Retention of palladium and phosphine ligands using nanoporous polydicyclopentadiene thimbles

Article abstract of DOI:10.1039/c1cc13221k

Thimbles composed of polydicyclopentadiene retained Pd and phosphines used in Buchwald-Hartwig and Sonogashira coupling reactions but allowed the products to permeate. The products were isolated in high yields on the exteriors of the thimbles with no detectable contamination from phosphine and with Pd loadings as low as < 5.5 ppm.

Full text of DOI:10.1039/c1cc13221k

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COMMUNICATION
Retention of palladium and phosphine ligands using nanoporous
polydicyclopentadiene thimblesw
Abhinaba Gupta,a Tyler R. Long,a David G. Rethwischb and Ned B. Bowden*a
Received 31st May 2011, Accepted 1st August 2011
DOI: 10.1039/c1cc13221k
Thimbles composed of polydicyclopentadiene retained Pd and
phosphines used in Buchwald–Hartwig and Sonogashira coupling
reactions but allowed the products to permeate. The products were
isolated in high yields on the exteriors of the thimbles with no
detectable contamination from phosphine and with Pd loadings as
low as o 5.5 ppm.
In our prior work mixtures of two to five molecules were
separated with membranes composed of PDCPD but the
separation of metals or phosphines from the products of a
reaction were not studied.7 In this article the separation of
both phosphines and Pd from the products of two Pd-coupling
reactions is demonstrated. Furthermore, the Pd and phosphines
were recycled five times. This work is critically important because
it demonstrates how commercially available, unmodified phos-
phines and Pd can be separated from the products of a reaction
though simple filtrations and recycled.
The removal of catalysts from products of reactions is critically
important in drug discovery, the synthesis of pharmaceuticals,
and in the academic laboratory.1,2 One critical reason for this
importance is that the upper limits of metals and organic
impurities in pharmaceutical drugs is determined by the FDA
and these values are often very low.3,4 For instance, the
allowed upper limit for Pd in a pharmaceutical drug is
approximately 20 ppm and requires extensive cleaning of the
final product.3,4 Phosphines are also an impurity in an active
pharmaceutical ingredient so their removal is necessary. A
second motivation to remove catalysts from products is their
high costs that make recycling them very desirable. For instance,
Pd coordinated to a new Buchwald phosphine catalyses reactions
with substrates that were previously unreactive,5 but their cost
(one mole of X-Phos costs $19 000 compared to $8700 for a mole
of Pd(OAc)2) makes recycling them very important.6
We investigated Buchwald–Hartwig and Sonogashira coupling
reactions that were catalysed by Pd coordinated to one of the
new Buchwald phosphine ligands (Fig. 1). These reactions
were completed on the interior of hollow, macroscopic thimbles
composed of PDCPD. The thimbles were 5 cm tall, 1.2 cm in
diameter, and possessed walls that were 0.10 cm thick. A
schematic of a thimble is found in the supporting information.
The reactions were run in solvent on the interior of thimbles
until they were complete and then the products were extracted
to the exterior of the thimbles by the addition of hexane only
on the exterior of the thimbles.
The hexane extracts were removed from the reaction vessel,
volatile organics were evaporated under vacuum, and the
crude products were initially characterized by 1H NMR
spectroscopy. No evidence of phosphine ligand was observed
despite the presence of two cyclohexyl and three isopropyl
groups on the phosphine ligand that would appear in an
We recently developed membranes based on highly cross-
linked polydicyclopentadiene (PDCPD) that separates organic
molecules with molecular weights from 100 to 600 g molÀ1
based on their cross-sectional areas (Fig. 1a).7 Molecules with
cross-sectional areas above ca. 0.50 nm2 did not permeate
these membranes and molecules with cross-sectional areas
below 0.38 nm2 permeated readily. Molecular weights and
presence of functional groups did not impact whether molecules
would permeate these membranes; for instance, nonaethylene
glycol monododecyl ether (MW: 583 g molÀ1) permeated
PDCPD but tributylamine (MW: 185 g molÀ1) did not permeate.
These membranes also separated constitutional isomers; triiso-
butylamine permeated PDCPD with a value for its flux at least
104 to 105 times greater than the value for tributylamine.
a Department of Chemistry, University of Iowa,
Iowa City, IA 52242, USA. E-mail: ned-bowden@uiowa.edu;
Fax: (319) 335-1270; Tel: (319) 335-1198
Fig. 1 (a) The polymerization of dicyclopentadiene with the Grubbs
catalyst resulted in a highly cross-linked matrix. (b) The structure of
X-Phos. (c) and (d) The Buchwald–Hartwig and Sonogashira coupling
reactions that were completed as a part of this work.
b Chemical and Biochemical Engineering, University of Iowa, Iowa
City, IA 52242, USA
w Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic detail. See DOI: 10.1039/c1cc13221k.
c
10236 Chem. Commun., 2011, 47, 10236–10238
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Table 1 Isolated yields and retention of Pd for Buchwald–Hartwig
and Sonogashira coupling reactions
Table 2 Permeation of NHPh2 and other molecules through the walls
of a PDCPD thimble
Se/Si of substratef
24 h 48 h
e
Isolated Retention Pd in product
yield (%) of Pd (%)a (ppm)b
Se/Si of NHPh2
Aryl halide Product
24 h
48 h
Substrate
a
PPh3b
0.93
0.86
0.55
0.29
0.86
0.86
0.86
0.86
1
1
1
1
1
1
1
1
1
1
1
1
1
1
r0.0085 r0.010
r0.0041 r0.0055
r0.0039 r0.0077
r0.0043 r0.0071
r0.0041 r0.0046
r0.0036 r0.044
r0.0041 r0.0078
r0.0035 r0.0064
r0.0033 r0.0059
r0.0032 r0.0054
85
94
99.69 113.5
PPh3c
PPh3d
PPh3b
PCy3
Z 99.98 r6.1
b
NPh3
NBu3
b
X-Phosb
91
90
95
99.3
99.98
99.1
228
0.05 Pd(OAc)2 + X-Phosb 0.85
b
0.05 Pd(OAc)2 + PPh3
Cholesterolb
0.85
0.85
0.85
0.86
0.86
5.9
0.43
0.61
0.7
0.80
1.0
1.0
1.0
Octadeceneb
Hexanoic acidb
Nitrobenzaldehydeb
314
0.75
a
The solvent on the interior and exterior of the thimbles was chloro-
93
94
Z 99.97 r5.5
Z 99.97 r5.8
b
form. The solvent was toluene. The solvent was hexane. The
c
d
e
solvent was methanol. The ratio of the concentration of NHPh2 on
f
the exterior (Se) to interior (Si) of the thimble. The ratio of the
a
concentration of the substrate on the exterior (Se) to the interior (Si) of
the thimble. Many of the substrates were not observed in the 1H NMR
spectra of aliquots removed from the exteriors of the thimbles so upper
limits are given.
Percentage of Pd that did not flux to the exterior of the thimbles.
Measured by ICP-OES.
b
1
unobstructed region of the H NMR spectra. The loadings of
Pd in the crude product were characterized by inductively
coupled plasma-optical emission spectroscopy (ICP-OES)
prior to any purification (Table 1). In all experiments, between
99.1% and 4 99.98% of the Pd added to the interior of the
thimbles did not permeate to the exterior which lead to
loadings of Pd in the crude product as low as o5.5 ppm.
Furthermore, the crude product was purified by column
chromatography and the isolated yields were between 85%
and 98%. The isolated yields demonstrated that the products
selectively permeated to the exterior of the thimbles in high
yields despite the low permeation of Pd and phosphines.
To further study the lower limit for the amount of X-Phos
that permeated PDCPD thimbles, the permeation of various
molecules through the walls of the thimbles were investigated
(Table 2). In these experiments diphenylamine (NHPh2) and a
second substrate were added to the interior of a thimble at a
1 : 10 molar ratio. Solvent was added to the interiors and
exteriors of the thimbles and the molecules were allowed to
permeate through the walls of the thimble. The concentration
of NHPh2 and the substrate were found on the exteriors and
interiors of the thimbles at 24 and 48 h. The results in Table 2
clearly demonstrate that PPh3, PCy3, NPh3, and NBu3, X-Phos
did not permeate the walls of the thimbles when toluene was
used as the solvent. Furthermore, PPh3 did not permeate the
walls of the thimbles when chloroform, toluene, hexane, or
methanol was used as the solvent but NHPh2 permeated the
thimbles with each of these solvents. The ability of 1-octadecene,
hexanoic acid, cholesterol, and nitrobenzaldehyde to permeate
the membranes was studied, and each of these molecules
permeated at reasonable rates.
the flux of PPh3, PCy3, NPh3, NBu3, and X-Phos through the
walls of the thimbles was at least three orders of magnitude
lower than that of NHPh2.
The large differences in flux resulted from small differences
in cross-sectional areas (Fig. 2).7 Phosphines and trisubstituted
amines possess rigid three-dimensional shapes and large cross-
sectional areas of at least 0.49 nm2. In contrast, molecules
that permeated PDCPD had lower cross sectional areas of
0.060 to 0.28 nm2 (see the supporting information for cross
sectional areas of all molecules in this article). It is notable
that cholesterol (MW: 387 g molÀ1) and octadecene (MW:
252 g molÀ1) permeated the thimbles but lower molecular
weight trisubstituted phosphines and amines did not permeate.
To study the effect, if any, that X-Phos had on the retention
of Pd, several experiments were conducted. First, X-Phos and
either Pd(OAc)2 or Pd2(dba)3 were added to the interior of the
thimble with toluene at the same ratio and concentration as was
used in the reactions listed in Table 1. Next, toluene was added
to the exterior of the thimbles and the system was stirred for
24 h. The solvent on the exterior of the thimble was removed
from the flask and the amount of Pd in that solvent was
analysed by ICP-OES. The percentage of the original amount
The flux of NHPh2 through the walls of the PDCPD thimbles
were measured as described in the supporting information. The
values for the flux were 8.81 Â 10À7 mmole cmÀ2 sÀ1 in toluene,
4.81 Â 10À7 mmole cmÀ2 sÀ1 in hexanes, and 3.39 Â
10À7 mmole cmÀ2 sÀ1 in methanol. In contrast, the upper limit for
Fig. 2 The ball and spoke models of (a) NHPh2, (b) PPh3, and
(c) cholesterol. The boxes around the images were used to determine
the cross-sectional areas as described in the supporting information.
c
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Table 3 Recycling experiments for a Buchwald–Hartwig coupling
reaction of bromotoluene and aniline
Pd to a polymeric ligand, attaching the catalyst to a solid
support which renders it heterogeneous, or the use of exotic
ligands that allow the catalyst to partition into a second
layer.2,3,8,9 These other methods require additional reactions
to change the structure of a catalyst and affect its reactivity. In
contrast, the method described in this article is successful for
commercially available phosphines and Pd sources and the
retention is implemented at the conclusion of the reaction.
This is a new approach to retention that may be generally
applicable to any ligands with cross-sectional areas larger than
ca. 0.50 nm2.
Concentration of
Cyclea NMR yield (%)b Retention of Pd (%)c Pd in product (ppm)d
1
2
3
4
5
94
94
93
92
93
99.997
99.993
99.979
99.71
0.85
2.41
7.65
109
99.36
241
a
b
The coupling reactions were completed at 80 1C for 7 h. These
values were found using tetraethylene glycol as an internal standard.
c
These values represent the amount of the Pd added to the interior
d
of the thimble that did not extract to the exterior. Measured by
We gratefully acknowledge support from the NSF
(CHE-0848162).
ICP-OES.
of Pd(OAc)2 and Pd2(dba)3 added to the thimbles that permeated
to the exterior of the thimbles was only 0.34% and 0.13%,
respectively. In identical experiments without X-Phos, only
0.37% and 0.32% of Pd(OAc)2 and Pd2(dba)3 permeated to
the exterior of the thimbles. Thus, the presence of X-Phos had
no measurable effect on the retention of either Pd(0) or Pd(II).
Although the exact mechanism for the retention of Pd is not
known, it is clear that very little Pd permeated PDCPD with or
without the presence of phosphines.
Notes and references
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The ability to recycle a Pd/phosphine catalyst was investigated
in a series of Buchwald–Hartwig coupling reactions between
4-bromotoluene and aniline using 5 mol% Pd(OAc)2 and
10 mol% X-Phos (Table 3). The reaction was completed on
the interior of a thimble and extracted to the exterior upon
completion. Fresh KOt-Bu, 4-bromotoluene, and aniline were
added at the start of each cycle, but Pd and X-Phos were only
added at the start of the first cycle.
The crude products were studied by 1H NMR spectroscopy
and no evidence of X-Phos was observed. The concentration
of Pd in the crude product was also investigated by ICP-OES.
In five cycles the amount of Pd that permeated to the exterior
was between 0.003 and 0.64% of the amount of Pd that was
originally added to the interior (Table 3). These reactions were
run for 7 h at 80 1C and all went to quantitative conversions.
To study catalyst stability, the reactions were run for only
3 h at 80 1C and then the product was extracted as before.
The conversions for 4 cycles were 84, 76, 74, and 73%
with retention of Pd between 99.97% and 99.77%. These
experiments demonstrated that the catalyst maintained its
activity throughout these experiments.
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The significance of this work is that the retention of Pd and
phosphines was successful in reactions that used commercially
available phosphines and Pd sources as homogeneous catalysts in
solvent that has been shown by others to facilitate these reactions.
No modifications to the catalyst or reaction conditions were
necessary to retain Pd and phosphines. Other methods to
retain and recycle Pd catalysts typically involve attaching the
c
10238 Chem. Commun., 2011, 47, 10236–10238
This journal is The Royal Society of Chemistry 2011