Experiment and Theory of Bimetallic Pd-Catalyzed α-Arylation and Annulation for Naphthalene Synthesis

Article abstract of DOI:10.1021/acscatal.1c02731

We report the synthesis of bimetallic Pd(I) and Pd(II) complexes with bidentate 2-phosphinoimidazole ligands and their catalytic activity to generate substituted naphthalenes. This process involves the coupling of an aryl iodide and 2 equiv of a ketone via sequential ketone α-arylation and then annulation to generate disubstituted and tetrasubstituted naphthalenes in a regioselective manner. Excellent substrate scope for both aryl iodide and ketone partners is demonstrated, including that for heteroaryl iodides. Bimetallic Pd complexes are much more reactive than monometallic Pd catalysts in this transformation. Density functional theory calculations, isotope effect experiments, and substrate competition experiments were used to examine bimetallic mechanisms, reactivity, and selectivity.

Full text of DOI:10.1021/acscatal.1c02731

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Research Article
Experiment and Theory of Bimetallic Pd-Catalyzed α‑Arylation and
Annulation for Naphthalene Synthesis
Chloe C. Ence, Erin E. Martinez, Samuel R. Himes, S. Hadi Nazari, Mariur Rodriguez Moreno,
Manase F. Matu, Samantha G. Larsen, Kyle J. Gassaway, Gabriel A. Valdivia-Berroeta, Stacey J. Smith,
Daniel H. Ess,* and David J. Michaelis*
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ABSTRACT: We report the synthesis of bimetallic Pd(I) and Pd(II)
complexes with bidentate 2-phosphinoimidazole ligands and their catalytic
activity to generate substituted naphthalenes. This process involves the
coupling of an aryl iodide and 2 equiv of a ketone via sequential ketone α-
arylation and then annulation to generate disubstituted and tetrasubstituted
naphthalenes in a regioselective manner. Excellent substrate scope for both
aryl iodide and ketone partners is demonstrated, including that for heteroaryl
iodides. Bimetallic Pd complexes are much more reactive than monometallic
Pd catalysts in this transformation. Density functional theory calculations,
isotope effect experiments, and substrate competition experiments were used
to examine bimetallic mechanisms, reactivity, and selectivity.
KEYWORDS: palladium(II) dimer, bimetallic catalysis, DFT calculations, α-arylation, naphthalene synthesis
INTRODUCTION
■
Homo- and heterobimetallic transition metal complexes
provide an innovative approach to catalyst development
because of the unique reactivity that can result from direct
metal−metal bonding cooperativity.1 A classic example of this
type of cooperative benefit is in dirhodium tetracarboxylate
catalysis where the presence of a second rhodium center helps
facilitate carbene catalysis.2 More recent examples of bimetallic
metal−metal bonding cooperativity in catalysis include
Mankad’s Cu−Fe-catalyzed arene borylation,3 Lu’s Ni−M
hydrogenations,4 and Uyeda’s Ni−Ni cycloaddition reactions,5
among others.6 Our groups have also used experiments and
theory to understand metal−metal cooperativity in Pd−Ti
allylic aminations.7 Each of these examples of bimetallic
catalysis achieves either increased efficiency and selectivity or
new reaction mechanisms that cannot generally or easily be
accessed with monometallic catalysts.
One potential advantage of having two metals participate in
a catalytic process is the opportunity to access less common
catalyst oxidation states that enable new types of reactivity and
mechanisms.8 For Pd, examples of accessing less common
oxidation states with bimetallic structures include Ritter and
Sanford’s Pd(II) dimers9 that can facilitate binuclear oxidative
addition to a Pd(III) dimer, which can circumvent forming
higher-energy Pd(IV) intermediates (Figure 1a).10 Hartwig,
Schoenebeck, Hazari, and others have also developed a diverse
set of lower oxidation state Pd(I) dimer precatalysts that
efficiently perform a range of cross-coupling reactions,
including Suzuki, Negishi, Sonogashira, and Buchwald−
Figure 1. (a) Examples of bimetallic Pd complexes in catalysis. (b)
Outline of bimetallic Pd catalysis in this work.
Received: June 18, 2021
Revised: July 16, 2021
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Hartwig amination reactions (Figure 1a).6,11 Pd(I) dimers can
also serve as precatalysts for the α-arylation of ketones and
esters, which is relevant to the work presented here.12 Several
recent studies have suggested that Pd(I) dimers can remain
intact during catalysis and enable cooperative bimetallic
catalysis.13 For example, Schoenebeck reported catalysis with
Pd(I) dimer [(t-Bu3P)PdI]2 that undergoes oxidative addition
across the Pd(I)−Pd(I) complex.13a
In this work, we report the discovery of a new class of stable
and catalytically active bimetallic Pd(I) and Pd(II) complexes
with bridging 2-phosphinoimidazole ligands.14 These new
complexes enable a previously unknown sequential ketone α-
arylation and annulation reaction that generates high yields of
difficult-to-synthesize disubstituted and tetrasubstituted naph-
thalenes in a single transformation (Figure 1b). The
naphthalene products are generated in a regioselective manner
across a broad range of iodide and ketone starting materials,
including heteroaromatic iodides. While synthetic approaches
to 1,3-disubstituted and tetrasubstituted naphthalenes have
been demonstrated previously, they generally require multistep
syntheses.15 This new transformation enables direct access to
substituted naphthalenes in a single step from commercially
available aryl iodides and methyl ketones. Substituted
naphthalenes have a variety of technological and pharmaco-
logical uses,16 including as templates to construct carbon
nanotubes17 and as proton-conducting solid electrolytes.18
Importantly, typical monometallic complexes show no or very
little reaction in this new process. Density functional theory
(DFT) calculations and isotope effect experiments provide key
insights into possible reaction mechanisms and bimetallic
reactivity.
Figure 2. Synthesis and structure of bimetallic Pd complexes.
The crystal structures of these bimetallic Pd complexes
provide additional insights into their structure and potential
reactivity (Figure 2c). In 4, the two palladium centers are held
within the van der Waals contact distance for a Pd−Pd bond
(Pd van der Waals radius = ∼1.6 Å), but the absence of
unpaired electrons prevents Pd−Pd bond formation (Pd−Pd
distance = 2.966 Å). The calculated formal shortness ratio
(FSR) of 1.16 for complex 4 is close to the limit for covalent
metal−metal bonding (FSR limit ≥ 1.22, see the Supporting
Information).21 Because the phosphinoimidazole ligand holds
the Pd centers in close proximity, there is distortion away from
a square planar geometry, likely to mitigate repulsion between
the filled dz2 orbitals of each Pd. The τ parameter for 4 is 0.16
(0 being square planar and 1 being tetrahedral), which shows
moderate distortion away from a perfect square planar
geometry.22
For Pd(I) dimer 5, the presence of unpaired electrons on
each Pd center leads to Pd−Pd bond formation with a distance
of 2.591 Å. The square planar geometry of the two palladium
centers and their oxidation states are also consistent with
metal−metal bond formation. The calculated FSR for complex
5 is 1.01, which represents a significantly higher bond order
than that with 4 and is consistent with the formation of a single
bond between the two palladiums. The M06 DFT-calculated
orbitals for 4 and 5 confirm that 4 lacks direct Pd−Pd covalent
bonding and the HOMO consists mainly of antibonding dz2
orbitals (Figure 3).23,24 The HOMO of 5, in contrast, shows a
direct Pd−Pd covalent bond.
RESULTS AND DISCUSSION
■
We began with the synthesis of new bimetallic Pd complexes
generated from 2-diphenylphosphino-1-arylimidazole ligands.
We found that the identity of both the ligand and the
palladium precursor had a significant impact on the complex
obtained. For example, when ligand 1 was mixed with PdCl2 in
methanol, only a monomeric Pd complex 2 was obtained,
where Pd was inserted between the P−C bond of the ligand
(Figure 2a). We recently demonstrated that this new N−H N-
heterocyclic carbene−palladium complex is highly active in
palladium-catalyzed Suzuki−Miyaura reactions.19 In contrast,
we found that if ligand 1 was first coordinated with a boron
Lewis acid to form 3, formation of a bimetallic Pd(II) complex
4 was observed upon addition of PdCl2 in dioxane (Figure 2b).
Bimetallic Pd(II) complexes similar to 4 have been previously
reported by Manzano but required the use of PdMeCl as a
precursor to obtain the bimetallic structure.14a Alternatively, if
Pd(OAc)2 was employed instead of PdCl2, Pd(I) dimer 5 was
obtained. The mechanism for in situ reduction of Pd(II)
precursors to Pd(I) dimer complexes was recently reported by
Schoenebeck and Colacot and likely involves the oxidation of
one-third of the phosphine ligand.20 This mechanism would
explain the modest yield of the reaction to form complex 5. We
believe that the presence of the boron ligand may help facilitate
faster ligand coordination via a transmetalation-like mecha-
nism. For example, when ligand 3 is added to PdCl2, complex 4
is generated in 66% yield after 18 h. However, when ligand 1 is
employed, which does not contain the boron Lewis acid,
complex 4 is isolated in 43% yield after 3 days in the absence of
methanol.
With two new bimetallic Pd complexes, one with Pd metal
centers in close proximity and one with a Pd−Pd covalent
bond, we next set out to explore the reactions that could
potentially exploit Pd−Pd cooperativity to achieve novel
reactivity. We were especially interested in reactions where
monometallic Pd catalysts either fail, are very slow, or are
unselective. We found that our Pd dimers could enable the
generation of 1,3-disubstituted and tetrasubstituted naphtha-
lenes via the coupling of aryl iodides and methyl ketones,
which represents a completely new approach to these
compounds. Table 1 reports the use of monometallic and
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product, respectively (entries 6 and 7). In addition, we found
that simply pre-stirring ligand 3 with PdCl2 or Pd(OAc)2 in
dioxane for 15 min led to the formation of bimetallic
complexes 4 and 5, respectively, as observed by 31P NMR
(see the Supporting Information). These in situ formed
catalysts had the same catalytic activity as that of isolated
complexes 4 and 5 (entries 8−9). Varying the Lewis acid in the
reaction demonstrated that while Cu(OTF) provided the
desired product in good yield, the reaction time was greatly
extended (entry 10). Other iron- or silver-based Lewis acids
(entries 11−13) and non-redox Lewis acids such as Zn(OTf)2,
Sc(OTf)3, and Yb(OTf)3 (see the Supporting Information)
failed to enable product formation. We also examined ligand 1
in catalysis, which lacks the boron Lewis acid, but it gave a
much lower yield (entry 14), presumably due to the formation
of lower concentrations of the active catalyst species. In
addition, N-arylimidazole ligands [N-(2,6-diisopropylphenyl)-
imidazole] that lack both the boron and 2-diphenylphosphino
groups provide no product in the reaction (entry 15).
Interestingly, the Pd(I) dimer (PtBu3)Pd2Br2, which is
known to perform ketone α-arylation reactions,12 did form a
small amount of product in the reaction (26%, entry 16).
Having established that bimetallic Pd catalysts provide
optimal production of naphthalenes, we explored the substrate
scope with respect to the aryl iodide coupling partner (Figure
4). For 4-substituted iodoarenes, we only observed a single
isomer with the addition of two acetophenone molecules.
Figure 3. M06/6-31G**[LANL2DZ for Pd]-calculated HOMOs of
model complexes for 4 and 5.23,24
Table 1. Optimization of Reaction Conditions
a
b
entry
Lewis acid
catalyst
PdCl2 + dppe
PdCl2 + BINAP
PdCl2 + DTBM-SEGPHOS
PdCl2 + c-hex-diamine
PdCl2 + PPh3
complex 4
complex 5
Pd(OAc)2 + 3
PdCl2 + 3
time
% yield
1
2
3
4
5
6
7
8
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
CuOTf
FeOTf
AgTFA
AgOAc
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
1 h
NR
NR
NR
NR
28
18 h
18 h
18 h
1 h
1 h
1 h
100 (89)
100 (84)
100 (90)
100 (93)
85
1 h
1 h
9
10
11
12
13
14
15
16
17
PdCl2 + 3
PdCl2 + 3
PdCl2 + 3
PdCl2 + 3
16 h
16 h
16 h
16 h
1 h
1 h
1 h
1 h
18 h
NR
NR
NR
45
NR
26
NR
NR
PdCl2 + 1
PdCl2 + ArImid
c
(PtBu3)2Pd2Br2
3
PdCl2 + 3
d
18
a
Reactions run with 0.5 mmol iodobenzene, 1.25 mmol acetophe-
none, and 0.025 mmol 4 or 5 or 10% ligand and 10% PdCl2 for in situ
b
reactions at 0.5 M in dioxane. Yields determined by 1H NMR
analysis of the crude reaction mixture by comparison to an internal
c
standard (isolated yields in parentheses). NR = no reaction. ArImid
d
= N-(2,6-diisopropylphenyl)imidazole. With 2 equiv of TfOH.
bimetallic Pd catalysts for the coupling of phenyl iodide and
acetophenone partners to generate naphthalene 6a. Entries 1−
5 show that the use of monometallic Pd catalysts either results
in no reaction or less than 30% yield. For example, PdCl2 with
dppe resulted in no reaction, and PdCl2 with BINAP,
SEGPHOS, or a diamine ligand resulted in no reaction even
after 18 h. However, there was a small yield (28%) of product
with PdCl2 and PPh3 (entry 5). Additionally, our monometallic
Pd catalyst 2 resulted in no reaction (see the Supporting
Information). In contrast to the general poor performance of
monometallic Pd catalysts, bimetallic catalysts 4 and 5 showed
high reactivity. Under our optimized conditions with 2.5 equiv
of ketone and 2 equiv of AgOTf in dioxane (optimal solvent,
see the Supporting Information) at 80 °C, the reaction
proceeded to 100% conversion with bimetallic complexes 4
and 5 and provided 89 and 84% yields of the naphthalene
Figure 4. Aryl iodide substrate scope. Isolated yields of the product
shown are for reactions run on a 0.5 mmol scale.
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Thus, the 1,3-disubstituted naphthalene product contains a
phenyl group beta to the carbon that originally contained the
iodide (6b−6g). Aryl iodides containing substituents at either
the meta- (6i−6l) or ortho-positions (6m−6o) also react to
give the naphthalene products in high yields. Aryl iodides with
meta-substituents also provided only a single observed
regioisomer, where cyclization occurred at the less hindered
position para to the substituent (6i−6l). Aldehyde functional
groups were not tolerated in the reaction (6h), nor were
cyanide or ester groups. Aryl bromides also did not lead to
product formation. 1,4-Diiodobenzene gave the anthracene
product in good yield via double cyclization (6q). Iodohetero-
cycles also provide annulation products. For example, 5-
iodoindole gave the corresponding homologated product (6r)
in high yield (70%). Other heterocycles, including 2- and 3-
iodothiophenes provided the product in 23% (6s) and 60%
(6t) yields, respectively, and 5-iododihydrobenzofuran gave
the product in 44% yield (6u). With all aryl iodide substrates
tested, only a single regioisomeric product was observed.
For the methyl ketone coupling partner (Figure 5),
acetophenone derivatives containing both electron-rich and
To experimentally examine ketone incorporation, we
performed the catalysis with simultaneous addition of two
different ketones (Figure 6). Addition of 4-methoxy
Figure 6. Heterocoupling selectivity in naphthalene synthesis.
acetophenone (1 equiv) and 4-trifluoromethyl acetophenone
(6 equiv) to iodobenzene provided product 8 in 40% yield.
The reaction required excess electron-deficient ketone because
homocoupling with the more electron-rich ketone was
observed as the major byproduct. With a 1:1 ratio of ketones,
homocoupling of the more electron-rich ketone was the major
product, and only an 18% yield of the heterocoupled product
was observed. This suggests that the more electron-rich
acetophenone undergoes addition to the aryl iodide at a faster
rate than the more electron-deficient ketone. With the
optimized number of ketone equivalents (6:1), the minor
heterocoupled isomer (where trifluoromethylacetophenone
was added first) was formed in only 6% yield, giving a 6.5:1
ratio of isomers.
With the demonstration that bimetallic Pd catalysts provide
superior performance to monometallic Pd catalysts, we next
executed DFT calculations and mechanistic experiments to
outline possible reaction mechanisms and understand the
reactivity and regioselectivity. First, we confirmed the necessity
of the bimetallic Pd catalyst. When Pd is left out of the reaction
(Table 1, entry 17), no product is observed. Also, added TfOH
(2 equiv) shows no reaction conversion, indicating that a
strong acid, such as TfOH, is unlikely to be generated and to
induce cyclization (Table 1, entry 18). When the reaction of 4-
chloroiodobenzene under standard conditions was stopped
after 30 min at ∼50% conversion, we isolated the arylated
ketone 9 as a major product (Figure 7a). This isolated
intermediate is consistent with our hypothesis that the reaction
proceeds via an initial bimetallic Pd-catalyzed ketone arylation
reaction, followed by the addition of a second equivalent of
ketone and then cyclization and aromatization. Indeed, we
found that when 2-phenylacetophenone was subjected to the
standard reaction conditions with 5 mol % catalyst 4, product
6a was isolated in 69% yield (Figure 7b). Interestingly, we also
found that Pd catalyst 4 was necessary for the cyclization
reaction to proceed efficiently as the reaction with 2-
phenylacetophenone conducted without the Pd catalyst or
with just ligand 3 gave only small amounts of the product (6%
and 19% yield, respectively). This may indicate that the Pd
catalyst participates in the cyclization event as well, potentially
as a strong Lewis acid after chloride extraction with silver
triflate. The addition of 1 equiv of TfOH to the cyclization
shown in Figure 7b also did not impact the rate of formation of
6a, suggesting that the TfOH generated in the reaction is not
solely responsible for inducing the cyclization step (see the
Supporting Information for conditions).
Figure 5. Methyl and dialkyl ketone substrate scope. Isolated yields of
the product shown are for reactions run on a 0.5 mmol scale.
electron-poor aromatic rings perform well in the reaction (7a−
7j). Substitution at the meta-position is well-tolerated (7h),
but ortho-substituents lead to lower isolated yields (7i and 7j).
We also investigated the use of dialkyl ketones and found that
acetone reacted to give the dimethylnaphthalene derivatives 7k
and 7l in modest yields. More hindered ketones such as methyl
isobutylketone gave higher yields of the products (7m and 7n).
We also tried 3-pentanone and found that the corresponding
tetrasubstituted naphthalene could be isolated in modest yield
with phenyl iodide (7o) but with much higher yield with 4-
iodoanisole (7p). 4-tert-Butylcyclohexanone also reacted to
give the tetrasubstituted naphthalene in excellent yield (91%,
7q). This one step, regioselective synthesis of tetrasubstituted
naphthalenes, provides access to core naphthalene structures
that cannot be easily synthesized via other methods.
Unfortunately, less hindered alkyl ketones such as 2-butanone
gave complex mixtures of regioisomeric products.
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enables sharing of the electronic burden of oxidation across
two metal centers, similar to the scenario proposed by Ritter.10
To directly examine possible bimetallic Pd-catalyzed ketone
α-arylation mechanisms, we used M06 DFT calculations with
continuum or continuum/explicit 1,4-dioxane solvent. This
functional provides the most generally accurate structures and
energies for second−row transition metal complexes.23 We
generally modeled the bimetallic catalyst as structure 11
(Figure 8a) and phenyl iodide and methyl phenyl ketone as
substrates.
Figure 7. Mechanistic experiments (see the Supporting Information
for reaction details).
We next conducted a kinetic isotope experiment to better
understand the cyclization portion of the mechanism (Figure
7c). We synthesized ortho-deuteroiodobenzene (10) to
perform a one-pot intramolecular competition experiment to
determine the preference for the reaction to proceed via
substitution of the hydrogen or deuterium atom. Based on the
ratio of H/D in product naphthalene, we calculated a kH/kD of
0.77 in the reaction. This inverse secondary kinetic isotope
effect suggests that the cyclization step of the reaction likely
involves rehybridization of an sp2 carbon, potentially through a
Friedel−Crafts-type mechanism. There is also the possibility of
the reaction proceeding through a 6-π-electrocyclic ring-
closure mechanism if elimination of water occurs before
cyclization. The inverse secondary isotope effect is also
inconsistent with a rate-limiting Pd-mediated C−H activation
event during cyclization.25
Typically, Pd-catalyzed α-arylations of ketones proceed
under Pd(0)/Pd(II) catalysis in the presence of a base via
oxidative addition into an aryl iodide.26 Pd(I)-catalyzed α-
arylations of carbonyl compounds also typically require
stoichiometric formation of the enolate species with the
base.12 With bimetallic catalyst 4, however, the reaction
proceeds under relatively oxidizing conditions (2 equiv
AgOTf; Ag+ potential vs NHE = ∼0.8 V), the addition of
organic or inorganic bases (Et3N, NaOtBu, and Cs2CO3) leads
to the complete loss of reactivity, and no product or ketone
arylation is observed. This suggests that one role of silver
triflate may be to help facilitate enolization of the ketone in the
absence of a strong base. We performed a deuterium exchange
experiment and found that stoichiometric silver triflate
facilitates deuterium transfer between deuterated and non-
deuterated acetophenones at 80 °C in the absence of catalyst 4
(see the Supporting Information). We also examined the
impact of oxygen on reactivity. There was no decrease in the
rate or yield when the reaction to form 6a was run under a
balloon of oxygen at 80 °C. While this does not exclude the
possibility of open-shell-type intermediates, it does suggest that
the reaction does not proceed through a Pd(0)-to-Pd(II)
catalytic cycle and likely occurs via higher-oxidation-state
dimeric Pd(III) or Pd(IV) intermediates. This could explain
why bimetallic catalysts 4 and 5 provide much higher yields in
the reaction because the bimetallic structure of the catalyst
Figure 8. (a) DFT-calculated thermodynamic values for bimetallic Pd
precatalyst conversion to a potential monometallic solvent complex
and Ag-induced chloride dissociation. (b) Representative oxidative
addition transition states. Catalyst phenyl groups were modeled as
methyl groups. TS1a and TS1b energies relative to 13+. TS1c
energies relative to 13. TS1d energies relative to 11. Relative Gibbs
energies (G) and enthalpies (H) are reported in kcal/mol.
When bimetallic Pd complexes are used, there is always the
possibility that the complex dissociates to form active
monometallic catalysts. Therefore, we calculated the energy
of transforming 11 into several possible monometallic
structures, such as monometallic 12 (Figure 8a). The direct
dissociation into a structure where each Pd center is ligated by
a single 2-phosphinoimidazole requires ΔG/ΔH = 37/54 kcal/
mol. This relatively high energy is the result of the 2-
phosphinoimidazole ligand only providing tight phosphine
coordination and weak imidazole donation to a single Pd
center, which is due to the P−C−N angle of 117° (Pd−P
distance = 2.25 Å and Pd−N = 3.96 Å). Therefore, our best
low-range estimate for bimetallic-to-monometallic conversion
was obtained using an explicit dioxane solvent. The energy of
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12 with explicit dioxane is ΔG/ΔH = 17/9 kcal/mol higher
than that of 11. While this energy alone does not rule out the
formation of reactive monometallic structures, the concen-
tration of this type of species would be small. Moreover, in
subsequent reaction steps, 12 would require more energy to
achieve the oxidative addition (see later calculations). The
poor simultaneous donation of both phosphine and imidazole
ligand arms to a single Pd metal center explains the formation
of 4 without Pd−Pd covalent bonding. Additionally, this
suggests that the mixing of 2-phosphinoimidazole with PdCl2
forms 4.
With the inability of the starting bimetallic Pd complex to
easily split into complete monometallic intermediates, we
examined many other possible activation routes to generate
reactive intermediates. We ruled out dimeric Pd(II)-to-Pd(I)
reduction through Cl2 reductive elimination that requires ΔG/
ΔH = 47/60 kcal/mol. We also examined the possibility that
11 acts as a one-electron donor to reduce phenyl iodide, but
this requires >100 kcal/mol and is unlikely due to the low
solvent polarity, although this value is overestimated due to the
calculation of charge-separated species. Electron transfer from
11 to Ag+ requires ΔG/ΔH = 31/30 kcal/mol. It is unlikely
that the phosphine ligand arm dissociates for 11 because even
with the dioxane solvent stabilizing the coordination vacancy,
this requires ΔG/ΔH = 27/17 kcal/mol. The imidazole ligand
arm, however, is more labile, requiring ΔG/ΔH = 3/−7 kcal/
mol for dissociation. This imidazole ligand arm dissociation
could provide a monometallic-like reaction pathway while
remaining as an overall bimetallic complex. Another reasonable
activation pathway identified by calculations is chloride
extraction from 11 to generate 13+ (Figure 8a). Starting
from 11 and AgOTf, chloride for triflate anion exchange to
form 13 is exergonic/exothermic with ΔG/ΔH = −3/−5 kcal/
mol, respectively. Generation of the cationic trichloride 13+
without an OTf anion coordination has ΔG/ΔH = 29/38 kcal/
mol, which suggests that the counterion, either the chloride or
OTf anion, would remain in the outer solvation sphere. This
also indicates that chloride and OTf anion exchange is likely
very rapid under catalytic conditions. Importantly, both
imidazole ligand arm dissociation and the thermodynamic
accessibility of 13 and 13+ provide possible pathways for
electrophilic-mediated substrate coordination and subsequent
C−I bond activation.
Figure 9. (a) Cationic bimetallic complexes containing bridging
halides. (b) X-ray structures of complexes 14 and 15. Anions
{tetrakis[3,5-bis(trifluoromethyl)phenyl]borate for 14 and OTf for
15} were omitted for clarity.
the presence of iodide in 15 suggests that oxidative addition/
reductive elimination occurred under these conditions where
the reductive elimination step produced phenyl chloride. This
result is consistent with the work reported by Schoenebeck
where halide exchange was shown to occur via an oxidative
addition mechanism to the bimetallic Pd(I) complex.12a To
confirm that the bridging species could be present during
catalysis, we used mass spectrometry to examine the reaction
mixture at the end of the reaction from entry 1 of Table 1. This
confirmed the presence of an iodide-bridged bimetallic Pd
complex (see the Supporting Information).
With both DFT and experiments indicating that a cationic
bimetallic Pd intermediate is viable, we then calculated
possible reactions between 13+ and phenyl iodide. We located
exergonic π (ΔG/ΔH = 4/−8 kcal/mol) and iodine σ (ΔG/
ΔH = 4/−9 kcal/mol) coordination intermediates. We
identified two types of transition states for oxidative addition.
TS1a connects the iodine-coordinated structure to the
Pd(Ph)(I) oxidative addition intermediate through a 1,2-
phenyl shift (Figure 8b). The second transition state located
(TS1b) is the more expected three-centered oxidative addition
process where Pd is inserted into the Ph−I bond. However,
there is very little overall difference between the bonding in
TS1a and TS1b, but there are subtle differences in bridging
chlorides. The ΔG⧧/ΔH⧧ values for TS1a and TS1b are 41/27
and 42/28 kcal/mol, respectively. We extensively examined the
possibility of the Ph−I bond being directly added across both
Pd metal centers. However, the reduced dimensionality energy
landscapes constructed only revealed the single metal center
oxidative addition saddle point (see the Supporting Informa-
tion). We also calculated the oxidative addition barrier with the
OTf anion in an outer-sphere coordination of the second Pd
metal center; however, the OTf anion remains close to the
second Pd metal center at about 2.7 Å (TS1c; ΔG⧧/ΔH⧧ =
48/34 kcal/mol). Because our thermodynamic calculations
suggest that chloride ligands can potentially be exchanged for
OTf anion ligands, we also calculated the oxidative addition
transition state with one or two chloride ligands replaced by
OTf anions. Generally, we found that the activation barriers for
one or two OTf ligands rather than chloride ligands are only a
few kcal/mol higher in energy than the transition states shown
in Figure 8b (see the Supporting Information). Therefore, it is
not possible to be definitive about the chloride or OTf anion
or a mixture coordinate to Pd metal centers during catalysis,
To establish the general viability of the proposed bimetallic
trichloride cationic complex, we synthesized the cationic BArF
4
salt 14 by treatment of complex 4 with 1 equiv of NaB(ArF)4
[Figure 9a, ArF = 3,5-(CF3)2C6H3]. Importantly, the resulting
isolated complex 14 is catalytically competent and has similar
reactivity to that of complex 4. In this X-ray structure and in
the optimized DFT structure, one of the three chlorides
provides a bridge to stabilize the vacant coordination site
resulting from chloride dissociation (Figure 9b, the Pd−Pd
distance is 2.772 Å).
To examine possible structures formed from the reaction of
4 with phenyl iodide, a stoichiometric amount of 4 was reacted
with phenyl iodide and silver triflate. This allowed the isolation
and X-ray structure of a bridging Pd−iodide species 15 with
two triflate ligands (Figure 9b). The lack of isolation of a Pd−
phenyl species is consistent with the DFT prediction that 16a
is relatively endergonic. The observation of this species, and
the calculated thermodynamics for chloride to OTf anion
ligand exchange indicate that chloride or OTf anions are
possible as ancillary ligands during catalysis. More importantly,
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and we speculate that there is likely a mixture of active
catalysts.
The oxidative addition transition state TS1a leads to the
Pd−phenyl intermediate 16a (Figure 10). In this intermediate,
of the imidazole raises the energy to ΔG/ΔH = 34/48 kcal/
mol. This indicates that the more donating Ph ligand creates a
larger preference for imidazole ligand dissociation (and anion
ligand dissociation).
Because the energy barriers for TS1a and TS1d are both
within the margin of error for DFT-type calculations, we
examined the rest of the catalytic cycle for both pathways. The
relatively high oxidative addition barrier between 13+ and the
α-CH bond in methyl phenyl ketone (57/42 kcal/mol)
indicates that the ketone does not react with Pd until after
intermediate 16 is formed. The acidity of the α-CH bond in
methyl phenyl ketone suggests that enolization provides a
pathway to generate Pd−acyl intermediate 17 (Figure 10).
While it is possible that Pd catalyzes ketone to enolate
formation, deuterium exchange experiments described above
using AgOTf show relatively rapid hydrogen−deuterium
exchange between two different ketones. Therefore, the Pd−
acyl intermediate can be achieved after AgOTf-induced
enolization. From both intermediates 16a and 16d and Ag
enolate, the halogen−ligand exchange reactions to give 17a
and 17d are both exothermic by more than 30 kcal/mol. As
expected, carbon coordination is ∼20 kcal/mol more
stabilizing than oxygen enolate coordination.
The barrier for reductive elimination from 17a to TS2a is
ΔG⧧/ΔH⧧ = 10/11 kcal/mol and generates α-phenyl ketone
as well as re-forms 13+ (Figure 10). This reductive elimination
occurs at a single Pd metal center. We also examined the
possibility of reductive elimination where the Ph and acyl
groups are on the opposite Pd metal centers. As with our
efforts to identify oxidative addition across two Pd metal
centers, we could not locate a transition state for this type of
reaction route. For the imidazole-dissociated pathway, the
reductive elimination barrier from 17d to TS2d has ΔG⧧/ΔH⧧
= 12/13 kcal/mol, again similar to the cationic pathway
barrier. After reductive elimination, it is lower in energy for the
imidazole ligand arm to re-coordinate with the Pd metal center
and re-form 11.
Based on our experimental and computational evaluations,
Figure 11 outlines two plausible bimetallic Pd catalytic cycles
and subsequent cyclization. The catalytic cycle shown in Figure
11a involves conversion of 4 into an active cationic bimetallic
Pd catalyst 19 through Ag-mediated chloride abstraction. The
cycle begins with oxidative addition at a single Pd metal center
to generate a Pd(III)−Pd(III)−phenyl intermediate containing
a relatively strong metal−metal interaction (20). This
intermediate can be considered a Pd(III) dimer because the
Pd−Pd bond distance (2.72 Å for 16a) is within the distance
for Pd−Pd bond formation. Subsequent enolization and
transmetalation facilitated by Ag generate a bimetallic Pd−
acyl intermediate (21) where reductive elimination forms the
α-arylation product 22 and reforms the cationic bimetallic Pd
intermediate. It is likely that both the chloride and OTf anion-
ligated species can promote catalysis in this cycle. Figure 11b
shows a potentially competitive catalytic cycle with 4
undergoing imidazole ligand arm dissociation to generate the
coordinatively unsaturated bimetallic active species 23.
Oxidative addition generates a Pd(IV)−Ph intermediate that
is not directly stabilized by the second Pd(II) metal center
(Pd−Pd distance = 3.99 Å). Subsequent transmetalation and
reductive elimination generate 22. The α-arylation process in
the formation of naphthalene products explains the observed
regioselectivity in the reaction. After ketone α-arylation, a non-
catalytic route to the naphthalene product involves the
Figure 10. DFT-calculated energies for oxidative addition inter-
mediates and reductive elimination (kcal/mol).
the halide ligands as well as the phenyl group are fluxional with
only a 4 kcal/mol preference for the phenyl group to be cis
compared to the second Pd metal center. In this cationic
bimetallic pathway, the Pd−Pd distance progressively
decreases. In neutral 13, the Pd−Pd distance is 2.94 Å and
decreases to 2.88 Å after chloride dissociation to 13+. At the
oxidized intermediate, 16a, the Pd−Pd distance is 2.72 Å. The
significant decrease in the Pd−Pd distance suggests that the
Pd(II) metal center likely donates electrons to the Pd(IV)
metal center, creating a Pd(III)−Pd(III) bonding-type
scenario.
While the oxidative addition activation barriers for 13+ are
potentially reasonable given the relatively elevated temper-
atures required for catalysis and experiments showing that
anionic ligand exchange is possible, we also examined oxidative
addition from neutral 13 with an imidazole ligand dissociated
(TS1d). Somewhat surprisingly, this oxidative addition
transition state has a lower barrier than TS1a, and this could
suggest that anion exchange or anion ligand dissociation is a
preequilibrium step. The oxidative addition barrier for TS1d
has ΔG⧧/ΔH⧧ = 35/23 kcal/mol relative to 11. This suggests
that a more reactive species is generated through imidazole
dissociation rather than chloride dissociation, although the
energies of these pathways suggest that both mechanisms are
viable for catalysis. Consistent with the idea that the bimetallic
Pd complex 11 partly unravels, the resulting Pd−Ph
intermediate, 16d, with imidazole not coordinated is
significantly lower in energy than a fully coordinated structure.
The ΔG/ΔH for 16d is 17/28 kcal/mol, while re-coordination
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phosphinoimidazole)PdCl2 is highly endothermic. For [(2-
phosphinoimidazole)PdCl]+, oxidative addition with phenyl
iodide only requires ΔG⧧/ΔH⧧21/8 kcal/mol. This indicates
that while the monometallic catalyst is potentially highly
reactive, ground-state accessibility inhibits catalysis through
this type of dimer-to-monomer pathway. Somewhat surpris-
ingly, the oxidative addition transition state energies for
[(imidazole)(PMe3)PdCl]+ and [(dppe)PdCl]+ with phenyl
iodide require ΔG⧧/ΔH⧧ = 20/6 and ΔG⧧/ΔH⧧ = 26/11
kcal/mol, respectively. Because these oxidative addition
barriers are relatively low, especially compared to TS1a and
TS1d, these types of cationic monometallic structures are likely
thermodynamically inaccessible. Indeed, calculation of AgOTf-
mediated chloride extraction shows that it requires >40 kcal/
mol to generate these cationic structures. This implies that one
major feature of the Pd bimetallic catalysis reported here is the
balance of generating reactive intermediates and the
subsequent ability of these intermediates to achieve oxidative
addition.
CONCLUSIONS
■
We have demonstrated that bimetallic 2-phosphinoimidazole-
derived Pd(I) and Pd(II) complexes enable the formation of
di- and tetrasubstituted naphthalene derivatives via a ketone α-
arylation/cyclization process. This new transformation pro-
vides easy and efficient access to substituted naphthalenes from
aryl iodides and methyl ketones and tolerates a range of
functional groups at the aryl iodide and methyl ketone
partners. DFT calculations and experiments were carried out to
examine possible reaction mechanisms and understand the
exceptional reactivity of our bimetallic catalysts. Two plausible
catalytic cycles emerged. The first involves the generation of a
cationic bimetallic intermediate, followed by oxidative addition
to form a Pd(III)−Pd(III)-like intermediate and then
transmetalation and reductive elimination. In the second and
lower in energy pathway (although within the error of DFT
calculations), catalysis can potentially occur through oxidative
addition with the neutral catalyst to generate a bimetallic
Pd(IV)−Pd(II) intermediate, which can also subsequently
undergo transmetalation and reductive elimination to generate
the initial α-arylation product. Ag-induced annulation forms
the final naphthalene products.
Figure 11. Possible catalytic cycles based on experimental and DFT
results. (a) Bimetallic catalytic cycle involving cationic structures and
a Pd(III)−Pd(III) intermediate. (b) Bimetallic catalytic cycle
involving neutral structures, imidazole ligand arm dissociation, and
a Pd(IV)−Pd(II) intermediate. (c) Mechanism of 1,3-naphthalene
formation.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c02731.
addition of a second equivalent of the enolate to intermediate
22 via an aldol condensation that would then provide 26
(Figure 11c). Friedel−Crafts-type cyclization by the attack of
the arene ring onto the pendant ketone then gives intermediate
27. Aromatization (via formal loss of AgOH) then occurs to
give naphthalene product 6.
We selected three different monometallic models to
compare to these bimetallic catalytic cycles. These include
the monometallic Pd complex from the dissociation of 11 [(2-
phosphinoimidazole)PdCl2], (imidazole)(PMe3)PdCl2, and
(dppe)PdCl2. The (imidazole)(PMe3)PdCl2 complex was
examined because the monometallic structures formed from
11 are likely not a good direct comparison since there is strong
phosphine coordination but weak imidazole coordination,
which is very different bonding than that observed in the fully
intact bimetallic complex.
■
sı
Experimental procedures, characterization data, spectral
images, computational details, and calculated energies
(PDF)
XYZ coordinates of key structures (XYZ)
X-ray crystallographic data for Pd(I) dimer 5 (CIF)
X-ray crystallographic data for Pd(II) dimer 4 (CIF)
X-ray crystallographic data for bridging iodide dimer 15
(CIF)
X-ray crystallographic data for bridging chloride BArF
4
dimer 14 (CIF)
AUTHOR INFORMATION
Corresponding Authors
We first calculated the barriers for oxidative addition of these
model monometallic complexes. Not surprisingly, because 2-
phosphinoimidazole provides poor imidazole coordination to a
single Pd metal center, the formation of fully monometallic (2-
■
Daniel H. Ess − Department of Chemistry and Biochemistry,
Brigham Young University, Provo, Utah 84602, United
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United States; orcid.org/0000-0003-3914-5752;
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Authors
Chloe C. Ence − Department of Chemistry and Biochemistry,
Brigham Young University, Provo, Utah 84602, United
States
Erin E. Martinez − Department of Chemistry and
Biochemistry, Brigham Young University, Provo, Utah
84602, United States
Samuel R. Himes − Department of Chemistry and
Biochemistry, Brigham Young University, Provo, Utah
84602, United States
S. Hadi Nazari − Department of Chemistry and Biochemistry,
Brigham Young University, Provo, Utah 84602, United
States
Mariur Rodriguez Moreno − Department of Chemistry and
Biochemistry, Brigham Young University, Provo, Utah
84602, United States
Manase F. Matu − Department of Chemistry and
Biochemistry, Brigham Young University, Provo, Utah
84602, United States
Samantha G. Larsen − Department of Chemistry and
Biochemistry, Brigham Young University, Provo, Utah
84602, United States
Kyle J. Gassaway − Department of Chemistry and
Biochemistry, Brigham Young University, Provo, Utah
84602, United States
Gabriel A. Valdivia-Berroeta − Department of Chemistry and
Biochemistry, Brigham Young University, Provo, Utah
84602, United States
Stacey J. Smith − Department of Chemistry and Biochemistry,
Brigham Young University, Provo, Utah 84602, United
States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c02731
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.J.M. acknowledges the donors of the American Chemical
Society Petroleum Research Fund for their support of this
research (PRF no. 56371-DNI1). D.J.M. also acknowledges
financial support provided by the Chemical Synthesis Program
of the National Science Foundation (CHE-1665015). D.H.E.
acknowledges the United States National Science Foundation
Chemical Catalysis Program for support (CHE-1764194). We
thank Brigham Young University and the Office of Research
Computing, especially the Fulton Supercomputing Lab.
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