Palladium N-Heterocyclic Carbene Precatalyst Site Isolated in the Core of a Star Polymer

Article abstract of DOI:10.1021/acs.orglett.5b02388

An approach for supporting a Pd-NHC complex on a soluble star polymer with nanoscale dimensions is described. The resulting star polymer catalyst exhibits excellent activity in cross-coupling reactions, is stable in air and moisture, and is easily recoverable and recyclable. These properties are distinct and unattainable with the small-molecule version of the same catalyst.

Full text of DOI:10.1021/acs.orglett.5b02388

Letter
pubs.acs.org/OrgLett
Palladium N‑Heterocyclic Carbene Precatalyst Site Isolated in the
Core of a Star Polymer
Konstantin V. Bukhryakov,†,‡ Clement Mugemana,†,‡ Khanh B. Vu,† and Valentin O. Rodionov*,†
́
†KAUST Catalysis Center and Division of Physical Sciences and Engineering, King Abdullah University of Science and Technology,
Thuwal 23955-6900, Kingdom of Saudi Arabia
S
* Supporting Information
ABSTRACT: An approach for supporting a Pd−NHC complex on a soluble star polymer with nanoscale dimensions is
described. The resulting star polymer catalyst exhibits excellent activity in cross-coupling reactions, is stable in air and moisture,
and is easily recoverable and recyclable. These properties are distinct and unattainable with the small-molecule version of the
same catalyst.
ransition-metal-catalyzed cross-coupling reactions, espe-
cially Pd-catalyzed ones, are one of the more powerful and
important strategies for creating C−C and C−heteroatom
bonds.1 Many homogeneous and heterogeneous forms of Pd
have been used in cross-coupling catalysis.2−5
examples of organocatalysis with these macromolecules have
been more prevalent than examples of metal-complex catalysis,
in part due to the difficulties involved in tethering of elusive
transition metal ions to carbon- and heteroatom-based
supports.
T
Heterogeneous and supported forms of Pd are stable and
easy to recycle and separate from reaction products. However,
the nature of the active sites of heterogeneous catalysts is often
uncertain.6 Some of the nominally heterogeneous Pd catalysts
operate by a homogeneous “catch-and-release” mechanism,4
which can lead to metal leaching and undesirable evolution of
the catalyst morphology.7,8 In contrast, molecular Pd catalysts
and precatalysts have well-defined structures, and their
properties are amenable to rational design.9 The specific
activity of such catalysts can be higher than that of
heterogeneous counterparts. However, recycling and reuse of
homogeneous catalysts is not trivial.2
Metal complexes immobilized on nanoscale supports could
offer the advantages of both homogeneous and heterogeneous
catalysts: well-defined structures, readily accessible catalytic
sites, and recyclability.10 Nature’s metalloenzymes operate on
this very principle. Chemist-designed, enzyme-inspired nano-
scale catalysts have been the focus of intensive investiga-
tion,11,12 and a number of successful designs have
emerged.13−16 Among the nanoscale catalyst supports,
branched constructs such as dendrimers and star polymers
are unique in that they can be designed to approximate some of
the key features of natural biopolymers.17−19 To date, striking
Here, we describe a Pd precatalyst system confined in the
core of a star polymer through a strongly binding, bulky N-
heterocyclic carbene (NHC) ligand. The NHC functionality is
incorporated into the macromolecule via a reliable and tolerant
copper-catalyzed azide−alkyne cycloaddition (CuAAC) reac-
tion.20,21 The resulting Pd−NHC star polymer is competent in
catalyzing Heck and Stille reactions and is highly stable to air
and moisture. As the Pd centers are site-isolated due to the
core−shell polymer topology, the propensity of Pd to aggregate
and form nanoparticles (NPs) is strongly inhibited. The
polymer catalyst can be recycled multiple times without a
loss of activity. This degree of site isolation is not attainable
with a more traditional cross-linked Merrifield-type resin.
We prepared the star polymer support through an adaptation
of a previously described arm-first strategy.22 Linear polystyrene
macroinitiator P1 with Mn ∼ 9700 g/mol and narrow
polydispersity was synthesized via nitroxide-mediated con-
trolled radical polymerization (NMP).23 P1 was used to
copolymerize divinylbenzene (DVB) and chloromethylstyrene
Received: August 18, 2015
© XXXX American Chemical Society
A
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Scheme 1. Synthesis of the Pd−NHC Star Polymer Catalyst
Figure 1. TEM images of (A) as-prepared polymer P3; (B) Hg-treated polymer P3; (C) Hg-treated polymer P3 after a Stille reaction; (D) reaction
mixture for a Stille coupling catalyzed by PEPPSI-IPr in a microwave reactor.
Table 1. Cross-Coupling Reactions with Pd−NHC Polymer Catalysts
a
b
c
d
e
Includes both Pd NPs and NHC-Pd. Isolated yield. Pd−NHC polymer treated with Hg. Pd−NHC on Merrifield resin. Performed in a
microwave reactor.
(CMS) with a 1:4:10 macroinitiator/DVB/CMS ratio (Scheme
1 B). The resulting star polymer was conveniently separated
from excess P1 by fractional precipitation in benzene/
methanol. Following that, the star polymer was treated with
NaN3 in DMF, which resulted in quantitative transformation of
core chloride functionalities to azides. The azide content of the
resulting star polymer P2 was 0.57 mmol/g. The star polymer
species thus prepared had an average hydrodynamic diameter of
∼12 nm in DMF, as determined by dynamic light scattering
(DLS). The Mw of the polymer, as determined by static light
scattering, was found to be ∼3.0 × 105 g/mol, corresponding to
∼25−30 arms per star.
NHCs are a privileged class of ligands in homogeneous
catalysis.24,25 In Pd-catalyzed cross-couplings, NHCs facilitate
both the initial oxidative addition and the final reductive
elimination steps of the catalytic cycle. Furthermore, the strong
B
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Pd−NHC bond keeps the metal attached to the ligand even
under vigorous reaction conditions, making NHCs attractive
for immobilizing transition metals.26−30 However, the sensi-
tivity of the NHC moieties has so far limited their
incorporation into any complex macromolecular architectures.
One of the most commonly used and versatile Pd−NHC
precatalysts is PEPPSI-IPr introduced by Organ31 (Scheme 1
A). We prepared compound 1, a “clickable” version of PEPPSI
NHC ligand precursor, and coupled it to the azide-function-
alized star polymer P2 using an established CuAAC protocol
(Scheme 1 B).16 The reaction progress was conveniently
monitored by the disappearance of the characteristic azide
absorption band (2097 cm−1) in the IR spectrum of the
polymer. As 1 features two alkyne groups, it is possible that
some of them remained unreacted. While we could not observe
any discernible signals of free alkyne groups in the NMR and IR
spectra of the polymer, we assume at least some free alkynes
remained in the core of the star polymer. The presence of these
alkynes should not be detrimental for any of the subsequent
experiments. An increase of the polymer’s apparent hydro-
dynamic diameter to ∼18 nm was observed by DLS (Figure
S31 and Table S2, SI). The comparison of intensity and volume
distributions revealed that this increase was due to the
formation of a limited number of larger aggregates, while the
size of the majority of the population remained unchanged
(Figure S32 and Table S2, SI). The NHC precursor polymer
was converted to its Pd complex via a reaction with PdCl2 and
3-chloropyridine, closely following the protocol established for
PEPPSI.31 This step led to a further increase in the apparent
DLS hydrodynamic diameter to ∼47 nm (Figures S31 and S32,
SI). We attribute this increase to the higher functionalization of
the polymer cores, as well as to the appearance of large Pd NPs
(see below). The star polymer fully retained its dispersibility
through the CuAAC and Pd metalation steps, and the
distribution of hydrodynamic diameters remained unimodal
and narrow. The presence of 1,2,3-triazoles, which are relatively
weakly binding monodentate ligands for late transition metals,
is not expected to interfere with the formation of the NHC
complexes.32
The Pd content in as prepared polymer P3 was determined
by ICP−OES to be 0.28 mmol/g. Transmission electron
microscopy (TEM) imaging of the polymer revealed a limited
number of large (∼30−40 nm) Pd NPs in the sample (Figure
1A and Figure S4, SI). To remove these, the solution of P3 was
stirred overnight with metallic mercury.33,34 TEM images after
this procedure indicated that all of the Pd NPs have been
amalgamated and removed from the polymer (Figure 1B and
Figures S6, SI). The Pd content of the Hg-treated star polymer
was 0.15 mmol/g, corresponding to the amount of metal
present as the desired Pd−NHC complex.
The as-prepared and Hg-treated Pd−NHC polymers were
evaluated for the catalysis of a Stille coupling between
iodobenzene and ethyl (Z)-3-(tributylstannyl)acrylate under
standard microwave reactor conditions (Table 1, entries 1 and
2). No special precautions have been taken to exclude water or
O2. Despite the higher content of Pd in the as prepared P3, the
yields obtained with both catalysts were identical. This suggests
that the large Pd NPs do not meaningfully participate in
catalysis. For all subsequent experiments, we used the as-
prepared P3 for the reasons of practicality.
However, drastically more Pd NPs formed in the reactions
catalyzed by small-molecule PEPPSI-IPr. After a Stille coupling
performed under the same conditions as the reaction with P3,
most of the PEPPSI-IPr was transformed into ∼17 nm NPs
(Figure 1D and Figure S2, SI). These NPs aggregated and
precipitated rapidly (Figure S10B, SI). The black precipitate
could not be reused for another cycle of catalysis. The crude
reaction product contained 666 ppm of Pd (and still 543 ppm
Pd remained after the product was purified by flash
chromatography). The typically accepted limit of Pd in
pharmaceutical products is 10 ppm.35
We explored the recyclability of the as prepared polymer
catalyst P3 using a model Stille coupling (Table 1, entry 1). As
the model reaction is incomplete after 30 min, these conditions
were convenient for evaluating any changes in the activity of
the catalyst. After each cycle, the mixture was filtered through a
0.2 μm PTFE membrane, and the polymer catalyst was
precipitated in methanol. The precipitate was dried under high
vacuum and used directly for subsequent runs. The activity and
solubility of the catalyst were unchanged after at least five cycles
(Figure 2). The color of the catalyst solution did not change
Figure 2. Recycling of Pd−NHC star polymer P3.
either, which suggests that the number and size of the large Pd
NPs remained relatively constant (Figure S10A, SI). The
workup of the reactions and catalyst recovery were facile: the
five cycles were performed in less than 8 h. Recovery of a
previously described polymer-supported Pd catalyst required 48
h of dialysis.30 The reaction product were analyzed by ICP−
OES to evaluate the extent of Pd leaching. After the first
catalytic cycle, ∼2.8 ppm of Pd was detected before any
chromatographic separation. The Pd content in the product
remained stable at ∼0.7 ppm for the subsequent runs.
To evaluate the difference between the star polymer and a
more traditional resin support, we coupled the NHC precursor
1 to azido-Merrifield resin (5% cross-linked). Despite the high
degree of cross-linking, all the azides in the resin were reactive
under our CuAAC protocol. During the metalation step, most
of the Pd was transformed into large NPs (Figure S8, SI). In
contrast with the star polymer, it was impossible to remove Pd
NPs from the resin by Hg treatment. The resin-supported
catalyst was significantly less active than the star polymer. At
least four times higher Pd loading was required for comparable
activity (Table 1, entries 1 and 10).
Unlike the cross-linked resin, the star polymer P3 exhibits
catalytic activity comparable to that of small-molecule PEPPSI
complex31 for a range of Still and Heck cross-couplings (Table
1). Some reactions proceeded readily at room temperature
(Table 1, entries 6, 7, and 9) and with loadings of Pd down to
0.1 mol % (Table 1, entry 9). This low Pd loading would be at
It is important to note that a small number of uniformly
dispersed ∼5 nm Pd NPs could be observed in the Hg-treated
P3 after the Stille reaction (Figure 1C and Figure S7, SI).
C
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(14) Huerta, E.; Stals, P. J. M.; Meijer, E. W.; Palmans, A. R. A.
Angew. Chem., Int. Ed. 2013, 52, 2906.
(15) Mugemana, C.; Chen, B.-T.; Bukhryakov, K. V.; Rodionov, V.
Chem. Commun. 2014, 50, 7862.
(16) Rodionov, V.; Gao, H.; Scroggins, S.; Unruh, D. A.; Avestro, A.
the lower practical limit even for the small-molecule PEPPSI
catalyst.
In conclusion, we have introduced the design and synthesis
of a Pd−NHC star polymer catalyst that exhibits excellent
activity in Heck and Stille reactions and is easily recycled
through precipitation without loss of activity. Site isolation of
Pd centers in the core of the polymer prevents the aggregation
of Pd into NPs, which in turn leads to good recyclability and
prevents leaching of Pd. The amount of leached Pd in the
product after using the Pd−NHC polymer catalyst was 3 orders
of magnitude lower than the amount found when using the
commercially available PEPPSI complex. We believe that the
site-isolation strategy we describe is general and applicable to
other organotransition-metal catalysts.
J.; Frec
(17) Hecht, S.; Frec
́
het, J. M. J. J. Am. Chem. Soc. 2010, 132, 2570.
́
het, J. M. J. Angew. Chem., Int. Ed. 2001, 40, 74.
(18) Gao, H. Macromol. Rapid Commun. 2012, 33, 722.
(19) Astruc, D.; Chardac, F. Chem. Rev. 2001, 101, 2991.
(20) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
(21) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057.
(22) Bosman, A. W.; Heumann, A.; Klaerner, G.; Benoit, D.; Frec
́
het,
J. M. J.; Hawker, C. J. J. Am. Chem. Soc. 2001, 123, 6461.
(23) Hawker, C. J.; Bosman, A. W.; Harth, E. Chem. Rev. 2001, 101,
3661.
ASSOCIATED CONTENT
(24) Valente, C.; Çalimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.;
■
Organ, M. G. Angew. Chem., Int. Ed. 2012, 51, 3314.
(25) Fortman, G. C.; Nolan, S. P. Chem. Soc. Rev. 2011, 40, 5151.
(26) Kim, J.-H.; Kim, J.-W.; Shokouhimehr, M.; Lee, Y.-S. J. Org.
Chem. 2005, 70, 6714.
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02388.
(27) Kim, J.-W.; Kim, J.-H.; Lee, D.-H.; Lee, Y.-S. Tetrahedron Lett.
2006, 47, 4745.
(28) Bergbreiter, D. E.; Su, H.-L.; Koizumi, H.; Tian, J. J. Organomet.
Chem. 2011, 696, 1272.
(29) He, Y.; Cai, C. Chem. Commun. 2011, 47, 12319.
(30) Karimi, B.; Akhavan, P. F. Chem. Commun. 2011, 47, 7686.
(31) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass,
G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem. - Eur. J. 2006,
12, 4743.
Additional experimental details and characterization
(TEM, EDX, SAED, 1H and 13C NMR, SEC, and
DLS) (PDF)
AUTHOR INFORMATION
■
Corresponding Author
(32) Suijkerbuijk, B. M. J. M.; Aerts, B. N. H.; Dijkstra, H. P.; Lutz,
M.; Spek, A. L.; van Koten, G.; Klein Gebbink, R. J. M. Dalton Trans.
2007, 1273.
(33) Mizuike, A.; Sakamoto, T.; Onishi, N. Microchim. Acta 1971, 59,
783.
(34) Sigeev, A. S.; Peregudov, A. S.; Cheprakov, A. V.; Beletskaya, I.
P. Adv. Synth. Catal. 2015, 357, 417.
(35) Guidelines for Elemental Impurities Q3D; U.S. Food and Drug
Administration, published online 2013. DOI: http://www.fda.gov/
downloads/drugs/guidancecomplianceregulatoryinformation/
guidances/ucm371025.pdf.
*E-mail: valentin.rodionov@kaust.edu.sa. Tel: +966-12-
8084592.
Author Contributions
‡K.V.B. and C.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Prof. Nikos Hadjichristidis (King Abdullah
University of Science and Technology) for helpful discussions.
This research was supported by King Abdullah University of
Science and Technology.
REFERENCES
■
(1) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062.
́
́
(2) Molnar, A. Chem. Rev. 2011, 111, 2251.
(3) Kohler, K.; Prockl, S. S.; Kleist, W. Curr. Org. Chem. 2006, 10,
1585.
(4) Astruc, D. Inorg. Chem. 2007, 46, 1884.
(5) Astruc, D.; Lu, F.; Aranzaes, J. R. Angew. Chem., Int. Ed. 2005, 44,
7852.
(6) Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. Adv. Synth. Catal.
2006, 348, 609.
(7) Narayanan, R.; El-Sayed, M. A. J. Am. Chem. Soc. 2003, 125, 8340.
(8) Narayanan, R.; El-Sayed, M. A. J. Phys. Chem. B 2005, 109, 12663.
(9) DeAngelis, A.; Colacot, T. J. In New Trends in Cross-Coupling:
Theory and Applications; Colacot, T. J., Ed.; Royal Society of
Chemistry: Cambridge, 2014; p 20.
(10) Uozumi, Y. Top. Curr. Chem. 2004, 242, 77.
(11) Lu, A.; O’Reilly, R. K. Curr. Opin. Biotechnol. 2013, 24, 639.
(12) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. Rev. 2002,
102, 3325.
(13) Helms, B.; Guillaudeu, S.; Xie, Y.; Mcmurdo, M.; Hawker, C.;
Frechet, J. Angew. Chem., Int. Ed. 2005, 44, 6384.
́
D
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