Understanding Anionic ligandless Palladium Species in the Mizoroki-Heck Reaction

Article abstract of DOI:10.1021/acs.inorgchem.8b00175

The anionic complex [NBu₄][Pd(DMSO)Cl₃], as a ligandless system, was shown to be an active catalyst in the Mizoroki-Heck coupling of aryl chlorides in the absence of strongly σ-donating ligands. To investigate the experimentally observed influence of halides and the amount of water on the catalytic activity, we employed a combination of experiments and theoretical calculations. The presence of water was shown to be critical for the formation of the active palladium(0) species by oxidation of in situ generated tributylamine. Oxidative addition to an anionic palladium(0) species was found to be the rate-determining step of the catalytic cycle. For the ensuing steps, both neutral and anionic pathways were considered. It was shown that, in the absence of strongly σ-donating neutral ligands, chloride ions stabilize the catalytic intermediates. Therefore, an anionic pathway is preferred, which explains the need for tetrabutylammonium chloride as an additive. The study of the influence of bromide ions on the catalytic activity revealed that the strongly exergonic displacement of the neutral substrates by bromide ions lowers the catalytic activity.

Full text of DOI:10.1021/acs.inorgchem.8b00175

Article
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/IC
Understanding Anionic “Ligandless” Palladium Species in the
Mizoroki−Heck Reaction
Felix Schroeter and Thomas Strassner*
Physikalische Organische Chemie, TU Dresden, Bergstrasse 66, 01062 Dresden, Germany
*
S Supporting Information
ABSTRACT: The anionic complex [NBu ][Pd(DMSO)Cl ], as
4
3
a “ligandless” system, was shown to be an active catalyst in the
Mizoroki−Heck coupling of aryl chlorides in the absence of
strongly σ-donating ligands. To investigate the experimentally
observed influence of halides and the amount of water on the
catalytic activity, we employed a combination of experiments and
theoretical calculations. The presence of water was shown to be
critical for the formation of the active palladium(0) species by
oxidation of in situ generated tributylamine. Oxidative addition to
an anionic palladium(0) species was found to be the rate-
determining step of the catalytic cycle. For the ensuing steps,
both neutral and anionic pathways were considered. It was shown
that, in the absence of strongly σ-donating neutral ligands,
chloride ions stabilize the catalytic intermediates. Therefore, an
anionic pathway is preferred, which explains the need for tetrabutylammonium chloride as an additive. The study of the influence
of bromide ions on the catalytic activity revealed that the strongly exergonic displacement of the neutral substrates by bromide
ions lowers the catalytic activity.
INTRODUCTION
neutral. Intense investigation of the oxidative addition step by
Amatore and Jutand led to the proposal of an anionic catalytic
cycle with short-lived pentacoordinate intermediates (Scheme
■
As one of the organic transformations honored with the Nobel
1
−4
5−7
Prize,
the Mizoroki−Heck reaction
has been and still is
86−88
8
−12
1G, H).
cross-couplings
palladium precatalysts in cross-coupling reactions.
mechanistic pathways have been the subject of detailed
Anionic species have been later identified in other
being intensely studied experimentally and theoretically.
8
9−95
and encouraged the use of anionic
The development of this powerful palladium-catalyzed C−C
bond-forming process enabled the facile synthesis of stilbenes
from styrene derivatives and aryl halides as target molecules for
9
6−105
Both
106−127
1
3−17
18−20
theoretical calculations.
medicinal
and materials
chemistry on a labora-
scale. A multitude of catalyst
systems has been established for the Mizoroki−Heck
2
1−23
24−27
We recently reported on the catalytic activity of an anionic
tory
and industrial
“
ligandless” palladium complex in the Mizoroki−Heck
105
−
2
8,29
30−33
reaction. The [Pd(DMSO)Cl ] anion (DMSO = dimethyl
3
reaction,
heterocyclic carbenes (NHCs)
preformed palladium nanoparticles
among them not only phosphines
and N-
3
4−50
sulfoxide) is capable of coupling activated aryl chlorides in
relatively short reaction times.
During the course of the optimization, we observed the
as ligands but also
5
1−54
and “ligand-free”
5
5−66
67−74
systems
in ionic liquids.
While aryl bromides are
following:
typically the coupling partner, many developed systems are also
able to couple the less reactive aryl chlorides.
The performance of these systems was rationalized on the
75−80
(1) The presence of a small amount of water was crucial for
product formation. The role of water in transition-metal
catalysis has often been neglected, although it can play an
basis of the identified mechanism of the reaction (Scheme
128−130
9
,81−85
important role.
For example, Rh- and Ir-catalyzed
1).
At first, a palladium(II) precursor is reduced to a
hydrogenations are largely both positively and negatively
neutral palladium(0) species (Scheme 1A). Then, oxidative
addition of an aryl halide takes place (Scheme 1B), followed by
ligand exchange (Scheme 1C) and migratory insertion of a
styrene derivative (Scheme 1D). The resulting palladium alkyl
complex undergoes β-hydride elimination, preferably yielding
the coordinated (E)-alkene, which subsequently dissociates
influenced by the presence of water, depending on its
1
31−133
concentration.
In the Suzuki−Miyaura cross-coupling,
water is thought to be responsible to form an anionic boronate
complex which is required for efficient transmetalation.
134−136
In Mizoroki−Heck and related cross-coupling reactions, water
(
1
Scheme 1E). Base-mediated reductive elimination (Scheme
F) regenerates the catalytically active species. In this
mechanism, all species involved in the catalytic cycle are
Received: January 25, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.8b00175
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Inorganic Chemistry
Article
Scheme 1. Commonly Proposed Mechanism of the
Mizoroki−Heck Reaction
Finally, we investigated the influence of bromide ions on
representative key steps of the catalyst activation and catalytic
cycle.
a
RESULTS AND DISCUSSION
■
Catalyst Activation. Experimental Observations. At first,
the palladium(II) precatalyst has to be reduced to palladium(0)
in order to enter the catalytic cycle. We looked into the Wacker
oxidation and treated complex 1a-NBu with styrene in the
4
absence of an aryl halide (Scheme 2a). Indeed, formation of
Scheme 2. Experimentally Observed Reduction of
a
Palladium
a
Legend: (A) catalyst activation; (B) oxidative addition to a neutral
Pd(0) species; (C) ligand displacement; (D) migratory insertion; (E)
β-hydride elimination and liberation of the product; (F) “classical”
reductive elimination, (G) formation of an anionic Pd(0) species; (H)
oxidative addition to an anionic Pd(0) species; (I) reductive
elimination via an anionic pathway; (J) reversible nanoparticle
formation; (K) irreversible palladium black formation.
has been demonstrated to induce and/or accelerate the
9
,137,138
reduction of a palladium(II) precursor to palladium(0)
by base-mediated oxidation of a phosphine ligand to the
8
6,139,140
corresponding phosphine oxide,
by Wacker oxida-
1
41
142−146
a
tion, or by oxidation of tertiary amines.
2) Product formation required the presence of tetrabutyl-
Legend: (a) reaction via Wacker oxidation; (b) reaction with styrene
and NBu , respectively, at room temperature; (c) competition
(
3
experiment between styrene and NBu . All products were identified
by GC-MS (respectively NMR) and compared to reference samples.
ammonium chloride (TBACl) as stabilizer. Jeffery was the first
to report that tetrabutylammonium salts enhance the perform-
3
5
5,147
ance of catalysts in the Mizoroki−Heck reaction.
It is
commonly proposed that the salt provides “electrosteric”
palladium black occurred. Moreover, GC analysis of the
reaction mixture revealed trace amounts of acetophenone
(see Figure S1 in the Supporting Information). The presence of
a base significantly accelerated the reaction, in accordance with
the mechanism of the Wacker oxidation, where key steps such
1
48
149
stabilization
serve as a reservoir for soluble palladium(0) species,
that the halide aids in the formation of an anionic palladium
and size control
of nanoparticles, which
59,150
and
8
7
species. The latter observation is especially relevant to our
catalytic system, since in the absence of strong σ-donating
ligands (e.g., NHCs, phosphines), the catalytic intermediates
may be stabilized by anionic halido ligands, which serve as
moderately strong σ-donors and π-acceptors.
3) The presence of bromide ions in the reaction mixture
1
63
as deprotonation of a palladium aqua complex
and
nucleophilic attack of a water molecule or hydroxide ion on
164,165
the coordinated alkene
are discussed.
151,152
However, we also found trace amounts of tributylamine,
which are also always present in a typical catalytic experiment
(see Figure S2 in the Supporting Information). These result
from base-mediated Hofmann elimination of the tetrabutylam-
monium cation. Additionally, in another control experiment,
formation of palladium black also occurred in the absence of
(
had a detrimental influence on the catalytic activity. This
finding was somewhat counterintuitive, since many catalyst
systems for the Mizoroki−Heck reaction rely on tetrabutyl-
153−156
ammonium bromide (TBABr) as an additive.
To rationalize these findings and to understand the origin of
styrene. In an NMR experiment, precatalyst 1a-NBu did not
4
−
the high catalytic activity of the [Pd(DMSO)Cl ] anion, we
react with styrene (Scheme 2b). Neither coordination of
styrene to the metal center nor reduction was observed. In
contrast, if precatalyst 1a-NBu4 is treated with excess
3
used a combined experimental and theoretical approach. For
density functional theory (DFT) calculations, we chose the
M06L functional, which has proven its reliability in
thermochemical calculations of transition metals and treatment
tributylamine (NBu ), formation of palladium black occurs
3
within 24 h (Scheme 2b) at room temperature. This
observation is accompanied by the disappearance of the
NMR peak assigned to ligated DMSO and the appearance of
two new signals, which can be assigned to butyraldehyde (see
Figure S3 in the Supporting Information). This is in accordance
with the findings by Shmidt and Trzeciak, who investigated the
157
of noncovalent interactions1, along with the 6-31+G* basis
58−161
set for treatment of anions.
Solvent effects were treated
62
1
implicitly with the SMD method, to account for the large
influence of solvation effects on charged structures. First, we
turned our attention to the precatalyst activation step. Then, we
calculated the mechanism of the Mizoroki−Heck reaction,
where we considered both an anionic and a neutral pathway.
143,144,166
reduction of palladium(II) by tertiary amines.
In the
last work, the aldehyde oxygen atom was found to originate
B
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Inorganic Chemistry
Article
from trace amounts of water, and it was also stated that water
accelerated the reduction of palladium.
favored. In contrast, several neutral palladium(II) species are
higher in energy than 1a (see Chart S1 in the Supporting
Information). We also considered the coordination of another
chloride ligand, yielding 1d. Compound 1d is slightly favored in
terms of free energy, in comparison to 1a. Species 1a,d both
coexist in solution, as will be discussed later (Table 2, see
below). Formation of a dimeric palladium(II) species, as in 1e,
is also disfavored. Thus, displacement of the DMSO ligand by
styrene or tributylamine, yielding the anionic complexes 1b,c,
respectively, seems to initiate the reduction step.
In a competition experiment between styrene and tributyl-
amine in dimethylacetamide (DMAc), using compound 1a-Na
in the absence of tetrabutylammonium ions, no acetophenone
was found. Instead, butyraldehyde formed, which was identified
as its p-chlorophenyl hydrazone derivative (Scheme 2c; see
Figures S4 and S5 in the Supporting Information). Thus, the
latter pathway appears to be preferred for catalyst activation.
Additionally, other stabilizers, which are not able to undergo
Hofmann elimination or β-hydride elimination, were tested in
We compared the energies of different palladium(0)
complexes to see which palladium(0) species would most
likely result from reduction (Chart 1b). Starting from a
dicoordinated species, which is often discussed as the species
105
the Mizoroki−Heck reaction with 1a-NBu . These reactions
4
did not lead to product formation. This is another sign that,
under catalytically relevant conditions, the oxidation of a
tertiary amine is necessary for efficient catalyst activation.
84,101
entering oxidative addition,
we compared different ligands
167−171
The thermolysis of palladium acetate
as a productive
in compounds 2a−c. Only styrene was able to efficiently
stabilize Pd(0) (2b), in contrast to other ligands (see Chart S2
in the Supporting Information). Upon comparing different
tricoordinated complexes, we identified the neutral complex 2d
and the anionic complex 2e as the most thermodynamically
favorable compounds, which also most likely coexist in solution,
on the basis of their energies. We chose compound 2e as our
reference point, since the anionic ligand renders the palladium
atom more electron rich, which in turn facilitates the following
oxidative addition. This will be discussed later in detail.
catalyst activation pathway could be excluded, since using
palladium acetate as a precatalyst did not lead to product
1
05
formation. In addition, the reaction proceeds efficiently with
other bases in the absence of acetate ions (see Table S1, entries
2
−4, in the Supporting Information).
On the basis of these results, both the Wacker oxidation and
the reduction by tributylamine may account for catalyst
activation. It has to be emphasized that both activation
pathways require stoichiometric amounts of water to take
place, which might explain the need for water in the Mizoroki−
Heck reaction using our catalyst system.
It should be mentioned that the Pd(0) compound 2e is most
172,173
likely in equilibrium with palladium nanoparticles,
which
Theoretical Investigation: Relevant Pd(II) and Pd(0)
Species. Since these experiments suggest two plausible
activation pathways, we used theoretical calculations to further
gain insight into this step. Therefore, we considered several
palladium(II) species as possible starting points for the
reduction (Chart 1a; see Figure S6 in the Supporting
Information). The displacement of the neutral DMSO ligand
with styrene, forming the anion 1b, is slightly exergonic.
Similarly, formation of the anionic tributylamine complex 1c is
may be catalytically active by themselves; however, these
nanoparticles are most frequently discussed to be a resting state
82,150,174−179
of the reaction.
The formation of palladium
nanoparticles has been confirmed by a mercury poisoning
105
test, where the yield dropped from 94%
to 7%. These
nanoparticles might aggregate in the presence of a large excess
of water, as has been shown for related Ru and Ir
131,133
nanoparticles.
Such a process in the present case might
explain why an excess of water larger than 50 μL is detrimental
105
to the catalytic activity of 1a-NBu4.
Chart 1. Plausible Palladium(II) and Palladium(0) Species
a
Wacker Oxidation. As one of the most important
in the Reaction Mixture
industrially relevant homogeneously catatalyzed
180−183
reactions,
the Wacker oxidation has been subject to
184
extensive experimental and theoretical studies. Typically, the
oxidation of ethylene to acetaldehyde is performed in acidic
aqueous solution at a low chloride ion concentration. Two
major mechanistic alternatives have been proposed. (1) An
inner-sphere attack of a hydroxido ligand occurs on the
coordinated alkene. This syn pathway may be operative at low
−
163,185−188
[
Cl ]; however, some ambiguity remains.
(2) An
outer-sphere attack of a water molecule takes place on the
164,165,189−192
coordinated alkene.
Nowadays, there is general
consensus that this so-called anti pathway is operative at high
−
184
[
Cl ].
Many groups strove to correlate experimental and
1
22,193−198
theoretical results,
and a great deal of effort was put
into the accurate description of water as a solvent, mostly by
employing explicit solvation models in static quantum
1
99−204
mechanical approaches,
simulations.
as well as molecular dynamics
2
05−208
The conditions employed in our work differ
greatly from the typical Wacker oxidation conditions. In
dimethylacetamide as solvent, the concentration of water is
ca. 100 times lower than that in pure water. In addition, basic
instead of acidic conditions are employed. Thus, we modeled
both syn and anti pathways.
a
298
(ΔG298) in kcal/mol. Energies are relative to 1a (2a,
ΔH
respectively).
C
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Inorganic Chemistry
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In the syn pathway, the DMSO ligand of 1a is displaced by
styrene (Scheme 3; see Figure S7 in the Supporting
Information).
Scheme 4. Catalyst Activation by Wacker Oxidation: Anti
Pathway
a
Scheme 3. Catalyst Activation by Wacker Oxidation: Syn
a
Pathway
a
ΔH (ΔG ;ΔG413) in kcal/mol. Energies are relative to 1a.
298
298
of a single water molecule on complex 8 is even less favorable
see Scheme S1 in the Supporting Information). Thus, the syn
(
pathway appears to be preferred for this particular system.
Reduction by Tributylamine. The reduction of palladium-
II) by tertiary amines is less well understood. At first, the
(
DMSO ligand in 1a is displaced by tributylamine. Following a
mechanistic proposal by Trzeciak, the palladium amine complex
1
e is subjected to a concerted metalation−deprotonation
(
cmd) reaction (Scheme 5; see Figure S9 in the Supporting
144
Information).
reported for similar systems.
This reaction pathway has frequently been
2
09−213
In complex 1c, two
2
chlorido ligands can be replaced by one acetate ligand in a η
fashion. The corresponding associative displacement of the
chlorido ligand by acetate (TS1c-1f) is connected to a high
barrier, especially at 140 °C. However, if the loss of a chloride
ligand occurs first, the resulting compound 10 can easily add an
acetate anion. Then, the acetato ligand can displace another
chlorido ligand via TS1f-11 , forming the chelate 11 . With
a
ΔH (ΔG ;ΔG413) in kcal/mol. rds denotes the potentially rate
298
298
determining step. Energies are relative to 1a.
Then, in an endergonic step, a chlorido ligand in 1b has to be
displaced by water. At room temperature, the corresponding
transition state TS1b-3 correlates with a barrier of +15.5 kcal/
mol, which is approximately as high as the ensuing transition
Cl
Cl
11 being 3.3 kcal/mol higher in energy than 1c, this process is
Cl
state for hydroxypalladation TS4 -5a, commonly deemed the
only slightly endergonic. Then, an intramolecular cmd process
Cl
rate-determining step. However, due to the entropic effect,
TS1b-3 becomes the sole rate-limiting step at 140 °C with a
barrier of +19.1 kcal/mol. For hydroxypalladation to take place
via TS4 -5a, deprotonation of 3 to 4 occurs first, which is
can take place via TS11 -12 , with a corresponding transition
Cl
Cl
state free energy of +14.6 kcal/mol. At 140 °C, this energy is
slightly lowered to +14.0 kcal/mol. This step appears to be the
rate-limiting step for this pathway. As can be seen in the
transition state geometry, the deprotonation is concerted and
involves a palladium−hydrogen interaction (Figure 1a).
Cl
Cl
feasible under the basic conditions. Dechelation in 5a leads to
the tricoordinate intermediate 5b . Thus, β-hydride elimi-
Cl
nation can take place via TS5b-6, which is linked to a relatively
small barrier of +9.6 kcal/mol. Ligand displacement in the
palladium hydride complex 6 by styrene and subsequent
tautomerization liberates acetophenone and the palladium
complex 7, which undergoes quick reductive elimination, as
will be discussed later in detail. Overall, this activation pathway
is strongly exergonic by −43.3 kcal/mol.
Displacement of the formed acetic acid in complex 12 by a
Cl
chlorido ligand yields compound 13. The corresponding
intermolecular process is disfavored. However, the transition
state geometry of TS10-13 is similar to that of TS10 -11 and
Cl
Cl
also involves a palladium−hydrogen interaction (Figure 1b)
The alkyl palladium complex 13 can easily undergo reductive
elimination, as is known for alkyl palladium complexes (Scheme
9
In the anti pathway, the neutral species 8 has to form, which
is sufficiently electrophilic for the nucleophilic attack by water
6; see Figure S10 in the Supporting Information). Opening of
the chelate to compound 14 results in a free coordination site,
and the subsequent β-hydride elimination can easily take place.
The corresponding transition state TS14-15a is only +2.7 kcal/
mol higher in energy than the reactant 14. In the resulting
enamine complex 15a, displacement of the enamine by styrene
yields compound 7, which is prone to reductive elimination, as
described above. Also, facile hydrolysis of the enamine to
butyraldehyde takes place and constitutes another major driving
force of the reaction. The corresponding formation of the
(Scheme 4; see Figure S8 in the Supporting Information). The
formation of strongly nucleophilic hydroxide ions from the
mildly strong acetate base is endergonic by +32.5 kcal/mol and
is thus unlikely. Following the water-chain model proposed by
2
00
Siegbahn, we calculated the attack of a water trimer on the
more stable complex 8 . However, the transition state TS8 -9 ·
t
t
t
3
H O has a free energy of +24.6 kcal/mol, which is significantly
2
higher than the highest barrier of the syn addition. The attack
D
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a
Scheme 5. Concerted Metalation−Deprotonation of Tributylamine
a
ΔH (ΔG ;ΔG413) in kcal/mol. Energies are relative to 1a.
298
298
Scheme 6. β-Hydride Elimination of the Alkyl Palladium
a
Complex 10
Figure 1. Transition state geometries for (a) TS11 -12 and (b)
Cl
Cl
TS10−13. Color code: H, white; C, gray; N, blue; O, red; Cl, green;
Pd, turquoise.
allylamine complex 15b is associated with a significantly higher
reaction barrier of +8.9 kcal/mol and is thus less likely. Overall,
this activation process is exergonic by −35.6 kcal/mol.
A nucleophilic substitution in compound 13 by hydroxide
ions or C−N bond cleavage in 13 is considered unlikely (see
Scheme S2 in the Supporting Information). In addition, the β-
146
hydride elimination from complex 10 is less favorable (see
Scheme S3 in the Supporting Information).
To conclude, it was shown experimentally and theoretically
that both Wacker oxidation and reduction by tributylamine are
viable pathways for the reduction of Pd(II) to Pd(0). However,
in direct comparison, reduction by tributylamine is more likely
because butyraldehyde was the only product observed in the
competition experiment between styrene and tributylamine. In
a
ΔH (ΔG ;ΔG413) in kcal/mol. Energies relative to 1a.
298
298
addition, a solution of tributylamine and 1a-NBu forms Pd(0)
+19.1 kcal/mol). In contrast, the highest barrier for the
reduction with tributylamine is calculated to be +14.0 kcal/mol
at 140 °C (TS11 -12 ). Thus, the calculations support the
4
at room temperature, whereas a solution of 1a-NBu and
4
styrene is stable for weeks. This pronounced difference can be
explained by the theoretical calculations described above. The
rate-determining step in the Wacker oxidation is the endergonic
Cl
Cl
preference for the latter activation mechanism.
Catalytic Cycle. Oxidative Addition. In the next step,
⧧
,413
displacement of a chloride ligand by water (TS1-b3, ΔG
=
oxidative addition of the aryl halide takes place (Table 1; see
E
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a
a
Table 1. Energies of the Oxidative Addition
Scheme 7. Migratory Insertion
2
98
298
298
entry
L
n
ΔG
ΔG
ΔG
1
6
6
TS16‑17
17
1
2
Cl
1
0
0
n
+12.6
+5.7
+20.5
+22.3
−10.3
−2.0
styrene
DMSO
L
3
+10.0
4
+28.8
413
−3.1
13
413
entry
ΔG
ΔG
ΔG
1
TS16‑17
17
4
5
6
Cl
1
0
0
+10.7
+5.3
+19.5
+22.9
+27.7
−11.7
−2.4
−3.2
a
ΔH (ΔG ;ΔG413) in kcal/mol. Energies are relative to 2e. Ar = 4-
298
298
styrene
DMSO
acetylphenyl.
+11.7
a
In kcal/mol. Energies are relative to 2e.
via TS17 ‑18 or geminal insertion via TS17 ‑18 is possible.
Cl
T
Cl
G
Figure S11 in the Supporting Information). Therefore, one
Due to the negligible steric effect of the chlorido ligands, the
calculated free energy difference of both transition states is as
low as 3.1 kcal/mol at 140 °C. This difference should
correspond to a terminal/geminal product ratio of about
98/2, which is consistent with GC analyses of the reaction
mixture, where no geminal product isomer was identified.
In the neutral pathway, the barrier of TSS8 ‑S9 for
styrene ligand in 2e has to be displaced by the substrate,
2
yielding the η -aryl complex 16. This process is endergonic and
contributes to the overall barrier that has to be overcome
during the oxidative addition. To find out, if a neutral or an
anionic palladium species undergoes oxidative addition more
easily, we chose the anionic complex 16Cl and the neutral
complexes 16 and 16 , having another styrene ligand or a
T
T
S
D
migratory insertion is reduced to +15.0 kcal/mol (relative to
2
DMSO ligand, respectively, as model systems. The η -aryl
compounds 16 and 16 are similar in energy, with respect to
S8 ), (see Scheme S4 in the Supporting Information). The
T
Cl
D
energy difference of +16.5 kcal/mol in the anionic pathway
2
e, while 16 is lower in energy.
between TS17 ‑18T and 17Cl is slightly higher. This
S
Cl
TS16 -17 is the transition state with the lowest barrier
dependence on the charge of the complex has been reported
Cl
Cl
119
height, relative to 2e, while TS16 -17D and TS16 ‑17 are
in the literature. However, displacement of a chlorido ligand
D
S
S
higher in energy. Although coordination of an anionic chlorido
ligand in 16Cl is less favored than that of the styrene ligand in
in 17Cl by a neutral ligand, such as DMSO, to form S8 is
T
highly endergonic, thus rendering the neutral pathway less
favorable overall. The selectivity-determining energy difference
of 2.6 kcal/mol between TSS8 ‑S9G and TSS8 ‑S9
T
1
6S, it renders the palladium center more electron rich and
facilitates the following oxidative addition. The same applies if
the free energies at 140 °C are considered. On comparison of
these energies, it is highly likely that oxidative addition occurs
from an anionic complex. Both transition state geometries are
similar and show similar bond lengths for the bonds that are
being formed and cleaved (Figure 2).
G
T
corresponds to a similar terminal/germinal ratio of about 96/4.
β-Hydride Elimination. Compound 18 is in equilibrium
T
with its other rotamers 18 and 18 (Scheme 8; see Figure S13
E
Z
in the Supporting Information). In compound 18 , both aryl
E
groups are in a gauche arrangement, and subsequent β-hydride
elimination via TS18 ‑19 leads to the E-configured alkene.
E
E
a
Scheme 8. β-Hydride Elimination
Figure 2. Transition state geometries of (a) TS16 ‑17 and (b)
Cl
Cl
TS17 ‑17 . Bond lengths are given in Å. Color code: H, white; C,
S
S
gray; N, blue; O, red; Cl, green; Pd, turquoise.
The resulting complex 17 can isomerize to the trans isomer
Cl
1
7t, which has been reported for related structures (Scheme
2
14−221
7).
However, 17 is higher in energy than 17 and thus
t Cl
is no resting state in this catalytic cycle.
Migratory Insertion. The following migratory insertion of
the styrene ligand into the palladium−aryl bond determines the
regioselectivity of the reaction (Scheme 7; see Figure S12 in the
a
ΔH (ΔG ;ΔG413) in kcal/mol. Energies are relative to 2e.
298
298
Supporting Information). From 17 , either terminal insertion
Cl
F
DOI: 10.1021/acs.inorgchem.8b00175
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
The (Z)-alkene is accessible by β-hydride elimination from
downhill, even upon incorporation of explicit microsolvation of
acetate by a water molecule, which shows that the reductive
elimination proceeds via a very small barrier, if any at all.
Overall, the catalytic cycle is exergonic by −37.9 kcal/mol
and thus thermodynamically favorable. At 140 °C, the overall
reaction free energy is reduced to −25.5 kcal/mol, which still
signals a highly favorable process.
Bromide Influence. Having established the overall reaction
mechanism, we turned our interest to the influence of bromide
ions on the catalyst performance. During catalysis, we noticed a
isomer 18 with ecliptic arrangement of the aryl groups. The
Z
transition state free energy difference of 4.8 kcal/mol largely
favors the E isomer, with a calculated E/Z ratio of >99/1. In a
typical catalytic run, the E/Z ratio was about 98/2. In the β-
hydride elimination, the neutral pathway is linked to both a
higher relative and absolute reaction barrier, but a comparable
E/Z ratio of >99/1, although the neutral palladium alkyl
complexes S9 , S9 , and S9 are slightly enthalpically favored
T
E
Z
in comparison to their anionic congeners 18 , 18 , and 18
T
E
Z
(
see Scheme S5 in the Supporting Information).
Reductive Elimination. The last step to regenerate the
decrease in catalytic activity of complex 1a-NBu , if bromide
4
1
05
ions were present, even in small quantities.
First, we
catalyst is reductive elimination (Scheme 9; see Figure S14 in
investigated if bromide ions are able to replace the chloride
ions in the anionic species 1a. By calculating the energies of the
bromide-containing complexes 1g−i, we found that each
displacement of a chlorido ligand by a bromido ligand leads
to a stabilization of the complex by about 8.6 kcal/mol (Chart
a
Scheme 9. Plausible Reductive Elimination Pathways
2
a; see Figure S15 in the Supporting Information). This trend
9
is in accordance with experimental studies.
Chart 2. Influence of Bromide Ions on the Complex
a
Stability
a
298
298
413
ΔH (ΔG ;ΔG ) in kcal/mol. Energies are relative to 2e. □
denotes a vacant coordination site. In compound 23 , the chlorido
t
ligand is located trans to the styrene ligand, whereas in 23 , these
c
ligands are arranged in a cis fashion.
the Supporting Information). Replacement of the stilbene
ligand by styrene liberates the reaction product and produces
complex 7, which also has been discussed as an intermediate in
the catalyst activation step (see above). We considered direct
attack of an acetate molecule via intermediate 22. However, we
were not able to locate 22, since it readily dissociates to form
the dicoordinate species 2b, acetic acid, and a free chloride
anion. Despite our efforts, we were not able to identify a
transition state for this transformation, but we believe it to
proceed in a nearly barrierless fashion. After coordination of
another styrene molecule, the anionic species 2e is regenerated.
We also considered initial displacement of a chlorido ligand
in 7 by styrene, which is an endergonic process. However,
addition of one acetate molecule to 20 again led to dissociation
of acetic acid and generation of compound 2e without the
location of intermediate 21. A coordination of acetic acid to the
palladium center was only observed in the tricoordinate
intermediate 24, which has to be formed via compound 23t.
In 24, the Pd−H bond length is 2.21 Å, which is significantly
a
ΔH (ΔG ;ΔG413) in kcal/mol. Energies are relative to 1a and 2l,
298
298
respectively.
Additionally, the dianionic complex 1j is lower in its free
energy than complex 1i, which shows that also a neutral ligand
can be displaced by bromide ions. The dimeric species 1l is
comparably favorable. In the palladium(0) anion 2e, displace-
ment of chloride by bromide, yielding 2f, is exergonic by −6.1
kcal/mol (Chart 2b; see Figure S15 in the Supporting
Information). These calculations show a clear preference for
palladium bromido species.
A similar observation can be made if 1a-NBu is treated with
4
the corresponding tetrabutylammonium halide salt (Table 2).
Using NMR, the displacement of the DMSO ligand by halides
can be monitored as the relative intensities of bound vs free
DMSO. Addition of 1 equiv of TBACl led to no change in the
relative intensity and thus nearly no displacement of DMSO.
With a 10-fold excess of TBACl, the ratio of 1a to 1d is about
1.6/1, which shows that both species coexist in equilibrium.
However, if 1 equiv of TBABr is added, much more free DMSO
longer than in 23 (1.55 Å). Thus, complex 24 can be described
t
as a palladium(0) complex with coordinated acetic acid. A
relaxed potential energy surface scan of the Pd−H bond
showed that formation of 24 from 23 proceeded smoothly
t
G
DOI: 10.1021/acs.inorgchem.8b00175
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Table 2. NMR Titration of 1a-NBu Leading to the
Displacement of DMSO
We also looked at the influence of bromide ions on the key
steps of the catalyst activation (Scheme 11; see Figure S17 in
the Supporting Information).
4
Scheme 11. Influence of Bromide Ions on Key Steps of the
a
Catalyst Activation
ratio 1/D
ratio 1/D
X = Cl X = Br
amt of NBu4X
amt of NBu4X
(equiv)
(equiv)
X = Cl X = Br
0
1
6.7/1
6.9/1
6.7/1
2.6/1
5
2.1/1
1.6/1
0.8/1
0.1/1
10
is detected. Ten equivalents of TBABr are able to completely
displace the DMSO ligand in 1a-NBu . This experiment shows
4
that bromide ions are more efficient in displacing neutral
ligands in comparison to chloride ions in complex 1a-NBu4.
This effect might be intensified by the increased tendency to
form dimeric μ-bromido palladium species. The displacement
of neutral ligands and formation of dimeric species in catalysis
9
3,222−224
was also observed by Hartwig and others.
In their
a
ΔH (ΔG ;ΔG413) in kcal/mol. Energies are relative to 4 and 11,
298
298
work, μ-halido complexes as a resting state were identified in
the presence of bromide and iodide ions, but not for chloride
ions.
To prove if a dimeric μ-bromido palladium complex could
also be the resting state of the presented reaction, we
investigated the reaction of 17 , which is the product of the
oxidative addition, with chloride and bromide ions (Scheme 10;
see Figure S16 in the Supporting Information).
respectively.
For example, the difference in the transition state energies of
the C−O insertion of the Wacker oxidation (TS4 ‑5a and
TS4 ‑5 ) is within the accuracy range of the DFT method
Cl
Cl
Br Br
Cl
(
Scheme 11a). For the oxidation of tributylamine, the effect is
somewhat more pronounced (Scheme 11b). In both cases, the
presence of bromide ions renders the process only slightly less
favorable. This is in accordance with the observation that the
a
Scheme 10. Potential Catalyst Resting States
105
complex [NBu] [Pd(DMSO)Br ] (1i-NBu )
also decom-
4
3
4
poses in the presence of tributylamine at room temperature,
yielding butyraldehyde and Pd black.
Finally, we investigated the influence of bromide ions on the
oxidative addition, which is the rate-determining step of the
catalytic cycle (Table 3; see Figure S18 in the Supporting
Information). Displacement of chloride by bromide in
compounds 16Cl and 17Cl is energetically favored, but the
relative reaction barrier height stays nearly the same. At 140 °C,
the energy difference between TS16 ‑17 and 16Cl is just
Cl
Cl
Table 3. Energies of the Oxidative Addition in the Presence
a
of Bromide Ions
a
ΔH (ΔG ;ΔG413) in kcal/mol. Energies are relative to 17Cl.
298
298
Displacement of the styrene ligand in 17 , forming the μ-
Cl
chlorido compound 25 , is only slightly exergonic at 140 °C,
Cl
indicating that both species can exist in equilibrium, with a
sufficient amount of 17 still present to undergo intramolecular
Cl
migratory insertion. Exergonic displacement of chloride by
bromide ions leads to complex 17 . Starting from 17 ,
Br
Br
2
98
298
298
298
298
298
entry
X
ΔG
ΔG
ΔG
− ΔG
TS16‑17
displacement of the styrene ligand to form the μ-bromido
species 25Br is exergonic by −17.8 kcal/mol at 140 °C. This
difference in energy is high enough that only small quantities of
16
TS16‑17
16
1
2
Cl
Br
X
+12.6
+5.7
+20.5
+14.4
+7.9
+8.7
4
13
413
1
7Br should exist in solution. This ultimately slows down the
entry
ΔG 16
ΔG TS16‑17
ΔG TS16‑17 − ΔG 16
migratory insertion. Judging from the experimental and
theoretical data, the presence of bromide ions in the reaction
mixture provides access to dimeric catalyst resting states, which
in turn slows the ensuing reaction steps.
3
4
Cl
Br
+10.7
+5.7
+19.5
+13.4
+8.8
+7.7
a
In kcal/mol. Energies are relative to 2e.
H
DOI: 10.1021/acs.inorgchem.8b00175
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
.1 kcal/mol higher than the difference between TS16 ‑17
Article
1
ments were carried out on an Agilent 7890A gas chromatograph and
an Agilent 5975 Series MSD.
Br
Br
and 16 . Thus, the influence of bromide ions on the oxidative
Br
Representative Catalytic Procedure. In a 10 mL crimp vial were
placed sodium hydrogen carbonate (185 mg, 2.2 mmol) and
tetrabutylammonium chloride (143 mg, 0.5 mmol), and the vial was
closed with a butyl rubber septum. The vial was evacuated and filled
with argon three times. Then, DMAc (5 mL), 4-chloroacetophenone
addition is negligible.
CONCLUSION
■
We have used experimental data together with computational
chemistry to gain insight into the mechanism of the Mizoroki−
Heck reaction of aryl chlorides catalyzed by the anionic
(
130 μL, 1 mmol), styrene (162 μL, 1.4 mmol), water (50 μL, 3
mmol), and the calculated amount of a catalyst stock solution in
DMAc were added via syringe. The vial was placed in a preheated
aluminum block and the solution stirred for 6 h at 140 °C. Then, 0.1
mL of the solution was removed, diluted with 4 mL of diethyl ether,
and filtered over a plug of silica, which was then rinsed by addition of 1
mL of DCM. The resulting solution was analyzed by GC. The yield is
given as an average of two runs.
Representative Catalyst Activation Experiment. In a 10 mL
crimp vial was placed 1a-Na (5 mg, 16 μmol), and the vial was closed
with a butyl rubber septum. The vial was evacuated and filled with
argon three times. Then, DMAc (2 mL), tributylamine (20 μL, 84
μmol), styrene (9 μL, 80 μmol), and water (20 μL, 1.1 mmol) were
added via syringe. The vial was placed in a preheated aluminum block
and the solution stirred for 2 min at 140 °C, during which it turned
from orange to black. The solution was cooled to room temperature,
complex 1a-NBu . It was shown experimentally that catalyst
4
activation from Pd(II) to Pd(0) takes place by oxidation of
tributylamine generated in situ, even at room temperature. We
present a viable mechanistic pathway for this oxidation by
theoretical calculations, which support the preference of this
activation pathway over the Wacker oxidation. This activation
pathway requires the presence of water to effectively function,
thus explaining the need for trace amounts of water in the
reaction. Several other activation pathways, e.g., Wacker
oxidation, could be excluded. The presence of palladium
nanoparticles as a catalyst reservoir has been confirmed by
mercury poisoning tests.
Subsequently, the mechanism of the Mizoroki−Heck
reaction itself was assessed. Oxidative addition to an anionic
palladium(0) species was found to be the rate-determining step
for this system. For the following steps, i.e. migratory insertion,
β-hydride elimination, and reductive elimination, a reaction
pathway comprising anionic palladium species is proposed.
These anionic species are stabilized by TBACl, which ensures a
sufficiently high chloride ion concentration. The selectivities
were explainable by the calculated energy differences of the
transition states. Overall, the reaction is exergonic by −37.9
kcal/mol.
4
-chlorophenylhydazine hydrochloride (20 mg, 0.1 mmol) was added,
and the solution was stirred for another 30 min. Then, 0.1 mL of the
solution was removed, diluted with 2 mL of diethyl ether, and filtered
over a plug of silica, which was then rinsed by addition of 1 mL of
DCM. The resulting solution was analyzed by GC.
Computational Details. All calculations were carried out with the
2
25
Gaussian 09, Rev. B.01 program package.
tional
the calculation of thermochemistry of transition-metal compounds.
The Hay-Wadt ECP was used for palladium. Bromine atoms were
treated with the 6-311G* basis set. The 6-31+G* basis set was used
for all other atoms.
keyword Grid = UltraFine was employed. All calculations were
performed with the continuum solvation model SMD with DMAc as
The M06L func-
2
26,227
was chosen as an established and reliable method for
157
2
28
2
29
1
58−161
For a more reliable optimization, the
The previous experimental work indicated a detrimental
influence of the presence of bromide ions on the catalytic
activity. Titration of compound 1a-NBu with TBABr and
162
4
solvent.
All geometries were optimized without any restriction.
investigation by NMR and quantum chemical calculations show
that halide exchange from chloride to bromide is favored,
yielding palladium bromide intermediates. These were
considered as active catalytic species; however, the calculations
show that the presence of bromide ions does not significantly
alter the relative height of the transition states in the respective
catalytic steps. Instead, bromido ligands strongly facilitate the
formation of μ-halido palladium dimers, thus displacing the
neutral substrates, which eventually leads to decreased catalytic
activity.
Overall, the experimental observations fit well with the
theoretical insight gained by computations. Furthermore, the
results show that under “ligandless” conditions and in the
presence of halide sources, soluble anionic palladium species
should be considered as the active species for all parts of the
catalytic cycle.
Frequency calculations were used to confirm the presence of a ground
state or transition state. Additional IRC calculations were performed
2
30,231
for ambiguous transition states.
Thermochemical data were
taken from frequency calculations at 298.15 and 413 K, respectively. If
298
not stated otherwise, all discussed values are the ΔG values. Images
2
32
were created with CYLview.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.8b00175.
Gas chromatograms, mass spectra, and NMR spectra of
representative activation experiments, additional schemes
and tables as described in the text, discussions of the
geometries of the intermediates and transition states, and
Cartesian coordinates and ZPEs of all compounds (PDF)
EXPERIMENTAL SECTION
■
General Considerations. All activation experiments were
performed under an argon atmosphere, except for NMR measure-
ments, which were performed in air. Dimethylacetamide (DMAc) was
distilled from CaH prior to use. Sodium acetate was dried at 130 °C.
Tetrabutylammonium chloride was dried at 60 °C overnight under
AUTHOR INFORMATION
■
Corresponding Author
*
E-mail for T.S.: thomas.strassner@chemie.tu-dresden.de.
high vacuum and stored in an MBraun glovebox. 1a-NBu , 1a-Na and
4
1
j-NBu4 were synthesized according to our previously reported
ORCID
105
procedure. All other chemicals were purchased from commercial
suppliers and used as received. H NMR spectra were acquired on a
Thomas Strassner: 0000-0002-7648-457X
1
Notes
Bruker NMR Avance 300 spectrometer and referenced internally using
the solvent residual signal (7.26 ppm for CDCl ). GC-MS measure-
The authors declare no competing financial interest.
3
I
DOI: 10.1021/acs.inorgchem.8b00175
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
(
21) Dounay, A. B.; Overman, L. E. The Asymmetric Intramolecular
ACKNOWLEDGMENTS
■
Heck Reaction. Chem. Rev. 2003, 103, 2945−2963.
We would like to thank the Zentrum fu
und Hochleistungsrechnen (ZIH) for allocating computing
time.
̈
r Informationsdienste
(22) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Palladium-catalyzed
cross-coupling reactions in total synthesis. Angew. Chem., Int. Ed. 2005,
44, 4442−4489.
(23) Heravi, M. M.; Hashemi, E.; Ghobadi, N. Development of
Recent Total Syntheses Based on the Heck Reaction. Curr. Org. Chem.
013, 17, 2192−2224.
24) de Vries, J. G. The Heck reaction in the production of fine
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