Separation of reaction product and palladium catalyst after a heck coupling reaction by means of organic solvent nanofiltration

Article abstract of DOI:10.1002/cssc.201100355

Organic solvent nanofiltration (OSN) is a recently commercialized technology, which we have used to develop a method for the separation of a target product and the Pd catalyst from a Heck coupling postreaction mixture. The experimental setup included comm

Full text of DOI:10.1002/cssc.201100355

DOI: 10.1002/cssc.201100355
Separation of Reaction Product and Palladium Catalyst
after a Heck Coupling Reaction by means of Organic
Solvent Nanofiltration
[a]
[b]
[b]
[a]
Anna Tsoukala, Ludmila Peeva, Andrew G. Livingston, and Hans-Renꢀ Bjørsvik*
Organic solvent nanofiltration (OSN) is a recently commercial-
ized technology, which we have used to develop a method for
the separation of a target product and the Pd catalyst from a
Heck coupling postreaction mixture. The experimental setup
included commercially available polyimide copolymer mem-
branes with molecular weight cut-off (MWCO) values in the
range of 150–300 Da, acetone as the solvent, and a working
pressure (N ) of 3 MPa. The investigation of the membranes re-
2
vealed that a membrane with a MWCO of 200 Da provided
quantitative retention of the Pd catalyst and quantitative re-
covery of the target product by means of a cross-flow dia-
nanofiltration procedure.
Introduction
One of the fundamental goals in organic synthesis is the for-
resistant nanofiltration membranes are commercially available:
[1]
[10]
[11]
[12]
[13]
mation of new CꢀC bonds and thus new carbon frameworks.
the DuraMem, SelRO, SolSep, and Starmem series of
[14]
A wealth of reactions and processes that involve transition-
metal catalysis have enhanced the organic chemist’s repertoire
of reactions and methods to provide access to new and short-
membranes and the Inopor series of ceramic membranes.
OSN is a pressure-driven membrane-based separation tech-
nique that permits the use of organic solvents instead of
water, which is used in many other liquid filtration techniques.
The nanofiltration membranes are manufactured from poly-
imide copolymers, such as the polyimide copolymer P84
[2]
er synthetic pathways towards highly complex molecules.
Although transition-metal catalysis plays an almost indispensa-
ble role in organic synthesis, such catalytic reactions are en-
cumbered with drawbacks. To obtain sound process economy
for an industrial process, it is necessary to establish effective
unit operations that will separate the transition-metal catalyst
[15]
(Figure 1).
The flow diagrams of two different setups for
OSN are shown in Figure 2.
[3]
from the reaction product. This will enable catalyst recycling
and allow the utilization of the reaction products as pharma-
ceutical chemicals, active pharmaceutical ingredients (APIs),
nutraceuticals, or as food or feed additives. Guidelines from
[
4]
the European Medicines Agency state that the daily permit-
ted oral exposure to Pd in a pharmaceutical ingredient should
[5]
be less than 10 mg of Pd per kilo of API (<10 ppm), which
places strict requirements on the purification process.
There are a number of methods that can be utilized for re-
Figure 1. The chemical structures of the two polymers that constitute the
polyimide copolymer P84.
[
6]
moving Pd catalysts from APIs, which are based on classical
unit operations and include distillation, extraction, crystalliza-
tion, and adsorption.
When such unit operations are to be used, various experi-
mental variables need to be investigated: the reaction environ-
ment, the physical and chemical characteristics of the com-
The polyimide copolymer (Figure 1) is an excellent material
for the preparation of membranes for nanofiltration because of
its outstanding resistance to a wide range of both polar and
[
5,7]
pound that is treated in the purification process,
and the
behavior and properties of the catalyst. To accomplish an ac-
[
8]
[a] Dr. A. Tsoukala, Prof. H.-R. Bjørsvik
Department of Chemistry
University of Bergen
ceptable residual Pd level, classical purification methods
often call for repeated purification cycles or a combination of
several methods. When several purification cycles or steps are
needed, the operating cost of the overall process increases at
the same time as the throughput and yield decreases.
Allꢀgaten 41 (Norway)
Fax: (+47)55-58-94-90
E-mail: hans.bjorsvik@kj.uib.no
[
b] Dr. L. Peeva, Prof. A. G. Livingston
Organic solvent nanofiltration (OSN) has been introduced as
a new separation/purification method and is still an emerging
Department of Chemical Engineering
Imperial College of Science, Technology, and Medicine
London SW7 2AZ (United Kingdom)
[
9]
technology in membrane science. At this time, a few solvent-
1
88
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2012, 5, 188 – 193

Separation of Product and Catalyst by Organic Solvent Nanofiltration
0
presence of a Pd catalyst with
microwave or thermal heating.
The Heck coupling reaction pro-
duces two productive isomers,
4
a (major isomer) and 4b, in a
good yield (67%) by using mi-
crowave (mW) heating.
Results and Discussion
In general, the design and devel-
opment of efficient, functional
methods for the isolation of
transition-metal catalysts from
postreaction mixtures by means
of OSN requires a significant mo-
lecular weight difference be-
tween the catalyst and the prod-
[16b,24]
uct to be separated.
Figure 2. a) Flow diagram for organic solvent dead-end nanofiltration. b) Organic solvent dia-nanofiltration. The
retentate of the OSN step 1 constitutes of the Pd catalyst, and the permeate contains the organic products and
the solvent. The retentate of the OSN step 2 constitutes of the target product, and the permeate is the solvent,
which can be recycled in the next filtration process cycle.
To identify 1) an appropriate
membrane that can deliver tran-
sition metal-free products, and
2) a suitable flow rate (mem-
brane flux), it is mandatory to
[
16]
polar aprotic solvents.
Such membranes have also been
screen various membranes that possess different molecular
[26]
shown to provide cost-effective and environmentally benign
separation and purification techniques that minimize the re-
quirement of solvents and waste side-streams compared to
classical separation/purification methods. Previously, OSN tech-
nology was utilized with first generation membranes (Star-
mem, Membrane Extraction Technology Ltd., UK) to isolate
transition-metal catalysts from Suzuki and Heck coupling post-
weight cut-off (MWCO) values.
The model Heck coupling reaction (Scheme 1, Step 2)
[23d]
is
0
II
catalyzed by Pd . Pd (OAc) was added to the reaction mixture
2
with PPh , which reacted in situ to produce the operational
3
0
ꢀ
catalyst [Pd (PPh ) OAc]
(MW=690.04 Da, 1 Da=1.66ꢂ
3
2
ꢀ
27
10 kg, Scheme 2). The molecular weight (MW) difference be-
tween the target intermediate 4 (MW=336.5 Da) and the Pd
catalyst appeared to be sufficient (DMW=690.04ꢀ336.5=
353.54 Da) to separate the catalyst from 4a and 4b.
[
17,18]
reaction mixtures.
These studies revealed that the method-
ology was suitable for 1) the removal of residual Pd up to ap-
proximately 95%, and 2) the separation of the product from
the catalyst and ionic liquid after ruthenium-catalyzed hydro-
Commercially available second-generation membranes
(Evonik MET Ltd, UK) with MWCOs of 300 Da (M ), 200 Da (M ),
1
2
[
19,20]
genation and Suzuki coupling reactions.
The results from
and 150 Da (M ) were screened, and the results of the rejection
3
these studies combined with the recent achievements in mem-
brane development spurred us to undertake the study dis-
closed herein with the goal to separate the target molecule
from the Pd catalyst that was used in a Heck coupling reac-
of Pd and the product are shown in Figure 3.
M exhibited an excellent rejection (100%) of Pd and a high
2
rejection (77%) of 4a and 4b. M demonstrated the complete
1
permeation of the product, but only a relatively low selectivity
[
21]
tion, which was the key step
of a new total synthesis of ide-
[
22]
benone (8, Scheme 1, Step 2).
An important aspect of this proj-
ect was to design and develop a
green, efficient, and high yield-
ing process. Moreover, the total
synthesis should preferably in-
volve readily available starting
materials and cost-optimized
synthetic methods because 8 is
of potential industrial interest for
use in pharmaceutical applica-
tions. 2-Bromo-3,4,5-trimetoxy-
methylbenzene (2) and 9-decen-
[
23]
1-ol (3) were coupled in the Scheme 1. Total synthesis of 8.
ChemSusChem 2012, 5, 188 – 193
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
189

H.-R. Bjørsvik et al.
The performance and permea-
bility of a membrane is correlat-
[27]
ed to the membrane flux, and
the oligostyrene test can be
used to explore the flux of a
[
25a]
membrane.
The results of the
ꢀ
2
ꢀ1
exploration of the flux [Lm h ]
of M , M , and M are shown in
1
2
3
[28]
Figure 5. M and M provided
2
3
a lower flux than M . However,
1
all three membranes demon-
strate suitable fluxes for our ap-
[
25]
Scheme 2. In situ production of the active catalytic species for the Heck reaction.
plication. Although M displayed
1
the highest flux, M2 displayed
the best total performance for our postreaction mixtures, as it
showed both a high retention of the Pd catalyst and a relative-
ly low retention of 4a and 4b.
The investigation of the performance of M , M , and M re-
1
2
3
vealed that M quantitatively trapped the Pd catalyst. However,
2
the recovery of the product from the postreaction mixture was
a problem, as it was also trapped. Dia-nanofiltration allows the
nanofiltration process to be repeated in a continuous fashion
(
Figure 2b).
The results of the dia-nanofiltration experiments are dis-
played in Figure 6, and reveal that the reaction product was
quantitatively recovered from the postreaction mixture after
six filtration cycles, and the Pd level was much lower than the
Figure 3. Rejection (%) of Pd and product from the nanofiltration of the
postreaction mixture by M –M
1
3
.
[5]
requirements set for pharmaceutical applications.
towards Pd and retained just 80%. This behavior may be relat-
ed to the formation of Pd species with molecular weights
lower than 300 Da that cannot be retained by M . M also pos-
Conclusions
1
3
We have successfully developed an OSN process for the sepa-
sessed a high selectivity towards Pd with a rejection of 90%
and a permeability of 50% for the product. The results with M3
were unexpected as it has the lowest MWCO of the three
0
ꢀ
ration of [Pd (PPh )OAc] and 4a and 4b found in a Heck cou-
3
pling postreaction mixture. A commercially available mem-
brane with a molecular weight cut-off value of 200 Da was
identified to be the most appropriate for the purpose.
membranes. The trials performed with M revealed both suit-
2
able flux and Pd catalyst rejection (Figure 4) for the separation
of the catalyst and product.
The purified product (a mixture of 4a and 4b) was quantita-
tively recovered from the postreaction mixture after five suc-
Figure 4. Molecular weight cut-off curves of M
1
–M
3
. Rejections (%) for the
1 2
Figure 5. The flux of the membranes M (MWCO 300 Da), M (MWCO
membranes from the oligostyrene test.
200 Da), and M (MWCO 150 Da).
3
1
90
www.chemsuschem.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2012, 5, 188 – 193

Separation of Product and Catalyst by Organic Solvent Nanofiltration
Synthesis of the olefin isomers
The olefin isomers 4a and 4b were synthesized by using a a mix-
ture of 2-bromo-3,4,5-trimethoxytoluene (2, 7.66 mmol, 2 g), dec-9-
en-1-ol (3, 12.5 mmol, 2.3 mL), triethylamine (14.3 mmol, 2 mL),
Pd acetate (0.20 mmol, 45 mg, 2.61 mol%), and triphenylphosphine
(
1
0.80 mmol, 210 mg), which was heated by using two methods.
) Thermal heating: The reaction mixture (without solvent) was
transferred to a thick-walled sealed tube reactor (Ø=20 mm, h=
50 mm). The reactor tube was flushed with nitrogen for 3 min,
the valve was closed, and the tube was heated at 1208C for
days. 2) Microwave irradiation: The reaction mixture was added
to tetrahydrofuran (1.5 mL) and transferred to a reactor tube
2.5 mL), which was then placed in the microwave reactor. The re-
1
3
(
action was conducted at approximately normal pressure at 1208C
for 30 min.
Isolation and purification of the postreaction mixture
Method 1 (classical): The sealed tube reactor (or microwave reactor
tube) was cooled to room temperature, and the reaction mixture
was filtered through a pad (1 cm) of celite to remove precipitated
catalyst. The celite pad was washed with diethyl ether (3ꢂ10 mL)
and the organic phases were combined, washed with water (1ꢂ
25 mL), and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the isolated solid was puri-
fied by using flash chromatography. The product was isolated as a
mixture of 4a and 4b in a yield of 60% (thermal) and 67% (micro-
Figure 6. Results of the dia-nanofiltration process for the separation of reac-
tion product and catalyst. The quantities of the reaction product in the per-
meate fraction were determined by using GC. The Pd quantities were deter-
mined by using ICP [ppm Pd]. FM=feeding mixture, which contained a Pd
quantity of 0.715 ppm.
1
wave). The yields were measured by using H NMR spectroscopy
1
with 3,4-dimethoxyacetophenone as internal standard. H NMR
(
400 MHz, CDCl ): d=1.28 (br, s, 9H), 1.54 (qn, 2H), 1.95 (q, 2H),
3
cessive filtrations in a purity that meets the health and safety
specifications stated by the European Medicines Agency for a
product to be used in a pharmaceutical product.
2.23 (s, 3H), 3.27 (d, 2H), 3.62 (t, 2H), 3.80 (t, 9H), 5.39 (m, 2H),
.50 ppm (s, 1H); MS: m/z (%)=336 (75), 221 (56), 195 (100), 190
80), 182 (95), 167 (25), 91 (22), 79 (12), 55 (34). R =0.32 (hexane
6
(
f
and ethyl acetate, 8:2).
Our catalyst/product separation process is beneficial from
several environmental and process points of view: 1) the ex-
pensive Pd catalyst is recovered for recycling, 2) the need for
solvent is substantially reduced compared to other separation
techniques, 3) the process waste streams are reduced, and
Method 2 (OSN): The filtration experiments were performed by
using a dead-end Sepa ST pressure cell (Osmonics, USA) with a
nanofilter (DuraMem membrane, Evonik MET, UK). The experiments
were conducted at room temperature under a pressure of 30 bar
(
N ) as the driving force of the filtration. Acetone was used as the
2
4) there is a reduction in energy consumption as this process
[29]
filtration solvent. M –M possessed an effective membrane area
1
3
does not need energy to strip off large volumes of solvent.
Our process can be used directly or be an excellent starting
2
of 14 cm (circular form, Ø=42 mm). The OSN membrane was
placed on a sintered metal disk that was inserted into the filter
housing and sealed to the filter body by using O-rings. A magnetic
stirrer plate and a Teflon coated magnetic stirrer bar were used to
avoid concentration gradients. The membranes were precondi-
0
ꢀ
point for other syntheses based on [Pd (PPh ) OAc] with a
3
2
MW of 690.04 Da as a catalytic system.
For application with other Pd-catalyzed coupling reactions, a
requirement is that the difference in molecular weight be-
tween the operating catalyst and the target molecule (with a
molecular weight lower than 337 Da) is at least 354 Da (DMW).
[27a]
tioned by using pure acetone.
acetone (200 mL) and loaded at a pressure of 30 bar. The permeate
150 mL) was collected and discarded, and the pressure was slowly
The filter cell was charged with
(
reduced to atmospheric pressure. The system was used to investi-
gate the MWCO of the membranes by using the oligostyrene
[25a]
method
after the preconditioning step and before OSN to eval-
uate the integrity of the membrane and the equipment and to
identify the presence of possible leaks owing to defects in the
membrane or around the membrane seal. A solution of oligostyr-
ene in acetone (100 mL) was transferred to the filtration cell. Pres-
sure was applied (3 MPA); and 50 mL of the solution was permeat-
ed through the membrane and collected. Three samples (1.5 mL
each) were withdrawn from the permeate, the retentate, and the
feed (the oligostyrene mixture) for analysis by using HPLC to deter-
Experimental Section
Starting materials, reagents, and solvents were purchased commer-
cially and were used without further purification unless otherwise
stated. The DuraMem membranes were purchased from Evonik
MET Ltd., U.K. The Heck coupling reactions were conducted by
using microwave irradiation as the energy source by using a Bio-
tage Initiator Sixty EXP Microwave System, which operates at 0–
4
00 W at 2.45 GHz in a temperature range of 40–2508C, pressures
mine the concentration of oligostyrene in the permeate (Cpermeate)
5
of 0–20 bar (1 bar=10 Pa), and reactor tube volumes of 0.2–
0 mL.
and retentate (Cretentate). The rejection of each solute (R) was esti-
i
2
mated by using Eq. (1).
ChemSusChem 2012, 5, 188 – 193
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
191

H.-R. Bjørsvik et al.
ꢀ
ꢁ
Cpermeate;i
Cretentate;i
R ¼ 1ꢀ
ꢁ 100%
ð1Þ
1 3
Table 1. ICP analysis of Pd in permeate and retentate from M –M .
i
M
MWCO [Da]
Pd concentration [ppm]
Rejection [%]
permeate
retentate
The estimated values of R were plotted against the molecular
i
M
M
M
1
2
3
300
200
150
0.079
0.000
0.040
0.639
0.400
0.414
87.6
100
90.0
weight of each membrane. After completing the oligostyrene test
run, the membrane was washed thoroughly with the filtration sol-
vent (acetone); and the preconditioning step was repeated.
OSN filtration: Triethylamine (leftover from the Heck coupling reac-
tion) was removed from the post reaction mixture by using a
rotary evaporator. A sample (0.2 g) of the amine-free mixture was
withdrawn, dissolved in acetone (50 mL), and transferred to the fil-
tration cell. The cell was pressurized (3 bar), and the permeate
Chemical analysis of oligostyrene samples by using HPLC
An HPLC system (Gilson) equipped with a Gilson 118 UV/Vis detec-
tor and an ACE 5-C18-300 column (Advance Chromatography Tech-
nologies, ACT, UK) was used for the analysis of the styrene oligo-
mers. The mobile phase was composed of 35 vol% analytical
grade water, 64.9 vol% tetrahydrofuran, and 0.1 vol% trifluoroace-
tic acid. The styrene oligomers were analyzed in the permeate,
retentate, and the feed mixture. A sample (1.5 mL) was taken from
each, the solvent was evaporated under reduced pressure, the resi-
due was redissolved in N,N-dimethylformamide (1.5 mL), and in-
jected into the HPLC.
(
25 mL) was collected. The pressure was then reduced slowly to
normal atmosphere. Samples (1.5 mL) were drawn from the perme-
ate and the retentate. These samples were analyzed by using in-
ductively coupled plasma (ICP) spectroscopy and HPLC to deter-
mine the quantities of Pd and 4a and 4b, respectively. Rejection of
solutes (Pd and product) was estimated by means of Eq. (1), and
the results for M –M are presented in Figure 2.
1
3
Determination of flux
Acknowledgements
The flux of the membranes was measured for the three filtration
steps 1) the preconditioning step, 2) the oligostyrene test, and
Financial support is gratefully acknowledged from EC Marie Curie
Action. Mr. Leif Riege (formerly Director of Technology at the De-
nomega Company, Norway) is acknowledged for his support and
encouragement through his positive management of our part of
the InSolEx project.
3
) the OSN. The flux, J , was estimated according to Eq. (2) and
v
plotted against time (Figure 4), in which V corresponds to the
2
volume of the permeate in L, A to the filter area in m , and t to
time in h.
V
A ꢁ t
Jv¼
ð2Þ
Keywords: heck reaction
nanofiltration · palladium · recycling
·
homogeneous catalysis
·
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1
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[
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2
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ꢀ1
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as well as the good solubility of our product.
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[
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2
2
Received: November 10, 2011
Published online on December 12, 2011
ChemSusChem 2012, 5, 188 – 193
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
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