Assessment of the intermediacy of arylpalladium carboxylate complexes in the direct arylation of benzene: Evidence for C-H bond cleavage by "ligandless" species

Article abstract of DOI:10.1021/ja1113936

Palladium-catalyzed direct arylations of benzene have been proposed to occur by the generation of a phosphine-ligated arylpalladium pivalate complex LPd(Ar)(OPiv) and reaction of this complex with benzene. We have isolated an example of the proposed intermediate and evaluated whether this complex does react with benzene to form the biaryl products of direct arylation. In contrast to the proposed mechanism, no biaryl product was formed from cleavage of the benzene C-H bond by LPd(Ar)(OPiv). However, reactions of LPd(Ar)(OPiv) with benzene and additives that displace or consume the phosphine ligand formed the arylated products in good yield, suggesting that a "ligandless" arylpalladium(II) carboxylate complex undergoes the C-H cleavage step. Consistent with this conclusion, we found that reactions catalyzed by Pd(OAc)₂ without a ligand occur faster than, and with comparable selectivities to, reactions catalyzed by Pd(OAc)₂ and a phosphine ligand.

Full text of DOI:10.1021/ja1113936

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pubs.acs.org/JACS
Assessment of the Intermediacy of Arylpalladium Carboxylate
Complexes in the Direct Arylation of Benzene: Evidence for C-H
Bond Cleavage by “Ligandless” Species
Yichen Tan and John F. Hartwig*
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801,
United States
S Supporting Information
b
Scheme 1. Synthesis of (PtBu3)Pd(Ar)(OPiv)
ABSTRACT: Palladium-catalyzed direct arylations of ben-
zene have been proposed to occur by the generation of a
phosphine-ligated arylpalladium pivalate complex LPd(Ar)-
(OPiv) and reaction of this complex with benzene. We have
isolated an example of the proposed intermediate and
evaluated whether this complex does react with benzene
to form the biaryl products of direct arylation. In contrast to
the proposed mechanism, no biaryl product was formed
from cleavage of the benzene C-H bond by LPd(Ar)-
(OPiv). However, reactions of LPd(Ar)(OPiv) with ben-
zene and additives that displace or consume the phosphine
ligand formed the arylated products in good yield, suggest-
ing that a “ligandless” arylpalladium(II) carboxylate com-
plex undergoes the C-H cleavage step. Consistent with this
conclusion, we found that reactions catalyzed by Pd(OAc)2
without a ligand occur faster than, and with comparable
selectivities to, reactions catalyzed by Pd(OAc)2 and a
phosphine ligand.
(PtBu3)Pd(Ph)(OAc) with 4-nitropyridine N-oxide formed the
arylated product.9 However, arylpalladium pivalate complexes
have not been studied either experimentally or theoretically, and
the reactions of isolated arylpalladium carboxylate complexes
with arenes have not been conducted.
We report the synthesis and characterization of the phosphine-
ligated arylpalladium pivalate complexes (PtBu3)Pd(Ar)(OPiv).
Inconsistent with previous proposals, the reaction of isolated
(PtBu3)Pd(Ar)(OPiv) with benzene does not form Ar-Ph pro-
ducts. However, reactions conducted with additives that displace
or consume the phosphine ligand promote the formation of the
arylated products, and these results and others reported herein
imply the involvement of “ligandless” arylpalladium(II) species in
the C-H cleavage step of the direct arylation of benzene.
The synthesis of (PtBu3)Pd(Ar)(OPiv) is outlined in Scheme 1.
PtBu3-ligated arylpalladium iodide 1 was prepared by the reaction of
Pd(dba)2 with PtBu3 in neat 2-iodotoluene. Reaction of 1 with
AgOPiv formed the PtBu3-ligated arylpalladium pivalate 2 in good
yield. Complex 2 was characterized by elemental analysis and NMR
spectroscopy. The solid-state structure of complex 2 was deter-
mined by single-crystal X-ray diffraction (Figure 1). The pivalate
ligand binds to the Pd center in an κ2-mode with Pd-O bond
distances of 2.124(4) and 2.301(4) Å. The longer Pd-O bond is
trans to the aryl group.
irect arylation, the reaction of aryl halides with arenes or
D
heteroarenes to form biaryl or aryl-heteroaryl products, is an
attractive alternative to traditional cross-coupling because it
occurs without the need to prepare organometallic or main-
group reagents.1 Early efforts to develop this process focused on
the direct arylation of heteroarenes,2 arenes with directing
groups,3 and electron-deficient arenes.4 In 2006, the direct
arylation of benzene was reported by Lafrance and Fagnou.5
Substoichiometric amounts of pivalic acid were used in the
reported catalyst system, and this carboxylic acid was proposed
to function as a proton shuttle during the aryl C-H cleavage
step.6
Despite the improvements in the reaction scope, little experi-
mental information on the mechanism of this reaction is avail-
able, especially on the mechanism of the cleavage of the C-H
bonds in arenes. Phosphine-ligated arylpalladium carboxylates
LPd(Ar)(OCOR) are typically proposed to react with hetero-
arenes or arenes to form biarylpalladium complexes through a
concerted metalation-deprotonation (CMD) pathway.7 DFT
calculations of this pathway have been conducted, and these
studies suggested that arylpalladium acetates are competent to
undergo C-H cleavage with various heteroarenes.8 Indeed, a
recent report from Fagnou’s group showed that the reaction of
The competency of complex 2 to be an intermediate in the
catalytic process was then assessed, and the results of these
studies are summarized in Table 1 (entry 1-3) and eq 1. To
provide a benchmark to compare the reactivity of 2, we con-
ducted the reaction of 2-bromotoluene with benzene catalyzed
by Pd(OAc)2 and PtBu3. This reaction formed 2-phenyl-toluene
in 71% yield (eq 1). In contrast, the stoichiometric reaction of
Received: December 17, 2010
Published: February 11, 2011
r
2011 American Chemical Society
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additives are summarized in Table 1 (entry 4-7). Reactions of 2
with benzene in the presence of a soluble NR4Br salt, the soluble
NR4OPiv salt, or O2 formed 2-phenyl-toluene (3) in higher
yields than in the absence of these additives. The reaction with
0.10 M added NHep4Br formed 3, but in just 30% yield with a
ratio of organic products 3/5 of only 1.3:1. However, the same
reaction at a concentration of complex 2 (0.003 M) that would be
closer to that in the catalytic system formed 3 in 51% yield.
Moreover, the ratio of 3/5 was 7.3, and this value matched that of
the catalytic system. Modest yields of 3 (49% and 63%,
respectively) and good ratios of 3/5 were also obtained from
the reaction with added NHep4OPiv or O2. We propose that
displacement of the phosphine ligand by the halide10 or pivalate
anion, or oxidation of the phosphine ligand by the oxygen
generates a “ligandless” arylpalladium species that undergoes
the C-H cleavage step.
To test our hypothesis that an intermediate lacking a phos-
phine ligand undergoes the C-H cleavage step, a reaction of
benzene with [Pd(o-Tol)Br2]22- (7) lacking a phosphine ligand
was conducted (eq 2) with a base and pivalic acid. The reaction of
7 with benzene in the presence of PivOH formed a 57% yield of
biaryl 3, and the ratio of 3/5 was again similar to that of the
catalytic process (7.0).11 These data support our hypothesis that
the C-H cleavage step occurs through an arylpalladium species
lacking a phosphine ligand.
Figure 1. ORTEP drawing of (PtBu3)Pd(2-MeC6H4)(OPiv) with 50%
ellipsoids. Hydrogen atoms have been omitted for clarity.
Table 1. Reactivity of Complex 2 with Benzenea
concn
yield yield yield
entry
of 2
additives
of 3
of 4
of 5
3/5
1
2
3
4
5
6
7
0.04 M
-
-
trace
trace
trace
30%
51%
27%
33%
45%
17%
31%
25%
26%
32%
20%
25%
-
-
-
0.003 M
0.003 M PivOH (0.03 M)
0.04 M NHep4Br (0.1 M)
0.003 M NHep4Br (0.1 M)
23% 1.3
7% 7.3
5% 9.8
<5% >12
If our proposal that the C-H bond cleavage step occurs by an
intermediate lacking a phosphine ligand is valid, and the C-H
bond cleavage step is turnover-limiting as proposed previously,5,9
the reactions of bromoarenes with benzene should form the
arylated product with faster rates when catalyzed by palladium in
the absence of phosphine. Indeed, the reactions of 4-bromoto-
luene with benzene catalyzed by Pd(OAc)2 alone occurred faster
than, and with comparable selectivities to, reactions catalyzed by
Pd(OAc)2 and a phosphine ligand. Under published conditions
with added Davephos,5 a 76% yield of 4-phenyl-toluene was
obtained, and the reaction reached full conversion after 10 h. In
comparison, the same reaction catalyzed by Pd(OAc)2 alone
formed 4-phenyl-toluene in 80% yield after only 4 h. These
results further support the proposal that C-H bond cleavage of
arenes occurs by arylpalladium species lacking a phosphine
ligand.12
0.003 M NHep4OPiv (0.1 M) 49%
0.003 M O2 (0.01 M) 63%
a Yield by GC/MS with an internal standard.
complex 2 with benzene in the presence of K2CO3 in DMA at
110 °C formed only trace amounts of 2-phenyl-toluene. The
major organic products were toluene and 2,20-dimethyl-biphenyl.
The major organometallic product (55% NMR yield) was
palladacycle 6 from intramolecular C-H bond cleavage of the
phosphine ligand. Attempts to suppress the formation of 2,20-
dimethyl-biphenyl by conducting the reaction with a lower
concentration of 2 that would be present in the catalytic system
led to similar results. Reaction of 2 in benzene in the presence of
PivOH also failed to form 2-phenyl-toluene. Thus, the PtBu3-
ligated arylpalladium pivalate complex 2 is not competent to be
the intermediate that cleaves the arene C-H bond in the
catalytic direct arylation process.
The absence of the product of the catalytic reaction in the
stoichiometric reactions of arylpalladium pivalate complex 2 led
us to study the effects of additives that could be present in the
catalytic system on the distribution of products. The catalytic
system forms a halide and pivalate anion, and it could contain
adventitious oxygen. The results of reactions containing such
To assess further whether the C-H cleavage step occurs
through such “ligandless” arylpalladium species, we studied
the product distribution from the reaction of 4-bromotoluene
with two distinct arenes catalyzed by Pd(OAc)2 with and
without a phosphine ligand. The results are provided in eqs 4
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and 5. The reaction of 4-bromotoluene with benzene and
benzene-d6 catalyzed by Pd(OAc)2 and Davephos formed a
5.4(1):1 ratio of 4-MeC6H4-C6H5 to 4-MeC6H4-C6D5. The
same reaction without an added ligand formed an indistinguish-
able 5.6(2):1 ratio of these products (eq 4). Likewise, the
selectivities from reactions of 4-bromotoluene with benzene
and fluorobenzene with and without a ligand were an indistin-
guishable 14(2):1 and 13(1):1 (eq 5), and the ratio of ortho,
meta, and para isomers of the fluorobiphenyl products were
indistinguishable (23:5:1 vs 24:4:1).
that are lower than those for neutral complexes containing hindered
phosphines. This observation suggests that catalysts for direct
arylation of unactivated arenes could be developed from systems
containing small anionic ligands or additives. Future studies will focus
on designing new methods for direct arylation of unactivated arenes
based on the principles revealed by these mechanistic studies.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, spectra
b
for all new compounds, and crystallographic data for 2. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
jhartwig@illinois.edu
’ ACKNOWLEDGMENT
We thank the NIH (GM-58108) for financial support and
Dale Pahls for helpful guidance and suggestions on the DFT
calculation. We thank Keith Fagnou for discussions at the
inception of these studies. We dedicate this paper to him.
’ REFERENCES
Finally, to assess the differences in barriers for cleavage of the
C-H bond in benzene by arylpalladium species ligated by PtBu3
and lacking a phosphine ligand in DMA solvent, we used density
functional theory (DFT) to compute the barriers for the reaction
of benzene with (PtBu3)Pd(Ph)(OPiv) and (DMA)Pd(Ph)-
(OPiv). The calculated free energy of activation (ΔG‡) for the
reaction of (DMA)Pd(Ph)(OPiv) with benzene was found to
be 31 kcal/mol at 25 °C. This barrier is much lower than the
42 kcal/mol barrier computed for the reaction of (PtBu3)Pd-
(Ph)(OPiv) with benzene (see the Supporting Information for
details). The relative magnitude of these barriers is consistent
with our proposal that the arylpalladium species lacking a
phosphine ligand in DMA is more reactive toward C-H bond
cleavage than is the phosphine-ligated 2.
In summary, studies of the reactions of the isolated arylpalla-
dium pivalate complex 2 with benzene have shown that this
complex is not chemically competent to be an intermediate in the
direct arylation of benzene. However, reactions of 2 conducted in
the presence of additives that displace or consume the phosphine
ligand in 2 did form the arylated products, suggesting that a
“ligandless” arylpalladium species is involved in the C-H
cleavage step. This conclusion is consistent with comparisons
of selectivities of catalytic reactions conducted with and without
added phosphine and with DFT calculations of the barrier of the
reactions of benzene with phosphine-ligated and solvent-ligated
arylpalladium pivalate complexes.
(1) For recent reviews on direct arylations, see: (a) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Campeau,
L.-C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35. (c)
Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48,
9792.
(2) (a) Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm.
Bull. 1989, 37, 1477. (b) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura,
M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. (c) McClure, M. S.;
Glover, B.; McSorley, E.; Millar, A.; Osterhout, M. H.; Roschangar, F.
Org. Lett. 2001, 3, 1677. (d) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J.
Am. Chem. Soc. 2005, 127, 18020. (e) Kobayashi, K.; Sugie, A.;
Takahashi, M.; Masui, K.; Mori, A. Org. Lett. 2005, 7, 5083. (f) Lane,
B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050.
(3) (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1740. (b) Satoh, T.; Kametani, Y.; Terao,
Y.; Miura, M.; Nomura, M. Tetrahedron Lett. 1999, 40, 5345. (c)
Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046. (d)
Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211.
(4) (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754. (b) Lafrance, M.; Shore, D.; Fagnou, K. Org.
Lett. 2006, 8, 5097.
(5) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(6) For recent reports on direct arylation of benzene under metal-
free conditions, see: (a) Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung,
K. H.; He, C.; Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010,
132, 16737. (b) Shirakawa, E.; Itoh, K.-I.; Higashino, T.; Hayashi, T. J.
Am. Chem. Soc. 2010, 132, 15537. (c) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu,
M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.; Shi, Z.-J. Nat.
Chem. 2010, 2, 1044.
(7) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem.
Soc. 2005, 127, 13754.
(8) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008,
130, 10848.
(9) Sun, H.-Y.; Gorelsky, S. I.; Stuart, D. R.; Campeau, L.-C.;
Fagnou, K. J. Org. Chem. 2010, 75, 8180.
(10) For recent report on displacement of a phosphine ligand by a
halide, see: Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 79.
(11) The remainder of the mass balance is toluene. At this point, we
have not been able to identify the source of the proton. Reactions in
We propose that the higher reactivity of the ligandless species
results in large part from differences between the steric properties
of 2 and those of the species formed by replacement of PtBu3
with DMA or halide. All isolated arylpalladium complexes ligated
by PtBu3 contain only three ligands.13 Thus, the higher coordi-
nate species along the pathway for cleavage of the C-H bond of
benzene would be expected to lie at high energy. In addition to
showing that the DMA-ligated complex reacts faster than the
phosphine-ligated species, our studies suggest that anionic
arylpalladium species cleave the arene C-H bonds with barriers
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DMA-d9 or with added D2O formed unlabeled toluene, and reactions
with tetraheptylammonium pivalate form more toluene than those with
pivalic acid and carbonate.
(12) For recent reports on direct arylation under ligand-free condi-
tions, see: (a) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.;
Tymoschenko, M. F. Org. Lett. 2003, 5, 301. (b) Fournier Dit Chabert,
J.; Joucla, L.; David, E.; Lemaire, M. Tetrahedron 2004, 60, 3221. (c)
Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem. 2005, 70, 7578. (d)
Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476.
(13) For recent reports on isolated arylpalladium complexes ligated
by PtBu3, see: (a) Stambuli, J. P.; Incarvito, C. D.; Buehl, M.; Hartwig,
J. F. J. Am. Chem. Soc. 2004, 126, 1184. (b) Yamashita, M.; Hartwig, J. F.
J. Am. Chem. Soc. 2004, 126, 5344. (c) Sergeev, A. G.; Spannenberg, A.;
Beller, M. J. Am. Chem. Soc. 2008, 130, 15549. (d) Denmark, S. E.; Smith,
R. C. J. Am. Chem. Soc. 2010, 132, 1243.
’ NOTE ADDED AFTER ASAP PUBLICATION
The Supporting Information published February 11, 2011,
showed coordinates for a different isomer than the one discussed
in the paper. The correct Supporting Information was published
February 18, 2011.
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