Two flavors of PEPPSI-IPr: Activation and diffusion control in a single NHC-ligated Pd catalyst?

Article abstract of DOI:10.1021/ol1027283

Abnormal reactivity has been observed in Negishi, Suzuki-Miyaura, and Kumada-Tamao-Corriu cross-couplings in which PEPPSI-IPr (where PEPPSI stands for pyridine enhanced precatalyst preparation, stabilization, and initiation and IPr refers to the NHC ligand) is employed, implicating the presence of two distinct Pd⁰ species in the catalytic cycle. Polybrominated arenes and organometallic reagents react selectively to give the product of exhaustive polysubstitution regardless of the initial reaction stoichiometry. Competition experiments suggest that, after an initial activation controlled oxidative addition, reductive elimination produces an ultrareactive Pd⁰ species which consumes all remaining C-Br bonds in the molecule under diffusion control.

Full text of DOI:10.1021/ol1027283

ORGANIC
LETTERS
2011
Vol. 13, No. 1
146-149
Two Flavors of PEPPSI-IPr: Activation
and Diffusion Control in a Single
NHC-Ligated Pd Catalyst?
Igor Larrosa,* Clara Somoza, Alexandre Banquy, and Stephen M. Goldup*
School of Biological and Chemical Sciences, Queen Mary UniVersity of London,
Joseph Priestly Building, Mile End Road, London, E1 4NS, U.K.
i.larrosa@qmul.ac.uk; s.m.goldup@qmul.ac.uk
Received November 10, 2010
ABSTRACT
Abnormal reactivity has been observed in Negishi, Suzuki-Miyaura, and Kumada-Tamao-Corriu cross-couplings in which PEPPSI-IPr (where
PEPPSI stands for pyridine enhanced precatalyst preparation, stabilization, and initiation and IPr refers to the NHC ligand) is employed,
implicating the presence of two distinct Pd0 species in the catalytic cycle. Polybrominated arenes and organometallic reagents react selectively
to give the product of exhaustive polysubstitution regardless of the initial reaction stoichiometry. Competition experiments suggest that, after
an initial activation controlled oxidative addition, reductive elimination produces an ultrareactive Pd0 species which consumes all remaining
C-Br bonds in the molecule under diffusion control.
The emergence of N-heterocyclic carbenes as ligands in
transition metal catalysis has had, and continues to have, a
significant effect on synthetic chemistry.1 Since the first
NHC-supported palladium-mediated cross-coupling was dis-
closed by Herrmann,2a this concept has proven to be
revolutionary, and almost all standard palladium mediated
C-C and C-heteroatom bond forming methodologies have
been shown to benefit from this new paradigm. Although
many early studies focused on the in situ preparation of
catalysts,1 a number of well-defined precatalysts1,2 have
been disclosed. Of special note are the pyridine enhanced
precatalyst preparation stabilization and initiation (PEPPSI)
catalysts of Organ and co-workers, able to carry out
extremely challenging transformations with low catalyst
loading.2f,j,k Further, the high stability of these precatalysts,
which can be purified by simple column chromatography
and stored under air, contrasts with some of the phosphine
(2) (a) Herrmann, W. A.; Elison, M.; Fischer, J.; Kocher, C.; Artus,
G. R. J. Angew. Chem., Int. Ed. 1995, 34, 2371. (b) Gsto¨ttmayr, C. W. K.;
Bo¨hm, V. P. W.; Herdtweck, E.; Grosche, M.; Herrmann, W. A. Angew.
Chem., Int. Ed. 2002, 41, 1363. (c) Cesar, V.; Bellemin-Laponnaz, S.; Gade,
L. H. Organometallics 2002, 21, 5204. (d) Navarro, O.; Kelly, R. A.; Nolan,
S. P. J. Am. Chem. Soc. 2003, 125, 16194. (e) Frisch, A. C.; Zapf, A.;
Briel, O.; Kayser, B.; Shaikh, N.; Beller, M. J. Mol. Catal. 2004, 214, 231.
(f) Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.;
O’Brien, C. J.; Valente, C. Chem.sEur. J. 2006, 12, 4749. (g) Organ, M. G.;
Abdel-Hadi, M.; Avola, S.; Hadei, N.; Nasielski, J.; O’Brien, C. J.; Valente,
C. Chem.sEur. J. 2007, 13, 150. (h) Esposito, O.; Gois, P. M. P.; Lewis,
A. K.; de, K.; Caddick, S.; Cloke, F. G. N.; Hitchcock, P. B. Organometallics
2008, 27, 6411. (i) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41,
1440. (j) Wurtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523. (k) Valente,
C.; Baglione, S.; Candito, D.; O’Brien, C. J.; Organ, M. G. Chem. Commun.
2008, 6, 735. (l) Winkelmann, O. H.; Riekstins, A.; Nolan, S. P.; Navarro,
O. Organometallics 2009, 28, 5809. (m) Tennyson, A. G.; Lynch, V. M.;
(1) For reviews on the use of NHCs in transition metal catalysis, see:
(a) Diez-Gonzalez, S.; Marion, N.; Nolan, S. P. Chem. ReV. 2009, 109,
3612. (b) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem.,
Int. Ed. 2007, 46, 2768. (c) Glorius, F., Ed.; N-Heterocyclic Carbenes in
Transition-Metal Catalysis; Springer: Berlin, 2007.
Bielawski, C. W. J. Am. Chem. Soc. 2010, 132, 9420
.
10.1021/ol1027283  2011 American Chemical Society
Published on Web 12/06/2010

supported catalysts which achieve similar transforma-
tions.3
During the attempted monobutylation of 1,4-dibromoben-
zene mediated by PEPPSI-IPr in the presence of 1 equiv of
n-BuZnBr we unexpectedly observed highly selective double
butylation (Scheme 1).2f In contrast, the corresponding
that it is general but also provides evidence that not all Pd0
species are created equally; indeed in PEPPSI-IPr mediated
cross-couplings it appears that some Pd0 species react under
activation control while others carry out oxidative addition
in a diffusion controlled fashion.
When 1,3-dibromobenzene (1b) was subjected to PEPPSI-
IPr mediated Negishi reaction conditions in the presence of
1 equiv of n-BuZnBr, an excellent selectivity of >99:1 for
1,3-dibutylbenzene (3b) was observed (entry 1, Table 1).
Scheme 1
.
Negishi Reaction between 1,4-Dibromobenzene and
n-BuZnBr
Table 1. Scope of PEPPSI-IPr Mediated Chemoselective
Negishi Cross-Couplinga
reaction mediated by Pd(PPh3)4 resulted, as expected, in
selective monobutylation of the dibromo starting material.4
A review of the literature on palladium mediated cross-
couplings revealed that a similar observation was made in
the context of Suzuki-Miyaura sp2-sp2 couplings of dibro-
moarenes mediated by Pd0/Pt-Bu3.5 The authors rationalized
their observation by proposing diffusion controlled oxidative
addition, with the Pd0 product of reductive elimination rapidly
oxidatively adding to the same substrate. This reaction has
since been applied to pseudoliving Suzuki-Miyaura poly-
condensations leading to the synthesis of controlled molec-
ular weight polyarenes and polyheteroarenes for electronic
applications, surface grafted and hyperbranched polymers.6
By analogy, the result shown in Scheme 1 implies that
PEPPSI-IPr has the potential to act as a phosphine-free
catalyst in catalyst transfer polycondensations, avoiding the
issues associated with the use of phosphine-supported
catalysts,7 with potential applications in the synthesis of
commercially important materials.8 Herein we report our
investigation of this phenomenon which not only confirms
a All reactions were carried out with 1 equiv of n-BuZnBr as outlined
in Scheme 1. See Supporting Information for further details. b Ratios of
fully butylated product to other butylated products as determined by GCMS
analysis. c Yields are defined relative to n-BuZnBr and were determined
by 1H NMR analysis of the crude reaction mixture using mesitylene as an
internal standard.
(3) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998,
37, 3387. (c) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2002, 41, 4746. (d) Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier,
T.; Monsees, A.; Fuhrmann, C.; Shaikh, N.; Dingerdissen, U.; Beller, M.
Chem. Commun. 2004, 38. (e) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555.
(f) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(4) The same result was observed when 2 mol% Pd(PPh3)4 was
employed, but 10 mol% was required in order to give reasonable
conversions.
(5) (a) Dong, C.-G.; Hu, Q.-S. J. Am. Chem. Soc. 2005, 127, 10006. (b)
A similar, albeit less selective outcome was observed in the coupling of
diiodoarenes mediated by Pd(PPh3)4. In this case the outcome was
rationalized as being due to selective double oxidative addition to the
substrate: Sinclair, D. J.; Sherburn, M. S. J. Org. Chem. 2005, 70, 3730.
(c) One example of the double substitution of 1,3-dichlorobenzene by NHC-
ligated Pd has been reported in the presence of an excess of the nucleophile:
Hartmann, C. E.; Nolan, S. P.; Cazin, C. S. J. Organometallics 2009, 28,
2915.
High selectivity for the doubly substituted product was
maintained even for the more hindered ortho substrate 1c
(97:3, entry 2). Remarkably, tribromobenzene 1d (entry 3)
and even tetrabromobenzene 1e (entry 4) showed similar
behavior, selectively affording the tri- and tetra-butylated
products (3d and 3e), respectively. In the case of tetrabro-
mobenzene an unexpected protodebromination side reaction
was observed and both tribromobenzene and tributyl benzene
were observed as side products, significantly decreasing the
yield of the expected product.9 The selectivity for exhaustive
butylation is not limited to simple polybromobenzenes; the
same phenomenon was observed when two or even four
bromine substituents were positioned at opposite extremes
of a biphenyl unit (entries 5 and 6).
(6) (a) Heeney, M.; McCulloch, I. Tetrahedron Lett. 2006, 47, 5143.
(b) Yokoyama, A.; Suzuki, H.; Kubaota, Y.; Ohuchi, K.; Higashimura, H.;
Yokozawa, T. J. Am. Chem. Soc. 2007, 129, 7236. (c) Huang, W.; Su, L.;
Bo, Z. J. Am. Chem. Soc. 2009, 131, 10348. (d) Beryozkina, T.; Boyko,
K.; Khanduyeva, N.; Senkovskyy, V.; Horecha, M.; Oertel, U.; Simon, F.;
Stamm, M.; Kiriy, A. Angew. Chem., Int. Ed. 2009, 48, 2695.
These results are consistent with a diffusion controlled
oxidative addition process as previously proposed for Fu’s
catalyst.5 However, given the recent speculation over the
Org. Lett., Vol. 13, No. 1, 2011
147

nature of the active species in PEPPSI-IPr mediated reac-
tions,10 an alternative hypothesis that PEPPSI-IPr selects for
more electron-rich substrates could not be ruled out. Thus,
we conducted a simple competition experiment between
4-bromotoluene (2h) and 1,4-dibromobenzene (1a): if the
observed selectivities were electronic in origin we would
expect to see consumption of 4-bromotoluene predominantly
while diffusion control would be expected to lead to a
statistical or near-statistical outcome, as previously reported
for Pd0/Pt-Bu3.5 To our surprise neither of these outcomes
were observed. Instead, selective conversion of 1,4-dibro-
mobenzene to 1,4-dibutylbenzene (3a) took place, indicating
that dibromobenzene is the more reactive coupling partner
(Scheme 2). It is clear from the high selectivity displayed
Scheme 3
.
Proposed Catalytic Cycle Operating under Both
Activation and Diffusion Control
Scheme 2. Competitive Negishi Cross-Coupling of
1,4-Bromotoluene and 1,4-Dibromobenzene
Pd0 species I (Scheme 3). If a Pd-Zn interaction was
responsible for activation of the Pd0 center, the effect would
be expected to disappear when other coupling methods are
used in which Zn is absent. Accordingly we investigated the
Suzuki-Miyaura coupling of n-heptyl-9BBN with 1,4-
dibromobenzene (Scheme 4, eq 1) mediated by PEPPSI-IPr.2j
for 1a over 2h not only that the first oxidative addition event
is activation controlled but also that the observed polybu-
tylation (Scheme 1 and Table 1) is not the result of selective
consumption of more electron-rich substrates.
Scheme 4. Suzuki-Miyaura (Eq 1) and
In order to rationalize our observations we propose that
at least two distinct Pd0 species carry out oxidative addition
in these reaction systems (Scheme 3). The dominant Pd0
species in the bulk, II, appears to react under activation
control to give “normal” selectivity, whereas a second Pd0
species, I, which results from reductive elimination, reacts
under diffusion control (Scheme 3). Although there has long
been a debate in the field of phosphine supported palladium
catalysis as to the nature of the species which undergoes
oxidative addition to the halo arene,11 to our knowledge this
is the first time that multiple active Pd0 species have been
required to explain the observed outcome of a single cross-
coupling reaction.12
Kumada-Tamao-Corriu (Eq 2) Couplings of
1,4-Dibromobenzene
A recently published DFT study on the Negishi reaction
between EtZnBr and EtBr mediated by PEPPSI-IPr identified
the initial product of reductive elimination to be a Pd0-ZnBr2
adduct in which a persistent Pd-Zn interaction is present.13
We postulated that this may correspond to hyper-reactive
In this case the selective production of the dialkylated product
was also observed indicating that this unusual behavior is
not limited to Negishi couplings with alkyl zincates.14
Further, the Kumada-Tamao-Corriu coupling of phenyl
magnesium bromide (Scheme 4, eq 2) also led selectively
to the difunctionalized product.2g These results indicate that
this unusual behavior is not limited to sp3-sp2 couplings
but is actually a general property of the PEPPSI-IPr pre-
catalyst.
Having determined the exhaustive substitution of poly-
brominated arenes to be a general property of PEPPSI-IPr
mediated cross-couplings, we briefly investigated the analo-
gous reactions of other di(pseudo)halo benzenes (Table 2).
In the case of 1,4-diiodobenzene, exhaustive butylation was
(7) (a) Goodson, F.; Wallow, T. I.; Novak, B. M. Macromolecules 1998,
31, 2047. (b) Jayakannan, M.; Lou, X.; Van Dongen, J. L. J.; Janssen,
R. A. J. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 1454. (c) Sakamoto,
J.; Rehahn, M.; Wegner, G.; Schlu¨ter, A. T. Macromol. Rapid Commun.
2009, 30, 653.
(8) (a) Koller, G.; Falk, B.; Weller, C.; Giles, M.; McCulloch, I. W.I.P.O.
Patent 2005/014691 A2, Feb. 17, 2005. (b) Heeney, M.; Zhang, W.; Duffy,
W. ; McCulloch, I.; Koller, G. W.I.P.O. Patent 2007/059838, May 31, 2007.
(9) Unfortunately, this protodehalogenation side reaction dominates in
the case of hexabromobenzene leading to a complex mixture of protode-
brominated starting material and polybutylated products.
(10) Manolikakes, G.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48,
205.
148
Org. Lett., Vol. 13, No. 1, 2011

the diffusion controlled reactivity of the Pd0 produced during
reductive elimination. Despite this high reactivity the system
still exhibits activation controlled behavior in the initial
encounter of Pd0 with the substrate in bulk solution leading
us to propose that these Pd0 species displaying distinctly
different reactivity are distinct entities. Although we have
yet to identify the origin of this duality of behavior, one
possibility is deactivation of the unicoordinate Pd0-NHC
species (I) produced during reductive elimination by reco-
ordination of the “throwaway” pyridine ligand to give a less
reactive dicoordinate Pd0 species (II).15 Our results suggest
that PEPPSI-IPr mediated polycondensations can be expected
to proceed by a catalyst-transfer chain-growth mechanism
with concomitant benefits in terms of product control. Despite
the success of phosphine supported catalysts in metal
mediated polycondensations16 drawbacks have been docu-
mented.7 Based on our results we propose that PEPPSI-type
catalysts have significant potential benefits in the synthesis
of functional polymers including the reduction in catalyst
loading, the potential to mount the kinetically stable Pd-NHC
unit on solid support,17 and the addition of sp3-sp2 and
sp3-sp3 coupling procedures, in which PEPPSI-IPr is
particularly competent, to the polymer chemists tool box.
Table 2. PEPPSI-IPr Mediated Negishi Cross-Coupling of
1,4-Dihaloarenesa
a All reactions were carried out with 1 equiv of n-BuZnBr as outlined
in Scheme 1. See Supporting Information for further details. b Yields of
1
2+3 are defined relative to n-BuZnBr and were determined by H NMR
analysis of the crude reaction mixture using mesitylene as an internal
c
1
standard. Ratios of 2:3 were determined by H NMR analysis.
once again observed (Table 2, entry 1). However, in the case
of dichlorobenzene 1l (entry 2) and ditriflate 1m (entry 3)
“normal” selectivity for the monobutylated product is
restored. This is reasonable since significantly higher activa-
tion barriers are associated with oxidative addition to Ar-Cl
and Ar-OTf bonds, and this increase in barrier height could
be expected to turn the diffusive separation of Pd0 species I
and the product of reductive elimination (Scheme 3) into
the preferred pathway.
Acknowledgment. This work was supported by EPSRC
and the Royal Society. S.M.G. thanks the Leverhulme Trust
for an Early Career Fellowship. S.M.G. is a Royal Society
Research Fellow. We thank Dr. Tom Sheppard (University
College London) for helpful discussions.
Supporting Information Available: Detailed experimen-
tal procedures. This material is available free of charge via
the Internet at http://pubs.acs.org.
In conclusion, we have observed the extremely selective
polyfunctionalization of polybromo aromatic compounds
mediated by PEPPSI-IPr which appears to be the result of
OL1027283
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Org. Lett., Vol. 13, No. 1, 2011
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