Experimental and theoretical study on the "2,2′-bipiridyl-Ni-catalyzed"hirao reaction of > P(O)H reagents and halobenzenes: A Ni(0) → Ni(II) or a Ni(II) → Ni(IV) mechanism?

Article abstract of DOI:10.1021/acs.joc.0c00804

It was found by us that the P.C coupling reaction of >P(O)H reagents with PhX (X = I and Br) in the presence of NiCl2/Zn as the precursors for the assumed Ni(0) complexant together with 2,2′-bipyridine as the ligand took place only with PhI at 50/70 °C. M06-2X/6-31G(d,p)//PCM(MeCN) calculations for the reaction of Ph2P(O)H and PhX revealed a favorable energetics only for the loss of iodide following the oxidative addition of PhI on the Ni(0) atom. However, the assumed transition states with Ni(II) formed after P-ligand uptake and deprotonation could not undergo reductive elimination meaning a "dead-end route". Hence, it was assumed that the initial complexation of the remaining Ni2+ ions with 2,2′-bipyridine may move the P-C coupling forward via a Ni(II) → Ni(IV) transition. This route was also confirmed by calculations, and this mechanism was justified by preparative experiments carried out using NiCl2/bipyridine in the absence of Zn. Hence, the generally accepted Ni(0) → Ni(II) route was refuted by us, confirming the generality of the Ni(II) → N(IV) protocol, either in the presence of bipyridine, or using the excess of the >P(O)H reagent as the P-ligand. The results of the calculations on the complex forming ability of Ni(0) and Ni(II) with 2,2′-bipyridine or the P-reagents were in accord with our mechanistic proposition.

Full text of DOI:10.1021/acs.joc.0c00804

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Article
An Experimental and Theoretical Study on the “2,2’ Bipiridyl
Ni Catalyzed” Hirao Reaction of >P(O)H Reagents and
Halobenzenes; A Ni(0)#Ni(II) or a Ni(II)#Ni(IV) mechanism?
György Keglevich, Réka Henyecz, and Zoltán Mucsi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00804 • Publication Date (Web): 14 May 2020
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The Journal of Organic Chemistry
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An
Experimental
and
Theoretical
Study
on
the
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“2,2’-Bipiridyl-Ni-Catalyzed” Hirao Reaction of >P(O)H Reagents and
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Halobenzenes; A Ni(0)→Ni(II) or a Ni(II)→Ni(IV) mechanism?
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György Keglevich,* Réka Henyecz and Zoltán Mucsi
Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
E-mail: gkeglevich@mail.bme.hu
ABSTRACT
It was found by us that the P–C coupling reaction of >P(O)H reagents with PhX (X = I and Br)
in the presence of NiCl2/Zn as the precursors for the assumed Ni(0) complexant together with
2,2’-bipyridine as the ligand took place only with PhI at 50/70 °C. M06-2X/6-
31G(d,p)//PCM(MeCN) calculations for the reaction of Ph2P(O)H and PhX revealed a
favorable energetics only for the loss of iodide following the oxidative addition of PhI on the
Ni(0) atom. However, the assumed transition states with Ni(II) formed after P-ligand uptake
and deprotonation could not undergo reductive elimination meaning a “dead-end route”. Hence,
it was assumed that the initial complexation of the remaining Ni2+ ions with 2,2’-bipyridine
may move the P–C coupling forward via a Ni(II)→Ni(IV) transition. This route was also
confirmed by calculations, and this mechanism was justified by preparative experiments carried
out using NiCl2/bipyridine in the absence of Zn. Hence, the generally accepted Ni(0)→Ni(II)
route was refuted by us, confirming the generality of the Ni(II)→N(IV) protocol, either in the
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presence of bipyridine, or using the excess of the >P(O)H reagent as the P-ligand. The results
of the calculations on the complex forming ability of Ni(0) and Ni(II) with 2,2’-bipyridine or
the P-reagents were in accord with our mechanistic proposition.
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Keywords: Hirao reaction, halogenobenzene, >P(O)H reagent, P–C coupling, Ni catalyst, 2,2’-
bipyridine, reductant, mechanism, theoretical calculations
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INTRODUCTION
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The Hirao reaction that is a P–C coupling between vinyl and aryl halides (mostly bromides)
and >P(O)H reagents, such as dialkyl phosphites, alkyl phenyl-H-phosphinates and secondary
phosphine oxides is in the focus these days. On the one hand, it is a useful synthetic procedure
to provide phosphonates, phosphinates and tertiary phosphine oxides,1,2 on the other hand, its
mechanism is also of interest. The Hirao P–C coupling is an up-do-date alternative of the
Michaelis–Arbuzov reaction or Friedel–Craft arylation involving the interaction of
bromoarenes with trialkyl phosphites, or the functionalization of arenes with phosphinoyl
chlorides, respectively.
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Originally, Hirao described the application of tetrakis(triphenylphosphine)palladium as the
catalyst,3–5 then different Pd(0) precursors, e.g. Pd(II) salts were also used together with mono-
or bidentate P-ligands.1,2,6 There is an agreement that the originally present, or the in situ formed
Pd(0) undergoes oxidative addition with the vinyl- or aryl bromide. This step is followed by a
ligand exchange connecting the >P(O)H reagent to the central Pd(II) ion. The final step of the
catalytic cycle is reductive elimination to furnish the P–C coupled product and the regenerated
Pd(0) catalyst.7–9 A more general scheme of the metal-catalyzed P–C couplings is shown in
Figure 1.
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Figure 1. General scheme for the Hirao reaction of ArX and YZP(O)H species. The metal (M)
can be Pd or Ni.
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It was an important observation that a suitable excess of the >P(O)H reagent, via its >P-OH
tautomeric form, may serve as the P-ligand, and hence, there is no need to add the usual
phosphines.10 And what is more, the excess of the P-reagent may also serve as the reducing
agent to convert Pd(II) to Pd(0). A refined mechanism supported by experimental data and
quantum chemical calculations was set up for the “P-ligand-free” accomplishment by us.11
Moreover, the structure of the catalyst was identified as (HO)Y2P---Pd(O)---PY2(OH) (where
Y = aryl, alkyl or alkoxy), and its formation was also evaluated.12 It is well-known that
secondary phosphine oxides existing under the Y2P(O)H ⇌ Y2POH tautomeric equilibrium
(where Y = aryl or alkyl)13 may be applied as preligands in transition metal complex
catalysts.14–17
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Ni-catalysis is another option to carry out P–C couplings. Typical cases for Ni-catalyzed
Hirao reactions were summarized in Table 1. The first group includes Ni(cod)2 as the catalyst
precursor. Surprisingly, it could be used without any added ligand (Table 1, entry 1).18
Recalling our experience with Pd (OAc)2,10 it is reasonable to assume that a part of the >P(O)H
reagent may have served as the P-ligand. In most of the cases, Ni(cod)2 was used together with
N-19 or P-ligands20–22 (Table 1, entry 2 and entries 3–5, respectively). It is also a possibility that
the P–C couplings are performed using Ni(0) catalysts prepared in situ from Ni(II) salts by
reduction with Zn (or Mg). In these cases, 2,2'-bipyridine was applied as a suitable ligand
(Table 1, entries 6 and 7).23,24 There seems to be an agreement that in the above instances a
Ni(0) → Ni(II) conversion is involved in the catalytic cycle. In just one case, a P-ligand was
used together with Zn as the reductant (Table 1, entry 8).25 Examples involving Ni(II) salts
together with mostly P-, and occasionally N- and O-ligands in the absence of an external
reducing agent represent special instances (Table 1, entries 9–12).26–29 The question arises if
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the reduction of Ni(II) can be assumed or not in these cases. Two P-ligand-free protocols
applying Ni(NO3)2-based nanoparticles30 or just NiCl231 (Table 1, entries 13 and 14) were also
described. In the latter variation, the authors of this article proved experimentally and by high
level quantum chemical calculations that, surprisingly, a Ni(II) → Ni(IV) transformation occurs
in the catalytic cycle, and the >P-OH tautomer of the P-reagent provides the ligand.32 Beside
aryl derivatives, 1,1-dibromo-1-alkenes were also used as starting materials in Ni-catalyzed
reductive type P–C couplings with diphenylphosphine oxide.33
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In this paper, we wish to investigate the P–C coupling reaction of halogenobenzenes (PhX,
X = Br or I) with diphenylphosphine oxide and ethyl phenyl-H-phosphinate using a Ni(II) salt
together with 2,2'-bipyridine, in the presence or absence of Zn as the reducing agent. The
purpose of this study is to clarify the oxidation state of Ni in the P–C coupling reactions under
discussion, and to set up a reliable mechanism utilizing preparative experiments and high level
quantum chemical calculations. It was also our aim to critically evaluate and interpret the
literature data accumulated on the reductive type of Hirao reactions.
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Table 1. Ni-Catalyzed P–C Coupling of Aryl Derivatives with >P(O)H Reagents
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aromatic
substrate
Ni catalyst
precursor
external reducing
agent
entry
1
N-, P- or O-ligand
base
solvent T (°C)/t
dioxane
yield (%) ref.
ArS(O)nMe
(n = 0–2)
Ni(cod)2
–
–
tBuONa/K
30–98
20
100/1 day
9
tBuOK
K2CO3
K2CO3
Cs2CO3
–
dioxane 90/16 h
dioxane 80/20 h
dioxane ~100/18 h
13–90
56–96
50–98
36–98
75–97
75
21
22
23
24
25
26
10
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2
3
4
5
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7
ArCN
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
NiCl2
8-hydroxyquinoline (N)
dppf (P)
–
ArOTf
ArOC(O)tBu
ArOPiv
ArX
–
dcype (P)
–
dcype (P)
–
PhMe
H2O
~100/1 day
70/1 day
2,2'-bipyridine (N)
2,2'-bipyridine (N)
Zn (2 equiv.)
Zn (2 equiv.)
PhI
NiCl2
–
DMF
50/1 day
ArOY
(Y = Ms, Ts)
8
NiCl2
/ dppf (P)
pyridine (N)
/ dppp (P)
Zn (1 equiv.)
DIPEA
DMF
29–87
27
140/1.5 day
9
ArB(OH)2
ArX
NiBr2
NiCl2
NiCl2
NiCl2
–
–
–
–
K2CO3
K3PO4
K2CO3 or tBuONa DMF
DCE
100/1 day
100/1 day
90/10 h
120/20 h
50–98
14–99
46–87
30–95
28
29
30
31
10
11
12
dioxane
ArX
ArO”act”a
/ PPh3 or DME (P or O)
/ dppp (P)
K2CO3
K2CO3
TEA
MeCN
MeCN
MeCN
Ni(NO3)2-
based NPb
13
ArBr
–
–
–
–
100/18 h
3–86
32
33
14
ArBr
NiCl2
31–92
150 (MW)/1 h
a”act”: activating group.
bNP: nanoparticle.
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RESULTS AND DISCUSSION
1. P–C coupling reactions under reductive conditions
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At first, we wished to compare the most important Ni(0)-catalyzed P–C coupling protocols
described in the literature. In our experiments, the coupling of bromobenzene or iodobenzene
with diphenylphosphine oxide served as the model reaction. In the first experiment, PhBr and
Ph2P(O)H were reacted in the presence of 10% of NiCl2 as the catalyst precursor, 2 equivalents
of Zn as the reductant, and 2,2'-bipyridine (20%) as the N-ligand in water as the solvent.
Applying the conditions (a 1 day heating at 70 °C) described by Zhao et al.,23 and following the
work-up suggested (filtration, extraction by DCM, drying and chromatography),
triphenylphosphine oxide (TPPO) was obtained in a low yield of 5% that could be confirmed
after a few repetitions (Table 2, entry 1). In comparison, the yield reported was 92%.23 In the
next experiment, iodobenzene was applied instead of PhBr. In this case, our confirmed yield
for TPPO was much better, 65% (Table 2, entry 2) that was still lower than the reported
outcome of 92%.23 It is obvious that PhI is more reactive than PhBr in the P–C couplings
investigated. Then, the similar “reductive” Hirao reaction of ethyl phenyl-H-phosphinate with
PhI was performed in DMF as the solvent, and heating the mixture at 50 °C for one day in the
presence of Zn, and in the absence of TEA as described by Japanese authors.24 At 50 °C, the
yield of ethyl diphenylphosphinate (76%), was almost the same reported (75%)24 (Table 2,
entry 3). At a somewhat higher temperature of 70 °C, the yield remained practically the same
(78%). Then, the previous reactions were repeated in the presence of two equivalents of TEA
as the base. At 50 °C, the experimental and literature yields were 85% and 99%,24 respectively
(Table 2, entry 4). Again no significant change could be observed after running the P–C
coupling at 70 °C, as the yield was 84%. One can see that the presence of TEA has only a slight
effect on the outcome (see Table 2, entry 3 versus entry 4). This may be due to the presence of
2,2’-bipyridine and Zn that may also act as bases.
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As a new combination, PhEtOP(O)H was also reacted with PhBr under the previous conditions,
but at 70 °C the reaction took place in a low useful conversion allowing a yield of only 15% for
Ph2P(O)OEt (Table 2, entry 5). Then, Ph2P(O)H was reacted with PhI and PhBr in DMF in the
presence of Zn as the reducing agent. These P–C couplings led to the formation of Ph3PO in
yields of 75% and 5%, respectively (Table 2, entries 6 and 7). The reaction of
bis(4-methylphenyl)phosphine oxide with PhI and PhBr under similar conditions applied for
the arylation of Ph2P(O)H led to similar results. The P–C coupling with PhI furnished
(4-MePh)2PhPO in a yield of 74%, but PhBr was found again to be unreactive allowing a yield
of 8% (Table 2, entries 8 and 9).
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Then, driven by curiosity, the P–C coupling of PhI with PhEtOP(O)H, Ph2P(O)H and
(4-MeC6H4)2P(O)H was performed in DMF at 70 °C for one day in the presence of TEA, but
in the absence of Zn. To our surprise, the expected products, phosphinate [Ph2P(O)OEt], and
phosphine oxides [Ph3PO and (4-MeC6H4)2PO] were formed, and could be isolated in yields of
71%, 80% and 75%, respectively (Table 2, entries 10–12). This means that, as a matter of fact,
there is no need for Zn as a reductant.
Changing for Hirao reactions performed in the absence of reducing agent and N-ligand, the
NiCl2-catalyzed P–C coupling of PhEtOP(O)H and Ph2P(O)H with PhBr was carried out in
MeCN using K2CO3 or Cs2CO3 as the base under MW irradiation. In this cases, the excess of
the >P(O)H reagent served as the P-ligand via its >P-OH trivalent form. After a MW irradiation
at 150 °C for 30 min, in agreement with our earlier experience,31,32 the corresponding products
Ph2P(O)OEt and Ph3PO were isolated in yields of 86% and 83%, respectively (Table 2, entries
13 and 14). Repeating the last experiment with the difference that 1.2 equivalents of Zn was
also added to the mixture before irradiation, the reaction went wrong, and only
triphenylphosphine could be isolated from the mixture. PPh3 could be isolated in a yield of 23%
(Table 2, entry 15). It means that the addition of Zn was harmful to the P–C coupling, and the
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Ph3PO formed in a lower conversion was reduced to PPh3 by the Zn under the conditions of the
reaction (150 °C/MW). The MW-assisted P–C coupling of PhBr with Ph2P(O)H was also
attempted in the presence of 2,2'-bipyridine as the ligand to the Ni catalyst using triethylamine
as the base and DMF as the solvent. After an irradiation at 150 °C for 1 h, the usual work-up
afforded Ph3PO in a yield of 71% (Table 2, entry 16).
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It can be said that in the experiments applying P-ligand and marked by Table 2/entries 13–15,
the Ni(II)→Ni(IV) protocol proposed earlier32 governs these P–C couplings. It is noteworthy
that 2,2'-bipyridine was also a suitable ligand in the reaction of PhBr with Ph2P(O)H under MW
irradiation (Table2/entry 16). The question emerges if the earlier assumed Ni(0)→Ni(II)
variation may remain valid for the “reductive” accomplishments, if the P–C couplings take
place also in the absence of Zn as the reductant? The answer is unambiguous “no”, and this
problem is investigated by theoretical calculations (see below).
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Table 2. Ni-Catalyzed P–C Couplings under Different Conditions
T/t
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8
NiCl2 (10%)
reducing agent
a
b
Y = Ph ( ), EtO ( ),
PhX
1
X = I, Br
+
PhYP(O)H
Ph2YP O
c
4-MeC6H4 ( )
ligand (20%)/base
solvent
2
3
9
entry X
Y
N- or P-ligand
external reducing base
agent (equivalent)
solvent
T (°C)/t
conversion
to Ph2YPOa (%) (%)
yield
yieldlit
(%)
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46
(%)
c
1
Br
Ph
2,2'-bipyridine
2,2'-bipyridine
2,2'-bipyridine
2,2'-bipyridine
2,2'-bipyridine
2,2'-bipyridine
2,2'-bipyridine
Zn (2)
Zn (2)
Zn (1.2)
Zn (1.2)
Zn (1.2)
Zn (1.2)
Zn (1.2)
Zn (1.2)
Zn (1.2)
–
–
H2O
70/1 dayb
5 (3a)
92 (3a)25
92 (3a)25
75 (3b)26
99 (3b)26
2
I
Ph
–
H2O
70/1 day
50d/1 day
50d/1 day
90
95
65 (3a)
76 (3b)
85 (3b)
15 (3b)
75 (3a)
5 (3a)
3
I
EtO
EtO
EtO
Ph
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
4
I
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
96
c
5
Br
I
70/1 day
6
70/1 day
100
c
7
Br
I
Ph
70/1 day
8
4-MeC6H4 2,2'-bipyridine
4-MeC6H4 2,2'-bipyridine
70/1 day
100
74 (3c)
8 (3c)
c
9
Br
I
70/1 day
10
11
12
13
14
15
16
EtO
Ph
2,2'-bipyridine
2,2'-bipyridine
70/1 day
97
71 (3b)
80 (3a)
75 (3c)
86 (3b)
83 (3a)
23 (4)f
71 (3a)
I
–
70/1 day
100
100
100
I
4-MeC6H4 2,2'-bipyridine
–
70/1 day
Br
Br
Br
Br
EtO
Ph
PhEtOP(O)H
Ph2P(O)H
–
150 (MW)/30 min
150 (MW)/30 min
150 (MW)/30 min
150 (MW)/30 min
85e (3b)33
79 (3a)34
–
Cs2CO3 MeCN
Cs2CO3 MeCN
100
c
Ph
Ph2P(O)H
Zn (1.2)
–
Ph
2,2'-bipyridine
aBased on relative 31P-NMR intensities.
Et3N
DMF
92
bNo significant improvement in the yield on reaction at 100 °C for 2 days.
cCould not be detected.
dNo significant change in the yield after carrying out the reaction at 70 °C for 1 day.
eIn the presence of 5% of nickel chloride.
fPPh3 (4) was the product.
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2. Theoretical calculations on the complexing ability
5
6
7
8
The complexation processes of Ni(0) and Ni(II) with 2,2’-bipyridine or the
PhYP(O)H ⇌ PhYPOH species (Y = Ph and EtO) were studied by computational method at
M06-2X/6-31G(d,p)//PCM(MeCN) level of theory (Figure 2). The two ligands [bipyridyl and
PhYP(O)H] present in the mixture may compete for the same Ni species. It is noteworthy that
a sharp difference can be observed between the complexation enthalpies of Ni(0) and Ni(II)
towards the two kinds of ligands under discussion (Table 3). In most cases, Ni(II) forms
significantly stronger complexes both with bipyridine, and the >P(O)H species, than Ni(0). The
differences in the enthalpy values may be measured in hundreds of kJ mol–1. According to the
enthalpies of complexation, Ni(0) prefers the >P-OH ligands to bipyridine, while the situation
is just the opposite for Ni(II). Ni with the higher oxidation state of II prefers the bipyridine
ligand and forms a more stable complex with this bidentate ligand, as compared to the complex
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formation with P-ligands.
Coordination
3
4
2
0
N
N
N
N
N
B
Ni
Ni
II
N
I
A
F
Ph
Y
P
N
Ni(Z)
N
N
O
Ph
L
Ni
H
Ni
VI
P
Y
Z = 0, II
0.0
N
O
OH
P
H
Y
Ph
VII
J
C
I
K
Ph
Y
OH Ph
Y
Y
Ph
P
P
P
P
D
E
HO
Ph
HO
OH
OH
Ph
Y
Ni
III
P
Y
Ni
Ni
P
Y P
Y
HO
Ph
OH
Ph
Ph
P
P
Y
Y
Ph HO
V
HO
IV
Figure 2. Summary of the complexation processes for Ni(0) and Ni(II). Letters A–L refer to the
single steps.
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Table 3. The enthalpy (H) and Gibbs free energy values (G) of the complexation of Ni(0)
and Ni(II) by >P-OH or bipyridine computed at M06-2X/6-31G(d,p)//PCM(MeCN) level of
theory, given in kJ mol–1. The meanings of letters A–L were defined in Figure 2.
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Ni(0)
Ni(II)
H
Y = Ph
Y = OEt
Y = Ph
Y = OEt
H
G
H
G
H
G
G
(kJ mol–1) (kJ mol–1) (kJ mol–1) (kJ mol–1) (kJ mol–1) (kJ mol–1) (kJ mol–1) (kJ mol–1)
A
B
C
D
E
F
G
H
I
–64.5
–301.1
–123.8
–132.8
–180.8
–118.8
161.0
17.9
–20.3
–244.8
–49.6
–53.2
–133.1
–62.1
149.9
61.3
–64.5
–301.1
–108.6
–168.3
–119.1
–130.0
171.0
41.3
–20.3
–244.8
–14.6
–106.3
–46.6
–84.4
160.3
99.6
–440.0
–343.7
–310.9
–263.3
–171.6
–143.0
200.7
–399.6
–282.9
–147.6
–224.1
–103.5
–98.5
–440.0
–343.7
–312.6
–181.1
–191.7
–118.8
224.9
75.7
–65.2
–214.4
–22.7
–149.2
–399.6
–282.9
–209.7
–134.0
–103.5
–62.1
220.8
136.9
–118.0
–201.9
–98.4
184.4
35.4
–10.1
75.0
52.1
–91.0
89.8
–12.3
–100.9
32.2
82.3
16.1
–63.4
J
K
L
–47.4
71.7
–44.7
2.0
–175.4
–3.8
–172.8
–69.3
–149.2
–83.9
–129.7
–60.7
–165.3
–109.4
–83.9
3. Theoretical calculations on the mechanism of the Ni-catalyzed P–C couplings
3.1 Thermodynamics of the P–C coupling reaction of >P(O)H species with
halogenobenzenes
M06-2X/6-31G(d,p) calculations suggested that the P–C couplings of Ph2P(O)H and
PhEtOP(O)H with halogenobenzenes are exothermic, and that the reaction with PhI is more
than two times exotermic than that with PhBr (Table 4).
Table 4. Thermodynamics of the Hirao reactions investigated.
catalyst
PhX
+
PhYP(O)H
Ph2YPO
+
Et3NH X
+
Et3N
1
2
a
3
b
a b
Y = Ph ( ), EtO ( )
X = I, Br
Y = Ph ( ), EtO ( )
Y = Ph
Y = OEt
X
H (kJ mol–1) G (kJ mol–1) S (kJ mol–1) H (kJ mol–1) G (kJ mol–1) S (kJ mol–1)
Br–
I–
–64.2
–153.9
–52.5
–139.3
–39.1
–49.0
–71.1
–160.8
–51.8
–138.5
–64.8
–74.7
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3.2 The course of the P–C couplings under reductive conditions [Ni(0)]
5
6
7
8
9
The reaction of Ph2P(O)H with PhI or PhBr served as the model reaction calculated by the
M06-2X/6-31G(d,p)//PCM(MeCN) method (Figure 3). The catalytic cycle starts with the
decomplexation of the rather stable bis[bipyridylNi(0)] complex (II) accompanied by the entry
of the halogenobenzene (1) reactant. Immediately a 2 complex (5) is formed, terminating the
aromaticity of the phenyl ring. After the rearrangement of the complex, i.e. after an oxidative
addition, the halogene is transferred and bound as an anion (Br– or I–) to the metal via a low
energy transition state (5*), and affords the corresponding intermediate (6) in an exothermic
manner, meanwhile a phenyl anion is also generated. Theoretically, the two electrons required
for the transformation outlined are covered by the oxidation of the Ni(0) to Ni(II). The
energetics of the subsequent elimination of the halogenide anion depend on the nature of the
halogene. The bromine anion is bound much stronger to the Ni atom than the iodine anion,
hence the enthalpy demand for the debromination and deiodination is +235.4 kJ mol–1 and +80.1
kJ mol–1, respectively. The resulting naked phenyl complex (7) is then attacked and complexed
by the Ph2P(O)H reagent, gaining some enthalpy. The intermediates (8) are then deprotonated
at the >P-OH moiety by TEA (that may be followed by a final rearrangement). However, the
species (9A and 9B) formed after deprotonation cannot undergo reductive elimination, as we
could not find a reaction coordinate connecting directly the minimum of 9A or 9B and the state
I+3a, meaning practically a “dead-end street”. Theoretically, in this elementary step a phenyl
anion should approach and attack a negatively charged >PO– anion, which is prevented by the
coulomb repulsion between them. Moreover, in this step, the Ni(II) should to be reduced by
getting back two electrons, meanwhile the quasi P(III) should be oxidized to P(V). The enthalpy
and energy values belonging to this dead-end street mechanism are listed in Table 5. Another
invalid mechanism was observed, when the primary P-complex was not deprotonated, but
directly attacked by the phenyl anion.
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8
It is assumed that the Ni2+ ions that are present in a low concentration allowed by the
thermodynamics of the red-ox system controlled by the Nernst equation may push the P–C
coupling further via the corresponding bipyridyl complex (see below).
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Figure 3. “Dead-end street” in the mechanism of the Ph2P(O)H +PhX (X = I, Br) reaction calculated by the M06-2X/6-31G(d,p)//PCM(MeCN)
method.
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Table 5. The enthalpy (H) and Gibbs free energy values (G) of the Hirao reaction with Ni(0),
5
6
computed at M06-2X/6-31G(d,p)//PCM(MeCN) level of theory, given in kJ mol–1.
7
8
9
X = Br
X = I
H (kJ mol–1) G (kJ mol–1) H (kJ mol–1) G (kJ mol–1)
10
11
12
13
14
15
16
17
18
19
20
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22
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5
6
7
8
79.8
–199.1
36.3
–96.3
–62.9
–108.7
69.8
–212.8
–11.7
–95.5
–58.7
–94.2
+113.8
–133.5
–53.4
–186.1
–167.9
–198.5
+102.0
–150.6
–98.4
–182.3
–161.7
–181.0
9A
9B
TS
I + 3a
II + 3a
DE*
DE*
37.7
–64.2
52.1
–52.5
–52.1
–153.9
–34.7
–139.3
*DE = does not exist.
3.3 A study on the acidity of the naked and complexed PhYP(O)H reagents
According the computational results, the deprotonation of the PhYP(O)H (2) species (Y = Ph
or EtO) by triethylamine (Figure 4, eq. 1 and Table 6, entry 1) is rather endothermic (H =
140.0/150.8 kJ mol–1), referring to their experimentally known weak acidic character. However,
if the PhYP(O)H reagent is complexed with the (Bipy)Ni(II) (VI/Ni(II)), the acidity is
significantly increased, and the deprotonation exhibits exothermic values (H = -50.3/-73.2
kJ mol–1) meaning a spontaneous loss of the proton (Figure 4, eq. 2 and Table 6, entry 2). In the
case of (Bipy)Ni(0)–PPhY(OH) complexes (VI/Ni(0)), in accord with the H values of 77.8
and 66.0 kJ mol–1, the acidity is rather weak (Figure 4, eq. 3 and Table 6, entry 4). A
deprotonation connected with the rearrangement of the P-complex (VIII) to the corresponding
O-complex (IX) may also occur, and the enthalpy change for the formation of the rearranged
product (IX) is more favorable than that for the corresponding P-complex (VIII) (Table 6,
entries 3 and 5 vs entries 2 and 4).
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Ph
Y
Ph
HP
O
P
Y
Et3N
+
eq. 1.
Et3NH
+
O
6
7
10
2
a
b
Y = Ph ( ), EtO ( )
a
b
Y = Ph ( ), EtO ( )
8
9
N
N
Ph
Y
(Z)
Ni
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P
Et3NH eq. 2.
+
O
N
N
Ph
Y
(Z)
Ni
VIII
(P-complex)
P
Et3N
+
OH
Ph
(Z)
Ni
Y
P
O
N
N
VI
(P-complex)
Et3NH eq. 3.
+
Z = 0, II
IX
(O-complex)
Figure 4. The acid-base equilibria for species 2 and VI in the presence of triethylamine. The
corresponding enthalpy values visualized in the right side are listed in Table 6, computed at
M06-2X/6-31G(d,p)//PCM(MeCN) level of theory.
Table 6. The enthalpy (H) and Gibbs free energy values (G) (in kJ mol–1) for the
deprotonation of species 2 and VI in the presence of triethylamine, computed at M06-2X/6-
31G(d,p)//PCM(MeCN) level of theory.
Y = Ph
Y = OEt
entry Ni(Z)
H (kJ mol–1) G (kJ mol–1) H (kJ mol–1) G (kJ mol–1)
1
2
3
4
5
–
eq. 1.
eq. 2.
eq. 3.
eq. 2.
eq. 3.
+140.0
–50.3
–112.7
+77.8
+26.1
+133.0
–48.3
–101.9
+79.6
+35.1
+150.8
–73.2
–193.4
+66.0
–38.8
+152.6
–63.7
–190.0
+72.7
–30.4
210
VIVIII
VIIX
VIVIII
VIIX
Ni(II)
Ni(0)
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3.4 The course of the P–C couplings in the absence of reductant
5
6
7
8
9
It was shown under point 3.2 that the Ni(0)Ni(II)Ni(0) sequence is not operable under
the reductive conditions applied, as the reaction pathway is disrupted in the last step. It was
assumed that the Ni(II)Ni(0) process does not have the sufficient electrochemical potential
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to oxidate P(III) to P(V) in the final step. We decided to return to the Ni(II)Ni(IV)Ni(II)
protocol, which was proved to be a realistic route applying P-ligands.32 The catalytic process
starting with Ni(II)-bipyridyl complex II was also evaluated by the M06-2X/6-
31G(d,p)//PCM(MeCN) method. The IIVIIVIVIII111213(14+3a) route
proposed was summarized in Figure 5, while the energetics are listed in Table 7. The reaction
starts with an endothermic ligand exchange process (IIVII), followed by the elimination of
one of the P-ligands (VIIVI) and a deprotonation (VIVIII) by NEt3. The next step involves
the coordination of the halogenobenzene reactant, which is much more favorable in case of
X=Br than in the instance with X=I. This refers to the much weaker C–I bond, which is
dissociated easier. It was found that the oxidative addition of PhX within Ni(II)-bipyridyl
complex 11 is realized via high energy state 12 with Ni(IV), affording the complex of product
(as 13) in a single step. The reduction of Ni(IV) in TS 12 to Ni(II), as in intermediate (13), is
connected with the oxidation of P(III) to P(V) (again in 13). It is worthy to mention that the
enthalpy barrier is much lower for the addition of PhI than that for PhBr (+58.1 kJ mol–1 vs
+201.3 kJ mol–1). This is in full agreement with our experimental findings (see Table 2, entries
2, 6 vs entries 1, 7). An efficient P–C coupling of PhBr with Ph2P(O)H applying 2,2'-bipyridine
as the ligand was possible only at a higher temperature of 150 °C under MW conditions (see
Table 2, entry 16). The enthalpy requirement of 201.3 kJ mol–1 for the 11→12 transformation
may be covered by MW irradiation. It was found earlier that the direct esterification of P-acids
characterized by H# of up to 186 kJ mol–1 can be performed under MWs.34,35
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The Ni(II)→Ni(IV) protocol discussed above using the bipyridine ligand has not only been
confirmed by our experiments and calculations, but it is also in agreement with the findings of
other authors, especially Zhao et al., who described a Ni(II)-catalyzed P–C coupling in the
presence of pyridine as the N-ligand in the absence of a reductant.26
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Our observation that the NiCl2/2,2'-bipyridine-catalyzed P–C couplings take place via the
Ni(II)Ni(IV) route and not via the Ni(0)Ni(II) protocol is in some respect groundbreaking,
as till date the latter possibility was assumed. Considering our earlier finding that the
Ni(II)/>P-OH-catalyzed Hirao reactions take also place via the surprising Ni(II)Ni(IV)
conversion,32 this realization may be of general value.
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Figure 5. Reaction mechanism of the Hirao reaction of Ph2P(O)H +PhBr or PhI, calculated at M06-2X/6-31G(d,p)//PCM(MeCN) level of theory.
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Table 7. The enthalpy (H) and Gibbs free energy values (G) of the Hirao reaction with Ni(II),
5
6
computed at M06-2X/6-31G(d,p)//PCM(MeCN) level of theory, given in kJ mol–1.
7
8
9
X = Br
X = I
H (kJ mol–1) G (kJ mol–1) H (kJ mol–1) G (kJ mol–1)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
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VIII
VII
IX
11
12
35.4
200.7
150.5
22.6
223.9
–133.4
–53.9
75.0
184.4
136.1
69.8
205.2
–87.5
–66.3
35.4
200.7
150.5
150.8
208.9
–198.9
–119.4
75.0
184.4
136.1
195.4
187.2
–153.0
–131.8
13+3a
14+3a
CONCLUSIONS
In summary, we found that the Hirao reaction of iodobenzene with diphenylphosphine oxide or
ethyl phenyl-H-phosphinate in the presence of NiCl2, 2,2’-bipyridine and Zn, as well as
triethylamine in DMF at 50/70 °C afforded the corresponding P–C coupled products Ph3PO and
PhEtOPO via the Ni(II)→Ni(IV) protocol. Preparative experiments showed that the presence
of Zn as a reductant had no impact on the course of the P–C coupling. Without Zn, the outcome
of the reaction was practically the same as that in the presence of the reductant. Moreover, high
level M06-2X/6-31G(d,p)//PCM(MeCN) calculations did not justify the Ni(0)→Ni(II)
transition assuming the reductive variation of the Hirao reaction. This kind of approach simply
led to a “dead-end street”. However, the Ni(II) →Ni(IV) driven P–C coupling was justified,
when 2,2-bipyridine was applied as the N-ligand. The enthalpy requirement of the oxidative
addition of PhX (X=Br and I) on the “N,N,P–Ni(II)” complex depended on the nature of the
halogene: PhI was more reactive than PhBr. It is recalled that the P–C coupling reactions of
PhBr and >P(O)H reagents took also place, when some excess of the reagent served as the P-
ligand (via the >P-OH tautomeric form) for NiCl2. Heating at 150 °C under MW conditions
allowed efficient phosphinoylation of PhBr. It can be concluded that the Ni(II)→Ni(IV)
mechanism seems to be general, no matter if a N- or P-ligand is used. The results of the
calculations on the competitive complexation of Ni(0) or Ni(II) with >P-OH or bipyridine were
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in agreement with our mechanistic calculations. Our experimental and theoretical results refuted
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the earlier assumed, but never proved Ni(0)→Ni(II) mechanism.
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EXPERIMENTAL SECTION
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General Information. All reagents and solvents were purchased in purities of >98% from
Sigma-Aldrich or TCI, and were used without further purification. The reactions under
traditional heating were performed in an oil bath.
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The MW-assisted experiments were carried out in a CEM® Discover Model SP (300 W)
focused microwave reactor equipped with a stirrer and a pressure controller using 100 W
irradiation under isothermal conditions. The reaction mixtures based on batches of 0.5 mmol
quantities were irradiated in sealed borosilicate glass vessel (with a volume of 10 mL) available
from the supplier of CEM®. The reaction temperature was monitored by an external IR sensor.
A scale-up to 1 mmol was not possible due to the limit of the MW device.
1
The 31P, 13C and H NMR spectra were taken in CDCl3 solution on a Bruker AV-300
spectrometer operating at 121.5, 75.5 and 300 MHz, respectively. The 31P chemical shifts are
referred to H3PO4, while the 13C and 1H chemical shifts are referred to TMS. The couplings are
given in Hz. The melting point of products 3a and 3c was determined using a Bibby Scientific
SMP10 Melting Point Apparatus.
General Procedure A: The Nickel-catalyzed P–C Coupling of Bromo-, or Iodobenzene
with >P(O)H reagents in the Presence of NiCl2 as the Catalyst Precursor and 2,2’-
Bipyridine as the N-Ligand.
To a test tube was added 0.0065 g (0.050 mmol) of nickel chloride, 0.60 mmol of the aryl halide
(1) (0.063 mL of bromobenzene or 0.067 mL of iodobenzene), 0.50 mmol of the >P(O)H
reagent [0.10 g of diphenylphosphine oxide (2a), 0.075 mL of ethyl phenyl-H-phosphinate (2b)
or 0.11 g of bis(4-methylphenyl)phosphine oxide (2c)], 0.016 g (0.10 mmol) of 2,2′-bipyridine,
1 mL water or DMF as the solvent. At certain cases (for details, see Table 2) zinc powder
[0.039 g (0.60 mmol) or 0.065 g (1.0 mmol)] and 0.14 mL (1.0 mmol) triethylamine was also
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measured in. The resulting mixture was stirred in an oil bath at the temperatures and for the
times shown in Table 2. The crude reaction mixture was filtrated and passed through a thin (2-
3 cm) layer of silica gel using ethyl acetate as the solvent. The crude product was analyzed by
31P NMR spectroscopy and further purified by column chromatography (see below).
As a representative example, the experiment covered by entry 11 of Table 2 was scaled up to a
double amount. In this case, the yield of 3a was 83%.
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General Procedure B: The MW-assisted Hirao Reaction of Bromobenzene with
Diphenylphosphine Oxide or Ethyl Phenyl-H-phosphinate in the Presence of NiCl2.
The MW-assisted reactions were performed according to our earlier methods.31,32 To a MW
glass vessel was added 0.0065 g (0.050 mmol) of nickel chloride, 0.052 mL (0.50 mmol) of
bromobenzene, 0.12 g (0.60 mmol) of diphenylphosphine oxide (2a) or 0.090 mL (0.60 mmol)
of ethyl phenyl-H-phosphinate (2b), 0.16 g (0.50 mmol) of cesium carbonate and 1 mL of
acetonitrile. In one case (Table 2, entry 15) 0.039 g of (0.6 mmol) zinc powder was also added.
The resulting mixture was irradiated in the MW reactor at 150 °C for 30 min for (see Table 2,
entries 13–15). The crude reaction mixture was filtrated and passed through a thin (2-3 cm)
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layer of silica gel using ethyl acetate as the solvent. The crude product was analyzed by P
NMR spectroscopy and further purified by column chromatography using silica gel and ethyl-
acetate – hexane as the eluent.
In one case (Table 2, entry 16), a mixture of 0.063 mL (0.60 mmol) of bromobenzene, 0.10 g
(0.50 mmol) of diphenylphosphine oxide (2a), 0.0065 g (0.050 mmol) of nickel chloride,
0.016 g (0.10 mmol) of 2,2′-bipyridine and 0.14 mL (1.0 mmol) triethylamine in 1 mL of DMF
as the solvent was irradiated at 150 °C for 1 h as above. Following a similar work-up,
triphenylphosphine oxide (3a) was obtained in a yield of 71%.
Triphenylphosphine Oxide (3a): Following the General Procedure A. (Table 2, entries 2 and
11) or the General Procedure B. (Table 2, entry 14) and after purification by column
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chromatography (silica gel and hexane–acetone (6:4) as the eluent), 3a was obtained as white
crystals in yields of 65/80/83% (0.090/0.11/0.12 g) (see Table 2, entries 2, 11 and 14,
respectively) and in purity of >98%. 31P NMR (CDCl3, 121.5 MHz) δ 29.1; 1H NMR (CDCl3,
300 MHz) δ 7.41–7.58 (m, 9H), 7.60–7.74 (m, 6H); 13C{1H} NMR (CDCl3, 75.5 MHz) δ 128.5
(d, J = 12.1), 131.9 (d, J = 2.7), 132.1 (d, J = 9.9), 132.6 (d, J = 103.2); mp. 155–156 °C; all
identical to those described in the literature.12,20,23
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Ethyl Diphenylphosphinate (3b): Following the General Procedure A. (Table 2, entries 4 and
10) or the General Procedure B. (Table 2, entry 13) and after purification by column
chromatography (silica gel and ethyl acetate–hexane (7:3) as the eluent, 3b was obtained as
colorless oil in yields of 85/71/86% (0.10/0.087/0.11 g) (see Table 2, entries 4, 10 and 13,
respectively) and in purity of ≥98%. 31P NMR (CDCl3, 121.5 MHz) δ 31.4; 1H NMR (CDCl3,
300 MHz) δ 1.37 (t, J = 7.1, 3H), 4.11 (quint, J = 7.1, 2H), 7.39–7.56 (m, 6H), 7.75–7.90 (m,
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4H) ; C{1H} NMR (CDCl3, 75.5 MHz) δ 16.5 (d, J = 6.6), 61.1 (d, J = 5.9), 128.5 (d, J =
13.1), 131.6 (d, J = 10.1), 131.8 (d, J = 137.0), 132.1 (d, J = 2.8); all identical to those described
in the literature.10,24,25
Bis(4-methylphenyl)phenylphosphine Oxide (3c): Following the General Procedure A.
(Table 2, entries 8 and 12) and after purification by column chromatography (silica gel and
hexane–acetone (6:4) as the eluent, 3c was obtained as white crystals yields of 74/75%
(0.11/0.12 g) (see Table 2, entries 8 and 12) and in purity of ≥96%. 31P NMR (CDCl3, 121.5
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MHz) δ 27.8; H NMR (CDCl3, 300 MHz) δ 2.39 (s, 6H), 7.18–7.35 (m, 4H), 7.36–7.76 (m,
9H); 13C{1H} NMR (CDCl3, 75.5 MHz) δ 21.6 (d, J = 1.4), 128.4 (d, J = 12.1), 129.2 (d, J =
12.5), 129.3 (d, J = 106.7), 131.7 (d, J = 2.8), 132.0 (d, J = 9.8), 132.1 (d, J = 10.3), 133.1 (d,
J = 104.2), 142.4 (d, J = 2.8); mp. 76-77 °C; all identical to those described in the
literature.12,19,25
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Triphenylphopsphine (4): Following the General Procedure B. (Table 2, entry 15) and after
purification by column chromatography (silica gel and hexane–acetone (6:4) as the eluent, 4
was obtained as a by-product as white crystals in a yield of 23% (0.030 g) and in a purity of
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≥98%. P NMR (CDCl3, 121.5 MHz) δ –5.7; H NMR (CDCl3, 300 MHz) δ 7.18–7.35 (m,
4H), 7.26–7.37 (m, 15H); 13C{1H} NMR (CDCl3, 75.5 MHz) δ 128.6 (d, J = 7.0), 128.8, 133.9
(d, J = 19.5), 137.3 (d, J = 10.7); mp. 79–80 °C; all identical to those described in the
literature.19,36
For the spectroscopic data of compounds 3a–c and 4 see the Supporting Information.
Theoretical calculations
All computations were carried out with the Gaussian16 program package (G16),37 using
standard convergence criteria for the gradients of the root mean square (RMS) Force, Maximum
Force, RMS displacement and maximum displacement vectors (3.0 × 10–4, 4.5 × 10–4, 1.2 × 10–
3 and 1.8 × 10–3). Computations were carried out at M06-2X level of theory.38 The basis set of
6-31G(d,p) was applied for C, H, O, P, N, Br, Ni and SDD/MWB46 for iodine.39 The vibrational
frequencies were computed at the same levels of theory, in order to confirm properly all
structures as residing at minima on their potential energy hypersurfaces (PESs).
Thermodynamic functions U, H, G and S were computed at 398.15 K. Beside the vacuum
calculations, the IEFPCM method was also applied to model the solvent effect, by using the
default settings of G16, setting the ε = 35.688.40 See the Supporting Information for details.
ASSOCIATED CONTENT
Supporting Information
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The Supporting Information (31P, H and C NMR spectra of the products, energetics and
geometrical data belonging to the theoretical calculations) is available free of charge on the
ACS Publications website at DOI: …….
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: gkeglevich@mail.bme.hu
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ORCID
György Keglevich: 0000-0002-5366-472X
Réka Henyecz: 0000-0003-2811-5304
Zoltán Mucsi: 0000-0003-3224-8847
Author Contributions
†All authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This project was sponsored by the National Research, Development and Innovation Office
(K119202). R. H. is grateful for the financial support of the Gedeon Richter's Talentum
Foundation.
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