Synthesis of Pd Complexes Containing Tailed NHC Ligands and Their Use in a Semicontinuous Membrane-Assisted Suzuki Cross-Coupling Process

Article abstract of DOI:10.1021/acs.oprd.8b00273

Homogeneous catalysis has proved to be a reliable method for preparing numerous molecular entities, but catalysts can be expensive and difficult to remove. Because of this, industry targets catalysts that are easily separated and recovered and feature increased turnover numbers. The ongoing shift from multipurpose batch reactors toward continuous manufacturing in fine chemicals synthesis results in a new set of catalyst requirements. This paper reports the design and use of Pd complexes suitable for a semicontinuous Suzuki cross-coupling reaction based on a membrane-assisted reactor. These Pd complexes contain tailed N-heterocyclic carbene (NHC) ligands, allowing internal catalyst recovery by organic solvent nanofiltration with top-layer-modified ceramic membranes. These membranes give selective nanofiltration of the catalyst based on a combination of size exclusion and affinity separation (solvent-solute-membrane interactions). The semicontinuous system developed led to significantly improved turnover numbers, simplified product isolation, and consequently reduced mass intensity by simply adding more of the reactants and reagents to the reaction vessel.

Full text of DOI:10.1021/acs.oprd.8b00273

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Full Paper
Synthesis of Pd complexes containing tailed NHC ligands and their use
in a Semi-continuous membrane assisted Suzuki cross coupling process.
Dominic Ormerod, Matthieu Dorbec, Eugen Merkul, Nadya Kaval, Nicolas Lefèvre,
Steven Hostyn, Lies Eykens, Jo Lievens, Sergey Sergeyev, and Bert U. W. Maes
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00273 • Publication Date (Web): 02 Oct 2018
Downloaded from http://pubs.acs.org on October 2, 2018
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Synthesis of Pd complexes containing tailed NHC ligands and their use in a
Semi-continuous membrane assisted Suzuki cross coupling process.
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Dominic Ormerod,a,* Matthieu Dorbec,a Eugen Merkul,b Nadya Kaval,b Nicolas Lefèvre,b Steven
Hostyn,b Lies Eykens,a Jo Lievens,a Sergey Sergeyev,b Bert U. W. Maes.b
a
VITO (Flemish Institute for Technological Research), Separation and Conversion Technology,
Boeretang 200, B-2400 Mol, Belgium.
b
University of Antwerp, Organic Synthesis, Department of Chemistry, Groenenborgerlaan 171, B-
2020 Antwerp, Belgium
Corresponding author:
Dominic Ormerod
Vito NV
Boeretang 200
B-2400 Mol
Belgium
Tel: +32 14 33 5650
Fax: +32 14 32 1186
E-mail: dominic.ormerod@vito.be
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Abstract
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Homogeneous catalysis has proved to be a reliable method of preparing numerous molecular
entities, but catalysts can be expensive and difficult to remove. Because of this, industry targets
catalysts which are easily separated, recovered and feature increased turnover numbers. The on-
going shift from multi-purpose batch reactors towards continuous manufacturing in fine chemicals
synthesis results in a new set of catalyst requirements. This paper reports the design and use of Pd
complexes suitable for a semi-continuous Suzuki cross coupling reaction based on a membrane
assisted reactor. These Pd complexes contain tailed NHC ligands allowing internal catalyst recovery
by Organic Solvent Nanofiltration (OSN) with top layer modified ceramic membranes. These
membranes give selective nanofiltration of catalyst based on a combination of size exclusion and
affinity separation (solvent – solute – membrane interaction). The semi-continuous system
developed led to significantly improved turnover numbers, simplified product isolation and
consequently reduced mass intensity by simply adding more of the reactants and reagents to the
reaction vessel.
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Keywords: Pd catalysts, organic solvent nanofiltration, ceramic membranes, mass intensity,
reduced catalyst load, semicontinuous processing.
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Introduction
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Recent decades have witnessed a significant growth in industrial interest in solvent based
separations using membranes stable to organic solvents,1-2 due in part to the non-thermal, hence
mild and energy efficient nature of the technique. Indeed, as up to 90% of chemical production
processes contain a separation procedure and these separations account for 40 to 70% of the
global capital and operational costs incurred by the process industry, there exists a clear need for
the development of cost efficient separation techniques. Separations with membranes stable to
organic solvents, often called Organic Solvent Nanofiltration (OSN), have also been shown to be
sustainable.3 Recent membrane developments include ceramic membranes with modified top
layers designed to effect separation not simply on size exclusion alone, but by additionally
exploiting solvent – membrane – solute interactions.4-6 These new membranes open up new
unique possibilities for homogenous catalysis. By designing the membrane surface and the catalyst
ligand a desired rejection profile and reaction performance should be achievable. Moreover, the
mild nature of membrane separations makes them particularly suited to integration within reaction
systems in which reaction and separation occur simultaneously, a particularly salient example
being catalyst reuse through efficient recovery. 7-9
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Homogeneous metal based catalysis is a technique that has achieved a high level of maturity, and is
often an indispensable and reliable method of synthesizing molecular entities produced within
several chemical industry sectors and especially in the fine chemicals industry.10 These catalysts
efficient as they are, can be expensive and difficult to remove after reaction. Because of this, for
industrial applications emphasis is placed upon increasing catalyst turnover numbers (TON) and
catalyst recovery. Strategies to increase catalyst TON are often based either on increasing their
stability or reaction rate (i.e. increase TOF), or developing methods to reuse the catalyst.11 In a
recent publication12 we demonstrated that it was possible to efficiently separate NHC based
palladium catalysts under different OSN processing methods namely, online, at-line and off-line
(Figure S1, supporting information) in a model Suzuki reaction of 4-chlorotoluene with (p-
methoxyphenyl)boronic acid. Though organometallic species were efficiently removed from
reaction products under all three processing methods, online (semi-continuous) processing failed,
with the palladium catalysts employed, as efficient catalyst separation was only achieved at the
expense of reaction efficiency. In contrast good yield and rejection of the organometallics could be
achieved with the at-line or off-line processing methods.
Because the catalyst load into the reaction is pre-determined with the off-line or at-line processing,
increasing TON by employing an internal membrane catalyst recycling system is somewhat more
complex than with the continuous process in which TON’s can be increased by simply continuing
the addition of reactants in to the reaction during the process. Therefore, determining the
minimum catalyst load for a reaction can be achieved in a single reaction, especially if in-line
monitoring is used. Something that usually requires several reactions with off-line or at-line
processes.
Under the semi-continuous reaction conditions previously used without success, at 30°C moderate
reaction yield was obtained with the NHC catalyst [1,3-Bis(2,6-diisopropylphenyl)imidazol-2-
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ylidene]chloro[3-phenylallyl]palladium(II), produced and sold by Umicore as CX-31. Under these
conditions rejection of the organometallics by the membrane was only 50%. By increasing the
operating temperature of the reaction – separation system to 50°C, high membrane rejection of
the organometallic species was obtained, thus accomplishing efficient separation but unfortunately
no internal catalyst recovery as the reaction yield falls to a poor 21%. The reason for the catalyst
deactivation was attributed to cluster formation, a known catalyst deactivation pathway.13 In order
to improve the performance of the continuous flow – membrane reactor system, not only are
improvements to the catalyst stability required but also harmonization of the catalyst performance
and desired rejection, so that the requisite membrane performance can be achieved without
deactivation of the catalyst.
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The modified ceramic membranes have already demonstrated that where there is high interaction
between the membrane surface and the solute in solution, rejection tends to be low and
conversely low interaction between the membrane surface and the solute gives high rejection.5 At
first glance the simplest method of varying the membrane – solvent – solute interactions, and thus
achieving the desired rejection profile, is to change the membrane. However, changing the
membrane does not affect the catalyst stability and therefore will not lead to a suitable internal
recovery system. To simultaneously achieve the goals of high rejection and improved catalyst
stability, changes need to be made to the catalyst itself. Thus, the requirements are a ligand that is
susceptible to the introduction of functional groups to achieve high membrane rejection by
exploiting the affinity aspects of the separation and not easily lost from the metal complex to
ensure the required catalyst stability. One such ligand type that is thermally and oxidatively stable,
forms thermodynamically strong M-L bonds and is susceptible to functionalization are the N-
heterocyclic carbenes (NHC).14 Furthermore, it has also been demonstrated that substitution in the
NHC ligand can inhibit cluster formation of the catalysts.15 The separation via OSN of palladium and
ruthenium complexes containing molecular weight increased NHC ligands has already been
reported.16-20 However, in these reported cases the OSN separation was exclusively based upon size
exclusion. Moreover, for the Pd catalysis there are a very limited number of examples reported of
the use of membranes in continuous processing; namely a Heck reaction21-22 and a Tsuji – Trost
reaction, both of which rely upon size exclusion to effect OSN separation.23 The object of this work
is, via judicious catalyst design, achieve internal recovery of the Pd catalyst in a semi-continuous
Suzuki reaction by means of OSN with modified ceramic membranes allowing separation based on
both size exclusion and affinity. A successful system will require the active catalyst to have
improved thermal and hydrolytic stability, be preferably easily synthesized and to give the desired
membrane rejection profile, this being the case not just for the organometallic species but for all
the reaction components. The Suzuki reaction of 4-chlorotoluene with (p-methoxyphenyl)boronic
acid was selected as a model reaction.
Experimental
General
Synthesis of Pd complexes is detailed within the supplementary information. The solvents used in
this study were ethanol and isopropanol, both of technical grade purchased from VWR (Belgium)
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and used without prior purification. Water was reverse osmosis purified water. Commercially
available membranes selected for this study were Inopor ceramic membranes from Inopor
(Veilsdorf, Germany). The C5, C8 or C8H4F13 modified ceramic membranes were Inopor membranes
modified in house to have n-alkyl chains on the membranes top layer. The membranes used in this
work were asymmetric tubular TiO2 membranes; length 120 mm or 250 mm outer diameter 10
mm, inner diameter 7 mm and top layer thickness of about 50 nm. All membrane experiments
were performed in a cross-flow filtration unit made in-house, pressurized with nitrogen gas.
Filtration experiments were performed with crossflow velocity of 2 m/s and unless otherwise
stated a transmembrane pressure of 10 bar.
4-Chlorotoluene, (4-methoxyphenyl)boronic acid, potassium formate and potassium –tert-butoxide
were purchased from Sigma- Aldrich (Belgium), Umicore cross coupling series catalysts, CX-21, was
purchased from Sigma- Aldrich (Belgium). All membrane experiments were performed in an in
house made cross-flow nanofiltration unit on lab scale.
Cross-coupling reactions were analyzed on a waters UPLC with a UV/Vis PDA detector. A Waters
Acquity BEH C18 column with dimensions of 2.1 x 50 mm, 1.7µm and a gradient of water,
acetonitrile buffered with 0.1% formic acid. The column temperature was 40°C and the detector
was used at a wavelength of 270 nm.
Analysis of Pd species was carried out using inductively coupled plasma atomic emission
spectroscopy (ICP-AES). After evaporation of the solvent from the sample the residue was digested
using aqua regia and diluted with deionized water to the required concentration range. The
samples were then analysed for metal content.
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Thin layer chromatography (TLC) was carried out on silica-gel plates (Merck F254). Spots were
detected with UV light and revealed with KMnO4 or ninhydrin solutions.
General cross coupling procedure with on-line membrane assisted processing
To the filtration apparatus fitted with a 120 mm single tube C8 functionalized ceramic membrane
(2.05.10-3 m2) was added 700 ml of a solution of Pd complex 8-c (69 mg, 0.05 mmol, 500 ppm) and
potassium formate (3.15 g, 37.5 mmol) in ethanol, previously degassed by bubbling nitrogen
through for 10 minutes. The circulation pump was switched on and the mixture circulated at 0.5
bar of nitrogen pressure until the internal temperature was 20°C. Connected to the filtration
apparatus via a pump and set up to perform constant volume diafiltration was a 300 ml solution of
4-chlorotoluene (12.66 g, 100 mmol, 1.0 eq), (4-methoxyphenyl)boronic acid (16.7 g, 110 mmol, 1.1
eq), potassium formate (1.05 g, 12.5 mmol) and potassium tert-butoxide (14.59 g, 130 mmol, 1.3
eq) in ethanol (diafiltration solution) also degassed by bubbling nitrogen through for 10 minutes
and kept under nitrogen atmosphere. The filtration loop system was brought under pressure (10
bar) and the diafiltration was started. It was realized in a semi-continuous mode (with valve V-1
closed and V-2 open, figure S1 supporting information) at 10 bars and a measured temperature in
the filtration loop between 23 ±2°C, while maintaining constant feed level. The volume inside the
filtration loop is kept constant via the controlled addition of the diafiltration solution containing the
reagents and base added slowly to a solution of the catalyst in the filtration loop, by the
diafiltration process. Addition of reagents to catalyst was used in the flow system to allow the
catalysts to be pushed towards higher turn-over numbers, simply by adding more reagent. The
permeate generated was added to the diafiltration solution maintained under N2 atmosphere. The
membrane flux was continually monitored. The reaction was allowed to proceed in such a manner
for 44 hours (corresponding here to 1.3 diafiltration volume)* with regular sampling of the
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filtration loop contents (retentate) and the membrane permeate (diafiltration solution which is
here the permeate in this semi-continuous mode) for analysis. The content of the diafiltration tank
A was then poured in a permeate tank. The diafilter tank A was then charged with fresh ethanol,
the valve V-1 was opened and the valve V-2 was closed. The diafiltration was continued till having
used more than 3 diafiltration volumes of EtOH (2.21 L which corresponds to 3.15 diafiltration
volumes) the permeate being collected in the permeate tank.
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The permeate (2.44 L) contained more than 90 % of the desired product with a palladium content
of 12 ppm, metal content was analyzed by ICP-MS.
The initial flux was 13 L/h.bar.m2 at 40 °C with a mixture EtOH/water 1/1 and 28 L/h.bar.m2 at 21 °C
with pure EtOH, went down to 0.8 L/h.bar.m2 during the reaction and went up to 0.95 L/h.bar.m2
during the constant diafiltration with fresh EtOH. The original flux of 13 L/h.bar.m2 at 40 °C with a
mixture EtOH/water 1/1 was recovered after a wash with a hot mixture of EtOH/Water.
The permeate was evaporated and dried in an oven at 100 °C for 48 h and the resulting powder
(23.8 g) was further analyzed. A purity of 66.1 % w/w was found while having a clean
chromatogram (Figure S2) the presence of salts explaining most certainly this value. The residual
palladium content was found to be 20 mg/Kg of the crude material which corresponds to a slightly
higher palladium contamination of 16 ppm than previously found. The yield of the reaction was
88%.
*This reaction time could be adapted by using a larger membrane surface.
General cross coupling procedure batch process.
A flask equipped with a magnetic stirring bar was charged with a Pd catalyst (0.025 mmol, 0.5 mol
%) , 4-methoxyphenylboronic acid (6 mmol, 1.2 eq) and potassium tert-butoxide (6.5 mmol, 1.3
eq). The flask was sealed with septum, and ethanol (4 mL,) was added via syringe. The mixture was
degassed for 3 min, the flask was filled with argon and the reaction mixture was stirred in a
preheated bath at 30o for 30 min. A degassed solution of 4-chlorotoluene (5 mmol, 1 eq) in ethanol
(2 mL) was added, and the reaction mixture was stirred at 30oC for 4 hours. 100 µl samples of the
reaction mixture were taken every 15 minutes and quenched by adding the sample to a vial
containing 500 µl of an aqueous saturated ammonium chloride solution.
Results & Discussion
Tailed NHC ligands and Tailed Palladium NHC complex synthesis
The chosen NHC ligand that formed the foundation for these tailed versions was the 1,3-bis-2’,6’-
diisopropylphenylimidazol-2-ylidene (IPr). Substitution of the 4-position of the aryl rings was
chosen as this would be remote from the catalytic center of the metal complex and therefore
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expected to minimally impact catalysis. Moreover substitution with highly bulky trityl groups in this
position has been previously shown to be possible without loss of catalytic activity of the Pd
complexes.15 The selected tails were intended to be hydrophobic, hydrophilic and flourophilic to
exploit the affinity OSN. A concise and general synthetic method for their introduction was
therefore required. The synthetic strategy of choice was the diversity-oriented route shown in
Scheme S1. Introduction of the tail was performed in a late stage of the synthesis using a
Sonogashira cross-coupling reaction. A chromatography-free, five step procedure afforded the
desired NHC precursors 4a–d with overall yields in the range of 21-28%, while the nature of the tail
only marginally affected the yield. Gram quantities of the tailed imidazolium chloride salts were
easily produced with this strategy.
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The first generation tailed Pd NHC complexes targeted were those resulting from the reaction of
the imidazolium chlorides 4a-d with Pd(OAc)2 in the presence of base (Scheme 1).24 This route
however, proved to be troublesome and low yielding mainly due to the required generation and
manipulation of the free carbene. Generation of the carbene in-situ and subsequent reaction with
Pd(OAc)2 did successfully lead to a chromatography free procedure to prepare the target Pd
complexes, of structure 6 containing a coordinated water molecule. Complex 5, synthesized using
the method described elsewhere,12 has previously been described in the literature as a catalyst for
aerobic oxidations rather than cross couplings.25
Scheme 1: Structure of Pd complex 5 and synthesis of tailed Pd NHC complexes 6 a-d from
imidazolium chloride salts 4 a-d
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These, aqua complexes tended to have somewhat limited stability and would decompose both, on
storage and in solution. Thus, a second generation of complexes were synthesized, the allyl
palladium complexes 8a-e, Scheme 2. The untailed version (CX-21) was introduced by Nolan26 and
is now commercially available (called CX-21) as part of the Umicore cross coupling portfolio.
Synthesis of the imidazolium salts was improved by performing an ion exchange reaction on the
chlorides 4a-e to yield the corresponding tetrafluoroborate salts 7a-e. These salts facilitated the
purification of the imidazolium salts and further enabled isolation of NHC Pd allyl chloride
complexes 8a-e in high purity.
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Scheme 2: Synthesis of tailed Pd allyl chloride complexes 8 a-e, yields shown are for the final
complex formation from the imidazolium tetrafluoroborate salts 7 a-e.
Tailed Pd NHC complex performance in model Suzuki cross coupling reaction
All Pd NHC complexes of types 6 and 8 proved to be effective catalysts for this model cross coupling
reaction, Table 1, when carried out under batch conditions; i.e. addition of catalyst to the reactants
and reagent at 30°C in an alcohol as solvent. The nature of the tail appears to be having minimal
effect on the yield of biphenyl 11 in a batch reaction. In a lab simulation of the semi-continuous
processing, in which a solution of t-BuOK, 9 and 10 are added to a solution of the catalyst at 30°C,
significant quantities of homocoupled product 12 are formed which were observed to a far lower
extent in the batch process. This could be suppressed when a mild reducing agent such as
potassium formate is added. 12, 27
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Scheme 3: The model reaction chosen to investigate the membrane process with tailed NHC Pd
complexes 6 and 8 was the Suzuki cross coupling of 4-chlorotoluene 9 and (p-
methoxyphenyl)boronic acid 10
Table 1: Catalyst performance in Suzuki cross coupling of 9 & 10a
Entry
1
Pd complex
Solvent
iPrOH
EtOH
iPrOH
iPrOH
iPrOH
iPrOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Yield 11 (%)
5
5
83
0
2
3
6a
86
84
85
83
99
98
97
99
89
89
4
6b
6c
5
6
6d
CX-21
8a
7
8
9
8b
8c
10
11
12
8d
8e
a) Reaction concentration 500 mM with respect to chlorotoluuene 9, 1
mol% catalyst, t-BuOK (1.3 eq), 30°C, 4 h, solvents degassed.
Membrane characteristics and requirements
Two parameters generally used to characterize a membrane are solute rejection and permeate
flux. Rejection is a measure of a solutes ability to permeate through the membrane thus, if a solute
has high rejection its concentration is low in the permeate. Membrane rejection (R) is a function of
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the solute concentration in both the permeate (Cp) and retentate (Cr) and is expressed as a
percentage, eq 1.
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ꢂꢃ
1 −
ꢂꢄ
ꢀ = ꢁ
ꢅ ∗ 100
(1)
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Membrane flux is a measure of the flow rate through the membrane and is determined by
measuring the permeate volume (V) per unit time (t) over a membrane of area (A), expressed as
Lm-2h-1, or if normalized to the applied pressure as Lm-2h-1bar-1 and termed permeance. Equations 2
& 3.
ꢇ
ꢆ = ꢈꢉ
(2)
ꢋ
ꢊ = ∆ꢌ
(3)
The membranes used in this study are principally ceramic membranes; chosen in part due to their
high chemical stability and resistance to swelling but also because the surface of the membrane
can be modified, resulting in a range of surface polarities. This leads to separations that are not
based on size exclusion alone but also the solvent-solute-membrane interactions (affinity aspects).
By way of comparison a tight and chemically highly stable polymeric membrane has also been used
in a number of experiments. Membrane characteristics are listed in table S1. Both contact angle
and water permeance are a measure of the membrane surfaces hydrophilicity and consequently
surface polarity.4, 28-29 The more hydrophilic a membrane is, the more the contact angle tends to
zero and also its water flux will be higher. Accordingly, hydrophilic membranes are more efficient in
highly polar solvent systems.
For the model cross coupling reaction used in this work the intention is to have a membrane that is
capable of high rejection of the catalyst and rejection as low as possible for the reaction product. In
an initial phase the rejection of the Pd aqua complexes 5 & 6 a-d in isopropanol at room
temperature was determined over a number of membranes (table 2). This was done in a unit of set
up very similar to that in Figure 1, V-2 is closed and V-1 open and there is no addition (solvent or
reactant and reagent solution) to the filtration unit under operation. A solution of the catalyst is
added to feed tank (B), the system brought under pressure and permeate collected. This gives the
rejection of the complexes alone and not under reaction conditions. The fact that the reference
untailed Pd complex 5 in general gives a higher rejection than the tailed counterparts is likely to be
due to its greater tendency to form clusters than membrane affinity aspects.
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Table 2: Rejection and permeance data for aqua complexes 5 & 6a-d in isopropanol over 3
different membranes
Rejection
(%)
Permeance
Entry
Membrane
Pd complex
5
(L m-2h-1bar-1)
9
1
86
0.6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
3
6a
6b
6c
6d
5
58
48
36
67
94
84
78
95
92
98
97
97
≥99
96
1.0
0.7
0.9nm TiO2
4
0.4
5
1.3
6
1.4
7
6a
6b
6c
6d
5
1.3
8
1.0 nm C5 TiO2
1.0
9
0.45
1.5
10
11
12
13
14
15
0.12
0.14
0.14
0.14
0.12
6a
6b
6c
6d
Duramem-200
a) Trans membrane pressure ceramic membranes 10 bar, polymeric membranes 20 bar.
Cross flow velocity 2 m/s, temperature rt.
The switch from the aqua complexes to the palladium allyl chloride complexes 8 was principally
due to the instability of the aqua complexes observed upon storage and the fact that the Pd allyl
chloride complexes allowed the use of ethanol as solvent (table 1). Moreover, ethanol is less
viscous than isopropanol and therefore also gives better membrane permeance than isopropanol.
The rejection and permeance data observed with complexes 5 and 6a-d indicated the type of
membranes that would be most suited for use under reaction conditions thus, rejection
measurements with the palladium allyl chloride complexes 8a-e were carried out directly in the
reaction mixture.
On-line semi-continuous OSN processing in cross-coupling reactions
As we earlier reported efficient removal of untailed commercial NHC Pd catalysts and good
reaction yield in the Suzuki reaction of 9 and 10 with either down-stream membrane processing
(off-line) or in a system in which a flow reactor is attached to an OSN filtration unit (at-line)12 is
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feasible. However, these untailed catalysts give poor performance in the semi-continuous mode of
operation (on-line), the latter was explored with tailed NHC Pd catalysts 8. A solution of base (t-
BuOH), potassium formate, 9 & 10 were added via a constant volume diafiltration to the OSN
system containing a solution of the catalyst. Constant volume diafiltration is the addition into the
OSN unit at the same rate that solution permeates through the membrane, thus the volume within
the unit remains constant.30 The object in these reactions is high rejection of the organometallic
species and as low as possible rejection of the reaction product. Because the tailed Pd NHC
complex is maintained under reaction conditions during the addition of reactant solution, catalyst
stability becomes of greater importance than in a batch reaction in which the catalyst is added in a
short time period at the start of the reaction. The membrane set – up used is shown in Figure 1.
Reactions are carried out in a semi-continuous mode, thus to remove issues related to residence
time of reactants and reagents with the catalyst, allowing complete conversion, total return of the
permeate is used during the reaction phase by having V-1 closed and V-2 open. The solution that
permeates the membrane contains reaction product as well as possibly starting materials. This
permeate solution is returned to the reaction vessel (feed tank B) via the diafiltration tank A. Total
return of permeate can be continued until it is deemed, via reaction monitoring, that the reaction
is either complete or catalyst efficiency is no longer sufficient. Whereupon V-2 is closed and V-1
opened allowing the separation of reaction product from the organometallic species.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1: Schematic view of the OSN system used for the semi-continuous reactions, everything in
the shaded zone is under pressure during operation. P1 is a circulation pump, P2 a diafiltration
pump. V1 and V2 are valves allowing either return of permeate via the diafiltration tank or
permeate removal. Trans membrane pressure: 10 bar, solvent: ethanol, membrane cross flow
velocity: 2 m/s.
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Table 3: Rejection over ceramic membranes of untailed & tailed Pd NHC catalysts used in the semi-continuous reactions
5
6
7
8
Pd rejection (%)
Reaction
catalyst temperature
(°C)
Molecular
mass
(g/mol)
entry
Yield (%)
1.0 nm C8
TiO2
0.9 nm C8H4F13
0.9 nm TiO2
TiO2
1
2
3
4
5
6
CX-21
23
23
23
23
23
23
571.5
891.9
912.1
1379.9
856.0
924.1
63
62
62
75
0
0
/
20
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8a
24
54
32
/
57
89
≥99
/
60
65
67
/
8b
8c
8d
8e
80
/
87
/
Reaction scale: 10 mmol with respect to chlorotoluene 9, 1 mol % catalyst, trans membrane pressure: 10 bar, solvent:
ethanol, membrane cross flow velocity: 2 m/s.
All reactions in table 3 were carried out with a catalyst loading of 1 mol% i.e. a substrate to catalyst
ratio of 100. Highest rejections were observed with the 1.0 nm C8 TiO2 membrane and the
perfluoroalkyl tailed Pd NHC complex 8c, being ≥ 99%. No reaction was observed with complex 8d,
the branched alkyl tail in this complex did appear to be unstable and decompose on standing.
Though CX-21 gave reaction yields comparable to the other tailed catalysts its rejection at 23°C was
low. At higher temperature untailed catalyst CX-21 forms Pd0 clusters which gives a good rejection
in membrane separation but then avoids catalyst reuse in a semi-continuous set-up. The obvious
consequence of the low rejection of untailed catalyst CX-21 are ineffective internal separation and
recovery of the catalytically active Pd complex. The reaction yields in table 3 are somewhat lower
than those observed in the batch reactions listed in table 1. This in part at least is due to the higher
concentration of the batch reactions as compared to the continuous membrane assisted reaction
i.e. at higher concentration complete conversion is achieved in a shorter time period.
Origins of Catalyst rejection profile
Catalyst rejection over the membranes can be clarified by taking Spiegler – Kedem theory into
consideration. A method of describing solute transport through a membrane that consists of two
terms, the first related to diffusion i.e. solubility effects and the second related to convection, pore
size and molecular volume. It has already been shown that further solution of this equation can
give solute rejection and that this rejection is a function of the reflection coefficient (σ), which is
dependent on the ratio of the solute size and the membrane pore size, and the ratio of solvent and
solute permeabilities (J/Pdiff).6, 31 If the J/Pdiff ratio is large (≥10), solute rejection approaches a
limiting value equal to the reflection coefficient and thus, solute transport is dominated by
convection and is due to size exclusion. If J/Pdiff is low then diffusion dominates the solute transport
and rejection is lower than the reflection coefficient (σ). Calculation of Pdiff and J/Pdiff for catalysts
8a, 8b and 8c in the same manner as previously reported31 shows clear differences in J/Pdiff
between the membranes (Table 4). Indeed, the rejection profile of catalysts 8b and 8c follow size
exclusion with the 1.0 nm C8 TiO2 membrane as would be expected from the J/Pdiff ratio. In contrast
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the rejection of the catalysts over the tighter 0.9 nm C8H4F13 TiO2, that might be expected to give
higher rejection than that of a membrane with pore size of 1.0 nm, give the best illustration that
solute transport is diffusion controlled because, not only do they give lower rejection than the
1.0 nm membrane but also there is little difference between the rejection of the three catalysts.
With the unmodified membrane again, diffusion is the controlling factor in the observed catalyst
rejection.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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56
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59
60
Table 4: Pdiff & J/Pdiff results for catalysts 8a,8b & 8c in ethanol over numerous membranes
entry
Catalyst
membrane
0.9 nm TiO2
Temp (°C)
J (Lm-2h-1)
Pdiff (Lm-2h-1)
J/Pdiff
0.3
1.4
1.7
1.4
11.4
2.4
0.5
60
Rejection (%)
1
2
3
4
5
6
7
8
9
23
23
23
23
23
23
23
23
23
3
5
9
24
57
60
54
89
65
32
≥99
67
8a
1.0 nm C8 TiO2
0.9 nm C8H4F13 TiO2
0.9 nm TiO2
46
14
1.4
8
32
1
8b
8c
1.0 nm C8 TiO2
0.9 nm C8H4F13 TiO2
0.9 nm TiO2
0.25
5
12
2.9
60
35
5.75
1
1.0 nm C8 TiO2
0.9 nm C8H4F13 TiO2
16
2.2
Process intensification with catalyst 8c
As highest rejection was observed with complex 8c this was the obvious choice of catalyst to use to
demonstrate the increased catalyst efficiency. Experiments were carried out in which initially the
substrate to catalyst ratio of 100 was increased to 400 (1 mol% to 0.25 mol% of catalyst) and then
further to 2000 (0.05 mol % catalyst). The results are summarized in table 5. Practically this was
carried out by simply increasing the concentration of the diafiltration solution in tank (A) (Figure 1),
and keeping the absolute quantity of catalyst in the system the same. The observed reduction in
membrane permeance as catalyst load is reduced is explained by the increase in concentration of
the solutions. The reaction was again carried out in the semi-continuous mode as above and
allowed to run with total return of the permeate (i.e. V-2 open V-1 closed, figure 1) until a volume
equivalent to at least one diafiltration volume32 had been added to feed tank (B) containing
catalyst from the diafiltration tank (A). For the experiments with the substrate/catalyst ratio of 100
and 400 the total return of permeate was allowed to run for 24 hours and for the
substrate/catalyst ratio of 2000 this was for 44 hours33, during which time the volume of solution
added to tank (B) was equivalent to two diafiltration volumes.
Once this reaction phase is complete V-2 was closed and V-1 opened. The contents of the
diafiltration tank (A) was added to the unit feed tank (B) and then the reaction product washed
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through the membrane into the permeate using three diafiltration volumes of ethanol. Between 90
and 95% of the reaction product is then found in the permeate phase.
6
7
8
9
The results in Table 5 show a clear and substantial improvement in mass intensity of the reaction.34-
35 The large reduction in mass intensity observed is principally due to the fact that on increasing the
scale of the reaction the solvent volume used to carry out the process remained the same as that
used with a substrate to catalyst ratio of 100. With just 500 ppm loading of catalyst, 88% yield of 11
product is obtained containing only 16 ppm of Pd contamination without performing any post
metal scavenging treatments. It should be noted that catalyst retention as noted in Table 5
represents the quantity of Pd recovered in the final retentate solution i.e. after washing the
reaction product through the membrane after reaction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5: Comparison of membrane and reaction performance on reduction of load of the catalyst 8c
in the Suzuki cross coupling of 9 & 10.
Substrate/catalyst ratio
Pre-catalyst load (ppm)
100b
10000
75
400c
2500
86
2000d
500
88
Yield (%)a
Av. Process Permeance (Lm-2h-1bar-1)
Catalyst retention (%)
6
2
0.8
96
90
96
Mass intensity (reaction)
424
/
155
355
51
Mass intensity (reaction & product isolation)
167
a Yield determined after evaporation of the permeate and HPLC purity analysis.
b Reaction scale: 10 mmol with respect to chlorotoluene 9.
c Reaction scale: 20 mmol with respect to chlorotoluene 9.
d Reaction scale: 100 mmol with respect to chlorotoluene 9.
Conclusions
Pd complexes containing a N-heterocyclic carbene backbone that have been modified with tails in
the aryl rings of the imidazolidene structure have been designed and synthesized. The substituent
in the Pd complex has a double role: a) to provide greater resistance to cluster formation than their
untailed commercial counterparts and thus increase the catalytic productivity in semi-continuous
reactions b) achieve high membrane rejection of the tailed Pd NHC complexes with top layer
modified ceramic membranes based on both size exclusion and affinity to render them suitable for
use in a membrane assisted process.
The tailed Pd NHC complexes synthesized proved to be efficient catalysts in a model Suzuki cross
coupling reaction and unlike the commercial untailed counterparts high (≥99%) membrane
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rejection was achieved with modified ceramic membranes. Their successful use in a semi-
continuous membrane assisted reactor was demonstrated allowing high yield, high TON values and
low residual Pd in the reaction product. Moreover, significant improvement of Process mass
intensity and high product recovery was achieved. A further advantage of the disclosed system is
that no specialist reactors or adaption of existing reactors is necessary as a nanofiltration unit is a
stand-alone commercially available unit that can be connected to existing reactors via standard
connections. Further studies are underway to further investigate the scope and limitations of these
tailed Pd NHC complexes.
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11
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Conflicts of Interest
There are no conflicts to declare
Acknowledgements
This study has been partially funded by the Flemish government agency for Innovation by Science
and Technology (IWT) within the framework of the SBO project, FunMem4Affinity, grant number
(IWT 110019) and the Hercules foundation (grant agreement AUHA/13005). The research leading
to these results has also received funding from the Innovative Medicines Initiative
(www.imi.euopa.eu) Joint Undertaking under grant agreement no. 115360, resources of which are
composed of financial contribution from the European Union’s Seventh Framework Programme
(FP7/2007-2013) and EFPIA companies’ in kind contribution.
Supporting information
Supporting information figures, shemes and tables
Synthesis of Pd complexes 6a-d and 8a-e.
NMR spectra of synthesized compounds
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