Synthetic and Mechanistic Interrogation of Pd/Isocyanide-Catalyzed Cross-Coupling: π-Acidic Ligands Enable Self-Aggregating Monoligated Pd(0) Intermediates

Article abstract of DOI:10.1021/acs.organomet.7b00035

Despite the large number of judiciously designed ligands that have been exploited in palladium-catalyzed cross-coupling protocols, the incorporation of ligands bearing appreciable π-acidic properties has remained significantly underexplored. Herein, we demonstrate that well-defined and low-coordinate Pd⁰ complexes supported by m-terphenyl isocyanides function as competent catalysts for the Suzuki-Miyaura cross-coupling of aryl bromides and arylboronic acids. Two-coordinate Pd(CNAr^Dipp2)₂ was active for the coupling of unhindered aryl bromides at room temperature in 2-propanol, while increasing the temperature to 60 °C allowed for the use of mono- or di-ortho-substituted aryl bromides. Oxidative addition of the aryl bromide was shown to proceed via a dissociative mechanism, implicating monoligated Pd(CNAr^Dipp2) as the catalytically active intermediate. Attempts to access this fleeting species via activation of the Pd^II monoisocyanide PdCl(η³-C₃H₅)(CNAr^Dipp2) with alkoxide base yielded the dinuclear Pd^I species (μ-C₃H₅)(μ-OⁱPr)[Pd(CNAr^Dipp2)]₂. Although dinuclear Pd^I complexes are often produced as off-cycle species when using complexes of the type PdCl(η³-allyl)L as precatalysts, this represents the first time that the comproportionation product (μ-allyl)(μ-Cl)[PdL]₂ has been observed to undergo nucleophilic substitution with alkoxide, despite the fact that activating conditions for these precatalysts typically employ alkoxide bases. Remarkably, this alkoxide complex can undergo β-hydride elimination with expulsion of acetone and propene to produce two equivalents of catalytically active Pd(CNAr^Dipp2), which can self-aggregate to yield the isolable tripalladium cluster Pd₃(η²-Dipp-μ-CNAr^Dipp2)₃. This cluster is catalytically competent for the Suzuki-Miyaura reaction and functions as a formal source of monoligated Pd(CNAr^Dipp2) in solution.

Full text of DOI:10.1021/acs.organomet.7b00035

Article
pubs.acs.org/Organometallics
Synthetic and Mechanistic Interrogation of Pd/Isocyanide-Catalyzed
Cross-Coupling: π‑Acidic Ligands Enable Self-Aggregating
Monoligated Pd(0) Intermediates
Brandon R. Barnett,‡ Liezel A. Labios,‡ Julia M. Stauber,‡ Curtis E. Moore, Arnold L. Rheingold,
and Joshua S. Figueroa*
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, Mail Code 0358, La Jolla,
California 92093-0358, United States
S
* Supporting Information
ABSTRACT: Despite the large number of judiciously designed ligands that have
been exploited in palladium-catalyzed cross-coupling protocols, the incorporation
of ligands bearing appreciable π-acidic properties has remained significantly
underexplored. Herein, we demonstrate that well-defined and low-coordinate Pd0
complexes supported by m-terphenyl isocyanides function as competent catalysts
for the Suzuki−Miyaura cross-coupling of aryl bromides and arylboronic acids.
Two-coordinate Pd(CNArDipp2)2 was active for the coupling of unhindered aryl
bromides at room temperature in 2-propanol, while increasing the temperature to
60 °C allowed for the use of mono- or di-ortho-substituted aryl bromides.
Oxidative addition of the aryl bromide was shown to proceed via a dissociative
mechanism, implicating monoligated Pd(CNArDipp2) as the catalytically active
intermediate. Attempts to access this fleeting species via activation of the PdII
monoisocyanide PdCl(η3-C3H5)(CNArDipp2) with alkoxide base yielded the
dinuclear PdI species (μ-C3H5)(μ-OiPr)[Pd(CNArDipp2)]2. Although dinuclear
PdI complexes are often produced as off-cycle species when using complexes of the type PdCl(η3-allyl)L as precatalysts, this
represents the first time that the comproportionation product (μ-allyl)(μ-Cl)[PdL]2 has been observed to undergo nucleophilic
substitution with alkoxide, despite the fact that activating conditions for these precatalysts typically employ alkoxide bases.
Remarkably, this alkoxide complex can undergo β-hydride elimination with expulsion of acetone and propene to produce two
equivalents of catalytically active Pd(CNArDipp2), which can self-aggregate to yield the isolable tripalladium cluster Pd3(η2-Dipp-
μ-CNArDipp2)3. This cluster is catalytically competent for the Suzuki−Miyaura reaction and functions as a formal source of
monoligated Pd(CNArDipp2) in solution.
In examining the nature of cross-coupling protocols that
engender the formation of monoligated Pd0 species, several
overarching design principles are evident. First, the supporting
donor ligand must bind tightly to the Pd center so as to
discourage precipitation of Pd metal and promote oxidative
addition. Furthermore, a ligand that presents a very large steric
profile is essential in order to foster coordinative unsaturation.
More elegant designs, such as biphenyl phosphines which can
form Pd−arene π-interactions15,24−27,33,34 and N-heterocyclic
carbenes (NHCs) which present a flexible steric profile,12,13
have also proven adept at promoting the formation of
monoligated Pd species and catalyzing challenging coupling
reactions. However, it is also noted that use of donor ligands
that meet these criteria can sometimes have deleterious effects
on the transmetalation and/or reductive elimination steps of
the catalytic cycle.25,35 It is therefore evident that a very
INTRODUCTION
■
Palladium-catalyzed cross-coupling reactions have gained a
preeminent place in the toolkit of synthetic chemists.1,2 The
versatility, generality and functional group tolerance exhibited
by such protocols as the Suzuki−Miyaura reaction1−5 and the
Buchwald−Hartwig amination6−9 have allowed for the
construction of a wide array of scaffolds obtained via the
formation of a new carbon−carbon or carbon−nitrogen bond.
Nearly all palladium-catalyzed cross-coupling schemes share a
mechanistic feature whereby oxidative addition of a C−X bond
occurs at a Pd0 center. In some cases, studies have shown that
oxidative addition occurs at a 14-electron Pd0L2 species.4,10
However, when sterically encumbering supporting ligands are
employed, the active species is often a monocoordinate 12-
electron Pd0−L complex.11 Such systems can display
remarkable activity, as ligand sets and reaction conditions
conducive to the formation and stabilization of Pd0L have
proven capable of effecting challenging couplings and operating
at extremely low catalyst loadings.12−32
Received: January 13, 2017
© XXXX American Chemical Society
A
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Table 1. Suzuki−Miyaura Substrate Scope for Room-Temperature Coupling Reactions
a
GC yield (isolated yield).
sensitive interplay between steric and electronic factors must be
considered in the design of highly active catalytic species.
Despite the numerous potential ancillary ligands that could
be used in Pd-catalyzed cross-coupling, triorganophosphines
and NHCs have dominated the development of reliable
catalytic systems.36−41 These ligands form robust bonds to
Pd on account of their strong σ-donor capabilities, and contain
steric profiles that can be systematically modulated.42 In
contrast, the use of π-acidic ligands in Pd-catalyzed cross-
coupling has been significantly underexplored.35,43−47 While
the use of strong σ-donor ligands promotes oxidative addition,
π-acidic ligands should increase the rate of reductive
elimination,48,49 and may also increase catalyst lifetimes by
stabilizing the Pd0 oxidation state.43,44 Such features may hold
promise in cross-coupling-based polymerizations, where
catalyst degradation processes often compete with polymer-
chain propagation.50−52 Futhermore, although the withdrawal
of electron density from Pd0 by π-acidic ligands may slow the
oxidative addition step, such a diminution of rate may be
beneficial in certain systems which suffer from off-cycle side
reactions from PdII intermediates (i.e., homocoupling and
hydrodehalogenation).35
propensity of isocyanide ligands to undergo migratory insertion
processes to yield iminoacyl ligands might be obviated in this
system.70 More recently, isolation of the trinuclear complex
Pd3(μ−η2:η1-PhNO)3(CNArDipp2
)
(10),71 which was pro-
3
posed to result from trapping of Pd(CNArDipp2) by nitro-
sobenzene followed by trimerization, alluded to the ability of
the encumbering m-terphenyl isocyanide to support mono-
ligated Pd0 in solution.
Accordingly, herein we detail the activity of m-terphenyl
isocyanide-supported complexes of palladium in catalyzing the
Suzuki−Miyaura cross-coupling reaction. Bis-isocyanide 1 is
compatible with a range of electronically diverse and hindered
aryl bromides, although di-ortho-substituted arylboronic acids
are not tolerated. Oxidative addition of Caryl-Br is shown
through kinetic analyses to occur via a dissociative mechanism,
indicating that monocoordinate Pd(CNArDipp2) is the active
intermediate. The search for highly active catalysts bearing a
Pd/isocyanide ratio of 1:1 resulted in the discovery of the
dinuclear PdI complex (μ-C3H5)(μ-OiPr)[Pd(CNArDipp2)]2
(4), which is produced upon activation of PdCl(η3-C3H5)
(CNArDipp2) (3) with NaOt-Bu in 2-propanol. The observation
of an alkoxide-bridged PdI complex is unique in the activation
of systems of the type PdCl(η3-allyl)L and allows for the
In an effort to expand the scope of ligand electronic
properties in palladium cross-coupling catalysis, we reported
production of 2 equiv of catalytically active Pd(CNArDipp2
)
the synthesis of the two-coordinate complex Pd(CNArDipp2
)
from 4 through a β-hydride elimination pathway. Importantly,
intermolecular self-trapping of Pd(CNArDipp2) provides access
to the isolable tripalladium cluster triangulo-Pd3(η2-Dipp-μ-
2
(1, ArDipp2 = 2,6-(2,6-(i-Pr)2C6H3)2C6H3), which represented
the first monomeric binary isocyanide complex of Pd0.53 The
monomeric nature of 1 is enforced by the m-terphenyl
isocyanide ancillary ligands,54−65 whereas less encumbering
isocyanides have been previously shown to give rise to
multinuclear Pd0 aggregates.66−69 Preliminary, unoptimized
screenings revealed that 1 could effect the coupling of mono- or
di-ortho-substituted aryl bromides with phenylboronic acid at
room temperature, affording the corresponding biaryls in high
yield (95%).53 Importantly, the isolable PdII intermediate trans-
PdBr(Mes)(CNArDipp2)2 (Mes = 2,4,6-Me3C6H2) was shown to
be unchanged upon heating to 80 °C, suggesting that the
CNArDipp2
) (8), which is also catalytically competent for
3
Suzuki−Miyaura cross coupling.
Delineation of Suzuki−Miyaura Cross-Coupling Cata-
lyzed by Pd(CNArDipp2)2 (1). Previously, we reported that
Pd(CNArDipp2)2 (1) was a competent catalyst for Suzuki−
Miyaura cross-coupling of aryl bromides with phenylboronic
acid in THF at room temperature.53 The unoptimized
conditions used in this report employed K3PO4 as the base
and a relatively high catalyst loading (5 mol %). Optimization
of reaction conditions revealed that catalyst loadings of 1 mol %
B
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Table 2. Suzuki−Miyaura Substrate Scope for Coupling Reactions Conducted at 60 °C
a
GC yield (isolated yield).
could efficiently effect cross-coupling with high selectivity and
yields using NaOt-Bu as the base in 2-propanol solution. At
room temperature, unactivated aryl bromides could be coupled
with various arylboronic acids bearing methyl- or phenyl-
substitution (Table 1, entries 1−10). Use of 1-bromonaph-
thalene also yielded the corresponding biaryls in good yields
(Table 1, entries 11−14). Although these conditions were not
suitable for the use of ortho-substituted aryl bromides,
increasing the temperature to 60 °C allowed for the coupling
of aryl bromide substrates bearing mono- or di-ortho-
substitution (Table 2, entries 1−8). In addition, 2,4-
difluorophenylboronic acid proved a viable coupling partner
under these conditions (Table 2, entries 9 and 10), which is
notable due to the difficulties associated with using electron-
deficient arylboronic acids in Suzuki−Miyaura coupling.72,73
Despite the readiness of 1 to couple unactivated and
hindered aryl bromides, aryl chlorides were generally unreactive
toward 1 under these conditions. Undoubtedly, this can be
traced to the attenuated σ-donor abilities of isocyanides relative
to phosphines and NHCs, as very electron-rich Pd0 centers are
needed for the oxidative addition of aryl chlorides to proceed
under mild conditions. Indeed, the isocyanide-containing
Suzuki−Miyaura coupling precatalysts PdCl2(CNR)2 reported
by Villemin necessitated harsh conditions (refluxing 1,4-
dioxane), high catalyst loadings (5 mol %) and long reaction
times (18 h) to accommodate activated aryl chlorides as
Figure 1. DFT-calculated 4d orbital manifold of the Pd(CNArDipp2
fragment.
)
coupling partners.47a Although Luzyanin and Hashmi have
reported isocyanide-containing PdII Suzuki−Miyaura precata-
lysts which can couple aryl chlorides at room temperature,
these complexes also employ strongly donating carbene
ancillary ligands.47b−d Density functional theory calculations
on the monocoordinate Pd(CNArDipp2) fragment reveal the
prevalence of π-backbonding interactions between the Pd dxz/
dyz and isocyanide π* orbitals (Figure 1), illustrating how the π-
acidic isocyanide ligands serve to attenuate the electron-rich
nature of the corresponding Pd0L adduct. However, these
interactions also serve to strengthen the Pd−CCNR interaction,
which should aid in preventing the precipitation of Pd black.
It should also be noted that 1 is unable to catalyze the
formation of tri- and tetra-ortho-substituted biaryls (Table 2,
entries 11, 12, and 14). Although the oxidative addition of
C
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hindered aryl bromides to 1 readily takes place at 60 °C,
attempts to use di-ortho-substituted arylboronic acids as
transmetalation reagents were unsuccessful regardless of aryl
bromide substitution pattern (Table 2, entries 12 and 13). This
observation suggested steric inhibition of the transmetalation
step due to the encumbrance of the m-terphenyl isocyanide
ligands. Indeed, very bulky ligands can have deleterious effects
with regard to coupling of hindered substrates, presumably due
to slowed rates of transmetalation.25
decrease the rate constant of the reaction by more than half
(kobs = 5.59(4) × 10−4 s−1). Saturation is reached with 0.5 equiv
of CNArDipp2, such that introduction of additional isocyanide
has no further effect on the observed rate constant (Table 3).
As 1 has been shown to resist ligation of a third isocyanide
ligand,53 these observations strongly suggest that oxidative
addition proceeds dissociatively, signaling the intermediacy of
monoligated Pd(CNArDipp2).
As a point of comparison to di-ortho-substituted MesBr,
oxidative addition of the unhindered aryl bromide m-XylBr (m-
Xyl =3,5-Me2C6H3) by Pd(CNArDipp2)2 (1) was also examined.
Using stoichiometric m-XylBr, this reaction proceeds very
cleanly to yield trans-PdBr(m-Xyl) (CNArDipp2)2 (2), which was
structurally characterized (Figure S34). Following the reaction
of 1 with 10 equiv of m-XylBr by 1H NMR spectroscopy at 25
Although cross-couplings mediated by preformed Pd0L2
species are often initiated by ligand dissociation, it is known
that a very sensitive balance of steric and electronic factors can
determine whether the oxidative addition step proceeds via an
associative or dissociative mechanism.10,74 In order to inter-
rogate whether cross-coupling in this system proceeds through
monoligated Pd(CNArDipp2) as the catalytically active inter-
mediate, a kinetic analysis of the oxidative addition of MesBr by
Pd(CNArDipp2)2 (1) was undertaken. Under pseudo-first-order
conditions (10 equiv of MesBr) at 25 °C, the consumption of 1
and formation of trans-PdBr(Mes)(CNArDipp2)2 proceeds to
completion within 1 h with a rate constant of kobs = 1.47(2) ×
°C again revealed a first-order dependence on 1 with kobs
=
2.46(3) × 10−3 s−1 (Figure 3). While this value of kobs is
1
10−3 s−1, as assessed by H NMR spectroscopy (Figure 2 and
Figure 3. Plot of ln[Pd(CNArDipp2)2] vs time, showing the
comparative observed rates of oxidative addition of MesBr and m-
XylBr under pseudo-first-order conditions (10 equiv of aryl bromide).
approximately a factor of 2 larger relative to that for the
oxidative addition of MesBr, the fact that both rate constants
are of the same order of magnitude strongly suggests that steric
inhibition in the transmetalation step is responsible for the
inability of this system to produce tri- and tetra-substituted
biaryls. Examination of the nature of transmetalation in this
system revealed that no biaryl product is obtained when the
NaOt-Bu base is omitted from the reaction mixtures.
Transmetalation in Suzuki−Miyaura coupling is often believed
to proceed from a boronate species formed by complexation of
base to the boronic acid.75 In this regard, aryltrifluoroborates
have been used as transmetallating agents that do not require
addition of an exogenous base.76−78 Notably, however, addition
of either K[PhBF3] or [n-Bu4N][PhBF3] (10 equiv) to 2-
propanol solutions of PdBr(Ar)(CNArDipp2)2 (Ar = Mes, m-
Xyl) does not result in transmetalation or biaryl production,
even upon prolonged heating at 60 °C. Addition of water as a
co-solvent, which has been shown to improve yields of cross-
coupling reactions using aryltrifluoroborates,79 did not alter the
reaction outcome, while use of both K[PhBF3] and NaOt-Bu
prompted only homocoupling to produce biphenyl. These
observations provide circumstantial evidence that transmetala-
tion may instead proceed through a transient Pd alkoxide
complex formed from nucleophilic substitution of the alkoxide
base at palladium following oxidative addition. Alternatively, as
Figure 2. Plots of ln[Pd(CNArDipp2)2] vs time, showing the rate
inhibition imposed by added equivalents of CNArDipp2 in the oxidative
addition of MesBr.
Table 3. Observed Rate Constants in the Oxidative Addition
of MesBr by 1 under Pseudo-First-Order Conditions (10
equiv of MesBr) as a Function of Added Equivalents of
CNArDipp2
equiv CNArDipp2
kobs (s−1
)
approx. rxn time (h)
0
1.47(2) × 10−3
5.59(4) × 10−4
7.24(5) × 10−5
2.49(4) × 10−5
2.52(2) × 10−5
1
0.10
0.25
0.50
1.0
3
10
>12
>12
Table 3). Plotting ln[1] versus time reveals a linear relationship
well past three half-lives, in accord with pseudo-first-order
conditions. Strikingly, the introduction of even small amounts
of exogenous CNArDipp2 results in a profound diminution of
reaction rate. As shown in Figure 2 and Table 3, the addition of
0.1 equiv of CNArDipp2 (with respect to 1) is sufficient to
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Scheme 1. Syntheses of PdCl(η3-C3H5)(CNArDipp2) (3) and Dinuclear Complexes 4−7
Pd hydroxo complexes have been shown to undergo rapid
transmetalation with arylboronic acids,80 the intermediacy of
Pd(OH)(Ar)(CNArDipp2)2 formed due to adventitious water
cannot be discounted.
Synthesis and Activation of Complexes Bearing a
Single CNArDipp2 Ligand per Palladium Center. Guided by
reports of highly competent cross-coupling catalyst precursors
bearing a Pd/L (L = PR3, NHC) ratio of 1:1,20−23,28 we
targeted a monoisocyanide PdII complex which could undergo
reduction to a catalytically active Pd0L species under Suzuki−
Miyaura coupling conditions. In particular, we took note of
work by Nolan, who showed that complexes of the type
PdCl(η3-allyl) (NHC) were highly active cross-coupling
catalysts.20,21,81−83 Notably, activation of these mono-NHC
PdII complexes could be achieved using NaOt-Bu in 2-
propanol,20,21,82 which is the same base and solvent
combination utilized in the optimized coupling conditions
Figure 4. Molecular structure of PdCl(η3-C3H5)(CNArDipp2) (3).
employed for Pd(CNArDipp2
) (1). Toward this end, the
2
Table 4. Yields of Biaryl Product in Suzuki−Miyaura Test
monoisocyanide complex PdCl(η3-C3H5)(CNArDipp2) (3) was
synthesized from [Pd(μ-Cl)(η3-C3H5)]2 and CNArDipp2 (2
equiv) and could be isolated as colorless crystals upon
crystallization from a THF/n-pentane solution at −35 °C
(Scheme 1). The FTIR spectrum of 3 displays a υ(CN) stretch
at 2172 cm−1, which is higher in energy than that of free
CNArDipp2 (2118 cm−1)57 and indicates that the isocyanide
ligand in 3 functions primarily as a σ-donor. Accordingly, the
Pd−CCNR distance in the solid-state structure of 3 (1.988(2) Å,
Figure 4) is longer than that observed for 1 (mean = 1.930(3)
Å),53 consistent with minimal Pd-to-isocyanide π-backdonation.
Screening of the catalytic competency of PdCl(η3-C3H5)
(CNArDipp2) (3) under Suzuki−Miyaura coupling conditions
was subsequently undertaken using the substrates m-XylBr and
PhB(OH)2. After 8 h at room temperature, only 5(1)% of the
desired biaryl coupling product had been produced as assessed
by GC-MS (Table 4; 5 runs), indicating inefficient activation of
precatalyst 3. It is noted that mono-NHC complexes bearing
unsubstituted allyl ligands can be sluggish toward activation at
room temperature, often requiring high temperatures to yield
the desired Pd0L active catalyst.20,83 However, aliquots removed
from attempted coupling reactions employing 3 after 1 h do not
reveal 1H NMR resonances corresponding to the intact
a
Reactions Using the Indicated Catalysts and Loadings
Pd catalyst
GC yield
Pd(CNArDipp2)2 (1, 1 mol %)
98(2)%
13(1)%
trace
Pd(CNArDipp2)2 (1, 0.1 mol %)
Pd(CNArDipp2)2 (1, 0.01 mol %)
PdCl(η3-C3H5)(CNArDipp2) (3, 1 mol %)
(μ-C3H5)(μ-OiPr)[Pd(CNArDipp2)]2 (4, 0.5 mol %)
Pd3(η2-Dipp-μ-CNArDiPP2)3 (8, 0.33 mol %)
5(1)%
25(5)%
83(8)%
a
All reported yields represent the mean value of at least three
independent runs.
precatalyst and instead indicated the formation of a new
species that is slow to effect cross-coupling.
Stoichiometric reactivity studies were undertaken in order to
assess the activation pathway of PdCl(η3-C3H5)(CNArDipp2
)
(3) under cross-coupling conditions. Addition of NaOt-Bu (1.0
equiv) to a suspension of 3 in 2-propanol proceeds initially to
E
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Figure 5. Molecular structures of dinuclear complexes 5, 6, and 7.
the new complex 4, which contains a magnetically desymme-
trized −ArDipp2 environment in its 1H NMR spectrum (Scheme
1). This transformation proceeds to completion over
approximately 2 h at room temperature, although the thermal
instability of 4 (vida infra) rendered isolated yields of pure
material consistently low. Yellow single crystals of 4 could be
grown from THF at −35 °C. Although unambiguous
crystallographic characterization was precluded by severe
positional disorder in the solid state, the data were consistent
with a dinuclear Pd complex with each Pd center bearing one
mononuclear complex 3 as a starting material, thus lending
credence to its proposed constitution. Furthermore, the
bridging tert-butoxide complex (μ-C3H5)(μ-Ot-Bu)[Pd-
(CNArDipp2)]2 (7) could be accessed upon addition of NaOt-
Bu to a solution of 6 in Et2O (Scheme 1 and Figure 5). As
1
anticipated, the H NMR spectrum of 7 displays a singlet at
1.16 ppm integrating to 9 protons and is devoid of the peaks
assigned to the OiPr ligand in 4. While 4 and 7 otherwise give
rise to similar 1H NMR and IR spectroscopic features, 7
exhibits superior kinetic stability and does not undergo
noticeable decomposition over the course of days in Et2O
solution at 20 °C.
1
CNArDipp2 ligand. The H NMR spectrum of 4 possessed
resonances consistent with the presence of an allyl group and
was devoid of an intense singlet expected for incorporation of a
tert-butoxide moiety. Interestingly, however, the appearance of
a septet at 4.27 ppm integrating to one hydrogen suggested the
presence of an isopropoxide group. These observations are
consistent with the assignment of 4 as the dinuclear PdI species
(μ-C3H5)(μ-OiPr)[Pd(CNArDipp2)]2. This finding is in accord
with the known propensity of precatalysts of the type PdCl(η3-
C3H5)L (L = phosphine, NHC) to form dinuclear PdI
complexes upon activation with base,84−91 although 4 is the
first, to our knowledge, which incorporates an alkoxide bridging
ligand. The isopropoxide ostensibly originates from solvent
leveling of the Brønsted base NaOt-Bu, suggesting that OiPr− is
the operative base under cross-coupling conditions.
With the formulation of 4 substantiated, its mechanism of
formation from PdCl(η3-C3H5)(CNArDipp2) (3) and NaOiPr
was examined under conditions where all organic byproducts
would be soluble. Accordingly, analysis of the reaction between
1
3 and 1.0 equiv of NaOiPr in C6D6 (20 °C) after 1 h by H
NMR spectroscopy and GC-MS revealed formation of acetone,
propene, and the chloride-bridged dimer (μ-C3H5)(μ-Cl)[Pd-
(CNArDipp2)]2 (6), with the latter subsequently undergoing
conversion to 4 at longer reaction times (Scheme 2). The
Scheme 2. Proposed Mechanism for the Formation of 4 from
3 and in-Situ-Produced NaOiPr
Further evidence for the identity of 4 was garnered by
synthetic elaboration. Addition of lithium diisopropylamide
(LDA) to a thawing Et2O solution of 4 proceeds via
substitution of the isopropoxide ligand to give the bridging
amide complex (μ-C3H5)(μ-NiPr2)[Pd(CNArDipp2)]2 (5,
Scheme 1). Structural characterization revealed retention of
the dinuclear [Pd(CNArDipp2)]2 core, with allyl and diisopro-
pylamido ligands that symmetrically bridge the two Pd centers
(Figure 5). In order to exclude the presence of a bridging
chloride ligand in 4, the dinuclear complex (μ-C3H5)(μ-
Cl)[Pd(CNArDipp2)]2 (6) was independently synthesized
through comproportionation of Pd(CNArDipp2
) (1) with
2
[Pd(μ-Cl)(η3-C3H5)]2 (0.5 equiv, Scheme 1 and Figure 5).
Complex 6 gives rise to 1H NMR and IR spectroscopic features
which are distinct from those of 4, while the only H NMR
1
peaks not arising from the −ArDipp2 groups are due to the allyl
ligand. Despite positional disorder of the bridging ligands of 6
imposed by crystallographic symmetry, the data could be
successfully modeled with 50:50 two-site disorder of both the
allyl and chloride ligands. Importantly, reaction of 6 with
NaOiPr in n-pentane/diethyl ether (ca. 5:1) results in
elimination of NaCl and formation of (μ-C3H5)(μ-OiPr)[Pd-
(CNArDipp2)]2 (4, Scheme 1). The spectroscopic features of 4
generated by this route are identical to those observed using
generation of these products is consistent with a pathway
proceeding through β-hydride elimination92,93 of acetone from
unobserved Pd(OiPr)(η3-C3H5)(CNArDipp2), which is reason-
ably generated by alkoxide-for-halide substitution at 3.
Reductive elimination of propene from the resulting allyl-
hydride intermediate produces monoligated Pd(CNArDipp2),
which can comproportionate with a second equivalent of 3 to
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afford 6 (Scheme 2). Nucleophilic substitution of the bridging
chloride in 6 with isopropoxide then yields 4 at later stages of
reaction. This final step is notable in that the dinuclear Pd(I)
complexes (μ-C3H5)(μ-Cl)[PdL]2 (L = phosphine, NHC)
produced upon activation of PdCl(η3-C3H5)L are most often
generated in the presence of a strong alkoxide base,78−85 yet
have not been reported to undergo substitution of the chloride
ligand. Allyl isopropyl ether was not detected in the reaction
between 3 and NaOiPr, illustrating that neither attack of
alkoxide at the allyl ligand nor C−O bond reductive elimination
from the putative Pd(OiPr)(η3-C3H5)(CNArDipp2) intermediate
are competing pathways in formation of monoligated Pd-
(CNArDipp2) in this sequence.
is thermally unstable and decomposes in solution over the
course of ca. 12 h at room temperature. This behavior differs
markedly from the other dinuclear complexes (μ-C3H5)(μ-
NiPr2)[Pd(CNArDipp2)]2 (5), (μ-C3H5)(μ-Cl)[Pd-
(CNArDipp2)]2 (6), and (μ-C3H5)(μ-Ot-Bu)[Pd(CNArDipp2)]2
(7), which do not undergo noticeable decomposition over this
time period. Analysis of the decomposition mixture of 4 by 1H
NMR spectroscopy and GC-MS indicated the clean formation
of acetone, propene, and a new isocyanide containing species.
This complex could be isolated as red crystals upon cooling of a
THF solution to −35 °C and was determined to be the
trinuclear, tris-isocyanide complex triangulo-Pd3(η2-Dipp-μ-
CNArDipp2)3 (8) by X-ray crystallography (Figure 7). Most
importantly, 8 reasonably results from trimerization of the
fleeting monoligated species Pd(CNArDipp2), which accounts
for the low cross-coupling activity observed when using dimer 4
as a precursor (Scheme 3). In support of this notion, 8 can be
The inability to directly detect Pd(OiPr)(η3-C3H5)-
(CNArDipp2) during the formation of chloride-bridged dimer
6 implies that the rates of β-hydride elimination, C−H
reductive elimination, and comproportionation shown in
Scheme 2 are faster than that of nucleophilic substitution of
3 by [OiPr]−. We believe that the relatively slow rate of this first
step is one of two significant contributing factors to the poor
catalytic performance observed when 3 is used as a precursor.
In this respect, it is important to note that Hazari and Colacot
have demonstrated that monomeric Pd(allyl)(Cl)L complexes
(L = NHC, PR3) are activated with strong bases to form
monoligated Pd0L intermeditates. However, these intermediate
species also rapidly comproportionate with Pd(allyl)(Cl)L
catalyst precursors to form dimeric (μ-C3H5)(μ-Cl)[Pd(L)]2
complexes in a deleterious off-cycle reaction that competes with
substrate oxidative addition.86−89 Nevertheless, these dinuclear
PdI complexes undergo disproportionation at room temper-
ature to regenerate monoligated Pd0L (0.5 equiv of per
dinuclear PdI complex), which can subsequently enter the
productive catalytic cycle.
Scheme 3. Generalized Disproportionation Process for a
Complex of the Type (μ-C3H5)(μ-X)[Pd(CNArDipp2)]2 and
a
Proposed Mechanism for the Formation of 8 from 4
In contrast, attempted coupling of m-XylBr and phenyl-
boronic acid using pure 4 as a catalyst precursor gave only poor
yields (25(5)%; 7 runs) of biaryl product at room temperature
(Table 4). This finding indicates that a significant barrier to
disproportionation exists for 4, a notion which we ascribe to the
differing electronic profiles of NHCs/phosphines versus those
of isocyanides. As NHCs and phosphines display σ-donor
capabilities superior to those of isocyanides, the Pd centers in 4
are likely to be more Lewis acidic compared to those in (μ-
C3H5)(μ-Cl)[Pd(L)]2 complexes (L = NHC, PR3), effectively
discouraging the Pd/bridging-ligand bond breaking which
accompanies disproportionation. In addition, the π-acidic
character of the isocyanides should serve to stabilize the
formally PdI oxidation state, thereby further disfavoring
disproportionation relative to PdI NHC/PR3 systems.88 Similar
effects were noted by Hazari in (μ-2-R-allyl)(μ-Cl)[Pd-
(NHC)]2 complexes, where installation of electron with-
drawing groups on the allyl ligands resulted in stabilization of
the dinuclear PdI complexes due to increased Pd-to-allyl π-
backdonation and biased the corresponding divalent PdCl(η3-2-
R-allyl) (NHC) precursor systems toward deactivation through
comproportionation.89 Accordingly, we believe this increased
stability of isocyanide-containing PdI also contributes to the low
catalytic performance originating from precursor 3.
a
Mechanism for formation of 8 from 4 illustrates how the
isopropoxide β-hydride elimination pathway allows for the production
of 2 equiv of monoligated Pd(CNArDipp2) despite the energetic
favorability of comproportionation.
accessed directly by addition of Li[HBEt3] to PdCl(η3-
C3H5)(CNArDipp2) (3) at low temperature, which results in
elimination of propene and LiCl and provides further evidence
for self-aggregation of Pd(CNArDipp2) to furnish trimeric 8.
Notably, this intermolecular self-aggregation using π-acidic
ligands is a complementary trapping strategy for “Pd0L”
intermediates, which are most often intercepted in solution
by addition of exogenous L-type donor ligands.11,71,81,94,95
As often implicated for Buchwald’s biaryl phosphines, the
isolation of 8 demonstrates that the m-terphenyl group can play
a complementary role in forming secondary interactions with
the unsaturated Pd0 centers, thus protecting against catalyst
decomposition and precipitation of Pd black.15,24−27,33,34
Although each of the flanking Dipp rings is magnetically
Isolation and Mechanism of Formation of a Trimeric
Pd3 Cluster from Self-Aggregation of a Pd0L Inter-
mediate. While pure (μ-C3H5)(μ-OiPr)[Pd(CNArDipp2)]2 (4)
does not serve as an efficient catalyst precursor at reasonable
reaction times, it does in fact provide a species capable of
marginal cross-coupling catalysis (Table 4). As noted above, 4
1
equivalent by H NMR spectroscopy at 20 °C, examination of
the solid-state structure reveals that they assist in the
stabilization of 8 by engaging in η2-C,C interactions with the
G
DOI: 10.1021/acs.organomet.7b00035
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Pd0 centers. The arene rings in 8 appear to act primarily as σ-
donors, as no significant degree of dearomatization resulting
from Pd-to-arene π-back-donation is seen. This is consistent
with the lability of the Pd−arene interaction that is reflected in
1H and 13C{1H} NMR spectra, which for 8 are symmetric and
do not contain upfield-shifted arene peaks. While this structural
feature is undoubtedly critical in facilitating the aggregation of
Pd(CNArDipp2), it should be emphasized that the strong π-
acidity properties of the ancillary ligand are likely also vital in
the stabilization of these highly reactive Pd0 centers, rendering
this system an intriguing counterpoint to monoligated Pd0
intermediates supported by biaryl phosphines.
With respect to the formation of trimer 8 from pure 4,
1
kinetic analysis by H NMR spectroscopy at 45 °C in toluene-
d8 shows that this is a first-order process, as plots of ln[4]
versus time are linear past three half-lives, and kinetic runs
using 7 or 14 mM solutions of 4 yield rate constants that are
identical within error (Figure 6). Importantly, the formation of
Figure 7. Molecular structure of Pd3(η2-Dipp-μ-CNArDipp2)3 (8). Note
that all Pd centers and isocyanide ligands are equivalent by
crystallographic symmetry. Selected bond distances (Å): Pd−Pd =
2.6353(5); Pd−C1 = 2.102(6); Pd1−C1′ = 2.103(4); Pd1−C15 =
2.479(4); Pd1−C16 = 2.312(4); C15−C16 = 1.411(7); C16−C17 =
1.413(7); C17−C18 = 1.372(7); C18−C19 = 1.402(7); C19−C14 =
1.393(7); C14−C15 = 1.423(6).
complexes (L = phosphine, NHC), which produces 1 equiv
of Pd0L as well as PdCl(η3-C3H5)L, which must be
subsequently activated. In the case of 4, formation of 2 equiv
of Pd(CNArDipp2) is made possible due to the aptitude of one
of the bridging ligands to undergo β-hydride elimination,
thereby effecting a net two-electron reduction of the [PdI]2
core. This further punctuates the apparent inertness of the
bridging chloride unit in phosphine and NHC (μ-C3H5)(μ-
Cl)[PdL]2 complexes toward nucleophilic substitution with
alkoxide base.84−89 However, the development of strategies or
conditions that foster alkoxide substitution in these species may
also enable secondary elimination pathways to become
available, thereby allowing dinuclear PdI complexes to rapidly
re-enter the cross-coupling catalytic cycle as Pd0L without
concomitant production of PdII species.
Despite the labile Pd-arene interactions, trinuclear 8 retains
its formulation in solution. Electrospray ionization-mass
spectrometry (ESI-MS) analysis of acetone solutions shows a
molecular ion peak (M+) of the expected mass and isotopic
distribution for intact 8 (Figures S1−2). Furthermore, 8 can
undergo addition reactions with neutral ligands while retaining
a trinuclear formulation (Scheme 4). Addition of CO (3.0
equiv) results in formation of triangulo-Pd3(μ-
CO)3(CNArDipp2)3 (9), which can be isolated as yellow crystals
from a diethyl ether solution at −35 °C. Crystallographic
characterization (Figure S40) reveals that 9 is isostructural to
its triplatinum congener triangulo-Pt3(μ-CO)3(CNArDipp2)3,98
and it correspondingly displays only one υ(CN) (2107 cm−1)
and υ(CO) (1871 cm−1) stretch in its IR spectrum consistent
with D3h symmetry. In addition, 8 reacts with 3 equiv of
nitrosobenzene to yield the known complex Pd3(μ−η2:η1-
PhNO)3(CNArDipp2)3 (10), which was initially isolated upon
reaction of nitrosobenzene with Pd(η2-N,O-PhNO)-
(CNArDipp2)2.71 Importantly, this process substantiates the
ability of 8 to mimic the reactivity of “Pd(CNArDipp2)”, as 10
Figure 6. Plot of ln[4] vs time for 7 and 14 mM solutions showing
that decomposition is first-order in (μ-C3H5)(μ-OiPr)[Pd-
(CNArDipp2)]2 (4).
both acetone and propene is observed in these solutions by 1H
NMR spectroscopy and GC-MS, while no allyl isopropyl ether
is detected. We believe that these observations are most
reasonably accounted for by β-hydride elimination from
transient Pd(OiPr)(η3-C3H5)(CNArDipp2), which can be
generated by disproportionation of (μ-C3H5)(μ-OiPr)[Pd-
(CNArDipp2)]2 (4). As discussed above, the proclivity of
dinuclear complexes 4−7 to undergo disproportionation is
believed to be significantly attenuated due to the π-acidic
properties of the isocyanide ligands. However, fast β-hydride
elimination from Pd(OiPr)(η3-C3H5)(CNArDipp2) can osten-
sibly compete with comproportionation, providing a pathway
by which monoligated Pd(CNArDipp2) can be rapidly produced
at the expense of the PdII comproportionation partner. With
regard to this proposed mechanism, it is also important to note
that direct β-hydride elimination from (μ-C3H5)(μ-OiPr)[Pd-
(CNArDipp2)]2 (4),96 followed by fast C−H reductive
elimination from a dinuclear PdI bridging-allyl/bridging-hydride
complex97 is also consistent with our kinetic data and the
observed organic byproducts and therefore cannot be ruled out.
Nevertheless, the unimolecular decomposition of 4 is
especially remarkable in that it yields 2 equiv of catalytically
active Pd(CNArDipp2). This is in contrast to the typical
disproportionation process seen for (μ-C3H5)(μ-Cl)[PdL]2
H
DOI: 10.1021/acs.organomet.7b00035
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
phosphine and NHC ligands commonly employed in Pd-
catalyzed cross-coupling and their significantly greater π-acidity
properties. As kinetic studies illustrated that oxidative addition
of aryl bromides occurs at the monoisocyanide Pd(CNArDipp2),
synthetic studies targeting competent catalysts bearing a Pd/
isocyanide ratio of 1:1 were undertaken. It was shown that
Scheme 4. Reactivity of 8 with CO and Nitrosobenzene
activation of the monoisocyanide PdCl(η3-C3H5)(CNArDipp2
)
(3) with alkoxide base first produces the dinuclear Pd(I)
complex (μ-C3H5)(μ-OiPr)[Pd(CNArDipp2)]2 (4), which sub-
sequently undergoes slow unimolecular conversion to give
monocoordinate Pd(CNArDipp2). The formation of 4 occurs
through nucleophilic substitution of (μ-C3H5)(μ-Cl)[Pd-
(CNArDipp2)]2 (6) with isopropoxide, a process which
apparently does not occur for the dinuclear Pd(I) species (μ-
C3H5)(μ-Cl)[PdL]2 (L = phosphine, NHC). β-Hydride
elimination from 4 then allows for the production of 2 equiv
of catalytically active Pd(CNArDipp2), as opposed to the
established disproportionation mechanism for (μ-C3H5)(μ-
Cl)[PdL]2, which yields Pd0L and PdIICl(η3-C3H5)L species (L
= phosphine, NHC). Most notably, intermolecular trapping of
Pd(CNArDipp2) produces the isolable tripalladium cluster
triangulo-Pd3(η2-Dipp-μ-CNArDipp2)3 (8). However, despite its
trinuclear formulation, 8 functions as a competent cross-
coupling precatalyst and acts as a source of the highly reactive
monocoordinate Pd(CNArDipp2) fragment in solution. The two
primary factors which render 8 isolable are the coordinating
abilities of the flanking rings of the m-terphenyl groups and the
π-accepting capabilities of the isocyano units, neither of which
have received significant attention in cross-coupling catalysis.
We envision that these findings will spur interest in the
incorporation of ligands bearing these structural and electronic
features into other Pd-catalyzed cross-coupling protocols. In
addition, these results suggest that the use of strongly π-acidic
ancillary ligands can play a complementary role to existing
cross-coupling schemes, especially when long catalyst lifetimes
or the retention of low-molecular-weight aggregated Pd0 species
in solution are desired.
was originally proposed to be generated upon trapping of a
monoligated Pd(CNArDipp2) complex with nitrosobenzene
followed by trimerization.71
Despite the propensity of 8 to yield new cluster compounds
in stoichiometric reactivity studies, it can still function as a
competent cross-coupling catalyst. Using the optimized room-
temperature catalytic conditions employed for Pd(CNArDipp2
)
2
(1) and a loading of 0.33 mol % (1 mol % Pd), trimer 8 can
couple m-XylBr and phenylboronic acid to generate the biaryl
product in 83(8)% GC yield (Table 4; 4 runs). This yield is
marginally lower than that obtained in the coupling of these
substrates using 1 mol % 1, which we tentatively ascribe to a
rate-limiting cluster fragmentation step. However, the catalytic
activity of 8 is far superior to that of PdCl(η3-C3H5)-
(CNArDipp2) (3), suggesting that 8 is capable of yielding
equivalents of “Pd(CNArDipp2)” which can rapidly enter the
cross-coupling catalytic cycle. This behavior is reminiscent of
that exhibited by the tripalladium isocyanide clusters Pd3(μ-
CNR)3(CNR)3, which in stoichiometric reactivity studies often
function as formal equivalents of Pd(CNR)2.66−69 It should be
noted that although 8 is relatively stable over the time frame of
the cross-coupling reactions it does undergo slow decom-
position in solution to give Pd(CNArDipp2)2 (1) and Pd black
over the course of approximately 1 week. However, control
experiments indicate that low catalyst loadings of 1 (0.1 and
0.01 mol %) give only minimal yields of biaryl product (13(1)%
and trace quantities, respectively) in the coupling of m-XylBr
and PhB(OH)2 (Table 4), illustrating that in situ produced 1
does not significantly contribute to the catalytic turnover
observed in runs using trimeric 8 as the precatalyst.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.7b00035.
Synthetic and catalytic procedures, spectroscopic, char-
acterization and kinetic data, results of computational
studies (PDF)
Cartesian coordinates (XYZ)
Crystallographic structure determinations of 2·0.5Et2O,
3·0.5Et2O, 5, 6, 7·C6H5F, 8·13THF, and 9·0.5Et2O
(CIF)
AUTHOR INFORMATION
Corresponding Author
*jsfig@ucsd.edu.
■
CONCLUSIONS
■
In this report, we have demonstrated that well-defined and
isolable Pd complexes supported solely by m-terphenyl
isocyanides can catalyze the Suzuki−Miyaura cross-coupling
reaction. The bis-isocyanide Pd(CNArDipp2)2 (1) was shown to
couple a variety of unactivated aryl bromides, including those
bearing mono- or di-ortho substitution, with arylboronic acids
under mild conditions. Aryl chlorides were shown to be
generally unreactive toward 1, presumably due to both the
decreased σ-donor abilities of isocyanides compared to the
ORCID
Joshua S. Figueroa: 0000-0003-2099-5984
Author Contributions
‡B.R.B., L.A.L., and J.M.S. contributed equally to the creation of
this work.
Notes
The authors declare no competing financial interest.
I
DOI: 10.1021/acs.organomet.7b00035
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
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ACKNOWLEDGMENTS
■
We are grateful to the U.S. National Science Foundation for
support (CHE-1464978 and Graduate Research Fellowships to
B.R.B. and L.A.L). J.S.F is a Camille Dreyfus Teacher−Scholar
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K
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