Efficient enhancement of copper-pyridineoxazoline catalysts through immobilization and process design

Article abstract of DOI:10.1039/c0gc00775g

Copper-pyridineoxazoline (Cu-pyox) complexes are poor homogeneous catalysts for asymmetric cyclopropanation reactions. Pyox ligands have been immobilized by polymerization of monomers possessing a vinyl group directly attached to position 6 with styrene a

Full text of DOI:10.1039/c0gc00775g

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PAPER
Efficient enhancement of copper-pyridineoxazoline catalysts through
immobilization and process design†
C. Aranda,a A. Cornejo,a J. M. Fraile,b E. Garc´ıa-Verdugo,c M. J. Gil,a S. V. Luis,c J. A. Mayoral,b
V. Martinez-Merino*a and Z. Ochoaa
Received 4th November 2010, Accepted 27th January 2011
DOI: 10.1039/c0gc00775g
Copper-pyridineoxazoline (Cu-pyox) complexes are poor homogeneous catalysts for asymmetric
cyclopropanation reactions. Pyox ligands have been immobilized by polymerization of monomers
possessing a vinyl group directly attached to position 6 with styrene and divinylbenzene. The
corresponding heterogeneous catalysts show a significant enhancement in enantioselectivity, up to
7-fold that of the analogous homogeneous Cu-pyox catalysts. This effect is due to a synergic effect
between the proximity of the polymeric backbone and the presence of a bulky substituent in the
chiral oxazoline ring around copper. The obtained values of enantioselectivity are similar to those
found with supported C2-symmetric bis(oxazolines), but with only half the chiral information
given the presence of only one oxazoline ring in pyox. Besides, the co-polymerization in the
presence of the right porogen inside a column allows the preparation of monolithic mini-flow
reactors. Continuous flow processes contribute to further improve the catalytic efficiency in both
classical solvents (dichloromethane) and neoteric greener ones, such as supercritical CO2. The use
of scCO2 as solvent yields the same selectivities obtained in batch processes in combination with
higher productivity avoiding the use of VOC.
of the success, at a laboratory scale, of many enantioselective
Introduction
homogeneous catalysts,2 only a few of them have found in-
Catalysis is one of the foundation pillars of green chemistry.
dustrial application,3 due to several issues that hamper their
The greenness of chemical transformations is closely related to
transference from lab to large scale processes. Chiral catalysts
the use of catalysts.1 Catalysis can improve the efficiency of a
are normally expensive and difficult to prepare through multi-
reaction by lowering the energy input required, by avoiding the
step synthetic sequences. Besides, a high catalytic loading (1–
use of stoichiometric reagents, and by obtaining higher product
10 mol%) is usually required. Furthermore, metal can leach from
selectivity. Furthermore, catalysts can be designed to mimic
the homogeneous catalyst into the products, being particularly
enzyme behaviour, leading to highly chemo- and enantioselective
unacceptable for pharmaceutical production. Therefore, easy
chemical transformations. This is of great importance, particu-
procedures for the isolation, recovery, and reuse of chiral
larly, for fine chemicals, drugs and agrochemicals, products in
catalysts are demanded.
general characterised by the presence of a diversity of stereogenic
The immobilization of chiral catalysts can help to overcome
centres.
some of above-mentioned issues.4 Moreover, it is considered
Among the different methodologies to synthesize enantiomer-
advantageous because of the ease of separation, with the
ically enriched compounds, the use of a chiral chemocatalyst
possibility of reuse, increasing in this way the productivity of the
represents in principle a highly attractive procedure. In spite
catalyst.5 However these advantages do not seem to be enough to
consider immobilized catalysts suitable for industry, mainly due
to the increase in cost associated with immobilization, together
with reduced activity and enantioselectivity reported in many
cases.6 Nevertheless, the covalent bonding of the chiral ligand to
an insoluble support remains the most popular immobilization
method, as it prevents the possible leaching of the valuable chiral
ligand.7
The synthetic effort must be then compensated by additional
advantages, such as improved activity, chemoselectivity,8 or
enantioselectivity, as a consequence of the “positive polymeric
aDepartment of Applied Chemistry, Universidad Publica de Navarra,
E-31006, Pamplona, Spain. E-mail: merino@unavarra.es
bInstituto de Ciencia de Materiales de Arago´n and Instituto Universitario
de Cata´lisis Homoge´nea, Universidad de Zaragoza-C.S.I.C., E-50009,
Zaragoza, Spain
cDepartment of Inorganic and Organic Chemistry, Universidad Jaume I,
E-12071, Castellon, Spain
† Electronic supplementary information (ESI) available: Synthe-
sis details and experimental procedures are given. See DOI:
10.1039/c0gc00775g
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effect”,9 and operational advantages, allowing process design
moving from batch to continuous flow processes, which leads
to cleaner, simpler and more efficient catalytic asymmetric
processes.10 In this paper, we describe the synthesis of supported
chiral catalysts, which are more efficient in terms of productivity
and (enantio)selectivity than the related homogenous ones,
being one of the few examples in which catalytic efficiency is
significantly enhanced by the immobilisation onto a polymeric
support.
the organic substrates (styrene 6.15 M, EDA 2.05 M and decane
0.41 M were delivered at a constant rate by an HPLC pump.
Both feed streams were mixed by a dynamic mixer before being
passed through the monolithic catalytic bed stabilized at 40 ◦C.
Products were collected after a single stage depressurization of
the fluid mixture by an electronic backpressure regulator and
analyzed.
Results and discussion
Immobilisation strategy: let the polymer play an active role!
Experimental
In general, a structural modification of the catalyst is required
in order to attach it to a polymeric support. This modification
can have a big impact on the efficiency of the corresponding
supported catalyst. Usually, the immobilisation is carried out
on commercially available polymeric supports, which are not
optimised for immobilisation, thus leading to deceiving catalytic
performances. Hence, it is generally concluded, not necessarily a
correct idea, that “the best homogeneous catalyst will remain
the best upon immobilization”, assuming that the polymeric
matrix can have either no effect, in the best case, or a negative
one, leading to less efficient catalysts upon the immobilisation.
Thus, since the pioneering work of Soai and coworkers, spacers
have been used to attach the ligand to the polymer by a point
remote from the active site (tail-tie, Fig. 1),13 hoping that the
catalyst will be able to mimic a solution-like behaviour reducing
any possible “polymeric (negative) effect”. This approach, not
always successful, disregards the role played by the polymeric
matrix, concentrating only on the simple isolation and ease of
reuse provided by the insoluble resin.
Safety note: Some of the experiments described in this paper
involve the use of relatively high pressures and require equipment
with the appropriate pressure rating. It is the responsibility of
individual researchers to verify that their particular apparatus meet
the necessary safety requirements.
All chemicals were reagent grade and used as purchased.
All reactions were performed under an inert atmosphere of
dry nitrogen. THF and toluene were distilled on sodium and
1
dichloromethane was distilled on phosphorous pentoxide. H
and 13C NMR spectra were recorded at 200 MHz and 50 MHz
in a Varian Gemini 2000 spectrometer at 293 K, using CDCl3
as the solvent. Chemical shifts are given in ppm using the
residual signal from CHCl3 as the reference. High resolution
mass spectrometry ESI+ spectra were recorded on a Bruker
MicroTOF-Q Spectrometer using MeOH as the solvent. IR
spectra were collected on a Nicolet Avatar 360 FT-IR spec-
trometer. The cyclopropanes used for analytical determinations
were synthesized an analyzed as previously reported.11 Asym-
metric cyclopropanation (ACP) yields and cis/trans ratio were
measured by GC using a HP-1 column. Enantiomeric excesses
were measured by GC using a CyclodexB column
The detailed syntheses and characterisation of the compounds
(1, 3–7 and 10–12) as well as corresponding polymers are given
in the ESI.†
Cyclopropanation under batch conditions
To a stirred solution of pyox (0.06 mmol) in anhydrous DCM,
Cu(TfO)2 (22 mg, 0.06 mg) was added. After 30 min stirring
the solution was microfiltered. To the resulting solution, styrene
(0.69 mL, 6.0 mmol) and a known amount of decane (ca. 80 mL)
were added. To this stirred solution 2 mL of a 1 M solution of
ethyl diazoacetate (EDA) in DCM were added during 2 h and
the resulting mixture was stirred overnight.
Cyclopropanation under continuous flow conditions
Fig. 1 Immobilization strategies for pyox ligands.
Continuous flow experiments were performed using a reactor
set-up as previously reported.12
A more difficult, but probably better, approach is the design of
both ligand and polymeric matrix specifically to obtain a given
supported catalyst. Accordingly, through the optimisation of
the ligand and support, the same matrix effect that leads to bad
results after immobilization of a good homogeneous catalyst
might be able to improve a bad one. Some results based on
systematic studies clearly reflect how the presence of the well-
designed support can be advantageous to increase the efficiency,
especially, in terms of activity and selectivity of the supported
species relative to that of the homogeneous ones.9
Using DCM as the solvent. A fresh mixture of styrene (1.5
M), EDA (0.5 M) and n-decane (0.14 M) in anhydrous DCM
was pumped through the monolithic column at different flow
rates using a HPLC pump. Samples were collected and analyzed
every 30 or 60 min. Significant results are given when the product
stream was stabilized after reaching the steady state (ca. 1 h).
Using scCO2 as the solvent. CO2 was pressurised and deliv-
ered by a refrigerated pump running in constant flow mode and
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Table 1 Routes used in the synthesis of 1a
Oxazoline-containing ligands are among the most useful
chiral ligands for enantioselective catalysis.14 Therefore their im-
mobilization by different methods has been deeply studied.15 The
complexes of pyridineoxazoline (pyox) with several metals have
been used as catalysts for different synthetic transformations
leading to moderate to good enantioselectivity.16–19 However, Cu-
pyox have shown poor performance in terms of enantioselectivity
in asymmetric cyclopropanation (ACP).20 Therefore, they would
be a good example to demonstrate that the polymeric matrix
might have a positive effect leading to more efficient catalysts
upon immobilisation.
Even considering the wide variety of applications of these
ligands, only two previous publications report the immobi-
lization of pyox ligands via covalent bonding to polymeric
supports.21,22 In both cases, the pyox ligand was separated from
the polymeric matrix by the introduction of a spacer (Fig. 1).
Here, we propose the immobilisation of the ligand to maximise
the possible polymeric effect. Hence the introduction of a vinyl
group directly in position 6 of the pyridine ring may favour any
steric hindrance or electronic effect provided by the polymeric
backbone.
Route
Solvent
Steps
Yield (%)
E factor
A
DCM
Toluene
Toluene
5
2
2
23
31
65
1982
358
137
B (path 1)
B (path 2)
needed in order to complete the reaction, and that chromatog-
raphy is required as a final purification step. However, in a
novel one-pot method to synthesize pybox ligands starting
from 2,6-pyridinedicarbonitrile,27 a stoichiometric amount of
aminoalcohol was used with Zn(TfO)2 as catalyst. Besides, only
aqueous workup of the reaction mixture was required. Using
this methodology, the compound 5 was obtained by reaction of
6 with (S)-valinol with 75% yield. Once again, bromine can be
replaced with a vinyl group via Stille coupling (Route B-Path 1,
Scheme 1).
Considering that the lowest yield was obtained in the Stille
coupling step of both synthetic routes (A and B-path 1,
Scheme 1), the synthesis of 6-vinyl-2-pyridinecarbonitrile (7)
was alternatively evaluated (route B-path 2). Thus compound 7
was prepared from 6 with good yield (78%). Subsequent reaction
of the nitrile 7 with the (S)-valinol and Zn(TfO)2 as catalyst
gave the ligand 2-[(S)-4,5-dihydro-4-isopropyl-1,3-oxazol-2-yl]-
6-vinylpyridine 1a (vinyl-pyox) with 83% yield.
It is noteworthy that the synthetic methodology based in the
route B-path 2 significantly reduced the number of steps as
well as isolation and purification of intermediates, leading to a
significant decrease in the E factor (Table 1). Besides, the global
yield for the synthesis of vinyl-pyox 1a was improved from 23%
yield (route A) to 65% yield (route B-path 2).
Once this synthetic methodology was optimised, the vinyl-
pyox ligand 1b derived from (S)-tert-leucinol was also prepared
following route B-path 2 with 52% global yield.
Synthesis and immobilisation of vinyl-pyox ligand
The synthesis of 6-vinyl-pyox ligand (1a) can be performed
following the Nishiyama protocol. This synthetic pathway
involves five reaction steps (route A, Scheme 1).23 Thus, the
compound 5 was obtained with an overall yield of 57% (referred
to the aminoalcohol). Finally, bromine was replaced by a vinyl
group via Stille coupling with 41% yield of 1a. Each step requires
the isolation and purification of the intermediates in a rather
tedious and wasteful synthetic procedure with moderate global
yield (23%).
The preparation of the corresponding supported ligands
was carried out by bulk polymerisation of 1 with styrene (8)
as co-monomer and divinylbenzene (DVB, 9) as cross-linking
agent in toluene at 80 ◦C for 24 h (Table 2). The content of
immobilized ligand was determined by nitrogen analysis, which
can be assimilated to that of the corresponding polymerization
mixture.
Table 2 Copolymerization conditions of vinyl-pyox ligandsa
Scheme 1 Reaction conditions. Route A: (i) COCl2, DMF, DCM; (ii)
(S)-valinol, DCM, Et3N; (iii) SOCl2, DCM; (iv) NaH, Et4NI, 18C6,
THF; (v) tributylvinyltin, Pd(PPh3)Cl2, toluene. Route B: Path 1: (vi) (S)-
valinol, Zn(TfO)2, toluene, reflux; Path 2: (vi) aminoalcohol, Zn(TfO)2,
toluene, reflux.
Polymer
1 (%)b 8 (%)b 9 (%)b % N mmol pyox/g Yield (%)c
PS-DVB-1a 6.9
PS-DVB-1b 7.0
42.1
42.0
50.9
51.0
1.58 0.55
1.79 0.64
99
99
a Toluene was used as porogen. Co-polymerization was initiated by
AIBN and carried out at 80 ◦C using a monomers/porogen mass ratio
of 2 : 3. b Expressed in % molar amount. c Compared with the content of
ligand in the initial mixture.
Alternatively, the oxazoline ring can be prepared in a single
step starting from the nitrile 6 and (S)-valinol in the presence
of a metal salt as a catalyst.24–26 The main drawbacks of this
synthetic methodology is the large excess of chiral aminoalcohol
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Batch ACP of styrene with EDA
supported Cu-pyox system, for similar polymeric composition
and ligand loadings, achieved slightly better chiral induction
than that obtained for related immobilized bis(oxazolines) with
only half of stereogenic centres involved in the asymmetric
induction (Fig. 3).28
Polymers PS-DVB-1a and PS-DVB-1b were complexed with
Cu(OTf)2, thoroughly washed and tested as catalysts for ACP in
batch processes. The results obtained are gathered in Fig. 2.
Fig. 3 “Chirality economy” of pyox vs. box in ACP.
Fig. 2 Enantioselectivity of homogeneous vs. heterogeneous pyox-
Cu(II) catalysts in the ACP between styrene and EDA. Reaction
conditions: styrene/EDA = 3, 6% catalyst, dichloromethane solvent,
rt, slow addition of EDA (data for pyox(iPr) from ref. 20).
In order to demonstrate this positive “polymeric effect”, a
ligand with a phenoxy spacer (12) was also synthesized start-
ing from 6-(4-bromophenoxy)-2-pyridinecarbonitrile (10). This
would be the immobilization choice if the common statement
“the support is a necessary evil, and the catalyst must be placed
far away from it in order to obtain a solution-like behaviour”
were assumed. In this case, if the catalysts will behave as in
solution, a reduction in enantioselectivity should be observed.
The compound 10 was obtained via nucleophilic replacement
of bromine of 6 by 4-bromophenoxyde anion with 83% yield
(Scheme 2). Stille coupling with tributylvinyltin led to 11 in 88%
yield. The subsequent oxazoline 12 was obtained by reaction
of 11 with (S)-tert-leucinol in 87% yield after purification.
Polymerisation of this monomer 12 with styrene 8 and DVB
9, under conditions similar to those previously employed (Table
2) yielded polymer PS-DVB-12.
In addition to the corresponding cyclopropanes, both ho-
mogeneous and heterogeneous Cu complexes yield diethyl
fumarate and maleate, resulting from EDA homo diazo cou-
pling. The polymeric catalysts gave lower yields, ca. 20%,
than the homogeneous ones, ca. 60%. It is worth noting that
Cu(II) has to be reduced to Cu(I) in the first step, before the
carbene intermediate formation. A lower reduction rate, as a
consequence of diffusion limitations, may account for this lower
yield. Regarding diasteroselectivity, a slight decrease from ca.
65–69% trans in homogeneous phase to ca. 56% trans with
the supported catalyst was also found. However, a remarkable
enhancement in enantioselectivity was observed.
In contrast with the almost no-enantioselection obtained with
both Cu-pyox(iPr) and Cu-pyox(tBu) catalysts in solution,20 the
analogous supported catalysts led to significant enantioselectiv-
ity values (Fig. 2), 46% ee (cis) and 40% ee (trans) for PS-DVB-1a
and 65% ee (cis) and 56% ee (trans) for PS-DVB-1b.
These results seem to indicate the positive role played by
the proximity of the polymeric backbone to the catalytic site.
The steric hindrance provided by the rigid highly cross-linked
polymeric backbone around the position 6 of the pyridine, in
connection with the chiral information in the oxazoline ring
with the bulky substituent, may increase the steric hindrance
in several of the possible transition states, responsible for the
enhancement in enantioselectivity. At the same time, this may
minimize the steric interaction between the phenyl group of
styrene and the ester group of the carbene, responsible for the
diastereoselectivity.
Scheme 2 Reaction conditions: (i) 4-bromophenol, K2CO3, DMF,
100 ◦C, (ii) tributylvinyltin, Pd(PPh3)Cl2, toluene; (iii) (S)-tert-leucinol,
Zn(TfO)2, toluene; (iv) 8 and 9, AIBN, toluene, 80 ◦C.
The catalytic behavior of the corresponding supported cop-
per(II) complex of PS-DVB-12 was evaluated for ACP bench-
mark reaction. It is noteworthy that the introduction of the
spacer, which pushes the polymeric matrix further away from
the catalytic center, led to a reduction of the enantioselectivity
compared with that obtained for the same catalyst closely
Furthermore, a certain “chirality economy” regarding the use
of starting chiral aminoalcohol was also observed. Indeed, the
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Table 3 Recycling of immobilized Cu-pyox complexes in batch ACPa
Supported pyox Run Yield (%) cis : trans % ee cisb % ee transb
Table 4 Preparation of mini-flow monolithic reactors by polymeriza-
tion conditions of vinylic pyox ligand with styrene (8) and DVB (9)
Mini-flow
reactor (pyox)
mmol pyox
vinyl-pyoxa 8a (%) 9a (%) dod/tolb per g
1a
Hom 55
31 : 69
44 : 56
44 : 56
44 : 56
48 : 52
50 : 50
8
4
PS-DVB-1a
1
2
3
4
5
17
30
30
28
22
46
47
48
42
39
40
40
37
32
29
Mf-R1 (i-Pr)
Mf-R2 (t-Bu)
Mf-R3 (t-Bu)
7.0 (1a)
6.7 (1b)
6.3 (1b)
41.8
63.0
45.1
51.2
30.3
48.6
4.5
5.1
4.8
0.38
0.42
0.44
a Expressed in % molar amount. b Dodecanol/toluene ratio (w/w). Co-
polymerization was initiated by AIBN and carried at 70 ◦C using a
polymeric mass/porogen mass of 2 : 3.
1b
Hom 64
36 : 64
43 : 57
44 : 56
45 : 55
47 : 53
47 : 53
10
65
64
59
57
50
8
PS-DVB-1b
1
2
3
4
5
18
41
42
43
19
56
57
51
51
43
as the cross-linking agent, with a mixture of toluene and 1-
dodecanol, as the porogenic agent (Table 4).12 The mini-flow
reactors were attached to a HPLC pump and after complexation
with Cu(OTf)2 a solution of EDA and styrene in DCM was
pumped through the reactor.32 The first measurements were
taken once the observed yields were stable. During this initial
period the solution of reagents, passing through the reactor,
acts as an additional “cleaning” agent for any non-specifically
bonded copper triflate.
The results for the continuous flow ACP using Cu-pyox(iPr)
catalytic mini-flow reactor (Mf-R1) are summarized in Table 5.
Two different reactor assemblies were evaluated. A continuous
single pass flow set-up was firstly used. Alternatively a semi-
continuous process, where the reaction mixture was recirculated
through the mini-flow reactor several times, was also assayed.
Some interesting features can be drafted when the results for
the flow processes are compared with those obtained for batch
analogous homogeneous or heterogeneous Cu-pyox catalyst:
(i) Yields in the range of those obtained for the homogeneous
catalysts (ca. 50% yield, Table 5) can be obtained under flow
conditions by simply adjusting the flow rate and the polymer
composition. In the flow process, the reactants are forced to go
through the channels defined by monolithic polymeric matrix
avoiding,33 to a great extent, diffusion limitations found for the
polymeric runs under batch conditions, increasing in this way
the conversion of EDA to cyclopropanes (ca. 20% for polymeric
batch catalyst vs ca 50% for flow processes).
PS-DVB-12
1
2
13
40
38 : 62
39 : 61
18
20
10
12
a Reaction conditions: styrene/EDA = 3, 6% catalyst, dichloromethane
solvent, rt, slow addition (2 h) of EDA. Yield of cyclopropanes and
selectivities determined by GC. b Major enantiomers: cis 1R,2S; trans
1R,2R.
attached to the polymeric backbone (Fig. 2). Thus, the positive
“polymeric effect” for the case of Cu-pyox catalyst directly
attached to position 6 of pyridine was confirmed.
Other important characteristic of the polymer supported
catalysts is that they can be easily separated and reused in
consecutive cycles. Therefore, the recyclability of the polymeric
Cu-pyox complexes was tested for ACP. The achieved results are
summarized in Table 3.
After the first cycle, the yield of cyclopropanes was increased
to reach values around 30% with PS-DVB-1a and 42% with
PS-DVB-1b. Both diastero- and enantioselectivity kept stable
for at least 3 successive runs. The productivity of the catalysts
was obviously increased by recycling and reuse. Thus, a 90%
increase in productivity, maintaining the enantioselectivities,
was obtained with PS-DVB-1a, while a 125% increase was
obtained with PS-DVB-1b.
From batch to continuous ACP
The supported copper catalysts derived from PS-DVB-1a
and PS-DVD-1b present some limitations related to diffusion
problems leading to lower yields than homogeneous system.
Besides, a drop on the catalytic efficiency was observed after
the third cycle. The use of monolithic materials prepared by
polymerisation can help to overcome these drawbacks avoiding
diffusion problems and improving the stability.29
Furthermore, these materials can be obtained as mini flow
catalytic reactors to easily develop continuous flow processes.30
These processes offer a number of potential advantages over
batch techniques, such as the possibility of optimizing the
reaction variables (stoichiometry, flow rate, temperature) inde-
pendently, making optimization easier.10,31 In fact, monolithic
polymers can solve problems, such as stagnation zones, hot-
spots, and large residence time distribution, produced in fix-
bed reactors prepared by random packing of the solid catalyst,
resulting in low process efficiency.10
(ii) Continuous flow processes led to higher chemoselectivities
towards the formation of cyclopropanes (ca. 67–70%) than those
achieved for the batch runs.
(iii) Enantioselectivities obtained under flow conditions were
similar than those corresponding to related heterogeneous
catalyst under batch conditions.
(iv) Processes based on the use of mini-flow reactors were, in
terms of productivity, quite superior to the batch processes. In
general, the small volume of the mini-flow reactor (ca. 660 mL)
and the prolonged use without the need for separation of the
catalyst lead to quite significant process intensification produc-
ing larger amount of cyclopropanes (CP) for a low volume
reactor (836 g L-1 vs. 21 or 6.5 g L-1 for the batch processes).
When the mini-flow reactor was assayed in a recirculation mode,
even though the conversion of EDA was slightly improved,
the productivity was clearly reduced (836 g L-1 vs. 50 g L-1)
as a larger reactor volume was used. A similar increase of
catalytic efficiency has been recently reported for other catalytic
monolithic microreactors.34
Different mini-flow reactors were prepared by a mixture of
vinyl-functionalized pyox ligands (1a and 1b), styrene and DVB,
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Table 5 ACP reaction catalyzed by Cu-pyox(iPr) in DCM as solventa
Homogeneous batch
Heterogeneous batch
Continuous single passf
Semi-continuous recirculationg
Support
—
55
55
8
PS-DVB-1a
Mf-R1
49
67
39
44
2.31
836
Mf-R1
56
70
38
40
2.31
50
Yield (%)a
17
17
46
40
0.20e
6
Chemoselectivityb
% ee (cis)c
% ee (trans)c
TOFd
4
0.86e
21
Productivity (g L-1)
a Yield of cyclopropanes (CP) and selectivities determined by GC. b Chemoselectivity = % yield CP/% conversion of EDA. c Major enantiomers: cis
1R,2S; trans 1R,2R. d TOF (CP-mmol pyox-mmol-1) h-1 = [EDA (mmol mL-1) ¥ flow (mL min-1) ¥ 60 (min) ¥ (% yield/100)]/[pyox loading (mmol
g-1) ¥ catalyst mass (g)]. e Operation time 12 h, reactor volume = 3 mL. f Flow rate 20 mL min-1, reactor volume = 0.66 mL g After the first 540 min
of flow operation (single pass), 10 mL of reagents solution was re-circulated through the column for 1860 additional min at 20 mL min-1, reactor
volume = 10 mL batch reactor + 0.66 mL monolithic reactor.
Table 6 ACP reaction in a continuous flow process using DCM as
Regarding stability, the most critical parameters such as
yield, cis/trans diastereoselectivity and cis and trans enan-
tioselectivities remained almost stable up to 14 h of constant
operation. After that time a slight decrease in activity was
generally observed. Fig. 4 gathers a representative example
(Cu-pyox(tBu) mini-flow reactor Mf-R2) of the results obtained
for these systems by extended use, under flow conditions. As
enantioselectivity remains constant during the time on stream,
it can be concluded that the oxazoline moiety remains intact
during operation. The observed loss of catalytic activity may
be attributed to leaching of copper. Indeed, when the mini-flow
reactors were reloaded with copper triflate,35 a recovery of their
activity took place maintaining the same level of selectivity.
Theoretical calculations [M06/6-31G(d,p)] point to that the
metal leaching could be a consequence of some decomplexation
induced by the formation of soluble ethyl maleate-Cu species.
solventa
Mini-flow
reactor
(pyox)
Yield Chemoselectivityb cis/
% ee % ee
cisc transc TOFd
(%)
49e
24f
(%)
trans
Mf-R1
(iPr)
67
49 : 51 39
44 : 56 60
44
57
2.64e
2.45
Mf-R2
59
(tBu)
a Yield of cyclopropanes (CP) and selectivities determined by GC.
b Chemoselectivity = % yield CP/% conversion of EDA. c Major
enantiomers: cis 1R,2S; trans 1R,2R. d TOF (CP-mmol pyox-mmol-1) h-1
= [EDA (mmol mL-1) ¥ flow (mL min-1) ¥ 60 (min) ¥ (%yield/100)]/[pyox
loading (mmol g-1) ¥ catalyst mass (g)]. e 20 mL min-1. f 23 mL min-1.
Once the efficiency of the Cu-pyox monolithic mini-flow
reactors had been proved for the continuous flow process
using DCM, the benchmark ACP reaction between styrene and
EDA was performed using scCO2 as solvent.36 The reaction
was carried out at 40 ◦C and 8 MPa. Thus, a mixture of
styrene/EDA (molar ratio = 3) was mixed with a stream of CO2
accounting the organic stream for a 10% of the total flow used.
Two freshly prepared reactors (Cu-pyox(iPr) Mf-R1 and Cu-
pyox(tBu) Mf-R3) were used for cyclopropanation experiments
using scCO2 as solvent. The results in terms of yield, selectivities
and productivity are gathered in Table 7.
The stability of the Cu-pyox(iPr) Mf-R1 and Cu-pyox(tBu)
Mf-R3 reactors during a prolonged operation time was tested
(see ESI†). In the case of Mf-R1, the column was stable for a 470
min run in scCO2, whereas in the case of Mf-R3 deactivation of
the reactor occurred at 930 min.
The cross-linking degree (Table 4) and catalytic activities (CP
yields, Table 7) were similar for both reactors. Furthermore their
chemoselectivity was moderately high, 56–62%, and similar to
those obtained with homogeneous catalysts or in continuous
flow using DCM. Regarding selectivities, both diastereo- and
enantioselectivity are constant along the operating time (see
Table 7). Enantioselectivities are similar to, or slightly lower than
those obtainedinDCM under flow conditions. The lowdielectric
constant of scCO2 and the higher operation temperature may
account for this slight reduction of ee. It is worth noting
that previous experiments on ACP in scCO2 catalyzed by
monoliths based in pybox-ruthenium complexes showed that no
Fig. 4 Long term use of the Cu-pyox(tBu) mini-flow reactor Mf-R2 in
continuous flow ACP in DCM as solvent (20 mL min-1).
The presence of a bulkier group in the oxazoline ring of
pyox ligand (tert-butyl Mf-R2 vs. isopropyl Mf-R1) led to
clearly improved enantioselectivities, as observed for the batch
processes with polymer supported Cu-pyox complexes (Table 6).
However, lower activity was also obtained with the Cu-pyox(tBu)
reactor Mf-R2 for similar ligand loading and flow rate. This
lower activity may be attributed to lower cross-linking degree in
Mf-R2.
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Table 7 ACP results in continuous flow reactors using scCO2 as solventa
Mini-flow reactor
t/min
Org. fl./mL min-1
Yield (%)a
Chemoselectivity (%)b
cis/trans
% ee cisc
% ee transc
Mf-R1 (iPr)
120d
165
270
470
50
50
20
50
45
41
42
28
59
57
58
56
48 : 52
48 : 52
47 : 53
47 : 53
40
38
38
37
39
37
38
37
Mf-R3 (tBu)
252d
697
927
20
15
10
47
47
42
61
62
61
46 : 54
45 : 55
45 : 55
57
54
52
55
52
49
a Yield and selectivities determined by GC b Chemoselectivity = % yield of cyclopropanes/% conversion of EDA. c Major enantiomers: cis 1R,2S;
trans 1R,2R. d First measure after stabilization of the reactor.
significant variation of the reaction parameters such as yield or
chemoselectivity was observed with the increase of the pressure,
although a slight decrease in regio- and enantioselectivity was
found for higher pressures.12b
Furthermore, the efficiency of the catalytic system was addi-
tionally improved by process design. Cu-pyox can be prepared
as mini-flow catalytic reactors allowing the development of
continuous flow processes moving away from traditional batch
processes. Flow processes based on the use of monolithic pyox
enable the catalyst stabilization, the easier and more effective cat-
alyst recycle enhancing catalyst turnover. Thus, the productivity
for the continuous flow processes can be significantly higher than
those found for the homogeneous traditional processes. Finally,
the greenness of the process was improved by the substitution
of a VOC solvent (DCM) for a more sustainable one such as
scCO2. The use of scCO2 provided the additional advantage of
the higher productivity than in DCM, while keeping the same
selectivities obtained in batch processes.
At first sight, it could seem that mini-flow reactors are less
stable using scCO2 than DCM. However the amount of EDA,
the main agent responsible for deactivation by promoting metal
leaching, that circulates through the column is remarkably
higher in runs performed using scCO2, 30.8 mmol for Mf-R1 and
22.6 mmol for Mf-R3, in comparison with 13.6 mmol for Mf-R1
and 11.2 mmol for Mf-R2 in DCM solution. If we also consider
the total production per volume in a given time, the value
obtained for Mf-R1 in scCO2 was noticeably higher than that
achieved in DCM (1402 g L-1 vs. the 836 g L-1). It is noteworthy
that this higher volumetric productivity was obtained in shorter
time, 165 min for scCO2 compared with 540 min for DCM, and
a total 3074 g L-1 during the total operation time of Mf-R1 (470
min). Hence, in scCO2 up to 1.5 mmol cyclopropanes per hour
can be obtained, whereas lower values around 0.13–0.21 mmol
h-1, were achieved in DCM. All these values show the fact that
the use of CO2 as solvent not only provides the replacement of a
volatile and harmful solvent, such as DCM, by a safer and non-
toxic one, but also significantly improves the processes in terms
of productivity. The lower density of the mixture of reactants
in CO2 might facilitate diffusion to reach the active sites of
the supported catalyst allowing the use of faster flow rates to
achieve same degree of conversion of EDA to the corresponding
cyclopropanes.
Acknowledgements
Support by the Spanish ‘Ministerio de Ciencia e Innovacio´n’
(CTQ2008-05138 and CTQ2005-08016, and Consolider Ingenio
2010 CSD2006-0003) is greatly acknowledged.
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990 | Green Chem., 2011, 13, 983–990
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