Distinguishing between pathways for transmetalation in Suzuki-Miyaura reactions

Article abstract of DOI:10.1021/ja1108326

We report a systematic study of the stoichiometric reactions of isolated arylpalladium hydroxo and halide complexes with arylboronic acids and aryltrihydroxyborates to evaluate the relative rates of the two reaction pathways commonly proposed to account for transmetalation in the Suzuki-Miyaura reaction. On the basis of the relative populations of the palladium and organoboron species generated under conditions common for the catalytic process and the observed rate constants for the stoichiometric reactions between the two classes of reaction components, we conclude that the reaction of a palladium hydroxo complex with boronic acid, not the reaction of a palladium halide complex with trihydroxyborate, accounts for transmetalation in catalytic Suzuki-Miyaura reactions conducted with weak base and aqueous solvent mixtures.

Full text of DOI:10.1021/ja1108326

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pubs.acs.org/JACS
Distinguishing Between Pathways for Transmetalation in
Suzuki-Miyaura Reactions
Brad P. Carrow and John F. Hartwig*
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801, United States
S Supporting Information
b
and organic solvent, transmetalation between a palladium center
that is ligated by common phosphines, such as PPh3 or PCy3,
occurs between the palladium hydroxo complex and a boronic
acid, not between the palladium halide complex and a trihydroxy-
borate, as often proposed.
ABSTRACT: We report a systematic study of the stoichio-
metric reactions of isolated arylpalladium hydroxo and
halide complexes with arylboronic acids and aryltrihydroxy-
borates to evaluate the relative rates of the two reaction
pathways commonly proposed to account for transmetala-
tion in the Suzuki-Miyaura reaction. On the basis of the
relative populations of the palladium and organoboron
species generated under conditions common for the cataly-
tic process and the observed rate constants for the stoichio-
metric reactions between the two classes of reaction com-
ponents, we conclude that the reaction of a palladium hyd-
roxo complex with boronic acid, not the reaction of a
palladium halide complex with trihydroxyborate, accounts
for transmetalation in catalytic Suzuki-Miyaura reactions
conducted with weak base and aqueous solvent mixtures.
Our experimental design to assess the different proposed
pathways focused on comparing the relative rates of the different
stoichiometric reactions between isolated arylpalladium com-
plexes and arylboron species. We studied the stoichiometric
reaction of an isolated arylpalladium halide complex and trihy-
droxyborate in one case and an isolated arylpalladium hydroxo
complex and boronic acid in the other. For this design, stable,
arylpalladium hydroxo and halide complexes containing the same
phosphine ligand were needed. The dimeric [(Ph3P)Pd(Ph)(μ-
OH)]2 (1) and (Ph3P)2Pd(Ph)(X) (X = I, Br, and Cl) are known
and were the hydroxo and halide complexes we used for one
study.5 Alkali salts of aryltrihydroxyborates were found to be
soluble in organic solvents in the presence of crown ether and
were the boronates we used for this study.6
he Suzuki-Miyaura reaction is one of the most practiced
T
classes of catalytic C-C bond formation. Although this
reaction is established to occur by oxidative addition, transme-
talation, and reductive elimination, the mechanism of the trans-
metalation step has been widely debated. Two pathways are
typically considered for transmetalation: conversion of an orga-
noboron compound by base to form a nucleophilic boronate,
followed by attack on a palladium halide complex (Scheme 1,
Path A) or conversion of a palladium halide to a nucleophilic
palladium hydroxo complex that subsequently reacts with a neu-
tral organoboron compound (Scheme 1, Path B).1 A number of
studies have led to the conclusion that transmetalation occurs
between the palladium halide and boronate, but data that indicate
transmetalation could occur between the boronic acid and
palladium hydroxo species have also been reported.2,3 Because
transmetalation is often proposed to be turnover limiting and to
dictate the choice of reaction conditions, a firm understanding of
the mechanism of this step is important for the use of this
common catalytic process.4
The reaction of hydroxo complex 1 with p-tolylboronic acid
(eq 1) at room temperature without base formed 4-methylbi-
phenyl within minutes in high yield (81%)7 from transmetala-
tion and reductive elimination.8,9 Similarly, the reaction of
(Ph3P)2Pd(Ph)(I) (2) with potassium p-tolyltrihydroxyborate
at room temperature formed 4-methylbiphenyl rapidly within
minutes in high yield (eq 2). The reaction of PhI with p-
tolylboronic acid catalyzed by Pd(PPh3)4 occurred in 96% yield
We report a systematic study involving the reactions of
isolated arylpalladium hydroxo complexes and arylpalladium
halide complexes containing the same ancillary ligands with aryl-
boronic acids and aryltrihydroxyborates. Equilibrium data for the
interconversion of boronic acid and trihydroxyborate, as well as
equilibrium constants for the interconversion of palladium hy-
droxo and halide complexes containing PPh3 and PCy3 (Cy =
cyclohexyl) as ligands have also been gained. Together, these
data provide strong evidence that, in the typical mixtures of water
Received: December 2, 2010
Published: January 31, 2011
r
2011 American Chemical Society
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over 3 h at 80 °C (eq 3). Both stoichiometric reactions are much
faster than the catalytic process and, therefore, could be the
transmetalation step on the catalytic cycle.
Scheme 1
The relative contribution of Path A and Path B to the
transmetalation sequence in the catalytic reaction is dictated by
the relative concentrations of the palladium halide and hydroxide,
the relative concentrations of boronic acid and trihydroxyborate,
and the relative rate constants for the two stoichiometric reactions
between palladium halide and boronate and between palladium
hydroxide and boronic acid (Scheme 2). The pathway with the
largest product of the rate constant, concentration of palladium
complex, and concentrations of boron reagent would be the one
by which transmetalation occurs. Thus, we studied the intercon-
version of palladiumhydroxo and halide complexes under aqueous
conditions common to the catalytic Suzuki-Miyaura reaction, the
equilibrium between boronic acids and trihydroxyborates, and the
rate constants for the two stoichiometric reactions.
Scheme 2
The combination of 4-fluorophenylboronic acid (0.060 M)
and the weak base potassium carbonate (0.03-0.15 M) typically
used in Suzuki-Miyaura reactions (eq 4) formed a mixture of
boronic acid and trihydroxyborate, as determined by 11B and 19
F
time required for acquisition of the 31P NMR spectrum (<5 min).
In addition to the formation of the corresponding aryl halide
complex (Ph3P)2Pd(Ph)(X) (X = I, Br, or Cl), monomeric
(Ph3P)2Pd(Ph)(OH) was detected.13 The concentration of aryl
halide complex was smaller (0.0028-0.0032 M) than the com-
bined concentration of the dimeric and monomeric palladium
hydroxo complexes (0.0077-0.0081 M) and appeared to be
insensitive to the identity of the halide.
Direct comparison of the relative stabilities of hydroxo and
halide complexes ligated by PPh3 is complicated by the con-
current equilibrium between the monomeric and dimeric forms
of the hydroxo complex. Thus, we also examined the equilibrium
between the hydroxo and halide complexes for a related series of
complexes ligated by PCy3, which are both monomers.13,14
NMR spectroscopy at room temperature in a 1:1 mixture of
acetone and water.10 The equilibrium of the boronic acid with the
trihydroxyborate occurred on the NMR time scale, as evidenced
by a single resonance at a chemical shift between that of the
boronic acid and trihydroxyborate. From the observed chemical
shift and the known chemical shifts of the boronic acid and
trihydroxyborate, the ratio of boronic acid to trihydroxyborate
could be determined. This ratio varied from 1:1 to 1:3 when the
concentration of base was increased from 0.03 to 0.15 M,
respectively. Lloyd-Jones et al. have studied this equilibrium in
aqueous THF mixtures; the populations of the free boronic acid
and trihydroxyborate were similar to each other when the ratio of
THF to H2O was ∼1:1.11,12 Thus, the concentrations of boronic
acid and trihydroxyborate are close to each other in organic
media containing weak base and water.
Equilibria between PCy3-ligated hydroxo and halide com-
plexes are summarized in eqs 6 and 7. In a 25:1 mixture of THF
and H2O, the equilibrium constant for formation of (Cy3P)2-
Pd(Ph)(I) (6) from the combination of (Cy3P)2Pd(Ph)(OH)
(5) (0.013 M) and tetrabutylammonium iodide (0.013 M) is
approximately unity (K = 1.1) at 20 °C. Palladium bromide 7 and
chloride 8 are more stable than iodide 6 (K = 9.3 and 23,
respectively) (eq 6), but the equilibrium constants are still small.
In a similar medium containing less water (THF:water = 50:1),
the equilibrium between hydroxo 5 and each of the halide
Our studies on the equilibria between palladium hydroxo and
halide complexes are summarized in eq 5.2e The exchange of the
halide in tetraalkylammonium halide salts (0.043 M) with the
hydroxide in complex 1 (0.011 M) in aqueous THF (25:1)
occurred upon mixing at room temperature, as determined by
31P NMR spectroscopy (eq 5). Equilibration was complete in the
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Scheme 3.
a -55 °C then rt. b Time to >95% conversion of 1 at -55 °C.
Figure 1. Decay of 1 (0.015 M) in the presence of p-tolylboronic acid
(0.15 M) and PPh3 (0.15 M) at -40 °C, and decay of 3 (0.030 M) in the
presence of potassium p-tolyltrihydroxyborate (0.15 M), PPh3 (0.15 M),
and 18-crown-6 in THF/H2O (50:1) at -30 °C as monitored by 31P
NMR spectroscopy.
The reaction of hydroxo complex 1 with arylboronic esters
was also monitored by 31P NMR spectroscopy. The reaction of 1
with catechol and neopentyl glycol esters of 4-fluorophenylboro-
nic acid at -55 °C occurred with rates that were similar to that of
the reaction of 1 with free boronic acid (Scheme 3). The
reactions of 1 with boronic esters formed an unidentified inter-
mediate at low temperature as the initial product, in a similar
fashion to the reaction of 1 with boronic acid (vide supra). This
initial product decayed to Pd(PPh3)n (n = 3, 4) upon warming to
room temperature. 4-Fluorobiphenyl was also observed by 19F
NMR spectroscopy upon warming. The more sterically hindered
4-fluorophenyl-boronic acid pinacol ester also reacted with
hydroxo complex 1 at -55 °C, albeit more slowly (>95% con-
version after 1.5 h) than did the catechol and neopentyl glycol
analogues. Thus, the reaction of 1 with all four neutral arylboron
compounds occurs faster than the combination of halide com-
plex 3 and trihydroxyborate. No reaction occurs between the
latter combination over the same period of time, even at -30 °C.
Assuming the borate analogues of the boronic esters do not react
faster than the trihydroxyborates, these data suggest that trans-
metalation during Suzuki-Miyaura coupling of boronic esters
also occurs by reaction of the neutral boron species with the
palladium hydroxide (Path B).
In conclusion, we have shown that the reactions of isolated
palladium hydroxide 1 with boronic acid and the reaction of
palladium iodide 2 with aryltrihydroxyborate both form biaryl
products rapidly in the absence of additives. Between these two
classes of reactions, transmetalation between an arylpalladium
hydroxo complex and a boronic acid would occur faster within
the catalytic cycle because (1) the populations of palladium
halide and palladium hydroxo complex are similar to each other
(2) and the populations of boronic acid and trihydroxyborate are
similar to each other in the presence of water and bases of the
strength of carbonates, and (3) the rate of reaction of hydroxo
complex with boronic acid is several orders of magnitude faster
than the reaction of halide complexes with trihydroxyborate. The
fast reaction of hydroxo complex 1 with arylboronic esters
suggests that Suzuki-Miyaura reactions with these substrates
also proceed by reaction of the neutral arylboron species with a
palladium hydroxo complex.
complexes (6-8) again contained substantial amounts of both
halide and hydroxide complexes (eq 7), but the concentration of
hydroxide 5 increased in all cases relative to the amount present
in the 25:1 mixture of THF and H2O. Presumably, the increased
population of hydroxo complex at lower [H2O] results from the
decreased hydration of free hydroxide ions. From these data, we
conclude that the concentration of palladium halide complex is
higher than the concentration of palladium hydroxide complex in
catalytic Suzuki-Miyaura reactions conducted with aqueous
solvent mixtures but that the populations of the palladium
hydroxo and halide complexes in eqs 5-7 differ by less than
an order of magnitude.
The observed rate constants for the reaction of hydroxide 1
with boronic acid and halide 3 with trihydroxyborate in a 50:1
mixture of THF/H2O were measured by 31P NMR spectroscopy.
The reaction of 1 (0.015 M) with p-tolylboronic acid (0.15 M)
in the presence of PPh3 (0.15 M) was monitored (Figure 1)
at -40 °C and occurred with an observed rate constant of 2.4 Â
10-3 s-1 15
. In contrast, no reaction was observed between halide
complex 3 and potassium p-tolyltrihydroxyborate (0.15 M) in the
presence of PPh3 (0.15 M) and 18-crown-6 at -30 °C over the
same period of time. In fact, less than 10% conversion of 3 occurred,
even after 11 h. These data indicate that the rate constant for
reaction of hydroxo complex 1 with boronic acid is much larger than
that for reaction of halide complex 3 with trihydroxyborate.
The rate constant for reaction of halide complex 3 with p-
tolyltrihydroxyborate at the -40 °C temperature of the reaction
of hydroxo 1 with boronic acid was calculated from activa-
tion parameters for the reaction of 3 with trihydroxyborate
(see Supporting Information). The estimated rate constant
at -40 °C from these data is 1.7 Â 10-7 s-1. This rate constant
is smaller than that for the reaction of hydroxo complex 1 with
boronic acid at the same temperature by a factor of ∼1.4 Â 104.
Because the populations of hydroxo and halide complexes are
similar and substantial amounts of boronic acid exist in media
containing a mixture of organic solvent and water, this large
difference in rate constants implies that the reaction of hydroxo
complex 1 with boronic acid is the pathway that accounts for
transmetalation in the catalytic Suzuki-Miyaura reaction. In fact,
this large difference implies that the reaction would occur
through the hydroxo complex, even under conditions that would
generate low concentrations of hydroxo complex 1 relative to
those of halide complexes 2-4.
These results provide the first quantitative assessment of the
rates of the two pathways and populations of the reactants in
these two pathways, but our conclusions must be made with
several caveats. First, the data we present here cannot be
extrapolated to all metal-ligand systems. Second, reactions with
stronger bases will contain more trihydroxyborate, and if the base
is sufficiently strong, then one might expect the borate pathway
(Path A) to become competitive with the hydroxo pathway
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(Path B). Although this is likely to be true, the majority of
catalytic Suzuki-Miyaura reactions are conducted with relatively
weak bases such as carbonate or phosphate. Third, Lloyd-Jones
et al. have recently reported that Suzuki-Miyaura reactions of
trifluoroborates occur through the free boronic acid after
hydrolysis.11 Thus, the mechanism for transmetalation in these
systems could also proceed by reaction of a palladium hydroxo
complex with boronic acid, but we have not yet assessed the rates
of reaction under these conditions. Finally, our data do not reveal
the intimate mechanism for transfer of the organic moiety from
boron to palladium. Nevertheless, we hope these data will
provide an anchor point to guide further mechanistic and com-
putational studies, and additional studies of the mechanism of
transfer of the organic fragment from boron to palladium will be
forthcoming.
(6) Cammidge, A. N.; Goddard, V. H. M.; Gopee, H.; Harrison,
N. L.; Hughes, D. L.; Schubert, C. J.; Sutton, B. M.; Watts, G. L.;
Whitehead, A. J. Org. Lett. 2006, 8, 4071–4074.
(7) Yields for organic products were determined by GC analysis
versus n-tetradecane as internal standard.
(8) A similar reaction was reported previously with no experimental
details in reviews by Suzuki and Miyaura. See ref 9.
(9) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.(b)
Miyaura, N. In Cross-Coupling Reactions; Miyaura, N., Ed.; Springer:
Berlin/Heidelberg: 2002; Vol. 219, p 11-59.
(10) Aqueous THF mixtures are biphasic in the presence of inor-
ganic base, whereas aqueous acetone mixtures remain homogeneous.
(11) Butters, M.; Harvey, J.; Jover, J.; Lennox, A.; Lloyd-Jones, G.;
Murray, P. Angew. Chem., Int. Ed. 2010, 49, 5156–5160.
(12) Lloyd-Jones et al. also reported that the population of free
boronic acid increases when the concentration of water is decreased.
(13) Grushin, V. V.; Alper, H. Organometallics 1996, 15, 5242–5245.
(14) (a) Grushin, V. V.; Alper, H. Organometallics 1993, 12, 1890–
1901. (b) Stambuli, J. P.; Incarvito, C. D.; B€uhl, M.; Hartwig, J. F. J. Am.
Chem. Soc. 2004, 126, 1184–1194. (c) Huser, M.; Youinou, M. T.;
Osborn, J. A. Angew. Chem. 1989, 101, 1427–1430. (d) Ozawa, F.;
Kawasaki, N.; Okamoto, H.; Yamamoto, T.; Yamamoto, A. Organome-
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimentalprocedures, prep-
b
aration of organoboron and palladium compounds, and kinetic
plots. This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) An intermediate (δ = 20.1 ppm) was detected as the initial
product, which decays to biaryl and Pd(PPh3)4 upon warming.
’ AUTHOR INFORMATION
’ NOTE ADDED IN PROOF
For related studies on transmetallation of boronic acids, see
Amatore, C.; Jutand, A.; Le Duc, G. Chem. Eur. J. 2011, doi:
10.1002/chem.201001911.
Corresponding Author
jhartwig@illinois.edu
’ ACKNOWLEDGMENT
We thank the NIH (NIGMS, GM 58108) for support of this
work and Johnson-Matthey for a gift of PdCl2.
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