Palladium-Catalyzed Aerobic Homocoupling of Alkynes: Full Mechanistic Characterization of a More Complex Oxidase-Type Behavior

Article abstract of DOI:10.1021/acscatal.8b01540

A combined experimental and computational approach has been used to shed light on the mechanism of the Pd-catalyzed oxidative homocoupling of alkynes using oxygen as the oxidant. Mechanistic understanding is important because of the synthetically relevant direct involvement of oxygen in the oxidative coupling and because of the presence of related processes as undesired side reactions in cross-coupling reactions involving terminal alkynes. A low-ligated [Pd(PPh₃)(alkyne)] complex is key in the process, and it can be conveniently generated from allylic palladium(II) complexes in the presence of a base or from Pd(I) allylic dimers as precatalysts. The catalytic coupling occurs by alkyne metalation to give an anionic [Pd(PPh₃)(alkynyl)]^- complex that is then oxidized by oxygen. The interaction with oxygen occurs only on this electron-rich Pd(0) anionic species and leads to a (κO,κO-peroxo)palladium(II) singlet intermediate that undergoes subsequent protonolysis to give a (κO-hydroperoxo)palladium(II) complex and then hydrogen peroxide. The second alkyne metalation occurs on a Pd(II) derivative to give a bis(alkynyl)palladium(II) complex that evolves to the product by reductive elimination as the product-forming step. This reaction is an oxidase-type process that, in contrast to most Pd-catalyzed oxidative processes, occurs without separation of the substrate transformation and the catalyst oxidation, with these two processes being intertwined and dependent on one another.

Full text of DOI:10.1021/acscatal.8b01540

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Article
Palladium-Catalyzed Aerobic Homocoupling of Alkynes: Full
Mechanistic Characterization of a More Complex Oxidase-type Behavior
Alberto Toledo, Ignacio Funes-Ardoiz, Feliu Maseras, and Ana Carmen Albeniz
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01540 • Publication Date (Web): 05 Jul 2018
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Page 1 of 13
ACS Catalysis
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Palladium-Catalyzed Aerobic Homocoupling of Alkynes: Full Mech-
anistic Characterization of a More Complex Oxidase-type Behavior
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Alberto Toledo, Ignacio FunesꢀArdoiz, Feliu Maseras * and Ana C. Albéniz *
†
IU CINQUIMA/Química Inorgánica. Universidad de Valladolid. 47071 Valladolid (Spain).
‡
Institute of Chemical Research of Catalonia (ICIQ). The Barcelona Institute of Science and Technology. Avgda. Països
Catalans, 16, 43007 Tarragona (Spain).
§
Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra (Spain).
Supporting Information Placeholder
ABSTRACT: A combined experimental and computational approach has been used to shed light on the mechanism of the Pdꢀ
catalyzed oxidative homocoupling of alkynes using oxygen as oxidant. Mechanistic understanding is important because of the
synthetically relevant direct involvement of oxygen in the oxidative coupling, and because of the presence of related processes as
undesired side reactions in crossꢀcoupling reactions involving terminal alkynes. A lowꢀligated [Pd(PPh )(alkyne)] complex is key in
3
the process and it can be conveniently generated from allylic palladium(II) complexes in the presence of a base or from Pd(I) allylic
–
dimers as precatalysts. The catalytic coupling occurs by alkyne metalation to give an anionic [Pd(PPh )(alkynyl)] complex that is
3
2
then oxidized by oxygen. The interaction of oxygen occurs only on this electron rich Pd(0) anionic species and leads to a κ ꢀperoxo
palladium(II) singlet intermediate that undergoes subsequent protonolysis to a κ ꢀhydroperoxide palladium(II) complex. The second
1
alkyne metalation occurs on the Pd(II) hydroperoxo derivative, this ligand acting as an internal base, to give a bis(alkynyl)Pd(II)
complex that evolves to the product by reductive elimination as the productꢀforming step. This reaction is an oxidaseꢀtype process
that, in contrast to most Pdꢀcatalyzed oxidative processes, occurs without separation of the substrate transformation and the catalyst
oxidation, both processes being intertwined and dependent of one another.
KEYWORDS: alkyne, CꢀC coupling, oxygen, oxidase, catalysis, palladium, reaction mechanisms, DFT
oxidation by Pd(II) is followed by aerobic oxidation of the
INTRODUCTION
reduced catalyst (Scheme 1, a). Several observations support
this mechanistic proposal: i) Pd(II) is an effective stoichioꢀ
metric oxidant for a variety of organic substrates, ii) molecuꢀ
lar oxygen is thermodynamically capable of oxidizing reꢀ
duced palladium under many conditions, and iii) the Pd
catalyst commonly decomposes into Pd black during the
reaction (via aggregation into Pd nanoparticles and/or bulk
metallic Pd, Scheme 1, b), a result that implicates the presꢀ
ence of a Pd(0) intermediate in the catalytic cycle. The inꢀ
trinsic instability of Pd(0) makes necessary to ensure an
efficient reaction between dioxygen and the reduced palladiꢀ
Selective aerobic oxidation of organic substrates is a key
challenge in modern chemistry, and homogeneous Pdꢀ
catalyzed oxidation reactions are situated among the most
1
promising and versatile strategies to achieve this goal. Efꢀ
fective transformations range from the classic alcohol oxidaꢀ
2
3
tion, or Wacker and related processes, to oxidative carꢀ
4
bonylation reactions, oxidative CꢀC, CꢀO, and CꢀN coupling
3
,5
reactions with alkenes, and the emerging CꢀH functionaliꢀ
6
zation. The scope and utility of Pdꢀcatalyzed aerobic oxidaꢀ
tion reactions have expanded significantly in the last years
thanks to the recent developments of efficient O ꢀcoupled
8
um catalyst, even if this reaction is not the turnoverꢀlimiting
2
step of the catalytic mechanism.
catalytic systems in the absence of cocatalytic and/or stoiꢀ
chiometric oxidants such as benzoquinone, Ag(I) or Cu(II)
Two main mechanisms have been proposed for the dioxyꢀ
2
7
genꢀcoupled oxidation of the catalyst: i) formation of a (κ ꢀ
salts. Molecular oxygen is the ideal oxidant due to its availꢀ
peroxo)palladium species by oxygenation of Pd(0) species
ability and the production of environmentally safe reduction
byproducts such as water and hydrogen peroxide (the latter,
itself a commercially important chemical). The catalytic
mechanism of these reactions where oxygen is the sole oxiꢀ
dant is believed to proceed through an “oxidase” style seꢀ
quence, consisting of two half reactions in which substrate
(Scheme 1b, pathway A), and ii) direct reaction of molecular
oxygen with a Pd(II) hydride intermediate (Scheme 1b,
9
pathway B). The actual oxidation route is strongly dependꢀ
ent on the particular palladium complex and its specific set
of ligands, and isolated complexes that illustrate both types
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Page 2 of 13
of reactivity have been reported. Mechanistic studies have classic mechanisms to systems in which an oxidant plays an
19, 24
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shown that pathway A (Scheme 1b) is more common. The
important role.
2
formation of Pd(II) κ ꢀperoxo complexes from [Pd(PR ) ]
3
n
1
0
and oxygen was studied in the 1960’s, and recent results
show that this is also possible for Nꢀdonor ligands and Nꢀ
1
1
heterocyclic carbenes, as well as their protonation to give
1
2
hydroperoxide derivatives. Even if a palladium hydrido
complex is formed in the reaction, it has been found that
reductive elimination of HX (the reverse reaction in pathway
13
B, Scheme 1b), or a hydrogen abstraction in the hydride
14
complex, 2 can drive the oxidation process towards Pd(0)
0
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and the κ ꢀperoxo complex. Nonetheless, some examples of
1
5
pathway B have also been documented, and in some comꢀ
1
6
Scheme 2. General proposed mechanism for the Pd-
catalyzed homocoupling of alkynes.
plexes both pathways are plausible. The study of the coorꢀ
dination of O to Pd(0) has also shown that the involvement
2
1
7
of superoxide species is possible.
Our former work on the study of the reactions of alkynyl
organometallics with palladium(II) allyl complexes showed
that the latter are suitable catalyst precursors in the transforꢀ
25
mation of C(sp) substrates. The reductive elimination of
allylꢀalkynyl in [Pd(allyl)(alkynyl)L] complexes is slow and
therefore, the allylic group is not prone to participate in a Cꢀ
C bond forming step. Its expected role is that of either a
spectator ligand (a good donor and small ligand, which fixes
a cis geometry), or a fragment that can facilitate the generaꢀ
tion of the active species. Indeed, we found that
[
Pd(allyl)Cl(PPh )] showed a good activity in the formation
3
of 1,3ꢀdiynes from alkynes. We report here the combined
experimental and computational mechanistic studies on this
system, which shows some interesting and unexpected feaꢀ
tures. We have analyzed in detail the formation of the active
Scheme 1. Representation of (a) a general Pd-oxidase
type catalytic process and (b) proposed mechanisms for
Pd(0) reoxidation with dioxygen.
low ligated “PdPPh L” species from the precatalyst, and we
3
have also found that the reactions with the alkyne (i.e. deproꢀ
tonation and formation of the Pdꢀalkynyl bonds) occur beꢀ
fore and after the actual oxidation with dioxygen. This is
different from the typical and wellꢀaccepted oxidase behavꢀ
ior, since the oxidation of the catalyst cannot be separated
from the substrate oxidation. The need of a “naked” anionic
A formal oxidaseꢀtype reaction is the Pdꢀcatalyzed oxidative
homocoupling of terminal alkynes. The formation of diynes
by oxidative CꢀC coupling of alkynes in the presence of
dioxygen has been known for a long time and it is catalyzed
by copper compounds (the Glaser reaction), and also by a
Pd(0) complex to coordinate the O enabling the oxidation
2
process is key in this case and might have a role in other
aerobic oxidative couplings of hydrocarbons.
1
8,19
combination of palladium and copper complexes.
A few
examples of this reaction can be found in the literature where
just Pd complexes as catalysts and dioxygen as oxidant are
used. Besides its synthetic interest in the formation of polyꢀ
RESULTS AND DISCUSSION
20
Aerobic synthesis of 1,3-diynes from alkynes catalyzed by
3
[
Pd(η -allyl)Cl(PPh )]. The alkyne homocoupling reaction
3
ynes, this reaction is also frequently observed as a competiꢀ
tive process in Sonogashira couplings. Although this is a
familiar and apparently simple reaction, its accepted mechaꢀ
nism is just based on reasonable hypotheses due to the lack
of detailed studies of the steps involved. Scheme 2 illustrates
the commonly proposed mechanism, where a palladium(II)
complex reacts sequentially with two alkyne molecules to
give a cisꢀbisalkynyl palladium(II) complex that undergoes a
reductive elimination leading to the diyne product and Pd(0)
was tested using 1ꢀethynylcyclohexene as reactant, sodium
3
acetate and 5 mol% of complex [Pd(η ꢀallyl)Cl(PPh )] (1) as
3
the catalyst in a mixture of acetone/water at room temperaꢀ
1
ture in the air. H NMR was used to monitor the course of
the reaction, since the alkene region of 1ꢀethynylcyclohexene
1
in H NMR does not overlap with any other reagent signals
and allows an easy follow up of the reaction by this techꢀ
nique. We were glad to observe the chemoselective forꢀ
mation of the dialkyne 2 and the absence of any byproduct
(Eq. 1).
18,20b,21
that needs to be reoxidized.
To address these questions, computational chemistry has
2
2
been demonstrated to be a valuable methodology. Particuꢀ
larly, Pdꢀcatalyzed crossꢀcoupling reactions have been extenꢀ
sively discussed in the literature, clarifying the role of the
different factors, such as ligand effects or oxidation states, in
23
the reactivity. Recently, the development of oxidative verꢀ
sion of catalytic couplings has prompted us to expand the
A screening of reaction conditions (Table 1) revealed that a
mixture water/acetone (1:1) and a 50% excess of sodium
2
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ACS Catalysis
acetate as the base in the open air gave good results (entry 1,
The effect of the amount of oxidant (O ) was evaluated by
carrying out experiments in sealed tubes with identical shape
2
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Table 1 and Eq. 1). Other solvents can also be used as long
as the acetate salt is soluble in them (entries 5 and 6, Table
1). However, the solvent mixture and the base depicted in
Eq. 1 are more convenient and environmentally friendly. The
diyne 2 is also formed in water but the reaction is less effiꢀ
cient (entry 3, Table 1). CsF can also be used as base (entry
in the optimized conditions. As mentioned before, the presꢀ
ence of oxygen is necessary (entry 10, Table 1) and a faster
reaction was observed when air was substituted by pure
oxygen (entries 11 and 12, Table 1). However, not only the
amount but also the diffusion rate of oxygen in the solution
appeared to be very important in controlling the reaction
rate. From the very first experiments, we realized that the use
of different reaction vessels under otherwise identical condiꢀ
tions resulted in different reaction rates; therefore, to ensure
comparable experiments, all the reactions in Table 1 were
carried out in round bottomed flasks of the same shape and
dimensions. Shorter reaction times were achieved by saturaꢀ
tion of the solvent just slowly bubbling air or pure oxygen.
The oxygen diffusionꢀcontrolled rate in aerobic Pdꢀcatalyzed
oxidations has been found and studied by Steinhoff and
7
, Table 1) but amines like DBU are inefficient.
No trace of the dialkyne 2 was observed when the reaction
was carried out in the absence of base, catalyst or oxidant.
Although the base is necessary, it is worth noting that a
substoichiometric amount of acetate is enough to perform the
reaction (entry 8, Table 1), and even the same amount as the
catalyst (5 mol%) produces the formation of 2 although very
slowly in this case (entry 9, Table 1). In order to probe the
possibility of a radicalꢀchain mechanism, we evaluated the
reaction in the presence of the radical inhibitor galvinoxyl,
and the formation of the dialkyne was essentially unaffected
by the presence of this additive. We tested the recyclability
of the catalyst solution and, after the reaction had finished, a
second portion of alkyne and base was added. The catalyst
was still active but the reaction conversion decreased signifiꢀ
cantly (17% of 2 in 22 h for the second addition).
0
1
2
3
4
5
6
7
8
9
0
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3
4
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7
8
9
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6
7
8
9
0
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4
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0
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4
5
6
7
8
9
0
26
Stahl. The low solubility of oxygen in water may be one of
the reasons of the reduced yields of the reaction in this solꢀ
vent (entry 3, Table 1).
Table 2. Synthesis of 2 catalyzed by different palladium
a
complexes in the conditions of Eq. 1.
Table 1. Synthesis of 2 catalyzed by complex 1 under
Entry Catalyst
Additive
% Conversion
a
b
different reaction conditions.
(Add/Pd mol ratio) (3 h/7 h/22 h)
66 / 83 / 100
1
2
3
4
5
6
1
Pd/C
0 / 0 / 0
b
c
d
Pd(OAc)2
0 / 6 / 10
Entry Oxidant Base
Solvent
2, % Crude yield
(3h / 7h / 22h)
66 / 83 / 100
29 / 39 / 90
c
Pd(OAc)2
PPh (2)
3
0 / 25 / 58
5 / 5 / 10
35 / 50 / 64
Pd(OAc)2
allyl acetate (5)
1
2
air
air
NaOAc
NaOAc
H O/Acetone
2
Pd(OAc)2
PPh (2) +
H O/Acetone
3
2
allyl acetate (1)
(1:3)
7
8
9
[Pd (dba) ]
0 / 0 / 0
4 / 21 / 79
3
4
5
6
7
8
air
air
air
air
air
air
NaOAc
H O
55 / 61 / 77
66 / 83 / 100
79 / 98 / 100
10 / 62 / 100
42 / 77 / 100
56 / 71 / 73
2
3
2
[Pd (dba) ]
PPh (2)
NBu OAc H O/Acetone
2
3
3
4
2
d
[Pd (dba) ]
PPh (2) +
25 / 84 / 100
NBu OAc Acetone
2
3
3
4
allyl acetate (10)
NBu OAc CH Cl
2
4
2
e
10
[Pd(PPh ) (MA)]
0 / 0 / 0
19 / 20 / 41
0/ 10 / 60
3
2
CsF
NaOAc
0.5)
NaOAc
0.05)
H O/Acetone
2
1
1
1
1
2
3
[Pd(PPh ) ]
3 4
H O/Acetone
2
1
PPh (1)
3
(
[Pd(µꢀCl)(allyl)]2
0 / 0 / 11
9
air
H O/Acetone
2
6 / 8 / 49
14
[Pd(µꢀCl)(allyl)]2
P(o-Tol) (2)
57 / 75 / 100
(
3
e
e
e
e
1
1
1
1
5
6
7
8
[Pd(µꢀCl)(allyl)]2
[Pd(µꢀCl)(allyl)]2
P(p-OMeC H ) (2) 30 / 79 / 100
1
1
1
1
0
1
2
3
N2
air
O2
air
NaOAc
NaOAc
NaOAc
NaOAc
H O/Acetone
0 / 0 / 0
6
4 3
2
P(C F ) (2)
0 / 0 / 0
0 / 28 / 68
0 / 0 / 0
H O/Acetone
2
37 / 67 / 100
90 / 100 / 100
22 / 83 / 100
6 5 3
[Pd(allyl)Cl(AsPh )]
H O/Acetone
2
3
f
[PdCl (dppe)]
H O/Acetone
2
2
+allyl
a) Reaction conditions: 0.85 mmol of alkyne at 25 ˚C in 8 mL of
acetone/water = 1:1 (v/v); 5 mol% of Pd; NaOAc (molar ratio
NaOAc/alkyne = 1.5) in the air (see Eq. 1). b) The reactions were
chemoselective, and conversion equals to crude yield, except when
noted; conversions were determined by integration of the alkene
acetate
a) All the reactions were carried out using 0.85 mmol of the
alkyne at 25 ˚C with 5 mol% of 1 in an open flask unless otherꢀ
wise noted; total volume of solvent: 8 mL. b) A molar ratio
base/alkyne = 1.5 was used, unless otherwise noted in parentheꢀ
1
signals of the cyclohexenyl group in H NMR. c) 16% of other
unidentified byproducts. d) The excess of allyl acetate led to 33%
of byproducts resulting from the 2:2 crossꢀcoupling of the alkyne
and the allylic fragment (ref. 25a). e) MA = maleic anhydride. f)
45% conversion in 8 days.
ses. c) H O/Acetone = 1/1 (v/v) unless otherwise noted. d) The
2
reactions were chemoselective and the crude yields were deterꢀ
mined by integration of the alkene resonances of the alkyne and
1
2
by H NMR. e) The reactions were carried out in tightly
closed flasks of the same shape and dimensions.
3
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The addition of an excess of allyl acetate, a Pd(0) reoxidant
by oxidative addition sometimes used in similar reactions,
did not have a beneficial effect (entry 13, Table 1).
With the optimized conditions in hand, the activity of other
palladium complexes was evaluated (Table 2). The use of
valve and saturated oxygenated acetone under 1 atm of oxyꢀ
gen, clean spectra were obtained and the formation of 2 was
monitored at 298 K (Eq. 2).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
7
other common Pd catalytic precursors such as Pd(OAc) or
2
Pd/C resulted in no reaction or traces of the dialkyne (entries
2
and 3, Table 2). The same behavior was found with [Pd(µꢀ
3
As it is collected in Table 1 (entries 10ꢀ12) we could observe
a qualitative dependence of the concentration of oxygen (air
Cl)(η ꢀallyl)] (entry 13, Table 2) or some common Pd(0)
complexes (entries 7 and 10, Table 2). The amount of PPh is
2
3
vs. O ). The gasꢀliquid mass transport limitation was again
2
crucial and the best reaction results were achieved when just
one phosphine per Pd was added (entry 8, Table 1). The
reaction was very slow with [Pd(PPh ) ] and the increase in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
demonstrated comparing the conversion when the operation
technique was changed: after 3 h in the conditions of Eq. 2,
3
4
under 1 atm of O , only 46 % yield of 2 was observed in an
2
yield at a late stage might be associated to oxidation of some
NMR tube vs 90 % in a Schlenk flask with continuous stirꢀ
of the PPh present (entry 11, Table 2). Also, a dramatical
3
26
ring. To avoid the rateꢀlimiting massꢀtransfer of oxygen gas
into the solution, the kinetic reactions were carried out in a
range of low concentrations of the catalyst (0.59−2.70 mM).
The solubility of oxygen in acetone under these conditions is
decrease in conversion was observed upon addition of an
equimolar amount of PPh to 1 (entry 12, Table 2). Complex
3
1
is clearly the best catalyst, used either preformed or generꢀ
ated in situ from a different palladium precursor and a comꢀ
30
close to 12 mM.
bination of PPh and an allylic source (entries 6 and 9, Table
3
Figure 1 (a) shows the monitorization results for the forꢀ
mation of dialkyne 2, up to 75% conversion. The reaction
time course shows a faster reaction in the first 30 min folꢀ
2
). Other arylphosphines with electronꢀdonating groups have
a similar efficiency than PPh , but the less donor P(C F )
3
6 5 3
resulted in no catalysis (entries 14ꢀ16, Table 2). Substitution
of the PPh for a more labile ligand such as AsPh led to a
lowed by a decrease of rate of approximately threefold: k
=
obs
3
3
ꢀ
1
ꢀ1
0
.149 min from 0 to 20% conversion vs k = 0.046 min
obs
worse conversion (entry 17, Table 2). [PdCl (dppe)] gave no
2
in the range 20ꢀ40% conversion). This behaviour can be
attributed to a product inhibition in the reaction and we corꢀ
roborated this effect by addition of dialkyne 2 (0.39 mg, 2.63
mM, equivalent to a 11% of conversion) when a 9 % of
conversion was achieved. We could observe the rate becomꢀ
reaction in 22 h (entry 18, Table 2) and only after a very long
reaction time (8 days) 45% yield of 2 was obtained.
The homocoupling reaction of a range of alkynes was exꢀ
plored using complex 1 as the best catalyst precursor in the
conditions of Table 1, entry 1. As can be seen in Scheme 3,
phenylacetylene and aromatic alkynes with electronꢀdonating
groups or weak electronꢀwithdrawing groups were found to
be good substrates for the formation of 1, 3ꢀdiynes. This
system also allows the homocoupling of nonꢀaromatic termiꢀ
nal alkynes. In contrast, those acetylenes with electronꢀ
withdrawing groups afforded the cyclotrimerization products
along with (R = pꢀCF ꢀC H , Scheme 3) or instead of the
ꢀ1
ing again three times slower, since kobs = 0.168 min up to
9
% conversion (before dialkyne addition) and k = 0.058
obs
ꢀ1
min between 10ꢀ20% conversion (Figure 1, b). It has to be
noted that an induction period of up to 10ꢀ15 min was often
observed in the experimental follow up (Figure 1 b, blue
plot) indicating that a slow generation of the active catalytic
species was taking place (see below).
3
6
4
desired dialkynes (R = CO Me). The cyclotrimerization of
2
this type of alkynes to give substituted arenes induced by
28
palladium complexes is well known, and both Pd(0), and
2
9
Pd(II) complexes can catalyze this reaction.
Figure 1. a) Time course for the formation of 2 catalyzed by
complex 1 in the conditions of Eq. 2 ([Pd] = 1.19 mM) and
expansion for the first 60 min of the reaction. b) Comparison of
time course for the formation of 2 in the experiment shown in
(a) (black) to that when external dialkyne 2 was added (blue).
Scheme 3. Aerobic synthesis of 1,3-diynes catalyzed by
complex 1.
We assessed the dependence of the rate on the concentration
of the reagents using the initial rates method and in each
experiment the reaction was monitored at least to 15% conꢀ
version to 2. The rate of product formation as a function of
Pd concentration was measured over a concentration range
of 0.59−2.70 mM, under the reaction conditions of Eq. 2.
The homocoupling of the alkyne showed a first order deꢀ
pendence on catalyst 1 (1.13 ± 0.08, Figure 2, a). We next
assessed the kinetic order in acetate and alkyne proceeding in
Kinetic experiments. Reactions leading to the formation of
1
the diyne 2 were monitored by H NMR. In order to have
reliable and reproducible conditions and ensure enough
oxygen solubility, we performed the reactions in acetone as
solvent (instead of the mixture waterꢀacetone), and
NBu OAc as a soluble base (Table 1, entry 5). In these conꢀ
4
ditions using an NMR tube equipped with a J. Young PTFE
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Rate dependence of the reaction depicted in Eq. 2 upon the concentration of: (a) complex 1 ([NBu OAc] = 36.48 mM, [1ꢀ
4
ethynylcyclohexene] = 23.7 mM, [1] = 0.59 – 2.70 mM); (b) the alkyne ([1ꢀethynylcyclohexene] = 12.15ꢀ48.6 mM, [NBu OAc] = 36.48
4
mM, [1] = 1.19 mM) and (c) the base ([NBu OAc] = 17.53ꢀ74.38 mM, [1ꢀethynylcyclohexene] = 23.7 mM, [1] = 1.19 mM).
4
a similar manner. The order in alkyne was determined by
varying the concentration of 1ꢀethynylcyclohexene from
1
2.15 to 48.6 mM (Figure 2, b). Under these conditions, the
reaction showed approximately a zero order dependence
0.17 ± 0.05). The order in acetate (Figure 2, c) was deterꢀ
(
mined by varying the concentration of tetrabutylammonium
acetate from 17.53 to 74.38 mM. Under these conditions, the
reaction showed approximately a zero order dependence on
acetate (0.18 ± 0.16). The kinetic isotope effect (KIE) was
determined by comparing the initial reaction rate of RC≡CH
to that of RC≡CD in separate experiments. A KIE (k /k ) of
When the reaction depicted in Eq. 3 was carried out at 243 K
in CDCl in the presence of an equimolar amount of 1ꢀ
3
3
ethynylcyclohexene the formation of complex [Pd(η ꢀ
C H )(C≡CR)(PPh )] (R = 1ꢀcyclohexenyl, 4a) was observed
3
5
3
H
D
mixed with complex 3 and the starting material 1. The equiꢀ
librium can be driven to the complete formation of 4 if a
tenfold excess of alkyne and acetate is used (Eq. 4). In this
1.97 ± 0.01 was obtained from these experiments. The presꢀ
ence of a KIE invokes the importance of the cleavage of CꢀH
bond, but the value is not large enough to ensure the CꢀH
n
3
1
reaction (R = Bu) we first observed the ligand exchange
activation is the rateꢀlimiting step. This KIE value could fit
well in one of the scenarios nicely collected by Simmons and
between chloride and acetate resulting in 3 and the gradual
formation of 4. After 14 h at 243 K, the σꢀalkynyl palladium
complex 4b was the only palladium complex present in the
reaction. The formation of the diyne product was not obꢀ
served.
32
Hartwig, in which the cleavage of the CꢀH bond is involved
before the rateꢀlimiting step. The zero order dependence in
alkyne, first order in catalyst and the strong dependence on
the oxygen concentration point to the oxidation as the rate
determine step (see below).
3
Reactions of [Pd(η -allyl)Cl(PPh )] under conditions
3
relevant to the catalysis: Formation of the active species.
The reactions of complex 1 with the reagents used in the
oxidative homocoupling were monitored, in acetoneꢀD or
6
1
31
CDCl at variable temperature by H and P NMR, in order
3
Complexes 4a,b were prepared before in our group by
transmetalation of an alkynyl group from tin to palladium.
to detect new species that could play a role in the catalytic
reaction. All the experiments were carried out in the air.
The addition of 1 to a solution of an equimolar amount of
NBu OAc in CDCl at room temperature led to the transforꢀ
25
However, in this case the alkynyl palladium complex is
detected and characterized by direct reaction of an alkyne
and a base. This is the proposed route for the formation of
the PdꢀC(sp) bond in the Sonogashira couplings but, surprisꢀ
ingly, there are very few examples of such a process leading
to well characterized palladium alkynyls without the assisꢀ
4
3
mation of 50% of the starting allylic complex into several
species (Eq. 3). The substitution of acetate for chloride led to
the formation of complex 3 (23%). Allyl acetate was present
as well, which is necessarily accompanied by the formation
of Pd(0) compounds. These species comproportionate with
the more abundant Pd(II) allylic complex 1 to give the Pd(I)
dimer 5 (25%) in a very efficient way since no other signifiꢀ
35
tance of an extra metal cocatalyst.
The reaction was also monitored in acetoneꢀD at 243 K
6
(Scheme 4). As shown in Figure 3, after 3 h at 243 K, the
solution contained 4a. The mixture did not change signifiꢀ
cantly until the temperature was raised to 298 K, where 4a
31
cative P NMR signals corresponding to decomposition
3
3,34
species were observed.
When the same reaction was
gradually disappeared and a new allylic Pd complex forms,
carried out in acetoneꢀD in analogous conditions, unreacted
3
6
which was identified as [Pd (η ꢀC H )(µꢀC≡CR)(PPh ) ] (7,
2
3
5
3 2
1
, 5 (46 %) and allyl acetate were formed but 3 was not
36
R= 1ꢀcyclohexenyl). Some allyl acetate was also observed
which reflects the occurrence of the decomposition of the
allylic Pd(II) compounds to Pd(0), the reactant species in the
formation of the Pd(I) complex 7. The formation of dialkyne
observed in this case. The dissociation of acetate in the more
polar and better coordinating acetone probably induces the
decomposition of 3 leading to a higher amount of Pd(0)
species and allyl acetate that, in turn, increase the amount of
5 detected.
2
was also observed. Eventually, the slow disappearance of 7
(hours) also occurred.
5
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cedure that the one we reported before for the Pd(II) comꢀ
plexes 4.
25
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
All the results obtained in the experiments described above
allow to draw a complete picture of the reactions that take
place on complex 1 under catalytic conditions (Scheme 5).
Three main processes occur: i) Deprotonation of the alkyne
and coordination of the alkynyl fragment to Pd(II) to give 4,
ii) decomposition of the Pd(II) allylic species by nucleophilic
attack of acetate to the allylic fragment to give allyl acetate
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Reactions of complex 1 with the alkyne in the
presence of base at variable temperature.
38
and Pd(0) species; iii) trap of the Pd(0) species by comproꢀ
portionation with Pd(II) complexes to give Pd(I) dimeric
allylic derivatives (5ꢀ7). The two latter reactions are favored
in acetone rather than in nonꢀcoordinating and less polar
chlorinated solvents. Only complexes 4 and 7 were detected
in the catalytic mixtures at room temperature. However, the
formation of the dialkyne is never observed from complex 4
in the monitorization experiments described above. Usually,
the product builds up along with the formation of byproducts
of the reduction of Pd(II) allylic complexes such as allyl
acetate. This strongly points to a Pd(0) derivative as the
actual active species in the reaction, which is coordinatively
unsaturated since just one phosphine per palladium is the
optimal metal to ligand ratio. Nonetheless, complex 4 is not
a dead end since it can revert to complex 1 by protonation, as
we have independently tested, and it can reenter the route to
3
Pd(0) via the putative cationic [Pd(η ꢀC H )(πꢀ
3
5
C≡CR)(PPh )]X in Scheme 5.
3
Scheme 5. Formation of the active Pd(0) species from
precatalyst 1.
31
1
Figure 3. P (top) and H NMR (bottom) spectra of the mixture
of 1 and tenfold molar amount of 1ꢀethynylcyclohexene and
NBu OAc in acetoneꢀD after a) 3 h at 243 K; b) 1 h at 293 K.
4
6
ꢀ
= alkyne; ∇=allyl acetate.
The disproportionation of the dimeric Pd(I) complex 7 can
regenerate the Pd(0) complex, so 7 is acting as a reservoir of
palladium active species. If this is the case, complex 7 (or a
suitable Pd(I) precursor) should be active in the aerobic
homocoupling of alkynes. We analyzed the activity of comꢀ
plex 5, which forms 7 in the presence of the alkyne and the
base (Eq. 5) in the same conditions used for 1 as catalyst
(Table 1, entry 1). As shown in Table 3, 5 is an active cataꢀ
lyst but a double Pd:alkyne ratio is needed to achieve a simiꢀ
lar yield to that obtained using 1 as catalyst (same mol%
amount of both complexes, entries 1 and 3, Table 3). Thus, 5
Although the acetate complex 3 was not detected in acetoneꢀ
D , its presence in the reaction media cannot be ruled out. In
6
an independent experiment 3 was generated in acetone from
complex
1
and AgOAc. The addition of 1ꢀ
ethynylcyclohexene led to the formation of 4a and the Pd(I)
3
derivatives 5, [Pd (η ꢀC H )(µꢀOAc)(PPh ) ] (6) and 7 as
2
3
5
3 2
minor species.
The identity of the Pd(I) complexes detected in our experiꢀ
ments was supported by the independent synthesis of comꢀ
37
plex 5, and the exchange of the chloro bridge for alkynyl to
(or 7) can generate the Pd(0) active species needed for catalꢀ
give 7, as shown in Eq. 5. The acetate complex 6 was obꢀ
ysis at a rate which is dependent on the ease of disproporꢀ
tionation of the complex and, overall, is less efficient that the
generation of the same species from 1. Interestingly, the
served when 5 was reacted with just NBu OAc in acetoneꢀ
4
D . Complex 7 was also formed by transmetalation of the
6
alkynyl group from tributylalkynyltin to 5, in a similar proꢀ
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ACS Catalysis
this complex of by double metalation on Pd(II) and the fact
aerobic homocoupling reaction occurs in the absence of base
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with complex 5 (entry 4, Table 3) but the dialkyne is not
formed with 1 unless a base is used. Therefore, the main and
indispensable role of the acetate salt must be the formation
of the catalytic active Pd(0) species from 1, whereas 5 can
produce those species by a disproportionation reaction.
When a base is absent just half of the Pd contained in 5 can
be transformed in Pd(0) and the remaining Pd(II) derivatives
do not decompose; thus, the differences in the crude yields
observed for entries 2 and 4 (Table 3) can be interpreted as a
result of two experiments with different amount of catalyst.
In recent years, the involvement of Pd(I) complexes in cataꢀ
lytically relevant coupling processes has attracted a lot of
that the reductive elimination is feasible, [PdCl (dppe)] is
extremely slow and not a competitive catalyst for the homoꢀ
coupling of terminal alkynes (entry 18, Table 2).
2
Computational studies. The experimental results reported
above suggest a complex mechanism where a Pd(0) complex
acts as catalyst, but cannot characterize all possible intermeꢀ
diates and have no access to transition states. Density funcꢀ
tional theory (DFT) calculations were undertaken to gather
more information about the detailed mechanism and energetꢀ
ics of the reaction. Ethynylbenzene was used as alkyne for
all the calculations. Solvation was included through the SMD
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
39ꢀ44
attention.
They may open up new mechanistic alternaꢀ
tives to the common operating routes. However, in most
cases they play a role of a source of reactive Pd(0) species,
4
5
as we believe it is the case here. The disproportionation of
Pd(I) allylic derivatives as a function of the nature of the
allylic fragment and the ligands involved has been studied in
47
37
implicit solvent method in all the calculations (acetone).
detail.
The initial mechanism was obtained using the B3LYPꢀD3
48,49
a
functional,
and a tripleꢀζ basis set plus complemented
Table 3. Synthesis of 2 catalyzed by the Pd(I) complex 5.
with diffusion and polarization shells. Then, after a benchꢀ
marking study including six functionals, we recalculated all
the pathways with the M06 functional, which gives the best
agreement with the experimental results. Further details on
the computational method are supplied in the Supporting
Information. A data set of all computational results is availaꢀ
Entry
[Pd]
Base
Conversion, %
b
(3h / 7h / 22h)
1
2
3
4
1 (5 mol%)
5 (2.5 mol%)
5 (5 mol%)
5 (2.5 mol%)
NaOAc
NaOAc
NaOAc
ꢀ
66 / 83 / 100
41 / 71 / 75
55 / 88 / 100
5 / 23 / 44
50
ble in the ioChemꢀBD repository. We label the species
characterized only computationally with the prefix c. The
computed thermodynamics of the overall coupling reaction
are favorable, as expected, and the reaction 2 HC≡CPh + O2
a) All the reactions were carried out using 0.85 mmol of the
alkyne at 25 ˚C in 8 mL of acetone/water = 1:1 (v/v) with
NaOAc (molar ratio NaOAc/alkyne = 1.5) in the air. The reacꢀ
tions were chemoselective and conversion equals to crude yield.
b) The reactions were chemoselective and the crude yields were
determined by integration of the alkene resonances of the alkyne
ꢁ PhC≡CꢀC≡CPh + H O , is exergonic by 26.9 kcal/mol.
2
2
1
and 2 by H NMR.
Our experiments stubbornly pointed to a Pd(0) complex as
the active catalyst that initiates the reaction. However, when
looking at the literature, all the proposals for the Pdꢀ
catalyzed oxidative homocoupling of alkynes involve two
consecutive metalations of an alkynyl group on a Pd(II)
complex, although there is no detailed study of these reacꢀ
tions (Scheme 2). We tried to detect a cisꢀbisalkynyl palladiꢀ
um(II) complex that would be formed after a second alkyne
metalation on 4, but we did not observe this intermediate in
any monitorization experiment of the reaction. Neither such
a complex nor the formation of the dialkyne product 2 were
observed when we added four equivalents of 1ꢀ
3
cyclohexenylethynyl lithium to a solution of [Pd(η ꢀC H )(µꢀ
3
5
Cl)] (See Scheme S1 in the Supporting information). Cisꢀ
2
bisalkynyl palladium(II) complexes are extremely rare but
complex 9 has been reported and characterized by reaction of
Figure 4. Free energy pathways of the precatalyst evolution and
the formation of the experimentally observed intermediates.
Energies in kcal/mol referred to 3.*:The free energy barrier
associated to TS-c3-c4 was estimated from that of the adduct
c3-OAc, as a potential energy scan shows no transition state..
[
PdCl (dppe)] with either an alkyne in NH (l) or the alkynyl
2 3
46
lithium derivative. As shown in Eq. 6, complex 9 led to the
diyne 2 as the major product when we monitored its slow
decomposition in acetoneꢀD (90% after 13 h at 283 K and 6
6
h at room temperature). Despite the possibility of reaching
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First Alkyne
Deprotonation
Second Alkyne
Deprotonation
Reductive
Elimination
Oxidation
Protonolysis
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
–
–
–
–
O
H
O
O
Ph3P
Pd
O
O
O
Ph3P
Pd
O
Ph
Pd
Ph3P Pd
Ph3P
O
c5-O -T
2
c5
Ph
Ph
c6-AcO
Ph
Ph
c9-OAc
MECP
19.1
AcO–
TS-c4-c5
1
8.5
O2 c5-O -T
2
2.1
TS-c6-yne-c8-OAc
Ph
HOAc
TS-c8-c9-OAc
+9.8
1
c5
.8
14.4
c4
6.1
c5-O2-S
6.5
AcO–
7
9.4 c6-yne-OAc
c6-yne
4
.4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
c6-AcO
2.5
AcOH
-
c8-OAc
-5.8
HOAc
H
AcO–
H2O2
HOAc
c9-OAc
-20.4
–
–
H
O
O O
Pd
Ph3P
O
Ph
Ph
H
O
O
O
O
Pd
Pd
Pd
Ph
Ph
Ph3P
Ph
Ph3P
Ph3P
Ph
c5-O2-S
c6-yne-OAc
c8-OAc
c6-yne
Ph
Figure 5. Free Energy profile for the oxidative homocoupling of alkynes starting with the in situ generated Pd(0) active species c4. Enerꢀ
gies in kcal/mol referred to 3.
We analyzed first the equilibria in the precatalytic process
described in Scheme 5 above. The computational results are
summarized in the free energy profile in Figure 4. The actiꢀ
vation of complex 1 starts with the slightly endergonic (0.7
kcal/mol) displacement of the chloride ligand by acetate,
yielding intermediate 3, also observed experimentally. We
will use this intermediate 3 as origin of energies. From this
point, two possibilities were considered: a neutral pathway
(in blue) and a cationic pathway (in green). The highest
activation free energy in Figure 4 is 22.7 kcal/mol (TS-c1-
c4) and the lowest free energy point is ꢀ2.8 kcal/mol (for
intermediate 7). This means that all intermediates shown in
Figure 4 are accessible under the experimental conditions.
Complex 4, among the most stable ones (ꢀ0.3 kcal/mol)
according to the calculation, was detected and characterized
during the NMR monitorization of the reaction. Complex c4,
postulated above as catalytically active because of the Pd(0)
oxidation state and its available coordination site, is also
accessible at 6.1 kcal/mol. We also explored other pathways
for the formation of the Pd(0) species, but all of them were
similar in energy (see Table S11). The dimeric intermediate
computed mechanism starts thus though alkyne activation
and can be divided in five steps: first alkyne deprotonation,
Pd oxidation, protonolysis of the PdꢀO bond, second alkyne
deprotonation and reductive elimination. In contrast, c4
reacts smoothly through TS-c4-c5 (at 18.5 kcal/mol) with an
acetate anion to deprotonate the coordinated alkyne, leading
to complex c5. Both intramolecular and intermolecular
routes are feasible for this step, being the transition state for
the external deprotonation just 1.4 kcal/mol lower in energy
(see Figure S45 for the internal deprotonation). An alternaꢀ
tive route for the reaction between complex c4 and alkyne,
starting with oxidative addition was also considered, and
found to be less efficient (see Figure S46).
Remarkably, triplet molecular oxygen is able to coordinate to
the anionic complex c5. Its coordination results in the superꢀ
oxo Pd(I) complex c5-O -T (Figure 6, left). The observed Oꢀ
O (1.240 Å) and PdꢀO (2.460 Å and 3.220 Å) bond distances
in the optimized structure, and the spin densities in oxygen
centers (0.82 and 0.88) and Pd (0.25) confirm the superoxo
2
11b,17b
character of the species (Figure 6, left).
This different
behavior with respect to oxygen of the neutral (c4) and aniꢀ
onic (c5) complexes points towards the need of an electron
rich Pd(0) center for the reaction to take place. The presence
of anionic nucleophilic Pd(0) intermediates has been also
proposed for the oxidative addition of aryl halides.
The η ꢀO superoxo complex c5-O -T evolves to the κ ꢀO
peroxoꢀpalladium complex c5-O -S through a minimum
energy crossing point structure (MECP). The MECP is necꢀ
essary for the crossing from the triplet to the singlet spin
states. The peroxo assignment for c5-O -S is supported by
the computed OꢀO (1.386 Å) and PdꢀO (2.030 Å and 2.017
Å) bond distances in the optimized structure (Figure S50,
supporting information). The MECP structure has a free
energy of 21.9 kcal/mol respect to the most stable species 7.
This is the rate determining step, although TS-c4-c5 is
close, explaining the little KIE (1.97) observed experimentalꢀ
ly. The structure is shown in Figure 6, right. The arrangeꢀ
7
, at ꢀ2.8 kcal/mol, also experimentally detected, is accessiꢀ
ble through comproprotionation of c4 and the more abundant
species 4.
51
The DFT studies on the precatalytic species fit perfectly with
the experimental data, where the detected intermediates by
NMR (3, 4, 7) are the lowest in energy, and with our proꢀ
posal of 7 as a plausible offꢀcycle resting state. The catalytiꢀ
cally active species c4 does not contain the allyl ligand,
which is thus absent from the catalytic cycle. The role of the
allyl group is nevertheless fundamental in the equilibria
depicted in Figure 4, allowing the formation of the reduced
Pd(0) complex through its elimination with acetate.
We then focused on the mechanism of the catalytic cycle.
Figure 5 shows the free energy profile obtained. We initially
explored the oxidation of the Pd(0) complex c4 by direct
interaction with oxygen, which would be consistent with the
wellꢀknown formation of peroxides upon reaction with
1
2
2
2
2
2
52
2
ment around Pd is similar to that of c5-O -T differing in a
2
10
[
Pd(PR ) ]. All attempts at finding a starting point where
O (in its triplet ground state) coordinates directly to the
metal in c4 failed, leading to the release of free O . The
lengthening of the OꢀO bond from 1.240 to 1.295 Å, and a
shortening of the PdꢀO bonds from 2.460 to 2.392 Å and
3.220 to 2.171 Å
3
4
2
2
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The validity of this mechanistic proposal was checked by an
1
2
3
4
5
6
7
8
additional experiment. The presence of hydrogen peroxide
was detected in a qualitative experiment by addition of an
aliquot of the crude mixture of the catalytic reaction (when
the conversion has reached a value of about 50%) to a pinkꢀ
ish aqueous solution of CoSO .7H O and NaHCO , observꢀ
4
2
3
54
ing the expected color change to green. Hydrogen peroxide
is not necessarily the final product, as palladium complexes
can also catalyze the decomposition of H O to oxygen and
2
2
Figure 6. Optimized structures of the superoxo intermediate c5-
water.
9
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1
1
1
1
1
1
1
1
2
2
2
2
2
2
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2
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5
5
6
O2-T (left) and the MECP (right) including relevant bond
lengths in Å (blue) and spin densities for the intermediate
(green).
The general picture of the alkyne homocoupling catalytic
cycle is summarized in Scheme 6. The oxidation is the highꢀ
est energy step and it is therefore turnoverꢀlimiting, which
agrees with the strong sensitivity of our experiments to the
amount of oxygen present. Moreover, this also agrees with
the nonꢀdependence of the reaction rate on the concentration
of alkyne or base. The mechanism also provides a rationale
for the need of only a catalytic amount of base for the cataꢀ
lytic process (Scheme 6). More base is needed when the
precatalyst used is 1, as the base is consumed in the precataꢀ
lytic processes that generate the Pd(0) active species
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Intermediate c5-O -S undergoes two lowꢀbarrier processes
2
that lead sequentially to c6-OAc and c6-yne. Protonolysis of
2
a PdꢀO bond of the κ ꢀO peroxo ligand by an external acetic
2
acid leads to c6-OAc, containing a hydroperoxo and an
acetate ligand, in a process similar to those reported by Stahl
12,13a
and coꢀworkers.
The acetate ligand is then replaced by
the second alkyne, resulting in complex c6-yne.
The next step is also formally simple: the hydroperoxo group
is protonated by HOAc exergonically, and then the resulting
intermediate c6-yne-OAc affords the acetateꢀassisted deproꢀ
tonation of the second alkyne. The transition state TS-c6-
yne-c8-OAc has a relatively high energy of 14.4 kcal/mol,
and it is shown in Figure 7. We also explored the CꢀH cleavꢀ
age assisted by the coordinated oxygen from the peroxo
group (TS-c6-c7) but the activation free energy barrier was
higher by 8.5 kcal/mol (Figure S48).
(Scheme 5 and Figure 4), than when the precatalyst is 5, as
c4 can be formed by disproportionation without the assisꢀ
tance of a base.
AcO–
Ph
Ph
Ph
H
AcO–
Ph
H
Ph P Pd
3
Ph
O
–
c4
AcOH
c9-OAc
Ph
O
Pd
–
3
P
AcOH
Ph3P
Pd
c5
Ph
Ph
AcO–
–
OH
Ph
Ph
O
2
O
Pd
Ph P
3
c7
–
O
O O
H
Pd
Figure 7. Optimized structure of TS-c6-c8-OAc. Relevant bond
distances, in Å, are highlighted.
O
3
Ph P
Pd
Ph
Ph
Ph
Ph
3
P
–
c5-O
AcOH
2
-S
H
O
Species c8-OAc is an anionic Pd(II) complex with two alꢀ
kynyl ligands and an acetate. It can an easily undergo reducꢀ
tive elimination through TS-c8-c9-OAc, which is only 9.8
kcal/mol above the reference. We also explored the direct
c6-yne
O
O
Pd
H
2 2
H O
AcO–
O
Ph P
3
c6-OAc
Ph
Ph
AcOH
reductive elimination
from the neutral species
[
Pd(II)(PPh )(alkynyl) ] (c8) but the transition state is more
Scheme 6. Catalytic cycle for the formation of diynes
from alkynes.
3
2
energetic, with an overall barrier of 19.3 kcal/mol (see Figꢀ
ure S49).The different behavior towards reductive eliminaꢀ
tion by c8 and c8-OAc confirms the critical role of ancillary
CONCLUSIONS
An efficient aerobic oxidative homocoupling of alkynes
5
3
ligands in this step. The resulting species c9-OAc contains
already the diyne product in the palladium coordination
sphere. Replacement of the diyne by a new alkyne will reꢀ
generate the catalyst and start over the catalytic cycle. The
coordination ability of the alkyne and the dialkyne are very
similar and the substitution of the dialkyne and the coordiꢀ
nated acetate for a new molecule of the terminal alkyne
needs of a controlled release of low ligated “PdPPh L” speꢀ
3
3
cies. Allylic palladium complexes of formulation [Pd(η ꢀ
C H )(PPh )X] are excellent precursors of those Pd(0) speꢀ
3
5
3
cies in the presence of acetate for several reasons. First, the
3
η ꢀallylic fragment stabilizes Pd(II) species and, being a
bidentate ligand, few additional ligands on the coordination
sphere of the metal are needed. The allyl is not prone to
participate in CꢀC coupling reactions (reductive elimination
reactions involving this group are slow) but it provides an
easy route to Pd(0) by nucleophilic attack of acetate on the
allylic fragment. Moreover, it allows the efficient formation
of stable Pd(I) dimers with an allyl bridge by comproporꢀ
(
going from c9-OAc to c4) is almost isoenergetic (ꢀ0.4
kcal/mol), which implies a small equilibrium constant of K =
.71. This indicates a competition of both unsaturated deꢀ
1
rivatives for coordination to the Pd(0) center that explains
the product inhibition observed.
9
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tionation, and this may help to avoid the decomposition of
Page 10 of 13
2014ꢀ068662). This collaborative work has benefited from the
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the reactive Pd(0) species by aggregation, while still being
able to release them to the catalytic cycle upon the reverse
Red de Excelencia CTQ2016ꢀ81923ꢀREDC (MINECO).
3
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disproportionation reaction. Thus, [Pd (µꢀη ꢀC H )(µꢀ
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3
5
C≡CR)(PPh ) ] (R= 1ꢀcyclohexenyl, 7), observed in the
3
2
catalytic reaction, can be considered as a catalyst resting
state out of the operating catalytic cycle. In fact, a (µꢀ
allyl)Pd(I) dimer can also be used as catalyst precursor for
the aerobic formation of diynes from alkynes.
Both the kinetic measurements and DFT calculations point to
the oxidation as the rateꢀlimiting step of the reaction. The
computational studies, supported by the experimental
framework, disclosed some new features. Interestingly, the
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tion process; a neutral “PdPPh L” (L =alkyne) is not nucleoꢀ
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philic enough to react with oxygen and reduce it. The CꢀH
activation of the alkyne previous to oxidation from Pd(0) to
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–
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as an internal base to deprotonate the second molecule of
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occurs on a Pd(II) bis alkynyl complex, but this is not
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activation steps. In contrast to most oxidaseꢀtype reactions,
the oxidized product formation and the catalyst oxidation
cannot be separated.
The origin of diynes as undesired byproducts in Sonogashira
couplings, can be explained just by the presence of oxygen,
however inadvertently, and the formation of low ligated
palladium(0) species, an actual intermediate in the cross
coupling catalytic cycle. If the synthesis of diynes is the
target process, the catalytic system described here is an effiꢀ
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Corresponding Author
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0799ꢀ10803. d) Iosub, A. V.; Stahl, S. S. PalladiumꢀCatalyzed
Aerobic Dehydrogenation of Cyclic Hydrocarbons for the Synthesis
of Substituted Aromatics and Other Unsaturated Products. ACS.
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Phenylacetic Acids by Kinetic Resolution. Angew. Chem. Int. Ed.
*albeniz@qi.uva.es (experimental)
*fmaseras@iciq.es (computational)
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016, 55, 2856ꢀ2860. f) Yang, Y.; Lan, J.; You, J. Oxidative CꢀH/Cꢀ
H Coupling Reactions between Two (Hetero)arenes. Chem. Rev.
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ASSOCIATED CONTENT
Supporting Information
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(
II
challenges of palladium ꢀcatalyzed oxidation reactions with molecꢀ
ular oxygen as the sole oxidant. Chem. Commun. 2009, 3854ꢀ3867.
b) Campbell, A. N.; Stahl, S. S. Overcoming the “Oxidant Probꢀ
Experimental details, selected spectra, kinetic data and computaꢀ
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potential energies (PDF). The Supporting Information is availaꢀ
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lem”: Strategies to Use O as the Oxidant in Organometallic CꢀH
Oxidation Reactions Catalyzed by Pd (and Cu). Acc. Chem.
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ACKNOWLEDGMENT
ACA thanks financial support from the Spanish MINECO
3
(SGPI, grant CTQ2016ꢀ80913ꢀP, BESꢀ2014ꢀ067770 fellowship
to AT) and the Junta de Castilla y León (grants VA051P17 and
VA062G18). FM thanks financial support from the CERCA
Programme (Generalitat de Catalunya) and from the Spanish
MINECO (CTQ2017ꢀ87792ꢀR and Severo Ochoa Excellence
Accreditation 2014ꢀ2018, SEVꢀ2013ꢀ0319). IFA acknowledges
a fellowship from the ICIQꢀSevero Ochoa programme (SVPꢀ
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1
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3
4
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0
1
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0
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Forbidden Reaction between L
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04.
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Pd ꢀHydroperoxide: Acid Catalysis and Implications for Pdꢀ
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2
007, 129, 4410ꢀ4422. c) Konnick, M. M.; Stahl, S. S. Reaction of
I
I
I
I
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/Pyridine Catalyst
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