeolites combined with immobilized
lipase catalyzing DKR of rac-1 in non-aqueous monophasic
systems has been studied in discontinuous way.10,11 In spite
of the different organic solvents assayed (e.g. toluene, hexane,
1,4-dioxane, etc.), as well as the reactions parameters (e.g.
temperature, acyl donor, etc.), the best results were relatively
poor (71% R-1-phenyletyl acetate yield and 87.5% ee after
6 h in toluene, improving to 82% yield and 83.1% ee after
48 h reaction time).11 The encapsulation of H-Beta zeolite with
polyelectrolytes did not improve these results (70% R-1 yield and
86% ee after 72 h in toluene).10
In this context, a (chemo)biocatalytic packed bed reactor,
based on both immobilized lipase (Novozym 435) and zeolite
particles coated with ILs, was developed to carry out the DKR of
rac-1 in scCO2 phase in continuous way (see Fig. 1B). The system
operated as a biphasic reactor, the substrates being transported
by the scCO2 phase to each catalyst microenvironment across the
IL shell, and the products returning to the supercritical phase.
The stereoselective action of the enzyme permits the preferential
conversion of R-1 to R-2, while the acidic catalysts provide in situ
racemisation of the S-1 unreactive enantiomer. In this way, the
product R-2 can theoretically be obtained optically pure with a
100% yield.13
Five different ILs, i.e. [Bmim][PF6], [Bdmim][PF6],
[Odmim][NTf2], [Toma][NTf2] and [Btma][NTf2], were
assayed, and each Novozym-zeolite-IL system was tested for
6 h. The obtained R-2 yield, eeR-2 and PrA yield in the steady
state are summarised in Table 2. As can be seen in entry 1, a
low eeR-2 value (16.4%) was obtained when catalyst particles
were assayed without IL coating, in spite of the reported4–7
excellent enantioselectivity of Novozym 435 for the kinetic
resolution of rac-1, suggesting that the acidic zeolite was
indeed interfering with the pH-sensitive enzyme. This fact
was in agreement with previous works where uncoated acid
catalysts (e.g. zeolites) combined with immobilized lipases were
assayed in DKR reactions.8,10 Furthermore, the observed high
content of PrA (58.7% of inlet acyl donor 3) at the outlet of
the reactor, corresponding to the hydrolysis of the excess of 3,
is worth noting. This fact could also be related with the loss
of enzyme enantioselectivity. In this way, the use of catalyst
particles coated with [Bmim][PF6] (entry 2) greatly improved
the efficiency of the system, because the racemizing activity of
the H-Beta zeolite coupled with the enzyme catalysis was able to
increase the R-2 yield up to 73.8%, while the enantioselectivity
of the enzyme remained unchanged (99.5% eeR-2). In this case,
the undesired hydrolysis of 3 at the reactor outlet was reduced
to 23.3% of its inlet concentration, suggesting that the transport
of uncontrolled amounts of water from the CO2 tank towards
the catalytic environment was limited by the water-immiscible
IL shell coating particles. The use of other water-immiscible ILs
to cover both Novozym and H-Beta zeolite particles (entries 3
Fig. 2 Time-course profiles of ee for the racemisation of S-1 with H-
Beta CP811E zeolite (᭺), and H-Beta CP811E (᭹), H-USY CBV720
(ꢀ) H-USY CBV400 (ꢀ) zeolites coated with [Btma][NTf2] in hexane at
50 ◦C.
catalyst for the proposed reaction in agreement with previous
works, since it was able to reduce the eeS-1 from 100 to 53.6%
in 3h. Note that no synthesis of 1-phenylethypropionate was
observed. However, the undesired hydrolysis of 3 catalyzed by
the zeolite that produces propionic acid (PrA) was also detected
(see Table 1). This fact was also observed when a silica gel
modified with benzenesulfonic acid (SCX) was used as catalyst
for the DKR of rac-1 in hexane or scCO2, and is obviously a
drawback for any continuous DKR process with an equilibrated
mass-substrate concentration at the reactor inlet.8
The fact that the GC chromatograms did not show any
production of acetophenone suggest that H-Beta zeolites cat-
alyzed racemization as Brønsted acids.3c,12 Coating of this H-
Beta zeolite with [Btma][NTf2] lead to a clear decrease in the
undesired hydrolysis of 3, which was accompanied by a loss in
the racemisation reaction rate. This fact could be related with
the enhancement of mass-transfer limitations into the hexane
media resulting from the IL-coating of zeolite particles.8 In
this way, the coating of acid H-Beta zeolites by polyelectrolyte
capsules to protect the pH-sensitive enzyme CALB has also
been described as an interesting strategy that enables both
catalysts to be used in a one-pot DKR of sec-alcohols.10 In our
previous studies,8 a full enzyme deactivation was also observed
when DKR processes were carried out by using a mixture of
both immobilized lipase and SCX catalyst particles without IL
coating, probably as a consequence of the acidification of the
enzyme microenvironment.
Fajausite (H-USY) type zeolites (i.e. CBV720 and CBV400)
coated with [Btma][NTf2] were also able to catalyze the racemi-
sation of S-1, but the observed racemisation reaction rate was
clearly lower than the one obtained for the H-Beta zeolite case
Table 1 Zeolites coated with IL-catalyzed racemization of S-1 in
hexane at 50 ◦
Zeolite
C
Rate (mmol PrA at 3 h
Si/Al IL
min-1 g-1)
(%)
H-Beta CP811E
H-Beta CP811E
H-USY CBV720 15
H-USY CBV400 2.5
75
75
None
165.6
37.3
24.7
6.9
8.5
1.4
1.2
0
[Btma][NTf2]
[Btma][NTf2]
[Btma][NTf2]
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Table 2 Continuous DKR catalyzed by both Novozym (1 g) and zeolite catalysts c◦oated with IL, by pumping a 3:1 (2:1 mol:mol) mixture at
6 mmol min-1 mass-flow rate into the scCO2 inlet flow (1 mL min-1) of the reactor at 50 C and 100 bar
Entry
Zeolite
IL
R-2 Yield (%)
eeR-2 (%)
PrAi (%)
1
2
3
4
5
6
7
8
CP811Ea
CP811Ea
CP811Ea
CP811Eb
CP811Ec
CP811Ec
CBV720c
CBV400c
None
48.0
73.8
75.5
67.7
59.5
72.3
72.0
98.0
16.4
99.5
82.1
95.7
96.2
>99.0
90.4
97.3
58.7
23.3
11.3
11.1
10.4
11.7
11.9
10.7
[Bmim][PF6]d
[Toma][NTf2]e
[Odmim]][NTf2]f
[Bdmim][PF6]g
[Btma][NTf2]h
[Btma][NTf2]h
[Btma][NTf2]h
a 200 mg. b 300 mg. c 500 mg. d Bmim: 1-butyl-3-methylimidazolium. e Toma: trioctylmethylammonium. f Odmim: 1-octadecyl-3-methylimidazolium.
g Bdmim: 1-butyl-2,3-dimethylimidazolium. h Btma: butyltrimethylammonium. i With respect the mass inlet flow.
to 6) provided propionic acid concentrations lower than 12% of
the inlet mass flow 3, but did not achieve a clear improvement
in either the R-2 yield or eeR-2, in spite of the increased amount
of zeolite assayed (from 200 mg to 500 mg).
slightly reduced eeR-2 (up to 93.5). Finally, when the◦reactor was
returned to the initial supercritical conditions (50 C and 100
bar) after 9 days of operation, both R-2 yield and eeR-2 profiles
returned to the activity levels shown at initial stages, remaining
then unchanged for an additional four days of operation.
The excellences of IL-coating biocatalyst particles, as protec-
tive agents that improve both activity and stability of lipases
in adverse processes (e.g. immobilization in sol-gel derived
silica, KR in scCO2 at 100 bar and 150 ◦C, etc), have been
demonstrated.14 The effects of changes in pressure and tem-
perature on enzyme-catalyzed reactions in scCO2 have recently
been reviewed.15 In the synthesis of butyl butyrate catalyzed
by Novozym 435 in scCO2, it was observed that, within the
range 40–60 ◦C, an increase in temperature improves the enzyme
activity at all the assayed pressures (80–150 bar). However, at
a fixed temperature in the above range, an increase in pressure
resulted in a decrease in the synthetic activity of the enzyme,
and this effect was attributed to the increase in the density of
scCO2.16 However, the effect of pressure on enantioselectivity is
indeed noteworthy, although the reason for this is not clear. For
example, Matsuda et al.17 reported how the enantioselectivity of
Novozym 435-catalyzed acetylation of rac-1-(p-chlorophenyl)-
2,2,2-trifluoroethanol with vinyl acetate in scCO2 gradually
decreased when the pressure increased from 80 to 190 bar, which
was also related with changes in scCO2 density. Conversely,
for the same immobilized lipase-catalyzed continuous kinetic
resolution of rac-1, it was reported that changes in pressure did
not greatly affect conversion or enantioselectivity.18
In spite of the low racemizing activity shown by fajausite (Y-
USY) type zeolites (see Table 1), both CBV720 and CBV400
chemical catalysts were seen to be suitable for the DKR process
of rac-1 in scCO2. The use of a Novozym/CBV720 mixture (2:1
w/w) coated with [Btma][NTf2] allowed an interesting activity
level (72% R-2 yield and 90.4% eeR-2, entry 7), which was similar
to that observed for H-beta zeolite (entry 2). However, the best
results (98% R-2 yield and 97.3% eeR-2, entry 8) were obtained
for the Novozym/CBV400 catalysts mixture (2:1 w/w) coated
with [Btma][NTf2].
Fig. 3 shows the operational stability profile obtained for the
continuous DKR process catalyzed by the Novozym 435/H-
USY CBV400 catalyst mixture coated with [Btma][NTf2] in
scCO2 under different conditions of pressure and temperature.
As can be seen, both R-2 yield and eeR-2 profiles remained
practically unchanged for 6 days of operation. At 50 ◦C,
the increase in scCO2 pressure to 120 bar involved a slight
improvement in eeR-2 (up to 98.8%), while the R-2 yield was
reduced to 80%. At a pressure of 120 bar, the subsequent increase
of temperature to 60 ◦C improved the previous R-2 yield (up
to 90%) maintaining the same level of eeR-2 (up to 99.5%) A
further decrease in pressure to 100 bar at the same temperature
(60 ◦C) allowed to improve the R-2 yield (up to 97.5%), but
Conclusions
The excellent suitability of the Novozym/H USY
CBV400/[Btma][NTf2] system for the continuous DKR
of 1 in scCO2 was clearly demonstrated. Once again, the
excellent protective effect of ILs against enzyme deactivation by
temperature, CO2 and/or acidic pH was observed.5,7 This work
clearly demonstrates the exciting potential of multi-catalytic
(enzymatic or chemo-enzymatic) systems in ILs/scCO2 for
synthesizing optically active pharmaceutical drugs in green and
clean non-aqueous continuous processes. In this way, the use of
co-solvents or surfactants may aids to overcome the limitations
of scCO2 to only dissolve hydrophobic compounds, allowing to
extend the proposed methodology to the hydrophilic cases.19
Fundamental studies on (bio)catalysis in IL/supercritical
Fig. 3 Operational stability for continuous DKR catalyzed by both
Novozym 435 (1 g) and zeolite CBV400 (0.5 g) coated with [Btma][NTf2]
(1 mL and 0.5 mL, respectively) in scCO2 at 2 mmol of 1 min-1 mass-flow
rate and (A) 50 ◦C and 100 bar, (B) 50 ◦C and 120 bar, (C) 60 ◦C and
120 bar and (D) 60 ◦C and 100 bar.
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fluid biphasic media should be carried out to establish clear
criteria for specifically pairing the most appropriate IL and
supercritical fluid with the corresponding (multi)catalytic
system or bioprocess.
6 M. J. Kim, H. M. Kim, D. Kim, Y. Ahn and J. Park, Green Chem.,
2004, 6, 471–44.
7 (a) P. Lozano, T. De Diego, D. Carrie´, M. Vaultier and J. L. Iborra,
Chem. Commun., 2002, 692–693; (b) M. T. Reetz, W. Wiesenhofer,
G. Francio and W. Leitner, Chem. Commun., 2002, 992–993; (c) P.
Lozano, T. De Diego, S. Gmouh, M. Vaultier and J. L. Iborra,
Biotechnol. Prog., 2004, 20, 661–669; (d) M. T. Reetz, W. Wiesenhofer,
G. Francio and W. Leitner, Adv. Synth. Catal., 2003, 345, 1221–
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Chem., 2004, 6, 466–470; (f) S. Cantone, U. Hanefeld and A. Basso,
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8 (a) P. Lozano, T. De Diego, M. Larnicol, M. Vaultier and J. L. Iborra,
Biotechnol. Lett., 2006, 28, 1559–1565; (b) P. Lozano, T. De Diego,
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Acknowledgements
This work was partially supported by CICYT (CTQ2005-
01571-PPQ and CTQ2008-00877), SENECA Foundation
(02910/PI/05 and 08616/PI/08) and BIOCARM (BIO-BMC
06/01-0002) grants. Authors thank M. Ramiro Martinez
(Novozymes, Spain) for the gift of enzymes.
9 P. Lozano, R. Piamtongkam, K. Kohns, T. De Diego, M. Vaultier
and J. L. Iborra, Green Chem., 2007, 9, 780–784.
10 A. F. Fois, A. Yap, A. F. Masters and T. Maschmeyer, Top. Catal.,
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