Understanding the Unusual Reduction Mechanism of Pd(II) to Pd(I): Uncovering Hidden Species and Implications in Catalytic Cross-Coupling Reactions

Article abstract of DOI:10.1021/jacs.7b01110

The reduction of Pd(II) intermediates to Pd(0) is a key elementary step in a vast number of Pd-catalyzed processes, ranging from cross-coupling, C-H activation, to Wacker chemistry. For one of the most powerful new generation phosphine ligands, PtBu₃, oxidation state Pd(I), and not Pd(0), is generated upon reduction from Pd(II). The mechanism of the reduction of Pd(II) to Pd(I) has been investigated by means of experimental and computational studies for the formation of the highly active precatalyst {Pd(μ-Br)(PtBu₃)}₂. The formation of dinuclear Pd(I), as opposed to the Pd(0) complex, (tBu₃P)₂Pd was shown to depend on the stoichiometry of Pd to phosphine ligand, the order of addition of the reagents, and, most importantly, the nature of the palladium precursor and the choice of the phosphine ligand utilized. In addition, through experiments on gram scale in palladium, mechanistically important additional Pd- and phosphine-containing species were detected. An ionic Pd(II)Br₃ dimer side product was isolated, characterized, and identified as the crucial driving force in the mechanism of formation of the Pd(I) bromide dimer. The potential impact of the presence of these side species for in situ formed Pd complexes in catalysis was investigated in Buchwald-Hartwig, α-arylation, and Suzuki-Miyaura reactions. The use of preformed and isolated Pd(I) bromide dimer as a precatalyst provided superior results, in terms of catalytic activity, in comparison to catalysts generated in situ.

Full text of DOI:10.1021/jacs.7b01110

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Article
Understanding the Unusual Reduction Mechanism of Pd(II) to Pd(I): Uncovery
of Hidden Species and Implications in Catalytic Cross-Coupling Reactions
Carin C. C. Johansson Seechurn, Theresa Sperger, Thomas
G. Scrase, Franziska Schoenebeck, and Thomas J. Colacot
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b01110 • Publication Date (Web): 16 Mar 2017
Downloaded from http://pubs.acs.org on March 16, 2017
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Understanding the Unusual Reduction Mechanism of Pd(II) to Pd(I):
Uncovery of Hidden Species and Implications in Catalytic Cross-
Coupling Reactions
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Carin C. C. Johansson Seechurn,† Theresa Sperger,‡ Thomas G. Scrase,† Franziska Schoene-
beck,*,‡ Thomas J. Colacot*,§
† Johnson Matthey Catalysis and Chiral Technologies, Fine Chemicals Division, Orchard Road, Royston, SG8 5HE,
U.K.
‡ RWTH Aachen, Institute of Organic Chemistry, Landoltweg 1, 52074 Aachen, Germany
franziska.schoenebeck@rwth-aachen.de
§ Johnson Matthey Catalysis and Chiral Technologies, Fine Chemicals Division, 2001 Nolte Drive, West Deptford, NJ
08066, U.S.A.
thomas.colacot@jmusa.com
ABSTRACT: The reduction of Pd(II) intermediates to Pd(0) is a key elementary step in a vast number of Pd-catalyzed
processes, ranging from cross-coupling, C-H activation to Wacker chemistry. For one of the most powerful new genera-
tion phosphine ligands, PtBu3, oxidation state Pd(I), and not Pd(0), is generated upon reduction from Pd(II). The mecha-
nism of the reduction of Pd(II) to Pd(I) has been investigated by means of experimental and computational studies for the
formation of the highly active precatalyst [{Pd(μ-Br)(PtBu3)}2]. The formation of dinuclear Pd(I) as opposed to the Pd(0)
complex, [Pd(PtBu3)2] was shown to depend on the stoichiometry of Pd to phosphine ligand, the order of addition of the
reagents and, most importantly, the nature of the palladium precursor and the choice of the phosphine ligand utilized. In
addition, through experiments on gram scale in palladium, mechanistically important additional Pd- and phosphine-
containing species were detected. An ionic Pd(II)Br3 dimer side product was isolated, characterized and identified as the
crucial driving force in the mechanism of formation of the Pd(I) bromo dimer. The potential impact of the presence of
these side species for in situ formed Pd complexes in catalysis was investigated in Buchwald-Hartwig, α-arylation and
Suzuki-Miyaura reactions. The use of preformed and isolated Pd(I) bromo dimer as precatalyst provided superior results,
in terms of catalytic activity, to catalysts generated in situ.
importance and ubiquity, there is surprisingly little
INTRODUCTION
understanding of the mechanism. To date, the reduc-
tion of Pd(II) precursors to form catalytically active
The quote in a recent issue of Chemical and Engineer-
ing News, “palladium is the king of transition metal
Pd(0) species has been proposed to be mediated by
catalysts”1 echoes with Trost’s 2015 statement, “palladi-
um has moved from being an esoteric metal of no
known use to one being among the most versatile type
of transition metal homogeneous catalyst of any metal
today”.2 The above statement is very appropriate today
as the status of palladium among its relatives has been
elevated to the metal of the 21st century. One of the
reasons behind the rapid ascendance of Pd is its ten-
dency to undergo a clean “two electron”-based reduc-
tion of Pd(II) complexes to Pd(0). This reduction is the
key step in the activation of many versatile precata-
lysts, but also a fundamental part of the mechanism of
cross-coupling or C-H activation processes. Despite its
either base (e.g. base in conjunction with an alcohol3 or
alkoxides4) or organometallic cross-coupling partners
such as organomagnesium, organozinc and
-
boronates.5 The studies of its efficiency, rate and
mechanism have led to novel insights and facilitated
the improvement of precatalysts.6 In addition, recent
research has uncovered that for some of the most suc-
cessful and widely used trialkylphosphine ligands,
particularly with PtBu3, Pd(II) precursors may not nec-
essarily be reduced to Pd(0) in the presence of excess
ligand or additional base, but instead to the odd oxida-
tion state complex Pd(I)-Pd(I) (Figure 1).7 The Pd-
PtBu3 system was identified relatively early on to per-
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form exceptionally well for challenging cross-coupling
This article seeks to unravel the origins of the unusual
reactions.8
formation of the observed Pd(I) complex and provide
an understanding of the underlying factors and mech-
anism of reduction of Pd(II) precursor complexes. For
the purpose of this study, PtBu3 was chosen as a repre-
sentative electron-rich trialkylphosphine ligand. This
ligand, along with few others, such as PiPrtBu2,15 have
been found to be crucial for the formation of the
Pd(I)dimer. A link to synthetically useful catalytic
transformations is ultimately also presented.
1
2
3
4
5
6
7
8
As part of the newer trends in cross-coupling, in recent
years much attention has been devoted to the devel-
opment of novel Pd-phosphine precatalysts for the in
situ formation of highly active twelve-electron based
monophosphine Pd(0)L as the catalytically active spe-
cies (Figure 1).9 In this context, the dinuclear Pd(I)
complex, [{Pd(µ-Br)(PtBu3)}2] identified as the first
example of the L1Pd(0) type precatalyst has been
shown to give exceptionally high catalytic activity in a
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RESULTS AND DISCUSSION
number of cross-coupling reactions.9a,
10
In the following sections conclusive evidence is being
presented on how Pd(II) is selectively reduced to Pd(I),
by systematically performing experiments in conjunc-
tion with theoretical calculations. The implication of
this reduction pathway in cross-coupling reactions
where the Pd(I) precatalyst is generated in situ, is illus-
trated by studying model amination, Suzuki-Miyaura
and α-arylation reactions.
With regard to synthetic procedures for the formation
,
of Pd(I) bromo dimer [{Pd(µ-Br)(PtBu3)}2],7b,
the
11 12
Colacot group identified
a method by treating
[Pd(cod)(Br)2] (cod = 1,5-cyclooctadiene) with one
equivalent of PtBu3 followed by the addition of NaOH
in MeOH. This atom economical method yielded the
Pd(I) dimer [{Pd(µ-Br)(PtBu3)}2] (1) in nearly quantita-
tive yield, notably with no sacrificial phosphine ligand.
Experimental Investigation of Reaction Pathway
for Formation of [{Pd(µ-Br)(PtBu3)}2], (1). A few
years ago, the Colacot group reported that upon treat-
ing [Pd(cod)(Br)2] with a NaOH (2 eq.) solution in
MeOH, followed by the addition of two equivalents of
PtBu3 exclusively assisted the formation of bisligated
Pd(0)L2 complexes (Scheme 1, a).16
Pd(II)X2 + n L
Pd(II)
Pd(I)
precatalyst
precatalyst
no
additives
reduction
additive
ArR
Scheme 1. Selective Reduction of Pd(II) to Pd(0) or
Pd(I).
Pd(0)Ln
ArX
reductive
elimination
oxidative
addition
1) 2 eq. NaOH, MeOH
tBu3P Pd(0) PtBu3
(a)
Ar
R
Ar
2) 2 eq. PtBu3, toluene
95%
LnPd(II)
-MeO(cod)
LnPd(II)
Br
Br
Colacot, 2010
mechanism known
X
Pd
Br
1) 1 eq. PtBu3, toluene
RM
MX
transmetallation
n = 1 or 2
tBu3P (I)Pd Pd(I) PtBu3 (b)
2) 1 eq. NaOH, MeOH
-(cod)
Br
Figure 1. Generation of monophosphine LPd(0) via the acti-
90%
7a-b
Colacot, 2011
mechanism unknown
vation of Pd(II) precatalysts,
Pd(I) dimer.7a,13
or via the halide-bridged
Concurrently in-depth computational and experi-
mental studies on the activation requirements and the
nature of the catalytically active species formed from 1
have been carried out by Schoenebeck and co-workers
and are in line with the reactivity of a monophosphine
Pd(0) species.7a,13 For related more robust Pd(I) dimers,
recent work by Schoenebeck and co-workers support-
ed that direct reactivity at Pd(I) may also be feasi-
ble.13,14
Although no sacrificial ligand was used for reducing
Pd(II) to Pd(0), the cod ligand in combination with
NaOH/MeOH was shown to be crucial in the reduc-
tion process of Pd(II) to Pd(0), where MeO-cod was
identified as a byproduct.16 However, as mentioned in
the introduction, reversing the order of addition, i.e.,
base is added (1 eq.) at the last step of the reaction and
by employing only one equivalent of PtBu3, quantita-
tive formation of the Pd(I) dimer, [{Pd(µ-Br)(PtBu3)}2]
(Scheme 1, b) was observed.12b While the mechanism
Scheme 2. Experimental Identification of Side Products in the Formation of Pd(I) Bromo Dimer.a
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Br
Br
Br
PtBu3 (6 eq.)
1
Br
PtBu3)(
Br
)
+
Pd PtBu3
Pd
+
(
tBu3P Pd
2
3
4
Br
2
1
64 % (67)
(2 eq.)
(2 eq.)
(2 eq.)
5
6
7
8
9
Br
Br
Br
Br
[BrPtBu3]2
Pd
Pd
c
( )
Br
Br
Br
Br
Pd
3
14 % (33)
(1 eq.)
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Br
Br
(6 eq.)
PtBu3 (9 eq.)
d
( )
+
Pd PtBu3
(BrPtBu3)(Br)
tBu3P Pd
2
1
89% (100)
(3 eq.)
(3 eq.)
PtBu3 (18 eq.)
b
e
( )
+
(BrPtBu3)(Br)
tBu3P Pd PtBu3
71%b (100)
(6 eq.)
(not isolated)
(6 eq.)
4
2
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aYields based on Pd, theoretical yields in parentheses. bisolated as a 93 : 7 wt% mixture of 4 : 1, as determined by 31P NMR.
for the reduction of Pd(II) to Pd(0) in (a) is well estab-
lished,16 the mechanism by which the Pd(II) starting
material is reduced to Pd(I) (b) is completely un-
known.
Side product 3 was also independently synthesized by
reacting purified PdBr2 with (BrPtBu3)(Br) (2) synthe-
sized for this study. This resulting Pd2(II)Br6 salt 3
(Scheme 3), was identical to the one isolated from
reaction c in Scheme 2. This experiment clearly sug-
gests that one third of the phosphine is converted to
phosphonium salt (2) with one third of the
[Pd(cod)(Br)2] remaining unreacted, hence explaining
the 67% theoretical yield of 1 in Scheme 2, c.
In contrast to the process by which Pd(II) is reduced to
Pd(0), the reduction of Pd(II) to Pd(I) proceeded also
in the absence of cod.17 The use of PdBr2 as starting
material, (see supporting information) also produced
the Pd(I) compound (1), thus excluding any participa-
tion of cod in the reduction mechanism.18 Notably, the
final isolated yield of 1 prepared from PdBr2 was only
half of that obtained from [Pd(cod)(Br)2] (50% and
89%, respectively). This can be explained by the fact
that [Pd(cod)(Br)2] is more soluble than PdBr2.
Scheme 3. Independent synthesis of side product 3
and crystal structure.a
Br
Br
Br
Br
Br
toluene
[BrPtBu3]2 (f)
Pd
Pd
PdBr2
+
(BrPtBu3)(Br)
Br
3
2
In order to systematically elucidate the reduction pro-
cess of Pd(II) to the unusual Pd(I) dimer species, we
carried out reactions by varying the number of equiva-
lents of PtBu3 ligand with respect to the Pd(II) precur-
sor, [Pd(cod)(Br)2] (Scheme 2), as phosphines are
known to reduce Pd(II). Employing one equivalent of
phosphine ligand, Pd(I) dimer 1 was isolated in 64%
yield (67% theoretical yield based on Pd) along with an
unusual Pd-containing side product (3), which was
unambiguously identified by elemental analysis, NMR
and a single crystal X-ray diffraction study to be
[Pd2Br6][PtBu3(Br)]2, containing a hexabromo-Pd(II)
dianion [Pd2Br6]2- and two tri(tert-butyl)phosphonium
bromide cations (Scheme 2, c). The formation of 3 is
proposed to be the result of the reaction between
[Pd(cod)(Br)2] with two equivalents of the phosphoni-
um byproduct 2 (Scheme 2, c). Importantly reaction (c)
had to be carried out on a larger scale (5 g scale), to
facilitate the isolation of the side product 3, as a key
intermediate in elucidating the mechanism.
87 %
aSelected Bond Lengths (Å) and Angles (deg): Pd1-Br5
2.450(5); Pd1-Br6 2.446(1); Pd1-Br3 2.410(1); Pd1-Br5-Pd2
90.0(0); Br5-Pd1-Br6 86.3(2); Br3-Pd1-Br5 91.8(2).
Subsequently, by increasing the mole ratio of PtBu3 to
[Pd(cod)(Br)2] to 1.5:1, a bromide salt (BrPtBu3)(Br) (2)
was obtained as a side product along with an isolated
yield of 89% of the Pd(I) dimer (1) (Scheme 2, d). The
yield of the Pd(I) dimer formed in reaction (d) is com-
parable to the yield of the previously reported process
(Scheme 1, b). Further scale up of the process (Scheme
2, d) to 125 g gave a near-quantitative yield of 1.
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Further increasing the ratio of phosphine to Pd(II) to
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1
2
3
4
5
6
7
8
3:1 resulted in the isolation of Pd(PtBu3)2 (4) in 95%
purity, by 31P NMR spectroscopy (Scheme 2, e). The
remaining 5% of the reaction mixture was identified as
the palladium(I) bromide dimer, 1. Although this
shows that no base is necessary for the reduction of
Pd(II) to Pd(0), the L2Pd(0) catalyst is obtained in a
purer form using the base-assisted process with
[Pd(cod)(Br)2] starting material (Scheme 1, b).16 A con-
trol experiment showed that by reacting Pd(I) bromo
dimer 1 with 3 additional equivalents of PtBu3 provided
mostly Pd(PtBu3)2 4.
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Precise monitoring of these reactions by NMR spec-
troscopy was not possible due to the difference in sol-
ubilities of the products (1, 2, 3 and 4). Pd(I) dimer 1
and L2Pd(0) 4 are soluble in toluene and benzene while
insoluble in methanol. The side products (2 and 3) are
soluble in methanol, but insoluble in toluene and ben-
zene.
DFT Calculations on the Potential Mechanism of
Reduction. With the above results in hand, we set out
to computationally evaluate potential mechanistic
pathways for the phosphine mediated formation of the
Pd(I) bromo dimer 1. The calculations at the CPCM
a Energies (in kcal/mol) were calculated at the CPCM (tolu-
ene) M06L/def2-TZVP//B3LYP/6-31G(d)(LANL2DZ) level of
theory.
Implication in Catalysis. Having identified (BrPt-
Bu3)(Br) (2), the [Pd2(II)Br6]2− salt (3), and in some
cases also [Pd(PtBu3)2] (4), as side products in the for-
mation of Pd(I) bromo dimer 1, we set out to investi-
gate whether these previously unidentified species
would have any impact in catalysis when precursors
such as PdBr2 or [Pd(cod)(Br)2] used under in situ con-
ditions.
(toluene)
M06L/def2-TZVP//B3LYP/6-
31G(d)(LANL2DZ) level of theory indicated that a di-
rect reductive elimination of Br2 from either
[Pd(PtBu3)(Br)2] (5) or [Pd(PtBu3)2(Br)2] (6) is energet-
ically not feasible since both reactions are highly endo-
thermic with ΔG of 54.2 and 28.7 kcal/mol, respective-
ly. This is in line with experiments, since all efforts to
detect Br2 in the reaction mixtures were unsuccessful.
In addition, a reductive elimination of [BrPtBu3]+ from
(PtBu3)2PdBr2 6 and concomitant salt formation was
found to be thermodynamically unfavorable (ΔG = 38.7
kcal/mol).
Scheme 5. Catalyst evaluation study in the coupling
of 2-chlorotoluene with 2,6-diisopropylaniline.a
Cl
H
N
0.5 mol% [Pd]
NH2
+
NaOtBu, toluene
100 °C, 3 hrs
Therefore, we investigated an alternative ligand-
assisted formal reductive elimination of Br2 from 6 or 7
(Scheme 4). This would form the observed side prod-
uct 2 (Scheme 2, (c)). Under reaction conditions ex-
plored in Scheme 2, (c), i.e. using an equimolar ratio of
Pd(II) to phosphine the Pd(I) dimer 1 would be ex-
pected to form. Notably, the concomitant formation of
[Pd2Br6][PtBu3(Br)]2 (3), by the reaction of bromide salt
2 with PdBr2 (Scheme 3) constitutes an energetic sink
and acting as the driving force for the reaction, thus
rendering Pd(I) bromo dimer 1 as the thermodynami-
cally most favorable species. All competing processes
such as the formation of bis- or monophosphine Pd(II)
(6 and 5, respectively) and dimerization of the latter to
form Pd(II) dimer 7 are thermodynamically less fa-
vored.
aConversions determined using GC/MS.
We decided to study two sets of Buchwald-Hartwig
model amination reactions. In one of these, sterically
hindered 2,6-diisopropylaniline was coupled with 2-
chlorotoluene in toluene at 100 °C, using NaOtBu as
the base. Catalytically active species formed from the
Scheme 4. Energetically available species relevant to
the proposed mechanism.a
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nation reaction, in this case, [Pd(cod)(Br)2] with added
1:1 reaction of Pd(dba)2 with PtBu3 were previously
reported to efficiently catalyze amination reactions.19
1
2
PtBu3 in a 1:1 ratio generates a catalytically active spe-
cies, although the reaction rate is slower than that of
the pre-formed 1. This result shows a similar trend to
the amination reactions (Scheme 5) and can be ex-
As summarized in the graph in Scheme 5, using 0.5
mol% Pd loading, pre-formed Pd(I) catalyst [{Pd(µ-
Br)(PtBu3)}2] 1 gave 100% conversion of the secondary
amine to the coupled product within 45 minutes. Un-
der identical conditions, the pre-formed L2Pd(0) cata-
lyst [Pd(PtBu3)2] 4 provided only 22% conversion to the
product, although the reaction time was extended to 3
hours. This reflects the requirement in this reaction for
the need for a L1Pd(0) based catalytically active pre-
formed 12-electron species, vs. the 14-electron pre-
formed, L2Pd(0). The in situ catalytic system from
PdBr2 with added PtBu3 afforded the coupled product
in very low conversion (0.8%), presumably due to the
poor solubility of PdBr2 in toluene. The catalyst formed
in situ from [Pd(cod)(Br)2] and added PtBu3 gave com-
parable results at this scale of operation in comparison
to the pre-formed [{Pd(µ-Br)(PtBu3)}2] (1), which gave
full conversion within ca. 45 minutes.
3
4
5
6
7
8
9
plained by the fact that
1 is generated from
[Pd(cod)(Br)2] and PtBu3. The slightly lower activity of
the 1:1 [Pd(cod)(Br)2]/PtBu3 system relative to the pre-
formed 1 is presumably due to the conversion of ca.
33% [Pd(cod)(Br)2] to 3 (Scheme 2, (c)).
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Scheme 7. Catalyst evaluation study in the mono-
arylation of acetophenone with 2-chlorotoluene.a
O
O
Cl
2.0 mol% [Pd]
+
NaOtBu, THF
60 °C, 180 mins
In order to further investigate the effect of the nature
of the precatalyst under less challenging conditions, a
room-temperature
coupling
reaction
of
2-
chlorotoluene with morpholine was evaluated, using
tetrahydrofuran as the reaction solvent. In this case,
Pd(I) dimer 1 was the only precatalyst yieldedany
product formation. Using 2 mol% Pd loading, 98%
conversion was observed within 120 minutes (Scheme
6, entry 1), while neither [Pd(PtBu3)2] 4 nor the in situ
[Pd(cod)(Br)2]/PtBu3 system provided any of the de-
sired coupling product (entries 2-3). This suggests that
under these reaction conditions, only preformed Pd(I)
dimer 1 is able to efficiently generate a catalytically
active Pd(0) species, explaining the superiority of the
precatalyst system under the specified reaction condi-
tions.
aConversions determined using GC/MS.
Finally, the impact of the choice of Pd precatalyst was
investigated in a room temperature Suzuki-Miyaura
reaction. Interestingly, despite our efforts in evaluating
different reaction conditions and by varying Pd load-
ings, it was not possible to achieve full conversion to
the desired product using 1 as the precatalyst. Howev-
er, 90% conversion in ca. 120 minutes was observed by
GC-MS (Scheme 8).The same reaction conditions were
used to evaluate preformed Pd(0)L2 catalyst 4 and the
catalyst generated in situ from 1:1 ratio of
[Pd(cod)(Br)2] toPtBu3. In contrast to the amination
and α-arylation reactions, preformed L2Pd(0) catalyst,
4 eventually gave the same conversion as that of 1. The
14 electron based L2Pd(0) catalysts are known to be
relatively more stable than the L1Pd(0) system from a
thermodynamic point of view. However, the initial
reaction rate was slower than that of the Pd(I) bromo
dimer 1. The maximum conversion achieved for this
Scheme 6. Room-temperature coupling of 2-
chlorotoluene and morpholine.a
O
Cl
H
N
2.0 mol% [Pd]
N
+
NaOtBu, THF
rt, 2h
O
entry
[Pd]:PtBu3
catalyst
conversion (%)
[Pd(ꢀ-Br)PtBu3]2
Pd(PtBu3)2
1
1:1
1:2
98
0
1
2
4
Pd(cod)Br2/PtBu3
3
1:1
0
aConversions determined using GC/MS.
Next, the impact of the precatalyst or Pd precursor was
investigated in mono-arylation of acetophenone with
2-chlorotoluene.
model
system
was
only
79%.
The
1:1
[Pd(cod)(Br)2]/PtBu3 in situ system gave a lower final
conversion to the desired product. This trend is similar
to the α-arylation reactions, where less amount of
Pd(I) precatalyst is formed when a 1:1 ratio of Pd to
PtBu3 is used (see Scheme 2, (c)).
Again, there is a striking difference between the use of
Pd(I) bromo dimer 1 and Pd(0) precatalyst 4. The use
of 1 resulted in 100% conversion in ca. 120 minutes,
whereas 4 did not provide any of the desired product
(Scheme 7). In contrast to the room temperature ami-
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It was therefore hypothesized that the role of the sub-
Scheme 8. Catalyst evaluation study in the coupling
of 2-chlorotoluene with (4-tert-butylphenyl)boronic
acid.a
1
2
3
4
5
6
7
8
sequently added base was necessary to convert 3 to 1.
Indeed, when 3 was treated with six molar equivalents
of methanolic NaOH at room temperature, 1 was iso-
lated in 89% yield (Scheme 9, entry 2), which corre-
sponds to one equivalent of base in the overall reaction
starting from [Pd(cod)(Br)2] (Scheme 2, c). Reducing
the amount of base to four equivalents resulted in an
incomplete reaction, where 1 was isolated in 62% yield
(entry 1). The use of a slight excess of base - eight
equivalents or 1:1.33 equiv. in the overall reaction from
[Pd(cod)(Br)2] – provided a mixture of 1 and 4 in a 9:1
ratio with a combined yield of 86% (entry 3).
2.0 mol% [Pd]
K3PO4
Cl
B(OH)2
+
THF/H2O
rt, 120 mins
aConversions determined using GC/MS.
9
In conclusion, in the model reactions the preformed
Pd(I) catalyst [{Pd(µ-Br)(PtBu3)}2] (1) gave higher final
10
11
12
13
14
15
16
17
18
19
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23
24
25
26
27
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29
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32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
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53
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56
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59
60
Scheme 9. The Role of Base in the Formation of Pd(I)
Bromo Dimer 1
Br
tBu3P Pd
Pd PtBu3
Br
1
Br
Br
Br
Br
Br
Br
NaOH/MeOH
[BrPtBu3]2
Pd
Pd
toluene/MeOH, rt
+
3
tBu3P Pd PtBu3
(1 eq.)
4
entry
eq. NaOH
% yield 1
% yield 4
1
2
4
6
62a
96
0
0
conversions and faster reaction rates than that of the
catalysts formed in situ from either [Pd(cod)(Br)2] or
PdBr2 with PtBu3. The well known preformed 14-
electron based Pd(PtBu3)2] (4) catalyst also gave inferi-
or results in most cases, with the exception of Suzuki
coupling. Based the mechanism elucidated in this
study, it is understandable that with a 1:1 Pd:PtBu3 ratio
for generating the in situ catalyst, ca. 33 % less of the
active Pd(I) dimer is formed . In addition, under the
conditions studied, if excess phosphine is present the
formation of 4 is possible, which has been shown to be
a less effective precatalyst in the model studies that we
studied. Although it is possible to carefully engineer an
efficient process using an in situ formed catalyst, it
may be very challenging to achieve a robust and repro-
ducible scale-up procedure due to the intrinsic subtle-
ties associated with the mechanism of formation of the
catalyst under the reactions employed for the specific
cross coupling reactions. Therefore, further studies are
needed in order to fully understand why, in the above
cases, the in situ processes are less efficient in compar-
ison to the preformed 1. Several factors such as solubil-
ity of Pd source, order of addition of reagents, mole
ratio of ligands to Pd, time of pre-mixing of Pd precur-
sor with the ligand, type of base, etc., need to be thor-
oughly investigated.
3
8
79b
7b
aUnreacted 3 observed. bCalculated from NMR
ratio (Combined yield of 86%).
Based on this study, the overall equation can be bal-
anced as 6 eq. of [Pd(cod)(Br)2] reacting with 6 eq. of
PtBu3 in the presence of 6 eq. of NaOH/MeOH to give
3 eq. of 1 and 6 eq. of NaBr. This corresponds to the 1:1
molar ratio of [Pd(cod)(Br)2] to NaOH base in Scheme
1, reaction (b).
Since the formation of 3 is proposed to be the crucial
thermodynamic driving force for the formation of
Pd(I) bromo dimer (1), this side product, 3, was also
thought to play an essential role in the ligand- assisted
reduction of Pd(II) to Pd(I) (Scheme 2, (d)). Pd(II)Br3
dimer salt 3 was therefore treated with three equiva-
lents of PtBu3. From this reaction, 1 was isolated in
97% yield (Scheme 10).
Scheme 10. The Role of Additional PtBu3 Ligand to
Equimolar Reaction.
Br
tBu3P Pd
Pd PtBu3
(1 eq.)
Br
97 %
Br
Br
Br
Br
Br
Br
toluene
MeOH
1
+ PtBu3
[BrPtBu3]2
Pd
Pd
+
3
Br[BrPtBu3]
The Role of Base or Additional PtBu3 in Equimolar
Reaction. Furthermore, we sought to identify the role
of the base in the equimolar reaction of [Pd(cod)(Br)2]
with PtBu3 (Scheme 1, (b)). As already stated, by omit-
ting the base in this reaction, [Pd2Br6][PtBu3(Br)]2 (3) is
obtained alongside [Pd(μ-Br)PtBu3]2 (1) (Scheme 2,
(c)).
(3 eq.)
(1 eq.)
2
(3 eq.)
Based on this, the overall equation can be balanced as
6 eq. [Pd(cod)(Br)2] reacting with 9 eq. PtBu3 to give 3
eq. of 1 and 3 eq. (BrPtBu3)(Br) 2 (Scheme 2, (d)). Two
equivalents of 1 is formed initially, alongside one
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Journal of the American Chemical Society
Supporting Information. Experimental and computational
equivalent of 3, as outlined in Scheme 2, equation (c).
1
2
3
4
5
6
7
8
procedures, spectral data and copies of spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
A further equivalent of 1 is then formed from the reac-
tion between one equivalent of 3 with 3 equivalents of
PtBu3. This corresponds to the here-in established 1:1.5
ratio of [Pd(cod)(Br)2] to PtBu3 required to make 1
without the added methanolic NaOH.
AUTHOR INFORMATION
Corresponding Authors
Based on these studies of the base-assisted and the
ligand-assisted reduction of Pd(II) to Pd(I), the pro-
posed common intermediate for both reactions is the
side product 3.
* franziska.schoenebeck@rwth-aachen.de (calculations)
* thomas.colacot@jmusa.com (experimental)
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Notes
The above experiments clearly demonstrate that the
mole ratio of base and ligand have a significant effect
on the active catalytic species generated while con-
ducting in situ reactions.
The authors of Johnson Matthey declare the following com-
peting financial interest(s): [Pd(μ-Br)PtBu3]2 is commercially
available through JMCCT (www.jmcct.com).
ACKNOWLEDGMENTS
We thank Dr. Andrew Bond at Cambridge University for X-
ray structure determination.
SUMMARY AND CONCLUSION
This study clearly elucidates the mechanistic features
behind the reduction of a Pd(II) precursor in the pres-
ence of a phosphine ligand to form an unusual Pd(I)
dimer species.
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