The Palladium Acetate-Catalyzed Microwave-Assisted Hirao Reaction without an Added Phosphorus Ligand as a “Green” Protocol: A Quantum Chemical Study on the Mechanism

Article abstract of DOI:10.1002/adsc.201700895

It was proved by our experiments that on microwave irradiation, the mono- or bidentate phosphorus ligands generally applied in the palladium(II)-catalyzed P–C coupling reaction of aryl bromides and dialkyl phosphites or secondary phosphine oxides may be substituted by the excess of the >P(O)H reagent that exists under a tautomeric equilibrium. Taking into account that the reduction of the palladium(II) salt and the ligation of the palladium(0) so formed requires 3 equivalents of the P-species for the catalyst applied in a quantity of 5–10%, all together, 15–30% of the P-reagent is necessary beyond its stoichiometric quantity. In the coupling reaction of diphenylphosphine oxide, it was possible to apply diethyl phosphite as the reducing agent and as the P-ligand. The reactivities of the diethyl phosphite and diphenylphosphine oxide reagents were compared in a competitive reaction. The mechanism and the energetics of this new variation of the Hirao reaction of bromobenzene with Y₂P(O)H reagents (Y=EtO and Ph) was explored by quantum chemical calculations. The first detailed study on simple reaction models justified our assumption that, under the conditions of the reaction, the trivalent form of the >P(O)H reagent may serve as the P-ligand in the palladium(0) catalyst, and shed light on the fine mechanism of the reaction sequence. The existence of the earlier described bis(palladium complex) {[H(OPh₂P)₂PdOAc]₂} was refuted by high level theoretical calculations. This kind of complex may be formed only with chloride anions instead of the acetate anion. The interaction of palladium acetate and Y₂P(O)H may result in only the formation of the [(HO)Y₂P]₂Pd complex that is the active catalyst in the Hirao reaction. The new variation of the Hirao reaction is of a more general value, and represents the greenest protocol, as there is no need for the usual P-ligands. Instead, the >P(O)H reagent should be used in an excess of up to 30%. Hence, the costs and environmental burdens may be decreased. (Figure presented.).

Full text of DOI:10.1002/adsc.201700895

Title: The Palladium Acetate-Catalyzed Microwave-Assisted Hirao
Reaction without an Added P-Ligand as a “Green” Protocol; A
Quantum Chemical Study on the Mechanism
Authors: György Keglevich, Réka Henyecz, Zoltán Mucsi, and Nóra Zs.
Kiss
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Advanced Synthesis & Catalysis
10.1002/adsc.201700895
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
The Palladium Acetate-Catalyzed Microwave-Assisted Hirao
Reaction without an Added P-Ligand as a “Green” Protocol; A
Quantum Chemical Study on the Mechanism
György Keglevich,* Réka Henyecz, Zoltán Mucsi and Nóra Zs. Kiss
a
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest,
Hungary; Phone: (+36)-1-463-1111/5883; Fax: (+36)-1-463-3648; e-mail: gkeglevich@mail.bme.hu
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. It was proved by our experiments that on
microwave irradiation, the mono or bidentate P-ligands
generally applied in the palladium(II)-catalyzed P–C
coupling reaction of aryl bromides and dialkyl phosphites
or secondary phosphine oxides may be substituted by the
excess of the >P(O)H reagent that exists under a
tautomeric equilibrium. Taking into account that the
reduction of the palladium(II) salt and the ligation of the
palladium(0) so formed requires 3 equivalents of the
P-species for the catalyst applied in a quantity of 5-10%,
all together, 15–30% of the P-reagent is necessary beyond
its stoichiometric quantity. In the coupling reaction of
diphenylphosphine oxide, it was possible to apply diethyl
phosphite as the reducing agent and as the P-ligand. The
reactivity of the diethyl phosphite and diphenylphosphine
oxide reagents was compared in a competitive reaction.
The mechanism and the energetics of this new variation
The first detailed study on simple reaction models
justified our assumption that, under the conditions of the
reaction, the trivalent form of the >P(O)H reagent may
serve as the P-ligand in the palladium(0) catalyst, and
shed light on the fine mechanism of the reaction
sequence. Existence of the earlier described bis(palladium
complex) {[H(OPh P) PdOAc] } was refuted by high
2 2 2
level theoretical calculations. This kind of complex may
be formed only with chloride anions instead of the acetate
anion. The interaction of palladium acetate and Y
may result in only the formation of the [(HO)Y
2
P(O)H
P] Pd
2
2
complex that is the active catalyst in the Hirao reaction.
The new variation of the Hirao reaction is of a more
general value, and represents the greenest protocol, as
there is no need for the usual P-ligands. Instead, the
>P(O)H reagent should be used in an excess up to 30%.
Hence, the costs and environmental burdens may be
decreased.
2
of the Hirao reaction of bromobenzene with Y P(O)H
reagents (Y=EtO and Ph) was explored by quantum
chemical calculations.
Keywords: cross-coupling; palladium catalyst; P ligands;
microwave heating; reaction mechanisms, energetics
Introduction
In respect of Pd catalysis, either Pd(PPh
3
) , or,
4
quite often, Pd(OAc) together with a mono and
2
The best method for the synthesis of
arylphosphonates is the Hirao reaction comprising a
P–C coupling between a dialkyl phosphite (H-
phosphonate) and an aryl or vinyl halide (mostly
bidentate P-ligand may be applied in the P–C
coupling reaction of aryl derivatives with >P(O)H
reagents. The senior author of this article with co-
workers were, who found that under microwave
(MW) conditions the Hirao reaction may take place
bromide) in the presence of Pd(PPh
3
) as the catalyst,
4
and in most cases, triethylamine as the base in
different solvents.[ Later on, different variations of
the Hirao reaction were described including in situ
formed Pd catalysts from suitable precursors (e.g.
in the presence of Pd(OAc)
usual P-ligand. NiCl could also be used under
similar conditions. This protocol was called as a
2
without the addition of a
1–8]
2
[21]
[22,23]
“P-ligand-free” P–C coupling reaction.
However,
Pd(OAc)
2
and PdCl
2
) and added mono- or bidentate
the situation is that, in these cases, a part of the
>P(O)H reagent present in the reaction mixture may
have served as the reducing agent, and as the P-ligand.
The “P-ligand-free” accomplishments mean a big
step further, as the use of expensive and air-sensitive
mono- and bidentate P-ligands may be avoided, thus
the costs and environmental burdens can be decreased.
Moreover, the realization of the Hirao reaction is
P-ligands, and extension to H-phosphinates, as well
as secondary phosphine oxides using different
arenes.[
9–14]
Moreover, Ni- and Cu complexes were
[9,10]
also applied as catalysts.
There were attempts to
elaborate green chemical accomplishments including
[15,16]
microwave (MW)-assisted methods,
and phase
transfer catalyzed protocols.[
17–20]
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700895
simplified if a single species may be the reagent, and,
at the same time, the reducing agent and the P-ligand.
The generally accepted catalytic cycle for the
Pd(0)-catalyzed Hirao reaction is shown in Figure 1.
According to this protocol, the main steps are the
oxidative addition of the aryl halide to the Pd(0)
complex (I) to give Pd(II) complex II, the change of
ligands that leads to key intermediate III, and the
reductive elimination providing the product
(1’) of the dialkyl phosphite or diphenylphosphine
oxide reagents (1) may play the role of the mono or
bidentate P-ligands added in all earlier cases into the
[21,22]
reaction mixtures.
The only requirement was to
add the >P(O)H species in a sufficient quantity so
that it should cover the stoichiometric quantity of the
reagent of the P–C coupling, and it should be enough
as P-ligand needed for the Pd complex (2) (0.20
equivalents if 10% of Pd(OAc) is used) (Scheme 2).
2
[24–30]
(
ArP(O)Y
2
), and regenerating the Pd(0) catalyst.
This occasion, the possible reductive role of the P-
reagent was neglected. To ensure an excess,
1
.5 equivalents of the >P(O)H reagent was used in
[21]
the first approach.
Scheme 2. In situ formation of the Pd(0) catalyst complex.
The possible role of secondary phosphine oxides
and related species as preligands in Pd complexes
including Pd(OAc) as the precursor was recognized
2
Figure 1. General scheme for the Pd-catalyzed Hirao
reaction.
[31,32]
by Ackermann.
We wished to evaluate the optimal quantity of the
P(O)H species using Pd(OAc) as the Pd precursor.
For this, the MW-assisted P–C coupling reaction of
bromobenzene and diethyl phosphite or
>
2
As a matter of fact, a few refinements of the above
cycle were also proposed by several authors. Such is
the incorporation of the P(III) tautomeric form of the
diphenylphosphine oxide was carried out using
different quantities (1.15–1.5 equivalents) of the P-
reagent in the presence of 1.1 equivalents of
>
P(O)H species in the primary Pd-adduct (II)
forming intermediate IV that undergoes
deprotonation by the base present in the mixture to
afford the secondary Pd-adduct (III’/III)
Scheme 1).[
a
triethylamine and, in most cases, 10% of Pd(OAc) in
2
a solvent (ethanol or acetonitrile) (Scheme 3). The
experimental data are listed in Table 1. The results of
the solvent-free accomplishments were also included.
25,29,30]
(
Scheme 1. Refinement of the II → III conversion in the
general scheme of the Hirao reaction.
Scheme 3. The model reaction investigated at different
molar ratios of the starting materials.
Our aim was to study the “P-ligand-free”
Pd(OAc) -catalyzed Hirao reaction for two simple
2
models. On the one hand, we wished to investigate
the role of the >P(O)H species. May it serve as the
reducing agent and as the P-ligand beside being the
reactant? On the other hand, we planned to evaluate
the fine mechanism of the simplified (“P-ligand-
free”) Hirao reaction in whole.
The experiments, where diethyl phosphite was
measured in a 1.5 equivalents quantity were carried
out at 120 °C for 0.5 h in the absence of any solvent
using 5% of Pd(OAc) , or in ethanol using 10% of the
2
catalyst to afford diethyl phenylphosphonate (4a) in
yields of 80% and 73%, respectively (Table 1/entries
1
and 2). Under conventional heating, the P-C
Results and Discussion
couplings remained incomplete. The thermal
variation of the MW-assisted experiment marked by
entry 1/footnote [b] of Table 1 led only to a
conversion of 52%. This experience underlines the
importance of MW irradiation in the protocol under
discussion. The solvent-supported P–C couplings
were repeated at a molar ratio of 1 and 1.3. It was
Experimental Results on the “P-ligand-free”
Hirao Reaction
As it was mentioned in the Introduction, we
elaborated a new version of the Hirao reaction. Our
idea was that under MW conditions the P(III) form
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700895
experienced that the use of only 1 equivalent of
acetonitrile may not be an entirely inert solvent. It is
noted that a series of solvents including toluene may
(
(
EtO) P(O)H gave product 4a in a lower yield of 54%
2
[9]
Table 1/entry 3). At the same time, the use of
.3 equivalents of the P-reagent resulted in a yield
74%) (Table 1/entry 4) comparable with that
obtained from the experiment applying
.5 equivalents of (EtO) P(O)H. Using acetonitrile
instead of ethanol, the yields were somewhat lower
Table 1/entry 5). Under the conditions applied,
serve as a medium for the Hirao reaction. Applying
only 5% of the Pd(OAc) together with 1.15
equivalents of diethyl phosphite, there was need for a
somewhat longer reaction time of
1
(
2
1
h
1
2
(Table 1/entry 6), but the yield (71%) was
comparable with the case covered by entry 4.
(
Table 1. Results of the MW-assisted Hirao reaction of bromobenzene with (EtO)
2
P(O)H or Ph
2
P(O)H carried out under
different molar ratios of the reagents using 1.1 equivalents of triethylamine as the base.
Y
Y
2
P(O)H
Pd(OAc)
%)
2
Solvent
T
(°C)
t
Conversion Yield Remark Entry
[
a]
(
(h)
(%)
(%)
quantity
(
equivalents)
EtO 1.5
EtO 1.5
EtO 1.0
EtO 1.3
EtO 1.3
EtO 1.15
5
–
120
120
120
120
120
120
120
150
150
150
150
150
150
120
110
0.5
0.5
0.5
0.5
0.5
1
97
100
80
73
ref. 21[b]
1
2
3
4
5
6
7
8
10
10
10
10
5
10
10
10
10
10
10
10
10
10
EtOH
EtOH
EtOH
MeCN
EtOH
EtOH
EtOH
EtOH
EtOH
MeCN
EtOH
EtOH
EtOH
not relevant 54
100
100
100
95
74
61
71
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1.3
1.3
1.0
1.2
1.3
1.0
1.0
1
0.5
0.5
0.5
0.5
0.5
100
87
not relevant 54
95
100
100
9
10
11
79
67
80
79
74
68
+ 30% (EtO)
+ 30% (EtO)
2
2
P(O)H[c] 12
[
d]
0.25 + 0.5 100
0.5
0.25
P(O)H
13
14
15
BuO 1.3
BnO 1.3
100
100
[
e]
BnOH
[f]
[
[
[
[
[
[
a]
b]
c]
b]
e]
f]
CEM Discover (300 W) applying 25–70 W.
Comparative thermal experiment led to a conversion of 52% and yield of 41%.
All components were reacted at once.
A pre-reaction was allowed between Pd(OAc)
To avoid transesterification.
2
and (EtO)
2
P(O)H for 15 min.
[33]
+
7
2
% of Ph P(O)(OBn) (δ
P
(CDCl
3
) 27.8 (δ
P
30.3), [M+H] = 309) was also present in the crude mixture as a by-
product.
Changing to diphenylphosphine oxide, in the first
presence of 1.3 equivalents of the P-reagent is more
advantageous than that of 1.2 equivalents. This must
be due to the fact that 10% of the >P(O)H species
should cover the reduction of Pd(II) to Pd(0). This
was confirmed experimentally by us, as from one of
the crude products (from the run covered by
Table 1/entry 4) we could detect the presence of
experiments it was applied in a quantity of 1.3
equivalents in the presence of 10% of the catalyst and
EtOH as the solvent. Carrying out the reaction at
1
20 °C for 1 h, the conversion was 95%
Table 1/entry 7), while the accomplishment at
50 °C for 0.5 h furnished triphenylphosphine oxide
4b) in a yield of 87% (Table 1/entry 8). The decrease
of the relative quantity of Ph P(O)H to 1 equivalent
led to a lower yield of 54% (Table 1/entry 9), as this
was observed also with (EtO) P(O)H. In case of 1.2
equivalents of Ph P(O)H, the yield of
triphenylphosphine oxide was 79% (Table 1/entry 10). reaction.
(
1
(
(EtO) P(O)OH (LC-MS, M+H = 154.04), which may
2
2
have formed as the oxidation product along with the
reduction of Pd(II) to Pd(0). To date, only in one case
was it suggested that a part of the P-ligand added to
the Pd(II) precursor is involved in the redox
2
2
[14]
Theoretically, triethylamine used as the
The use of acetonitrile as the solvent led again to a
lower yield (Table 1/entry 11).
base may also act as a reducing agent, but applying it
even in a 5-fold excess, the reduction was found
much slower, than that with a trivalent P-species, in
It can be seen that 1 equivalent of the >P(O)H
species (1) is not enough to ensure a complete
[34]
the given case PPh
3
.
Comparison of the yields
reaction, as, using 10% of Pd(OAc) , 20% of the P-
2
(87% and 79%) of the experiments marked by entries
reagent is consumed by the formation of the Pd
complex. Moreover, it also turned out that the
8 and 10 of Table 1 refers to the role of (EtO)
as a reductant.
2
P(O)H
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700895
The optimized P–C couplings were then extended
to one equivalent of bromobenzene were performed
to the reaction of dibutyl phosphite and dibenzyl
phosphite with bromobenzene. The corresponding
dialkyl phosphonates (4c and 4d) were obtained in
yields of 74% and 68%, respectively (Table 1/entries
in the presence of 10% of Pd(PPh
3
)
4
and
1.1 equivalents of triethylamine in ethanol as the
solvent. After a 20 min’s irradiation at 120 °C, the
31
reaction was interrupted, and analyzed. The P NMR
spectrum revealed the presence of 50% of
1
4 and 15). In the latter case, benzyl alcohol was
applied as the solvent to avoid transesterification, and
the formation of Ph P(O)(OBn) as a minor by-
triphenylphosphine oxide,
phenylphosphonate and
suggesting that Ph
39%
11%
of
diethyl
P(O)H,
2
(EtO)
2
product was inevitable. Dibenzyl phosphite is
obviously more reactive than dialkyl phosphites.
In whole, the protocol elaborated by us seems to be
of a more general value.
2
P(O)H is slightly more reactive,
than (EtO)
reaction.
2
P(O)H in the intrinsic P–C coupling
We were successful in preparing complex
[HO(EtO) Pd (2, Y= EtO) in a separate experiment
reacting Pd(OAc) with 1.3 equivalents of
(EtO) P(O)H at 120 °C for 30 min. P NMR shift of
the Pd complex (2, Y= EtO) was in agreement with
The message of our experiments is that in the “P-
ligand-free” Hirao reaction, 1.3 equivalents of the
]
2 2
2
3
1
>
P(O)H reagent should be used if the Pd(OAc)
2
2
catalyst is applied in a quantity of 10%. On a larger
scale, starting from 2.0 mmol of bromobenzene
instead of 0.05 mmol, 2.5% of the catalyst was
enough. In this case, 1.075 equivalents of the diethyl
phosphite were used, and the yield of phosphonate 4a
was 72%.
[11]
that reported by Kalek et al.
complex was then tested in the reaction of
(EtO) P(O)H with PhBr carried out as above. Diethyl
This prepared
2
phosphonate (4a) was obtained in a yield of 72%
proving that the in situ formed catalyst is identical to
species 2 (Y= EtO).
It is also noted that regarding the palladium salt
precursors, Pd(OAc)
2
is the best choice due to its
It is worth noting that Buono et al. described the
formation of another kind of complex from the
lipophilicity.[ However, we plan to try out also
PdCl that will be a subject of another study.
It was an interesting challenge to try, if in the P–C
coupling of PhBr and Ph P(O)H it is possible to use
EtO) P(O)H as the reducing agent of Pd(II) and as
9]
2
reaction of Pd(OAc) with a series of secondary
2
phosphine oxides applied in a two equivalents
quantity. The outcome is exemplified on the reaction
2
(
2
of Ph P(O)H performed in toluene at 60 °C for 2 h.
2
the P-ligand for the Pd formed. For this, the Hirao
Complex 5 was isolated in a yield of 54% (Scheme 4).
However, due to the low solubility of complex 5 in
most organic solvents, a complete characterization
reaction was carried out in the presence of
1
(
(
equivalent of Ph
EtO) P(O)H in two variations. In the first case
Table 1/entry 12), all components were measured in,
2
P(O)H and 0.3 equivalents of
[35]
2
was not possible.
and reacted. In the second instance (Table 1/entry 13)
a 15 min pre-reaction was allowed for Pd(OAc) and
EtO) P(O)H at 150 °C. As can be seen, the outcome
of the two reactions was similar (the yield was ca.
0% in both cases), but the P–C couplings under
2
(
2
8
discussion were somewhat less efficient as compared
to the control experiments marked by Table 1/entry 8.
Hence, it is possible to use (EtO)
ligand and the reducing agent, when the coupling
reagent is Ph P(O)H. In this way, a part of the
expensive Ph P(O)H may be substituted by
EtO) P(O)H. It is also obvious that there is no need
for a pre-reaction to form the active Pd(HOP(OEt)
2a) catalyst.
The reactivity order of the two >P(O)H species
used in our study was also a question. The
comparison of the reactivity of (EtO) P(O)H and
Ph P(O)H is not easy, as there are three independent
2
P(O)H as the P-
Scheme 4. Assumed formation of bis(palladium complex)
from Pd(OAc) and Ph P(O)H.
5
2
2
2
2
(
2
The activity of complex 5 in a [2+1] cycloaddition
)
2 2
[35]
model reaction was rather low. Later on, when the
(
complex was formed in situ by the reaction of
Pd(OAc)
2
and Ph P(O)H, the [2+1] cycloaddition
2
reaction was much more efficient according to the
2
[36]
yield of 60% reported.
2
We believe that in the later cases not complex 5,
and consecutive reaction steps: reduction of the Pd(II)
to Pd(0) (1.,), ligation of the Pd(0) so formed (2.,),
and the P–C coupling itself (3.,). As regards the gross
but the in situ formed [(HO)Ph
Y=Ph) may have been the real catalyst.
2
P] Pd complex (2,
2
Comparative theoretical calculations suggested that
while complex 5 is not a stable formation, the dimer-
like complex with two chloride anions (5’) may exist.
Let us start with the latter complex. In case of
chloride anion, the formation of the monomeric
reactivity, (EtO)
than Ph P(O)H, if the reaction times required at
20 °C using 1.3 equivalents of the >P(O)H species
2
P(O)H seems to be more reactive
2
1
and 10% of the catalyst in EtOH as the solvent are
compared (Table 1/entries 4 and 7). To be able to
decide on the reactivity of the >P(O)H species in the
P–C couplings, concurrent reactions comprising
–
–
(
OY
2
P)(HOY P)Pd(II) Cl species (where Y = Ph or
2
MeO) and their dimerization calculated at the
B3LYP/6-31G(d,p)//PCM(MeCN) level of theory is
energetically favourable (Table 2), and the dimeric
0.5 equivalents of both Ph
2
P(O)H and (EtO) P(O)H
2
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201700895
–
forms represent well-ordered and almost symmetrical
structures for both variations (Figure 2). The high
exothermicity provides enough driving force to
overcome the unfavourable entropy factors (ca.
In the case of OAc ion, the formation of the
–
OAc–
monomeric
( OY
2
P)(HOY
2
P)Pd(II)
is
energetically also favourable, however, the formation
of the dimers is endothermic (for Y = Ph, H =
–1
–1
–1
–1
1
70/178 J mol K ).
+82.3 kJ mol , for Y = MeO, H = +20.7 kJ mol ),
hence they cannot exist in the reality (Table 3). In
both cases, the dimeric forms represent disordered
and unsymmetrical structures (Figure 3).
Figure 2. Stereostructure of the monomeric and dimeric
chloride anion containing palladium complexes.
Table 2. Theoretical study on the formation of monomeric and dimeric Pd(II) complexes from PdCl
calculated at the B3LYP/6-31G(d,p)//PCM(MeCN) level.
2 2
and Y POH
Y
Step 1
PdCl
Step 2
2
+ 2 Y
2
POH  monomeric form
G S
2 monomeric forms  dimeric form (5’)

H
1
1
1
H
2
G
2
S
2
–1
–1
–1
–1
–1
–1
–1
–1
(
kJ mol )
(kJ mol )
–189.8
(J mol K )
–217.1
(kJ mol )
–118.9
(kJ mol )
ca. –70.5
–100.6
(J mol K )
–170.2
Ph
MeO
–254.5
–273.0
–214.7
–195.4
–153.8
–178.4
2 2
Table 3. Theoretical study on the formation of monomeric and dimeric Pd(II) complexes from Pd(OAc) and Y POH
calculated at the B3LYP/6-31G(d,p)//PCM(MeCN) level.
Step 1
Step 2
Pd(OAc)
2
+ 2 Y
2
POH  monomeric form
G S
2 monomeric forms  dimeric form (5)
Y

H
1
1
1
H
2
G
2
S
2
–
1
–1
–1
–1
–1
–1
–1
–1
(
kJ mol )
(kJ mol )
–201.0
(J mol K )
–170.0
(kJ mol )
+82.3*
(kJ mol )
+153.6*
+86.8*
(J mol K )
–237.5*
Ph
MeO
–252.0
–222.9
–171.9
–170.2
+20.7*
–220.2*
*Thermodynamic corrections were calculated from IR frequency calculations in vacuo and added to the PCM energy values.
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201700895
exothermic manner. In this structure, the two Pd
ligands are in the cis disposition, but this complex (8)
is transformed into the more stable trans variant (9).
After the oxidative addition, the bromide anion is
eliminated from complex 9 in an endothermic way
–
1
(
1
ca. +90 kJ mol ), resulting in cationic intermediate
0. During our study, the bromide anion is kept on
the side of the complex as a counter ion. In the next
step, the empty position of species 10 is occupied by
another unit of P(OH)Y to afford complex 11,
2
–
1
–1
gaining 70.0 kJ mol and 46.7 kJ mol enthalpies for
the cases of Y = OEt (a) and Y = Ph (b), respectively.
Here, the more exothermic process (10a  11a) may
be explained by the less sterical hindrance for the
ethoxy intermediate 11a. Then, the P–OH function of
the entering P-reagent is deprotonated in an
exothermic way by the triethylamine present in the
mixture, resulting zwitter ionic complex 12. The
significant difference between the enthalpy of the
–1
deprotonation of 11a (–41.9 kJ mol ) and that of 11b
–1
(
–0.30 kJ mol ) may be explained by considering the
stability of the zwitterions 12a (R=OEt) and 12b
R=Ph) formed. Due to the better electron donating
Figure 3. Stereostructure of the monomeric and dimeric
(
acetate anion containing palladium complexes.
ability of the ethoxy groups, the formation of
intermediate 12a is more favourable. It is noted that
the deprotonation of catalyst 2 would be highly
A Mechanistic Study on the Catalytic Cycle
+
unfavourable. (For the transformation 2  2–H ,
–
1
when Y = EtO, a ΔH of 33.2 kJ mol , while when
It is generally accepted that in the cross coupling
reactions, a Pd(0) species is involved in the first stage
of the catalytic cycle. For this, first of all, the Pd(II)
should be reduced to Pd(0), presumably, a part of the
–1
Y = Ph, a ΔH of 60.2 kJ mol was calculated in our
preliminary study.) The species with the deprotonated
P-ligand then undergoes a rearrangement via
transition state 13TS to form the C–P bond through a
moderate activation barrier (13TS). Here, the lower
activation enthalpy is exhibited by 13TSb meaning
that intermediate 12b with phenyl groups may be
stabilized faster. In contrast to this, the preceding
deprotonation of species 11 is more favourable for
the ethoxy substituted case. Finally, the complex of
>
P(O)H component serves as the reducing agent.
Then, the Pd(0) formed coordinates two >P–OH
ligands. In our case, there was no added P-ligand in
the reaction mixture.
The mechanism of the Hirao reaction was
calculated by the B3LYP/genecp//PCM(MeCN)
method. The 6-31G(d,p) basis set was chosen for
CHOBrP, while SDD(MWB28) for the Pd atom. The
schematic representation of the catalytic cycle is
shown in Figure 4, while the energy diagram in
Figure 5. The energetics calculated were summarized
in Table 4.
the product (14) is dissociated to PhP(O)Y (4),
2
catalyst 2 and the bromide anion in an exothermic
way rendering the overall process irreversible. After
regeneration, Pd(0) catalyst 2 is ready for the next
catalytic cycle. The considerable enthalpy gain
accompanying the 6  4 transformation means an
irreversible process.
In the first step of the catalytic cycle, which is the
oxidative addition sub-process, the active form of the
Kalek and Stawinski proposed another possibility
according to which the coordination of the dialkyl
phosphite to Pd via the P=O group facilitates its
deprotonation, and formation of the ligand exchange
catalyst {2, Pd(0)[P(OH)Y
2
] } and the reagent PhBr
2
(
3) forms a weak complex by coordination of the
phenyl ring and the Pd. This state may be considered
as the starting point of the catalytic cycle. Then, the
Pd is inserted into the C–Br bond via a low energy
[27]
product.
–1
(
ca. 57 kJ mol ) TS (7TS) resulting in species 8 in an
6
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Advanced Synthesis & Catalysis
10.1002/adsc.201700895
Figure 4. Schematic representation of the detailed catalytic cycle of the Hirao cross-coupling.
Figure 5. Schematic representation of the enthalpy change in the course of the reaction mechanism for Y = OEt (black)
and Y = Ph (red). Values calculated by the B3LYP/genecp//PCM(MeCN) method. The 6-31G(d,p) basis set was chosen
for CHOBrP, while SDD(MWB28) for the Pd atom. Bold numbers represent the differences of several selected
transformations.
7
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Advanced Synthesis & Catalysis
10.1002/adsc.201700895
–
1
–1
–1
Table 4. Enthalpy, Gibbs free energy (kJ mol ) and entropy (J mol K ) values of the reaction mechanism (see Figure 4
and 5) of the Hirao cross coupling, calculated by the B3LYP/genecp//PCM(MeCN) method. The 6-31G(d,p) basis set was
chosen for CHOBrP, while SDD(MWB28) for the Pd atom.
Y = OEt
Y = Ph

H
G
S
H
G
S
–1 –1
–
1
–1
–1 –1
–1
–1
(
kJ mol )
(kJ mol )
(J mol K )
(kJ mol )
(kJ mol )
(J mol K )
6
TS
8
0.0
55.8
0.0
69.6
0.0
0.0
58.5
0.0
83.9
–82.3
–93.5
–10.3
15.1
19.5
92.5
46.6
–128.7
0.0
7
–46.6
–57.8
–57.3
–35.5
–239.5
–266.1
–271.9
–203.8
–53.9
–85.3
–104.6
–89.6
–89.6
–296.0
–311.7
–299.3
–335.0
–60.6
–111.0
–113.9
–27.7
–97.7
–139.6
–41.1
–149.1
–166.6
–93.8
–96.8
–17.2
–26.3
–60.3
39.9
–113.5
–120.2
–26.4
–73.1
–73.4
3.2
9
1
1
1
0
1
2
1
3TS
1
4
–88.3
–150.5
–53.2
–146.8
–
4
+2+Br
resulting mixture was irradiated in a closed vial in a CEM
Discover (300 W) microwave reactor at the temperatures
and for the times shown in Table 1, entries 4, 6, 8, 14 and
Conclusions
Investigating the MW-assisted Hirao reaction of
bromobenzene and (EtO) P(O)H or Ph P(O)H in the
1
5. The reaction mixture was purified by column
2
2
chromatography using silica gel and hexane – ethyl acetate
as the eluent to give dialkyl phenylphosphonates 4a, 4c
and 4d as colourless oils, or triphenylphosphine oxide 4b
as white crystals. For compound characterization, see
Table 5. See the Supporting Information for more
spectroscopical data.
presence of triethylamine in ethanol, it was found that
the trivalent form of the >P(O)H reagent may serve as
the P-ligand in the Pd(0) catalyst formed by the
reduction of Pd(OAc) by the effect of the >P(O)H. It
2
means that if 10% of the catalyst precursor is used,
there is need for 1.3 equivalents of the >P(O)H
reagent. It is noteworthy that the protocol elaborated
requires MW irradiation, as on conventional heating,
the P–C couplings remain incomplete. It was also
Table 5. Identification of the products.
lit
[M+H]+found [M+H]+requires
Comp. δP(CDCl)
3
δ
P
[
[
[
[
a]
b]
c]
d]
[21]
[21]
[22]
[15]
4
4
4
4
a
b
c
18.8
29.5
18.8
19.8
19.7
30.3
19.4
19.8
215.0838
279.0941
271.1461
339.1133
215.0837
279.0939
271.1463
339.1145
possible to use (EtO)
2
P(O)H as the reducing agent
and the P-ligand in the coupling reaction of
d
Ph
Ph
2
P(O)H. The reactivity of (EtO)
2
2
P(O)H and
From the experiments [a]covered by entry 4 of Table 1,
b]covered by entry 8 of Table 1, [c]covered by entry 14 of
P(O)H was evaluated by a competitive reaction.
[
The novel role of the >P(O)H species was justified by
a detailed experimental and theoretical study. This
latter shed light on the fine mechanism of the Hirao
reaction involving the >P(O)H reagent as the P-ligand.
Table 1, [d]covered by entry 15 of Table 1.
In a scaled-up procedure, 2.0 mmol (0.21 mL) of
bromobenzene, 2.15 mmol (0.28 mL) of diethyl phosphite,
Existence
H(OPh P)
of
PdOAc]
the
was refuted by theoretical
P] Pd complex, an in
earlier
described
[
2
2
2
0
.05 mmol (0.011 g) of palladium acetate, 2.2 mmol
calculations. Only the [(HO)Ph
2
2
(0.31 mL) of triethylamine and 4 mL of ethanol were
measured in, otherwise the reaction was performed as
above. The work-up afforded 0.31 g (72%) of diethyl
phenylphosphonate 4a.
situ formed catalyst in the Hirao reaction investigated
by us, may be formed from Pd(OAc) and Ph P(O)H.
2
2
The new and simplified version of the Hirao reaction
is of general value, and represents the greenest
protocol. Costs and environmental burdens are saved,
as there is no need for mono- and bidentate P-ligands.
The P–C Coupling of Bromobenzene with
Diphenylphosphine oxide in the Presence of
Diethyl Phosphite as the P-ligand
To 0.011 g (0.05 mmol) of palladium acetate was added
0
.02 mL (0.15 mmol) of diethyl phosphite and 0.25 mL
Experimental Section
ethanol, then a pre-reaction was carried out in a closed vial
in a CEM Discover (300 W) microwave reactor at 120 °C
for 30 min. After that, 0.05 mL (0.50 mmol) of
bromobenzene, 0.10 g (0.50 mmol) of diphenylphosphine
oxide, 0.08 mL (0.60 mmol) of triethylamine and 0.75 mL
of ethanol was added. In case of Table 1/entry 12 all
components were reacted at once. The resulting mixture
was further irradiated at 150 °C for 30 minutes. The
reaction mixture was purified by column chromatography
using silica gel and hexane – ethyl acetate as the eluent to
give triphenylphosphine oxide 4b as white crystals.
General Procedure for the Reaction of
Bromobenzene with >P(O)H Reagents
To 0.05 mL (0.50 mmol) of bromobenzene was added
0
.011 g (0.05 mmol) of palladium acetate and 0.65 mmol
of the >P(O)H reagent ˙(diethyl phosphite: 0.08 mL,
dibutyl phosphite: 0.13 mL, dibenzyl phosphite: 0.14 mL,
or diphenylphosphine oxide: 0.13 g), 0.08 mL (0.60 mmol)
of triethylamine and 1 mL of ethanol (or benzyl alcohol) as
2
+
the solvent. (In case of 5% of Pd
salt, 0.005 g
(
(
0.025 mmol) of palladium acetate and 0.07 mL
0.60 mmol) of diethyl phosphite was measured in.) The
8
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Advanced Synthesis & Catalysis
10.1002/adsc.201700895
Concurrent P–C Couplings of Bromobenzene with References
Diphenylphosphine oxide and Diethyl Phosphite in
the presence of Pd(PPh
3
)
4
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[
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[
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[
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–4
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–3 –3
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[
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Supporting Information for details.
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This project was sponsored by the National Research
Development and Innovation Fund (K119202). NZK was
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1
0
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Advanced Synthesis & Catalysis
10.1002/adsc.201700895
FULL PAPER
The Palladium Acetate-Catalyzed Microwave-
Assisted Hirao Reaction without an Added P-
Ligand as a “Green” Protocol; A Quantum
Chemical Study on the Mechanism
Adv. Synth. Catal. 2017, Vol. Page – Page
György Keglevich,* Réka Henyecz, Zoltán Mucsi,
Nóra Zs. Kiss
1
1
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