A Dichotomy in Cross-Coupling Site Selectivity in a Dihalogenated Heteroarene: Influence of Mononuclear Pd, Pd Clusters, and Pd Nanoparticles-The Case for Exploiting Pd Catalyst Speciation

Article abstract of DOI:10.1021/jacs.1c05294

Site-selective dihalogenated heteroarene cross-coupling with organometallic reagents usually occurs at the halogen proximal to the heteroatom, enabled by intrinsic relative electrophilicity, particularly in strongly polarized systems. An archetypical exam

Full text of DOI:10.1021/jacs.1c05294

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A Dichotomy in Cross-Coupling Site Selectivity in a Dihalogenated
Heteroarene: Influence of Mononuclear Pd, Pd Clusters, and Pd
Nanoparticlesthe Case for Exploiting Pd Catalyst Speciation
Neil W. J. Scott, Mark J. Ford, Neda Jeddi, Anthony Eyles, Lauriane Simon, Adrian C. Whitwood,
Theo Tanner, Charlotte E. Willans, and Ian J. S. Fairlamb*
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ABSTRACT: Site-selective dihalogenated heteroarene cross-cou-
pling with organometallic reagents usually occurs at the halogen
proximal to the heteroatom, enabled by intrinsic relative electro-
philicity, particularly in strongly polarized systems. An archetypical
example is the Suzuki−Miyaura cross-coupling (SMCC) of 2,4-
dibromopyridine with organoboron species, which typically exhibit
C2-arylation site-selectivity using mononuclear Pd (pre)catalysts.
Given that Pd speciation, particularly aggregation, is known to lead
to the formation of catalytically competent multinuclear Pdn
species, the influence of these species on cross-coupling site-
selectivity remains largely unknown. Herein, we disclose that
multinuclear Pd species, in the form of Pd3-type clusters and
nanoparticles, switch arylation site-selectivity from C2 to C4, in
2,4-dibromopyridine cross-couplings with both organoboronic acids (SMCC reactions) and Grignard reagents (Kumada-type
reactions). The Pd/ligand ratio and the presence of suitable stabilizing salts were found to be critically important in switching the
site-selectivity. More generally, this study provides experimental evidence that aggregated Pd catalyst species not only are
catalytically competent but also alter reaction outcomes through changes in product selectivity.
corresponding C−X derivative.6 Switching site-selectivity in
INTRODUCTION
■
the cross-coupling reactions of dihalogenated heteroarenes,
Dihalogentated organic compounds, particularly heteroarenes,
serve as synthetically useful structural templates for increasing
molecular complexity. They enable multiple modes of
which effectively possess biased intrinsic reactivity (through
relative electrophilicity), is a difficult task. For 2,4-dibromopyr-
idine 1, it is very challenging, as C2 site-selectivity dominates
as described in the extensive screening work carried out by
Cid7 and Zhou et al.8,9 There are only a few examples where
atypical C4 site-selectivity in cross-coupling is known.10 A C4
site-selective Suzuki−Miyaura cross-coupling example on 1
was reported by Hardie and Willans et al.,11 which employs
Pd-NHC precatalysts, possessing distinctive ligand architec-
tures. For the best precatalyst, C4:C2 site-selectivity was
∼10:1. However, as is common to an eclectic array of
dihalogenated heteroarene substrates, diarylation was found to
be a competing process and overall product yields were
moderate as a consequence (∼35% for monoarylation
connectivity, providing access to a vast array of compounds
with interesting properties, from agrochemicals and pharma-
ceuticals to advanced materials.1,2 Classical cross-coupling
reaction methodologies are powerful tools for enabling site-
selective processes to be realized, as outlined in two critical
reviews by Fairlamb in 20073 and Spivey et al. in 2017.4
Leading examples are given in Scheme 1, showing the
preferred cross-coupling site for a series of dihalogenated
heteroarenes. Normally, site-selectivity is seen at halogens
activated by the ring heteroatom, either through proximity or
favorable bond polarization in the extended π-ring system.
Houk et al. explained the origin of normal site-selectivity in the
context of the distortion of the C−X bond from a given
substrate and interaction energies on approach to the active
Pd0Ln catalyst.5 Consideration can further be made for the
bond dissociation energies (BDE) at different C−X bonds.
Handy et al. demonstrated that cross-coupling site-selectivity
Received: May 22, 2021
Published: June 21, 2021
1
could be predicted, with caveats, by comparing the H NMR
chemical shifts of the parent heteroarenethe most
deshielded proton being the typical site for coupling in the
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© 2021 American Chemical Society
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to be the dominant catalytically active species in SMCCs, can
aggregate to form higher order Pd nanoparticles that are
capable of mediating further substrate turnover. A serious
question facing the field of cross-coupling catalysis is the
involvement of small Pdn clusters (n < 13), as such species
provide a potential bridge from mononuclear Pd1 species to Pd
nanoparticles (PdNPs).28 Indeed, in a recent study Li et al.29
Scheme 1. Site-Selectivity in Suzuki−Miyaura Cross-
Couplings of Heteroarenes, Exemplified by Dihalogenated
a
Pyridines and Related Derivatives
presented some evidence that [Pd3(μ-Cl)(μ-PPh2)2-
30,31
(PPh3)3]+
not only was an active Pd catalyst for SMCCs
but also appears to invert the order of the oxidative addition
and transmetalation steps within the catalytic cycle, proposing
the activation of the aryl halide as being less like oxidative
addition and more like σ-bond metathesis. Our recent findings
showed that similar [Pd3(μ-Cl)(μ-PPh2)2(PPh3)3]X cluster
species derive from a Pd3(OAc)6/6PPh3 precatalyst, by
reaction of an organohalide (R−X, including 2-bromopyridine)
with the intermediate formed PdI dinuclear species.32 The
outcome sparked our interest in understanding how higher
order Pd species might affect site-selectivity in cross-coupling
reactions of 2,4-dibromopyridine 1 with organoboronic acids
2, as well as other nucleophiles, such as Grignard reagents. We
were encouraged as [Pd3(μ-Cl)(μ-PPh2)2(PPh3)3]X species
were found to be more active in the reported SMCC reactions
than Pd0(PPh3)3 (in terms of substrate turnover frequency).
[Pd3(μ-X)(μ-PR2)2(PR3)3]X species have been invoked as
catalytically relevant species under a range of conditions.29,33,34
Schoenebeck et al. have investigated the use of multinuclear
catalysts for chemoselective cross-coupling reactions at
substrates containing two or more different (pseudo)halide
identities. For example, the reactivity of [Pd(μ-I)(Pt-Bu3)]2
enabled successive selective couplings at Br then OTf then Cl
sites on aromatic substrates.35,36 A Pd3 cluster catalyst, derived
from highly active [Pd(μ-Br)(Pt-Bu3)]2,37 facilitated selective
cross-couplings at aryl iodide over the less activated aryl
bromide sites.34 Additionally, a nanoparticulate active catalyst,
derived in situ from Pd2(dba)3, was found to enable
chemoselective cross-couplings between aryl iodides and
arylgermanes.38 Despite the clear synthetic utility of chemo-
selective reactions at multiply halogenated compounds for
rapid molecular diversification, the preferential site of cross-
coupling is generally quite clear-cut, defined by the BDE of the
C−X bond (e.g., for halides (X), I < Br < Cl ≪ F).3,4 We note
that regioselective control of cross-coupling at substrates
featuring multiple halogens of the same type (i.e., with similar
BDEs) constitutes a greater challenge than a chemoselective
approach involving different halogens.
In this paper we examine the behavior of Pd3-type cluster
and Pd nanoparticle catalysts that derive from Pd(OAc)2/
nPPh3 precatalyst systems under working reaction conditions.
Varying the number of PPh3 ligands (relative to Pd) enables us
to switch between higher order Pdn catalysis and mononuclear
Pd1 catalysis. This has an impact on switching regioselectiv-
itythe reaction outcomefrom typical C2 to atypical C4, in
2,4-dibromopyridine 1 cross-couplings with either organo-
boronic acids 2 (SMCC reactions) or Grignard reagents 5
(Kumada−Corriu type reactions). The activity of PdNPs is
modulated by additive stabilizing salts, which proved to be
critical in switching catalyst site-selectivity. While PdNPs are
established cross-coupling catalysts, this is the first time that
site-selectivity in a dihalogenated heteroarene has been
reversed through exploitation of conditions that facilitate the
in operando (under working reaction conditions) generation of
Pd nanoparticles.
a
A guiding example, for which many catalyst systems/reaction
conditions have been investigated, is given, showing high C2 site-
selectivity.
product). Dai et al. switched the site-selectivity in Suzuki−
Miyaura cross-coupling reactions (SMCCs) involving 2,4-
dichloropyridine using a Q-Phos/Pd(OAc)2 precatalyst
system, resulting in a marginal bias toward the atypical C4-
arylated product, but accompanied by low yields.12 Higher C4-
selectivities at 2,4-dichloropyridine were obtained by changes
to exogenous ligands at Pd, as reported in 2020 by Yang et al.13
The background literature therefore highlights that switches
from typical to atypical site-selectivity are feasible, but that
fundamental reasoning is frustratingly lackingthe focus has
often been placed on ligand changes, assuming a mononuclear
Pd catalyst.14−17 While logical, in our opinion Pd catalyst
speciation is a bigger issue, where changes in mechanism might
better account for typical to atypical site-selectivity changes.
Our research group has been engaged in understanding the
role played by catalytically competent aggregated Pd clusters
and nanoparticles in SMCCs, and related cross-couplings, for
many years.18−23 We presented the first compelling exper-
imental evidence implicating heterogeneous surface catalysts in
SMCCs,24,25 which is supported by recent evidence using time-
resolved fluorescence studies26 and surface-enhanced Raman
spectroscopic techniques.27
The knowledge outlined above is important in the context of
understanding that mononuclear Pd species, generally thought
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RESULTS AND DISCUSSION
■
A benchmark SMCC test reaction [1] is shown in Scheme 2,
involving 2,4-dibromopyridine 1 and p-fluorophenyl boronic
acid 2a to give three products: 3aC2−Ar, 3aC4−Ar, and 3adiaryl
.
The calculated bond dissociation energies for the C2−Br and
C4−Br bonds in 1 were calculated to be 63.3 and 66.9 kcal
mol−1 respectively (determined by Density Functional Theory
calculations using the B3LYP/DGTZVP level of theory),
which indicate that the C2−Br bond is weaker that the C4−Br
bond, mirroring the expected typical site for functionalization.
The reaction conditions described in Scheme 2 [1] are
drawn from our earlier studies,32 informed by the work of
Jutand et al.39 The reaction conditions benefit from being
homogeneous (THF/H2O/[n-Bu4N]OH base at 40 °C, with a
ratio of THF:H2O of 1:1). The high basicity ensures that the
dominant boron species present in solution is the aryl boronate
species 2a′, stabilized by an nBu4N+ cation [2].40a,b We
anticipated the importance of this in terms of exploiting site-
selectivity changes brought about by Pd catalyst speciation,
under varying Pd/ligand ratios. Consistent with the findings
reported by Cid,7 our reaction conditions employing Pd-
(PPh3)4 as the catalyst, gave rise to typical C2 site-selectivity at
1 although conversion was low at 40 °C. The latter finding
parallels the low reactivity of 2-bromopyridine under identical
conditions (i.e., the presence of higher PPh3 equivalents results
in lower catalyst efficacy).32
Figure 1. Summarizing Pd catalyst efficacy under different precatalytic
Pd:PPh3 regimes, showing reaction conversions of which product
selectivities for the SMCC (Scheme 2) of 1 with p-fluoro-
phenylboronic acid 2a to give typical product 3aC2−Ar and atypical
product 3aC4−Ar and bis-arylated product 3adiaryl
.
= 2 or 3), and/or anionic derivatives, are formed from the
Pd(OAc)2/nPPh3 ratios of 1:3 or 1:4, respectively.32,42−45
Altering the Pd(OAc)2/nPPh3 ratio to n = 2.5 results in a
switch in site-selectivity to the atypical 3aC4−Ar product.
Concomitant with this switch in site-selectivity is an increase in
substrate 1 conversion, an outcome particularly evident on
lowering nPPh3 in the system to n < 2. The highest catalyst
efficacy and C4-site selectivity are seen for Pd(OAc)2/nPPh3,
in a 1:1 or 1:1.5 ratio. Of particular note is the activity
observed for the [Pd3(μ-Cl)(μ-PPh2)2(PPh3)3]Cl cluster
precatalyst (referred to as ‘Pd3Cl2’ in Figure 1). This latter
finding correlates with the Pd/P ratio in the Pd3Cl2 cluster
which contains three donating PPh3 ligands (1 PPh3 per Pd)
and two pseudohalogen-like anionic PPh2 ligands (the average
oxidation state per Pd being 4/3). Where n = 0, thus under an
exogenous phosphine ligand-free regime, the reactivity drops
off significantly, although overall 3aC4−Ar product selectivity is
maintained. Hence, under our SMCC conditions, merely
changing the Pd(OAc)2/nPPh3 ratio results in a switch in site-
selectivity and catalyst efficacy, with markedly increased
reaction conversions and higher selectivity for the atypical
3aC4−Ar product.
Scheme 2. Benchmark SMCC of 1 with p-Fluoro-
phenylboronic Acid 2a To Give Typical Product 3aC2-Ar
,
Atypical Product 3aC4-Ar, and Diarylated Product 3adiaryl [1];
the Proposed Equilibrium for 2a and n-Bu4NOH, Which Is
Expected to Lie to the Right-Hand Side Is Shown in [2]
With the knowledge that Pd(OAc)2 and 1 equiv of PPh3
provided increased C4-site selectivity in SMCC reactions of 1,
we investigated whether other aspects of the conditions
contributed to the atypical site-selectivities (Scheme 3) of 1
with p-anisylboronic acid (2b), which gave overall 3bC4−Ar
selectivity under “benchmark” conditions (entry 1, Table 1).
C2-selectivity was also observed when employing Pd2(dba)3·
CHCl3 (ca. 93% purity)41 with 2 or 4 equiv of PPh3 under the
identical conditions {forming Pd0(dba)3−n/(PPh3)n where n =
1 or 2}. Significant differences in catalyst efficacy were revealed
using Pd3(OAc)6/PPh3 precatalyst ratios, hereafter referred to
as Pd(OAc)2/nPPh3 (where n = 0.5 to 4) under conditions as
summarized in Scheme 2. For each catalytic regime, the
conversion of 1 to products 3aC2−Ar, 3aC4−Ar, and 3adiaryl is
given in Figure 1 (note that competing homocoupling
reactions/protodebromination or protodeborylation were not
observable).
Scheme 3. Testing Additive and Base Effects for the SMCC
between 1 and 2b
For the Pd(OAc)2/nPPh3 ratios of 1:3 or 1:4, C2-site
selectivity was observed, giving 3aC2−Ar as the major product,
an outcome consistent with that observed, including lower
product conversions, for the ubiquitous Pd0(PPh3)4 catalyst
system. It is well established that Pd0(PPh3)n species (where n
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Table 1. Modifying the Base and Additives in the SMCC
Reaction between 1 and 2b (Scheme 3)
3bC2−Ar
:
3bC4−Ar:3bdi-
Conv
a
a
aryl
Precatalyst
Entry
Base
Additive
(%)
Pd(OAc)2/
1PPh3
1
2
3
4
5
6
7
8
9
n-Bu4NOH
KOH
KOH
n-Bu4NOH
KOH
n-Bu4NOH
KOH
none
none
n-Bu4NBr
none
n-Bu4NBr
none
none
n-Bu4NBr
n-Oct4NBr
100
89
88
100
100
100
92
10:70:20
26:46:28
3:70:26
18:58:24
8:79:6
15:69:16
38:38:24
9:82:10
7:90:3
Pd(OAc)2/
2PPh3
Pd3Cl2
KOH
KOH
94
100
a
Determined by 1H NMR analysis of the crude reaction mixture, after
1 h.
Using KOH (aq.) as the base in place of n-Bu4NOH (aq.)
(entry 2, Table 1) resulted in a marginal reduction in
conversion but, more strikingly, a marked reduction in site-
selectivity, as exemplified by the reduced 3bC4−Ar:3bC2−Ar ratio
when using a Pd(OAc)2/1PPh3 catalytic system. This
observation indicated the cation of the base, n-Bu4NOH(aq.),
as a critical factor in the higher site-selectivities observed.
Indeed, employing KOH (aq.) base alongside an n-Bu4NBr
additive increased the 3bC4−Ar:3bC2−Ar site-selectivity at the
expense of relatively higher amounts of 3bdiaryl (entry 3, Table
1). Cations have been shown to be able to influence SMCC
reaction rates, principally the transmetalation step,39,46−48 but
to our knowledge this is the first example of such a cation
affecting the site-selectivity outcome of a cross-coupling
reaction involving a dihalogenated heteroarene. Using a
Pd(OAc)2/2PPh3 catalytic system alongside a KOH (aq.)/n-
Bu4NBr base system similarly boosted C4 selectivity (entries 4
and 5, Table 1). Analogous observations were made employing
catalytic Pd3Cl2 (entries 6−9, Table 1). Arguably the best
outcome in terms of global 3bC4−Ar product selectivity was
obtained using Pd(OAc)2/2PPh3 or Pd3Cl2 along with KOH/
n-Bu4NBr (entries 3 and 5 respectively). Switching to the
longer-chain quaternary ammonium salt n-octylammonium
bromide (n-Oct4NBr) in place of n-Bu4NBr gave the highest
product selectivity for 3bC4−Ar (entry 9, Table 1).
Figure 2. Product distribution of 3bC4−Ar, 3bC2−Ar, and 3bdiaryl as
functions of time in the SMCC reaction between 1 and 2b. Using (A)
Pd3Cl2 and (B) Pd(OAc)2/2PPh3 as the precatalyst.
comparable overall reactivities with time. In both cases 3bC4−Ar
was the predominant product, the quantity of which reached a
maximum conversion at approximately 35 and 25 min for
Pd3Cl2 and Pd(OAc)2/2PPh3, respectively. After this time,
3bC4−Ar was slowly converted into 3bdiaryl while the amount of
3cC2−Ar remained approximately constant. This study indicated
that, with the Pd loading fixed at 3 mol %, the Pd(OAc)2/
2PPh3 catalyst is marginally more efficacious than Pd3Cl2,
accounting for the increased 3bdiaryl conversion observed with
Pd(OAc)2/2PPh3, compared with Pd3Cl2 in Table 1.
Given our observations on the importance of the Pd/PPh3
ratio and aliphatic cation n-Bu4N+ as necessary requirements
for atypical 3bC4−Ar site-selectivity in SMCCs, it was decided to
assess whether such effects emerge in the Kumada cross-
coupling of 1 with phenylmagnesium bromide (5) forming
3cC4−Ar, 3cC2−Ar, and 3cdiaryl (Scheme 5).
An assay was designed to track the product evolution of
3bC4−Ar, 3bC2−Ar, and 3bdiaryl products over time in the SMCC
reaction between 1 and p-anisylboronic acid 2b, enabled by the
Pd(OAc)2/2PPh3 and Pd3Cl2 catalyst systems and an n-
Bu4NOH(aq.) base (Scheme 4, Graphs A and B Figure 2) .
Graphs A and B (Figure 2) show that employing Pd3Cl2 or
Pd(OAc)2/2PPh3 as a precatalytic system resulted in broadly
Scheme 4. Conditions, Reagents, and Catalysts Used for
Kinetic Product Distribution Analysis in SMCC Reactions
of 1
The Pd(OAc)2/nPPh3 ratio and catalyst prestir time (in
THF) were altered, with reactions being run in the presence
and absence of n-Oct4NBr, enabling conversions of 1 and
selectivity changes to monoarylated products: 3cC4−Ar and
3cC2−Ar to be fully assessed (Table 2).
In the absence of n-Oct4NBr, high selectivity for the 3cC2−Ar
product was observed (entries 2−4,Table 2). Selectivity for
3cC2−Ar remained, albeit diminishing, when the catalyst prestir
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Taking the Pd2(dba)3·CHCl3/2PPh3 catalyst system (Figure
3A), the most active aryl boronic acid is para-anisylboronic
acid 2b, affording high selectivity for 3bC2−Ar, although
competing 3bdiaryl is apparent. Similar behavior was noted for
para-methyl phenylboronic acid 2d and phenylboronic acid 2e.
The response of the Pd3Cl2 cluster catalyst to changes in the
para Z-substituents of the phenylboronic acids is predictable,
in that high selectivity for the 3C4−Ar products were recorded
(Figure 3B). A similar but more subtle response is seen for the
Pd(OAc)2/1PPh3 catalyst system (Figure 3C).
Scheme 5. Conditions for the Kumada Cross-Coupling of 1
with Phenylmagnesium Bromide 5
a
a
A plot of ΔΔG‡ against σP reveals the reaction sensitivity to
the phenylboronic acid para-substituent Z (Figure 4). One
sees that Pd3Cl2 cluster and Pd(OAc)2/1PPh3 catalyst systems
behave quite differently to Pd2(dba)3·CHCl3/2PPh3. The
magnitude for the gradient (∼0.24) for the latter catalyst
system is in-keeping with the presumption that the aryl boronic
acid substituent ought not to affect site-selectivity in 1, as
oxidative addition occurs prior to transmetalation for
mononuclear Pd catalysts. However, larger gradients are seen
for the Pd3Cl2 cluster (∼0.77) and Pd(OAc)2/1PPh3 (∼0.48),
providing evidence that these catalyst systems behave in a
similar manner.
Given the response of the SMCC reactions of 2,4-
dibromopyridine 1 toward the ubiquitous ligand PPh3, we
decided to screen other widely used phosphorus-containing
ligands (Scheme 7, Figure 5). We tested catalyst mixtures with
Pd(OAc)2/ligand ratios of 1:2 in the reaction of 1 with
phenylboronic acid 2c to give products 3cC2−Br, 3cC4−Br, and
3cdiaryl. Based on consumption of 1 we see low conversions to
Variables changed are highlighted in bold.
time was extended to 24 h (entry 5, Table 2). Employing n-
Oct4NBr instigated a switch in site-selectivity favoring 3cC4−Ar
as the major product, thus mirroring the requirement for a
quaternary ammonium salt observed for C4-site-selectivity in
the SMCC regime vide supra.
Lengthening the prestir time to 24 h resulted in a moderate
increase in 3cC4−Ar:3cC2−Ar site-selectivity from 3.2:1 to 5.1:1,
accompanied by an increase in conversion. The outcome
provides an indication that an active and selective Pd catalyst
species was generated during this time. The catalyst, generated
from Pd(OAc)2 and 4PPh3, prestirred alongside n-Oct4NBr
(0.5 h, THF), led to 3cC2−Ar product selectivity, confirming the
dual requirement of a high Pd:P ratio as well as an additive salt
for overall 3cC4−Ar selectivity under the specified conditions.
To gain insight into the mechanistic dichotomy in site-
selectivity seen for 1, the effect of para-aromatic substituents
on reaction conversion and site-selectivity was assessed in the
SMCC reactions employing appropriate substituted arylbor-
onic acids (Figure 3 and Scheme 6).
the monoarylated products, albeit with a bias toward 3cC4−Ar
.
However, the dominant product is 3cdiaryl resulting from
diarylation.
The model SMCC reaction was carried out with a series of
para Z-substituents to determine whether an electronic
contribution influenced the overall site-selectivity, in selecting
the C2−Br or C4−Br bonds in 1. Three different precatalytic
systems were employed for this part of the study: first,
Pd2(dba)3·CHCl3 (∼93% purity) with 2 PPh3, which proved
to be an effective 3C2−Ar site-selective catalyst under the
conditions. Second, the 3C4−Ar site-selective catalyst systems,
namely Pd3Cl2 cluster and Pd(OAc)2/1PPh3, were assessed
(Figure 3).
An important observation from this series of experiments is
that the greater the electron-withdrawing capacity of the Z-
substituent, the higher the selectivity for the atypical 3C4−Ar
product. Concomitant with these observations was lower
overall product conversions, indicating that the transmetalation
step as rate-determining or that, in some form, the Z-
substituent influences reaction site-selectivity involving 1.
POST-RATIONALIZATION AND FURTHER
ANALYSIS
■
The important take-home message from the examples
presented thus far is that a switch in site-selectivity for the
C4−Ar product in SMCC and Kumada cross-coupling reactions
3
occurs when a quaternary ammonium salt n-R4NX (R = butyl
or octyl, X = Br− or HO−) is employed alongside a low
catalytic equivalence of nPPh3 per Pd(OAc)2 (where 0.5 < n ≥
2.5 in the case of the SMCC reaction). The results point to the
existence of different mechanisms being available to Pd, as the
Pd(OAc)2/nPPh3 ratios are changed; i.e., the Pd catalyst
speciation is different, which is in-keeping with our earlier
studies.32 The higher C2 site-selectivity for 3C2−Ar using higher
equivalences of PPh3 relative to Pd mirrors that reported by
Cid et al.7 using a Pd0(PPh3)4 catalyst which is closely related
Table 2. Changes in Conversion of 1 and Product Site-Selectivity Outcomes, upon Changing Reaction Variables in Kumada
Cross-Couplings (Scheme 5)
a
a
Entry
Pd(OAc)2:nPPh3
Catalyst prestir time (h)
n-Oct4NBr
Conv (%)
3cC2Ar:3cC4Ar:3cdiaryl
1
2
3
4
5
6
7
8
No cat.
1:4
1:2
1:1
1:1
1:1
1:1
1:4
0.5
0.5
0.5
0.5
24
0.5
24
0.5
−
−
−
−
−
+
0
N/A
83:0:17
91:3:6
100
100
99
85
83
96
96
84:6:9
80:11:8
21:68:12
15:77:8
67:26:7
+
+
a
1
Determined by H NMR of the crude reaction mixture after 1 h.
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Figure 3. Effect of product selectivities in SMCC reactions as a function of catalyst system employed and para-substituent on the phenylboronic
acid substrate. (A) Using Pd2(dba)3·CHCl3/2PPh3. (B) Pd3Cl2. (C) Pd(OAc)2/1PPh3.
Scheme 6. Conditions, Reagents, and Catalysts Used for
para-Substituent Analysis of Site-Selective SMCC Reactions
at 1
Scheme 7. Conditions and Reagents Used for Determining
the Effects of a Variety of P-Ligands on Site-Selective SMCC
Reactions at 1
a
Determined by 1H NMR analysis of the crude reaction mixture, after
1 h.
Figure 5. Performance of phosphorus-containing Pd precatalysts
systems in site-selective Suzuki−Miyaura cross-coupling of 1.
observations by Cid et al.,7 we found that the direct reaction of
1 with Pd0(PPh3)4 in toluene at 23 °C (Figure 6) gave the C2-
oxidative addition product OAC2−Br as the major regioisomer
(OAC2−Br/OAC4−Br ≈ 25:1 by 31P NMR spectral analysis of a
crude reaction mixture).
The major regioisomer OAC2−Br was characterized by X-ray
diffraction analysis (corroborated by NMR spectroscopic
analysis of the single crystal analyzed by X-ray diffraction).
Cid et al. characterized the dinuclear Pd complex, OAC2−Br‑dinuc
(Figure 6), resulting from loss of PPh3 from OAC2−Br and
subsequent dimerization of the putative 14-electron PdII
species. These results indicate that oxidative addition of
Pd0(PPh3)n (n = 2 or 3) is the starting point for the SMCC of
1 when Pd0(PPh3)4 or Pd(OAc)2/≥3PPh3 is used as the
precatalyst system, accounting for the overall C2 site-selectivity
Figure 4. Plot of ΔΔG‡ against σP for para-substituent changes in
SMCC reactions of 1 with p-Z-C6H4-B(OH)2 (2a−f).
to the [Pd0(PPh3)n(OAc)]− active species that arises from
Pd(OAc)2/≥3 PPh3.32,42−45 Indeed, in our study, in line with
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Figure 6. Confirmation of mechanistic reasoning for C2−Br site-
selectivity in the reaction of Pd0(PPh3)4 with 1 at 23 °C.
observed in our study, in addition to the previously reported
cross-coupling reactions involving 1.7,8
Further experiments however showed that by stirring a
solution of Pd(OAc)2 and 1 PPh3 at 0 °C for 5 min, layering of
the solution with hexane and subsequent storage at −18 °C led
to the growth of reddish-brown crystals. These have been
confirmed by single crystal X-ray diffraction analysis to be the
dinuclear PdII complex [PdII(μ2-OAc)(κ-OAc)(PPh3)]2 (4),
containing bridging and terminal acetate groups, with one
terminal PPh3 ligand at each Pd center (Figure 7A). The
1
structure of 4 was also confirmed by H NMR spectroscopic
Figure 7. Analysis of the THF-d8. solution arising from the mixture of
Pd(OAc)2/1PPh3. (A) XRD structure of a single crystal of 4 is shown
(selected atoms). (B) 1H NMR analysis, confirming solution presence
of 4 ca. 10 min after mixing at 25 °C. (C. i. and ii.) 31P NMR spectral
data and reaction speciation, showing the decay of 4 and growth of
multiple P-containing species over 12 h, 25 °C.
analysis to be the major solution species formed immediately
after mixing Pd(OAc)2 and 1 PPh3 (diagnostic peaks for the
acetoxy methyl group at δH 1.34 ppm) (Figure 7B). We did
not see any evidence of low-ligated phosphine adducts of
Pd3(OAc)6.49,50 The broadness of the single methyl resonance
(for the OAc ligands) suggests that the two acetate
environments are in exchange at 25 °C, supported by the
proximal relationship as indicated in the solid-state.
Complex 4 was originally reported by Wilkinson et al., who
described it as unstable in the solid-state51we concur with
this description but were fortunate in being successful in
obtaining a solid-state structure. Interestingly, the reactivity of
4 under (hydrogenative) reducing conditions has been
investigated.52,53
We further investigated the solution behavior of 4 in dry d8-
THF at room temperature by 31P NMR spectroscopic analysis
(Figure 7C). Over time, a darkening of the solution was noted
concomitant with the formation of multiple different
phosphorus-containing species (Figure 7C. ii.). While Pd-
(OAc)2/2 or ≥3PPh3 is known to reduce/activate at the
expense of concomitant oxidation of PPh3 via. trans-[Pd-
(OAc)2(PPh3)2], in this case, OPPh3 was only observed as a
minor biproduct of the process. 1H NMR spectroscopic
analysis of the post reaction solution indicated that Ac2O
formed as a major byproduct, alongside AcOH, in a 1:3 ratio,
respectively. This observation points toward 4 facilitating a
different mechanism for activation of Pd(OAc)2 in the
presence of 1 equiv of PPh3, when compared with trans-
[Pd(OAc)2(PPh3)2].32,42−45 TEM analysis of the decomposed
solution of 4 (after overnight reaction at room temperature)
demonstrated the presence of large, spherical Pd particles
(micron-sized).32 When Pd(OAc)2 was similarly treated with
2PPh3 at room temperature, a dinuclear PdI species was found
to be transiently stable in THF. The observation that optimal
catalyst activity and selectivity occur when relatively low
precatalytic ratios of PPh3 to Pd(OAc)2 are employed, i.e.
enabling formation of aggregated Pd clusters and particles,
strongly correlates with the observed reactivity and selectivity
involving cross-coupling reactions of 1, in keeping with
differences in reactivity seen for the related 2-bromopyridine
substrate.32 Scheme 8 summarizes our overall findings, linking
catalyst speciation under differing Pd(OAc)2/nPPh3 regimes.
In addition to the Pd/P ratio, a key requirement for high
3C4−Ar selectivity is the presence of a quaternary ammonium
salt R4NX (R = n-butyl or n-octyl, X = Br−, OH−). The latter
requires further comment and experimental corroboration, as
there is a wealth of literature that explores the stabilization of
highly active anionic PdNP catalyst species by salts. Dupont et
al. reported that catalytic Pd particles, generated by in situ
reductive activation of a palladacyclic compound, could be
stabilized by imidazolium salts for applications in Heck
coupling.54 The immediate electropositive outer layer of a
metal nanoparticle can be stabilized by anions, the sterics and
basicity of which influence PdNP stability.55,56 In a regime
analogous to the electrical double layer, the anionic layer can in
turn be stabilized by a layer of cations. Astruc et al. explored
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Scheme 8. Dichotomy in Site-Selectivity at 1: Different Pd
Species Arising from Different Ratios of Pd(OAc)2/nPPh3
Result in Different Cross-Coupling Selectivities under
Cross-Coupling Conditions
MECHANISTIC HYPOTHESES
■
Given that such profound site-selectivity changes are seen for
cross-couplings of 2,4-dibromopyridine 1, on changing Pd
catalyst speciation in the presence of stabilizing salt additives, a
discussion concerning the mechanistic implications is
pertinent. If one assumes that only mononuclear Pd species
are the relevant catalyst species (dependent on reaction
conditions), then selection of the C2−Br over C4−Br bond
occurs on activation of 1 by a Pd0(PPh3)n complex (where that
n is typically ≥2).7 A neutral pathway is depicted in Scheme
9A. Here, the relative rates of oxidative addition would explain
the typical site-selectivity for C2−Br, presuming this step is
irreversible and that the associated higher intrinsic electro-
Scheme 9. Mechanistic Hypotheses: (A) Catalytic Cycle
Involving Mononuclear Pd Species, via Classical Pd
Intermediates or Alternative Route Involving a SNAr-Type
Mechanism; (B) Catalyst Cycle Based on That Evidenced
by Li et al.29 Involving Pd3 Cluster Species; (C) Proposed
Involvement of Higher Order Pd Agglomerates (Note: Only
Details of Key Steps Are Shown − trans−cis Isomerizations
this electrosteric stabilization in the design of bespoke
architectures for the stabilization of PdNPs.57,58 This valuable
prior knowledge underpins our hypothesis that electrosteric
stabilization of PdNPs is critical to the site-selectivity switch
seen in the cross-coupling reactions of 1. Thus, stabilized
PdNPs, formed in situ from either precatalysts Pd(OAc)2 and
1PPh3 or Pd3Cl2 by additive or in situ generated salts, are the
catalyst species responsible for this atypical selectivity and
relatively high activity, compared to that of the dominant
mononuclear catalytic species generated from Pd(OAc)2 and
≥3PPh3, Pd(PPh3)4, or Pd2(dba)3·CHCl3/2PPh3.
a
and Ligand Dissociation/Association Are Involved)
We have tested our hypothesis further and shown that a tris-
imidazolium tribromide salt can effectively stabilize PdNPs
enabling a marked rise in site-selectivity at 1, exhibiting a
3bC4−Ar:3bC2−Ar ratio of 17.6:1, with a relatively low formation
of 3bdiaryl product (see Supporting Information (SI) for further
details).
The notion that changes to Pd catalyst speciation might
result in different chemoselectivities has been reported by
Schoenebeck et al., elaborating on earlier findings by Fu et
al.14,16,59 They rationalized that cross-coupling selectivities at
4-chlorophenyl triflate occurred at the C−Cl site in reactions
catalyzed by [Pd0(L)1] and the C−OTf side in reactions
catalyzed by the analogous [Pd0(X)(L)]− complex (where X =
an anion present in the system, L = PtBu3). In this case,
however, both active catalysts were proposed to be
mononuclear Pd0 ligated species (based on experimental and
computational evidence). Indeed, subsequent work used 4-
chlorophenyl triflate as a probe to differentiate between
mechanisms arising from a dinuclear PdI precatalyst.60 Our
work has similarly shown two different mechanisms for the
activation of different sites of the dibrominated heterocycle 1.
However, in the case of selectivity for the C4 position, under
the reaction conditions that we have identified, it is highly
unlikely that such mononuclear Pd0 species can be present, an
assertion based on what is known about Pd speciation as the
Pd(OAc)2/nPPh3 ratio is altered (vide supra).32
Finally, the synthetic utility of the Pd3(OAc)6/3PPh3
catalytic system was demonstrated in the synthesis of a novel
2,4-disubstituted pyridine by successive C4-selective arylation
by an SMCC reaction at 1, followed by an Ullman
etherification61 at its C2-position (see SI for further details).
a
Note: (P) = PPh2; P = PPh3; X = anion, e.g. Br or OH.
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philicity of this bond lowers the barrier to its activation. The
case for this catalytic cycle has been made strongly elsewhere;7
however, oxidative addition must be reversible (in Scheme 9A)
in order to account for our experimental observations.
Switching site-selectivity from C2−Br to C4−Br, i.e. 3C4−Ar
over 3C2−Ar, arguably requires a quite different ligand
environment,14,59,60,62 or a complete change in mechanism.
We have not shown anionic mononuclear Pd species here, but
clearly in the presence of n-R4NBr, such a pathway could be
operative, with n-R4N+ acting as the stabilizing cation.43,45,63
Maes and Jutand et al.64 have reported strong evidence for
the existence of an SNAr mechanism for the activation of 5-
substituted-2-bromo-pyridines, which is therefore shown in A
for the C2-arylation pathway, important given the structural
similarity to 1.
An alternative mechanism based on the strong experimental
support reported by Li et al. “Pd3 cluster” catalysis is shown in
Scheme 9B.29 In this case the Pd3Cl2 cluster catalyst, via
formation of a Pd3-hydroxo species, was proposed to activate
the organoboronic acid first, the adduct of which could then
activate the aryl halide. Inversion of the oxidative addition/
transmetalation steps could explain the higher than expected Z-
substituent sensitivity in the site-selective SMCC reaction
involving 1, particularly in the region where Pd3 clusters/Pd
nanoparticles are catalytically competent (Figure 3 and Figure
4).
A third scenario (Scheme 9C) highlights the potential role
of Pd nanoparticles (agglomerates) in the activation of 1, in
essence like the mechanism depicted in Scheme 9B. The Pd
nanoparticles are shown ligated by PPh3 and halide ligands, as
it is established that such stabilizing surface interactions are
important.65,66 In this case, an aryl boronate complex could be
activated by the Pd nanoparticle surface, prior to oxidative
addition of the C4−Br bond of 1. The interaction of base and
anionic aryl boron species at Pd nanoparticle surfaces has been
proposed by El-Sayed et al.67 Such a situation aligns with the
Z-substituent effect (aryl boronic acid) on reaction efficacy and
site-selectivity. The scenario also fits with the observed
speciation arising from Pd(OAc)2/1PPh3 vide suprathe
optimized catalyst system. There can be no doubt that the
mechanistic complexity presented in Scheme 9 requires
significant independent investigation. (We have embarked on
computational studies (DFT) to support the mechanistic
hypotheses described in Scheme 9. However, we are yet to
obtain reasonable results, as the conformational flexibility in
these large Pd3Cl2 cluster species, and related downstream
intermediates, is high, leading to local energy minima. We
selected to not simplify the Pd3 structural models, as the ligand
microenvironment surrounding these is clearly important in
stabilization and in controlling how substrates approach the Pd
centers and their activation.) We anticipate that specialist
experimental methods (real-time fluorescence26 and X-ray
absorption spectroscopy24,25) might reveal insight into the
underlying catalyst speciation behavior and complexity.
for the Pd(OAc)2/≤2PPh3 catalytic system, atypical C4-
selectivity is seen, an outcome that is mirrored using the
Pd3Cl2 cluster catalyst. The addition of a quaternary
ammonium salt proved to be a critical additive for atypical
C4-selectivity, supporting the hypothesis that high site-
selectivity is attributable to PdNPs formed in situ, for which
the quaternary ammonium salt plays a stabilizing role. The
hypothesis was supported using a bespoke tris-imidazolium
tribromide salt, capable of stabilizing Pd nanoparticles.54,55,57
Addition of such a salt to the SMCC reaction system led to a
significant increase in the C4-selectivity. Our findings mark the
first examples of site control of a dihalogenated heteroarene,
switching between two halogens of the same type, while using
the same Pd source [Pd3(OAc)6] and the same ligand type
PPh3. It underlines the importance of controlling precise
metal−ligand ratios for optimal catalyst performance. Interest-
ingly, in the context of site-selective SMCCs, Spivey et al.4
stated that “...caution must be applied when trying to rationalise
switches in site-selectivities as a function of changes of conditions as
the observed products may not arise from the ligated species
expected.” We can now confirm that is the case, but that
reaction outcomes can be controlled through understanding
fundamental changes in Pd catalyst speciation.
More generally our study has demonstrated that the activity
of well-established Pd catalyst mixtures can be very easily
altered by small changes to the reaction conditions. We can
recognize that understanding and controlling catalytic
speciation may allow simple Pd catalytic precursors and simple
inexpensive ligands (e.g., PPh3) to exhibit unique properties in
catalytic cross-coupling chemistries. Such an approach could
be potentially exploited to avoid the use of expensive ligand
architectures. Furthermore, our approach to understanding the
Pd catalyst speciation may serve to complement understanding
in other powerful site-selective cross-couplings.12,13,68−71
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05294.
Full procedures, compound characterization data,
catalysis studies, and X-ray details (PDF)
Accession Codes
CCDC 2060853−2060856 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Ian J. S. Fairlamb − Department of Chemistry, University of
York, Heslington, York, North Yorkshire YO10 5DD, United
Kingdom; orcid.org/0000-0002-7555-2761;
Email: ian.fairlamb@york.ac.uk
CONCLUSIONS
■
In conclusion, our studies have shown that site-selective cross-
couplings of 2,4-dibromopyridine 1 are affected by the type of
catalyst system used and catalyst speciation that ultimately
results under working reaction conditions. The observations
are clear for both SMCC and Kumada cross-coupling
reactions. We have confirmed that Pd(OAc)2/≥3PPh3, and
related catalyst systems, enable typical C2-selctivity. However,
Authors
Neil W. J. Scott − Department of Chemistry, University of
York, Heslington, York, North Yorkshire YO10 5DD, United
Kingdom
Mark J. Ford − Bayer AG, 40789 Monheim, Germany
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(7) Sicre, C.; Alonso-Gómez, J. L.; Cid, M. M. Regioselectivity in
alkenyl(aryl)-heteroaryl Suzuki cross-coupling reactions of 2,4-
dibromopyridine. A synthetic and mechanistic study. Tetrahedron
2006, 62, 11063−11072.
(8) Zhou, Q.; Zhang, B.; Su, L.; Jiang, T.; Chen, R.; Du, T.; Ye, Y.;
Shen, J.; Dai, G.; Han, D.; Jiang, H. Palladium-catalyzed highly
regioselective 2-arylation of 2,x-dibromopyridines and its application
in the efficient synthesis of a 17β-HSD1 inhibitor. Tetrahedron 2013,
69, 10996−11003.
(9) Zhang, B.; Chen, R.; Jiang, H.; Zhou, Q.; Qiu, F.; Han, D.; Li,
R.; Tang, W.; Zhong, A.; Zhang, J.; Yu, X. Palladium-catalyzed highly
regioselective 2-alkynylation of 2,x-dihalopyridines. Tetrahedron 2016,
72, 2813−2817.
(10) Rao, M. L. N.; Dhanorkar, R. J. Triarylbismuthanes as
Threefold Aryl-Transfer Reagents in Regioselective Cross-Coupling
Reactions with Bromopyridines and Quinolines. Eur. J. Org. Chem.
2014, 2014, 5214−5228.
(11) Fowler, J. M.; Britton, E.; Pask, C. M.; Willans, C. E.; Hardie,
M. J. Cyclotriveratrylene-tethered trinuclear palladium(II)-NHC
complexes; reversal of site selectivity in Suzuki-Miyaura reactions.
Dalton Trans. 2019, 48, 14687−14695.
(12) Dai, X.; Chen, Y.; Garrell, S.; Liu, H.; Zhang, L.-K.; Palani, A.;
Hughes, G.; Nargund, R. Ligand-dependent site-selective Suzuki
cross-coupling of 3,5-dichloropyridazines. J. Org. Chem. 2013, 78,
7758−7763.
(13) Yang, M.; Chen, J.; He, C.; Hu, X.; Ding, Y.; Kuang, Y.; Liu, J.;
Huang, Q. Palladium-Catalyzed C-4 Selective Coupling of 2,4-
Dichloropyridines and Synthesis of Pyridine-Based Dyes for Live-Cell
Imaging. J. Org. Chem. 2020, 85, 6498−6508.
(14) Proutiere, F.; Schoenebeck, F. Solvent Effect on Palladium-
Catalyzed Cross-Coupling Reactions and Implications on the Active
Catalytic Species. Angew. Chem., Int. Ed. 2011, 50, 8192−8195.
(15) Keylor, M. H.; Niemeyer, Z. L.; Sigman, M. S.; Tan, K. L.
Inverting Conventional Chemoselectivity in Pd-Catalyzed Amine
Arylations with Multiply Halogenated Pyridines. J. Am. Chem. Soc.
2017, 139, 10613−10616.
(16) Schoenebeck, F.; Houk, K. N. Ligand-controlled regioselectivity
in palladium-catalyzed cross coupling reactions. J. Am. Chem. Soc.
2010, 132, 2496−2497.
(17) Golding, W. A.; Schmitt, H. L.; Phipps, R. J. Systematic
Variation of Ligand and Cation Parameters Enables Site-Selective C−
C and C−N Cross-Coupling of Multiply Chlorinated Arenes through
Substrate−Ligand Electrostatic Interactions. J. Am. Chem. Soc. 2020,
142, 21891−21898.
Neda Jeddi − Department of Chemistry, University of York,
Heslington, York, North Yorkshire YO10 5DD, United
Kingdom
Anthony Eyles − Department of Chemistry, University of
York, Heslington, York, North Yorkshire YO10 5DD, United
Kingdom
Lauriane Simon − Department of Chemistry, University of
York, Heslington, York, North Yorkshire YO10 5DD, United
Kingdom
Adrian C. Whitwood − Department of Chemistry, University
of York, Heslington, York, North Yorkshire YO10 5DD,
United Kingdom; orcid.org/0000-0002-5132-5468
Theo Tanner − Department of Chemistry, University of York,
Heslington, York, North Yorkshire YO10 5DD, United
Kingdom
Charlotte E. Willans − School of Chemistry, University of
Leeds, Leeds LS2 9JT, United Kingdom; orcid.org/0000-
0003-0412-8821
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05294
Funding
The research was principally funded by Bayer AG (CropS-
cience Division), supported by EPSRC grants (EP/K039660/1
and EP/R009406/1).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project was funded by Bayer AG (PhD studentship to
NWJS). We thank the University of York for supporting NMR
spectrometers & X-ray equipment, and EPSRC for NMR
upgrades (EP/K039660/1). C.E.W. acknowledges EPSRC
funding (EP/R009406/1). We gratefully acknowledge the
efforts of Dr. Peter Karadakov (York) in conducting several
exploratory DFT studies to explore our mechanistic hypoth-
9
eses presented in Scheme , and Dr. J. M. Lynam for many
discussions regarding this work. We acknowledge the X-ray
Diffraction service in York for their valuable work (Dr. Sam
Hart and Dr. Rachel Parker).
(18) Baumann, C. G.; De Ornellas, S.; Reeds, J. P.; Storr, T. E.;
Williams, T. J.; Fairlamb, I. J. S. Formation and propagation of well-
defined Pd nanoparticles (PdNPs) during C−H bond functionaliza-
tion of heteroarenes: are nanoparticles a moribund form of Pd or an
active catalytic species? Tetrahedron 2014, 70, 6174−6187.
(19) Hurst, E. C.; Wilson, K.; Fairlamb, I. J. S.; Chechik, V. N-
Heterocyclic carbene coated metal nanoparticles. New J. Chem. 2009,
33, 1837−1840.
(20) Williams, T. J.; Reay, A. J.; Whitwood, A. C.; Fairlamb, I. J. S. A
mild and selective Pd-mediated methodology for the synthesis of
highly fluorescent 2-arylated tryptophans and tryptophan-containing
peptides: a catalytic role for Pd0 nanoparticles? Chem. Commun. 2014,
50, 3052−3054.
(21) Reay, A. J.; Neumann, L. K.; Fairlamb, I. J. S. Catalyst Efficacy
of Homogeneous and Heterogeneous Palladium Catalysts in the
Direct Arylation of Common Heterocycles. Synlett 2016, 27, 1211−
1216.
(22) Bray, J. T. W.; Ford, M. J.; Karadakov, P. B.; Whitwood, A. C.;
Fairlamb, I. J. S. The critical role played by water in controlling Pd
catalyst speciation in arylcyanation reactions. React. Chem. Eng. 2019,
4, 122−130.
(23) Reay, A. J.; Fairlamb, I. J. S. Catalytic C−H bond
functionalisation chemistry: the case for quasi-heterogeneous
catalysis. Chem. Commun. 2015, 51, 16289−16307.
REFERENCES
■
(1) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Privileged scaffolds
for library design and drug discovery. Curr. Opin. Chem. Biol. 2010,
14, 347−361.
(2) Golding, W. A.; Pearce-Higgins, R.; Phipps, R. J. Site-Selective
Cross-Coupling of Remote Chlorides Enabled by Electrostatically
Directed Palladium Catalysis. J. Am. Chem. Soc. 2018, 140, 13570−
13574.
(3) Fairlamb, I. J. S. Regioselective (site-selective) functionalization
of unsaturated halogenated nitrogen, oxygen and sulfur heterocycles
by Pd-catalysed cross-couplings and direct arylation processes. Chem.
Soc. Rev. 2007, 36, 1036−1045.
(4) Almond-Thynne, J.; Blakemore, D. C.; Pryde, D. C.; Spivey, A.
C. Site-selective Suzuki-Miyaura coupling of heteroaryl halides -
understanding the trends for pharmaceutically important classes.
Chem. Sci. 2017, 8, 40−62.
(5) Legault, C. Y.; Garcia, Y.; Merlic, C. A.; Houk, K. N. Origin of
regioselectivity in palladium-catalyzed cross-coupling reactions of
polyhalogenated heterocycles. J. Am. Chem. Soc. 2007, 129, 12664−
12665.
(6) Handy, S. T.; Zhang, Y. A simple guide for predicting
regioselectivity in the coupling of polyhaloheteroaromatics. Chem.
Commun. 2006, 299−301.
9691
https://doi.org/10.1021/jacs.1c05294
J. Am. Chem. Soc. 2021, 143, 9682−9693

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(24) Ellis, P. J.; Fairlamb, I. J. S.; Hackett, S. F. J.; Wilson, K.; Lee, A.
F. Evidence for the Surface-Catalyzed Suzuki−Miyaura Reaction over
Palladium Nanoparticles: An Operando XAS Study. Angew. Chem., Int.
Ed. 2010, 49, 1820−1824.
(25) Lee, A. F.; Ellis, P. J.; Fairlamb, I. J. S.; Wilson, K. Surface
catalysed Suzuki-Miyaura cross-coupling by Pd nanoparticles: an
operando XAS study. Dalton Trans. 2010, 39, 10473−10482.
(26) Costa, P.; Sandrin, D.; Scaiano, J. C. Real-time fluorescence
imaging of a heterogeneously catalysed Suzuki−Miyaura reaction.
Nat. Catal. 2020, 3, 427−437.
(27) Zhao, Y.; Du, L.; Li, H.; Xie, W.; Chen, J. Is the Suzuki-Miyaura
Cross-Coupling Reaction in the Presence of Pd Nanoparticles
Heterogeneously or Homogeneously Catalyzed? An Interfacial
Surface-Enhanced Raman Spectroscopy Study. J. Phys. Chem. Lett.
2019, 10, 1286−1291.
(28) Eremin, D. B.; Ananikov, V. P. Understanding active species in
catalytic transformations: From molecular catalysis to nanoparticles,
leaching, “Cocktails” of catalysts and dynamic systems. Coord. Chem.
Rev. 2017, 346, 2−19.
(29) Fu, F.; Xiang, J.; Cheng, H.; Cheng, L.; Chong, H.; Wang, S.;
Li, P.; Wei, S.; Zhu, M.; Li, Y. A Robust and Efficient Pd3 Cluster
Catalyst for the Suzuki Reaction and Its Odd Mechanism. ACS Catal.
2017, 7, 1860−1867.
(30) Coulson, D. R. Ready cleavage of triphenylphosphine. Chem.
Commun. (London) 1968, 1530−1531.
(31) Dixon, K. R.; Rattray, A. D. Trinuclear palladium clusters:
synthesis and phosphorus-31 nuclear magnetic resonance spectra of
[Pd3Cl(PPh2)2(PPh3)3][BF4] and related complexes. Inorg. Chem.
1978, 17, 1099−1103.
(32) Scott, N. W. J.; Ford, M. J.; Schotes, C.; Parker, R. R.;
Whitwood, A. C.; Fairlamb, I. J. S. The ubiquitous cross-coupling
catalyst system ‘Pd(OAc)2’/2PPh3 forms a unique dinuclear PdI
complex: an important entry point into catalytically competent cyclic
Pd3 clusters. Chem. Sci. 2019, 10, 7898−7906.
(33) Campos, J.; Nova, A.; Kolychev, E. L.; Aldridge, S. A Combined
Experimental/Computational Study of the Mechanism of a
Palladium-Catalyzed Bora-Negishi Reaction. Chem. - Eur. J. 2017,
23, 12655−12667.
(34) Diehl, C. J.; Scattolin, T.; Englert, U.; Schoenebeck, F. C− I-
Selective Cross-Coupling Enabled by a Cationic Palladium Trimer.
Angew. Chem. 2019, 131, 217−221.
(35) Kalvet, I.; Magnin, G.; Schoenebeck, F. Rapid Room-
Temperature, Chemoselective Csp2−Csp2 Coupling of Poly(pseudo)-
halogenated Arenes Enabled by Palladium(I) Catalysis in Air. Angew.
Chem., Int. Ed. 2017, 56, 1581−1585.
(36) Keaveney, S. T.; Kundu, G.; Schoenebeck, F. Modular
Functionalization of Arenes in a Triply Selective Sequence: Rapid
C(sp2) and C(sp3) Coupling of C−Br, C−OTf, and C−Cl Bonds
Enabled by a Single Palladium(I) Dimer. Angew. Chem., Int. Ed. 2018,
57, 12573−12577.
the Suzuki−Miyaura Coupling Reaction. Organometallics 2021, 40,
1120−1128.
(41) Zalesskiy, S. S.; Ananikov, V. P. Pd2(dba)3 as a Precursor of
Soluble Metal Complexes and Nanoparticles: Determination of
Palladium Active Species for Catalysis and Synthesis. Organometallics
2012, 31, 2302−2309.
(42) Amatore, C.; Jutand, A.; M’Barki, M. A. Evidence of the
Formation of Zerovalent Palladium from Pd(OAc)2, and Triphenyl-
phosphine. Organometallics 1992, 11, 3009−3013.
(43) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A.; Meyer, G.
Evidence for the Ligation of Palladium(0) Complexes by Acetate
Ions: Consequences on the Mechanism of Their Oxidative Addition
with Phenyl Iodide and PhPd(OAc)(PPh3)2 as Intermediate in the
Heck Reaction. Organometallics 1995, 14, 5605−5614.
(44) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A. Rates and
Mechanism of the Formation of Zerovalent Palladium Complexes
from Mixtures of Pd(OAc)2 and Tertiary Phosphines and Their
Reactivity in Oxidative Additions. Organometallics 1995, 14, 1818−
1826.
(45) Amatore, C.; Jutand, A. Anionic Pd(0) and Pd(II)
intermediates in palladium-catalyzed Heck and cross-coupling
reactions. Acc. Chem. Res. 2000, 33, 314−321.
(46) Amatore, C.; Jutand, A.; Le Duc, G. Kinetic data for the
transmetalation/reductive elimination in palladium-catalyzed Suzuki-
Miyaura reactions: unexpected triple role of hydroxide ions used as
base. Chem. - Eur. J. 2011, 17, 2492−2503.
(47) Amatore, C.; Jutand, A.; Le Duc, G. The Triple Role of
Fluoride Ions in Palladium-Catalyzed Suzuki−Miyaura Reactions:
Unprecedented Transmetalation from [ArPdFL2] Complexes. Angew.
Chem., Int. Ed. 2012, 51, 1379−1382.
(48) Amatore, C.; Le Duc, G.; Jutand, A. Mechanism of Palladium-
Catalyzed Suzuki-Miyaura Reactions: Multiple and Antagonistic Roles
of Anionic “Bases” and Their Countercations. Chem. - Eur. J. 2013, 19,
10082−10093.
̌
̌
̊
̌
̌
(49) Vána, J.; Lang, J.; Soltésová, M.; Hanusek, J.; Ruzicka, A.;
Sedlák, M.; Roithová, J. The role of trinuclear species in a palladium
acetate/trifluoroacetic acid catalytic system. Dalton Trans. 2017, 46,
16269−16275.
̌
(50) Vána, J.; Hanusek, J.; Sedlák, M. Bi and trinuclear complexes in
palladium carboxylate-assisted C−H activation reactions. Dalton
Trans. 2018, 47, 1378−1382.
(51) Stephenson, T. A.; Wilkinson, G. Acetato complexes of
palladium(II). J. Inorg. Nucl. Chem. 1967, 29, 2122−2123.
(52) Moiseev, I. I.; Stromnova, T. A.; Busygina, I. N.; Tihonova, N.
Y.; Kozitsyna, N. Y.; Ellern, A. M.; Antipin, M. Y.; Struchkov, Y. T.
Oxidation of bridging groups by carboxylate coordinated ligands in
palladium clusters. J. Cluster Sci. 1992, 3, 411−421.
(53) Berenblyum, A. S.; Knizhnik, A. G.; Mund, S. L.; Moiseev, I. I.
Mechanism of the formation of palladium complexes serving as
catalysts in hydrogenation reactions. J. Organomet. Chem. 1982, 234,
219−235.
(37) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Unparalleled rates for
the activation of aryl chlorides and bromides: coupling with amines
and boronic acids in minutes at room temperature. Angew. Chem., Int.
Ed. 2002, 41, 4746−4748.
(54) Cassol, C. C.; Umpierre, A. P.; Machado, G.; Wolke, S. I.;
Dupont, J. The role of Pd nanoparticles in ionic liquid in the Heck
reaction. J. Am. Chem. Soc. 2005, 127, 3298−3299.
̈
(55) Ozkar, S.; Finke, R. G. Nanocluster Formation and Stabilization
(38) Fricke, C.; Sherborne, G.; Funes-Ardoiz, I.; Senol, E.; Guven,
S.; Schoenebeck, F. Orthogonal Nanoparticle Catalysis with Organo-
germaniums. Angew. Chem., Int. Ed. 2019, 58, 17788−17795.
(39) Amatore, C.; Jutand, A.; Le Duc, G. Mechanistic Origin of
Antagonist Effects of Usual Anionic Bases (OH−, CO32−) as
Modulated by their Countercations (Na+, Cs+, K+) in Palladium-
Catalyzed Suzuki-Miyaura Reactions. Chem. - Eur. J. 2012, 18, 6616−
6625.
(40) (a) Pagett, A. B.; Lloyd-Jones, G. C. Suzuki−Miyaura Cross-
Coupling. In Organic Reactions; Denmark, S. E., Ed.; Wiley & Sons:
New York, 2019; Vol. 100, pp 547−620. (b) Payard, P.-A.; Bohn, A.;
Tocqueville, D.; Jaouadi, K.; Escoude, E.; Ajig, S.; Dethoor, A.;
Gontard, G.; Perego, L. A.; Vitale, M.; Ciofini, I.; Wagschal, S.;
Grimaud, L. Role of dppf Monoxide in the Transmetalation Step of
Fundamental Studies: Ranking Commonly Employed Anionic
Stabilizers via the Development, Then Application, of Five
Comparative Criteria. J. Am. Chem. Soc. 2002, 124, 5796−5810.
(56) Ornelas, C.; Ruiz, J.; Salmon, L.; Astruc, D. Sulphonated
“Click” Dendrimer-Stabilized Palladium Nanoparticles as Highly
Efficient Catalysts for Olefin Hydrogenation and Suzuki Coupling
Reactions Under Ambient Conditions in Aqueous Media. Adv. Synth.
Catal. 2008, 350, 837−845.
(57) Deraedt, C.; Astruc, D. Homeopathic” Palladium Nanoparticle
Catalysis of Cross Carbon−Carbon Coupling Reactions. Acc. Chem.
Res. 2014, 47, 494−503.
(58) Chernyshev, V. M.; Khazipov, O. V.; Eremin, D. B.; Denisova,
E. A.; Ananikov, V. P. Formation and stabilization of nanosized Pd
particles in catalytic systems: Ionic nitrogen compounds as catalytic
9692
https://doi.org/10.1021/jacs.1c05294
J. Am. Chem. Soc. 2021, 143, 9682−9693

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
promoters and stabilizers of nanoparticles. Coord. Chem. Rev. 2021,
437, 213860.
(59) Littke, A. F.; Dai, C.; Fu, G. C. Versatile Catalysts for the
Suzuki Cross-Coupling of Arylboronic Acids with Aryl and Vinyl
Halides and Triflates under Mild Conditions. J. Am. Chem. Soc. 2000,
122, 4020−4028.
(60) Proutiere, F.; Aufiero, M.; Schoenebeck, F. Reactivity and
stability of dinuclear Pd(I) complexes: studies on the active catalytic
species, insights into precatalyst activation and deactivation, and
application in highly selective cross-coupling reactions. J. Am. Chem.
Soc. 2012, 134, 606−612.
(61) Zhao, X.; Chen, H.; Xing, S.; Yuan, W.; Wu, L.; Chen, X.; Zhan,
C.-G. Regioselective synthesis of 2- and 4-diarylpyridine ethers and
their inhibitory activities against phosphodiesterase 4B. J. Mol. Struct.
2019, 1196, 455−461.
(62) Kim, S.-T.; Kim, S.; Baik, M.-H. How bulky ligands control the
chemoselectivity of Pd-catalyzed N-arylation of ammonia. Chem. Sci.
2020, 11, 1017−1025.
(63) Roy, A. H.; Hartwig, J. F. Oxidative Addition of Aryl Sulfonates
to Palladium(0) Complexes of Mono- and Bidentate Phosphines.
Mild Addition of Aryl Tosylates and the Effects of Anions on Rate
and Mechanism. Organometallics 2004, 23, 194−202.
(64) Maes, B. U. W.; Verbeeck, S.; Verhelst, T.; Ekomié, A.; von
̀
Wolff, N.; Lefevre, G.; Mitchell, E. A.; Jutand, A. Oxidative Addition
of Haloheteroarenes to Palladium(0): Concerted versus SNAr-Type
Mechanism. Chem. - Eur. J. 2015, 21, 7858−7865.
(65) Son, S. U.; Jang, Y.; Yoon, K. Y.; Kang, E.; Hyeon, T. Facile
Synthesis of Various Phosphine-Stabilized Monodisperse Palladium
Nanoparticles through the Understanding of Coordination Chemistry
of the Nanoparticles. Nano Lett. 2004, 4, 1147−1151.
(66) Xue, T.; Lin, Z.; Chiu, C.-Y.; Li, Y.; Ruan, L.; Wang, G.; Zhao,
Z.; Lee, C.; Duan, X.; Huang, Y. Molecular ligand modulation of
palladium nanocatalysts for highly efficient and robust heterogeneous
oxidation of cyclohexenone to phenol. Sci. Adv. 2017, 3, e1600615.
(67) Narayanan, R.; El-Sayed, M. A. FTIR study of the mode of
binding of the reactants on the Pd nanoparticle surface during the
catalysis of the Suzuki reaction. J. Phys. Chem. B 2005, 109, 4357−
4360.
(68) Palani, V.; Hugelshofer, C. L.; Kevlishvili, I.; Liu, P.; Sarpong,
R. A Short Synthesis of Delavatine A Unveils New Insights into Site-
Selective Cross-Coupling of 3,5-Dibromo-2-pyrone. J. Am. Chem. Soc.
2019, 141, 2652−2660.
(69) Strotman, N. A.; Chobanian, H. R.; He, J.; Guo, Y.; Dormer, P.
G.; Jones, C. M.; Steves, J. E. Catalyst-Controlled Regioselective
Suzuki Couplings at Both Positions of Dihaloimidazoles, Dihaloox-
azoles, and Dihalothiazoles. J. Org. Chem. 2010, 75, 1733−1739.
(70) Tang, D.-T. D.; Collins, K. D.; Glorius, F. Completely
regioselective direct C−H functionalization of benzo[b]thiophenes
using a simple heterogeneous catalyst. J. Am. Chem. Soc. 2013, 135,
7450−7453.
(71) Handy, S. T.; Zhang, Y. A Solvent-Induced Reversal of
Regioselectivity in the Suzuki Coupling of Pyrrole Esters. Open Org.
Chem. J. 2008, 2, 58−64.
9693
https://doi.org/10.1021/jacs.1c05294
J. Am. Chem. Soc. 2021, 143, 9682−9693