Some mechanistic aspects of a nickel-catalyzed electrochemical cross-coupling between aryl halides and substituted chloropyridazines

Article abstract of DOI:10.1016/j.electacta.2010.02.092

The nickel-2,2′-bipyridine catalyzed electrochemical cross-coupling reaction between an aryl halide and a chloropyridazine was investigated by an electrochemical study. The electrochemical behavior of the divalent nickel complex is affected by the presenc

Full text of DOI:10.1016/j.electacta.2010.02.092

Electrochimica Acta 55 (2010) 4495–4500
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Electrochimica Acta
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Some mechanistic aspects of a nickel-catalyzed electrochemical cross-coupling
between aryl halides and substituted chloropyridazines
Karène Urgina, Rachid Barhdadia,∗, Sylvie Condona, Eric Léonela, Muriel Pipelierb,
Virginie Blotb, Christine Thobie-Gautierb, Didier Dubreuilb
a Equipe d’Electrochimie et Synthèse Organique, Institut de Chimie et des Matériaux Paris-Est, CNRS UMR 7182, Université Paris Est Créteil Val de Marne,
2 rue Henri Dunant 94320 Thiais, France
b Université de Nantes, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UFR des Sciences et des Techniques, UMR CNRS 6230,
2 rue de la Houssinière, B.P. 92208, 44322 Nantes Cedex 3, France
a r t i c l e i n f o
a b s t r a c t
The nickel-2,2ꢀ-bipyridine catalyzed electrochemical cross-coupling reaction between an aryl halide and
a chloropyridazine was investigated by an electrochemical study. The electrochemical behavior of the
divalent nickel complex is affected by the presence of pyridazine rings which act as co-ligands of nickel.
Cyclic voltammetry indicates that the cross-coupling reaction involves first a rapid oxidative addition of
the chloropyridazine on the electrogenerated zerovalent nickel complex. The coupling product is then
obtained by reaction with the aryl halide.
Article history:
Received 30 November 2009
Received in revised form 20 February 2010
Accepted 27 February 2010
Available online 6 March 2010
Keywords:
Electrosynthesis
Arylpyridazines
© 2010 Elsevier Ltd. All rights reserved.
Catalyzed
Nickel-2,2ꢀ-bipyridine complexes
Cyclic voltammetry
1. Introduction
through various cross-coupling reactions based on boron [22–30],
tin [23,31–33] or zinc [10,29,34] derivatives. However these valu-
Pyridazinyl rings are present in various biological and
pharmacological active molecules [1,2]. Antibacterial, antifun-
gal, anti-inflammatory [3], antirheumatic [4] and antiepileptic
[5–7] activities have been reported. Some pyridazine derivatives
appear also to be potential drugs against Alzheimer’s diseases
[8,9]. In organic chemistry, pyridazinyl rings are valuable pre-
cursors for pyrroles via chemical [10,11] or electrochemical
[11–13] nitrogen extrusion. Pyridazines play also an impor-
tant role as metal complexing agents [14]. Moreover, associated
with other heteroaryl (e.g. pyridinyl) rings, pyridazines can be
employed for the synthesis of grid-type architectures through self-
assembly processes involving metallic ions such as Cu(I) or Ag(I)
[15,16].
able methods require the preparation of an organometallic aryl
compound which does not match with all functional groups.
Metal catalyzed electrochemical homo- and cross-coupling
reactions involving aromatic halides have been extensively used
[35,36]. The coupling of an aryl halide with a heteroaryl (e.g.
pyridinyl, pyrimidinyl, pyrazinyl) halide was studied by Gosmini
et al. who reported efficient electrosyntheses catalyzed by nickel-
2,2ꢀ-bipyridine (Ni-bpy) complexes [37,38].
Using a similar approach, we have reported recently the synthe-
sis of aryl- and heteroaryl-substituted pyridazines and we focused
on the Ni-bpy catalyzed electrochemical cross-coupling reaction
between 3-chloro-6-methoxy- or 3-chloro-6-methyl-pyridazine
and various functionalized aryl or heteroaryl halides [39].
Substituted pyridazines can be prepared by condensation of
1,4-dicarbonyl compounds with hydrazine [17–20] or inverse
cycloaddition of rich dienophiles to electrophilic 1,2,4,5-tetrazine
[10,21]. Another route is the well-known transition metal cat-
alyzed carbon–carbon bond formation from pyridazinyl halides.
By this way, substituted arylpyridazines have been synthesized
In this previous work, we observed that the success of the
reaction was strongly dependent on the nature of both the aryl
halide and chloropyridazine partners: yields in cross-coupling
product ranged from very poor to almost quantitative. In order
to explain these scattered results, we decided to study the elec-
trochemical behavior of compounds involved in the electrolytic
reaction (aryl halide, chloropyridazines, Ni-catalyst) individually
on the one hand and mixed on the other hand. The aims of the
present work are to clarify the mechanism of this Ni-catalyzed
electrochemical cross-coupling reaction and consequently to find
∗
Corresponding author. Tel.: +33 149781134; fax: +33 149781148.
E-mail address: Barhdadi@glvt-cnrs.fr (R. Barhdadi).
0013-4686/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.electacta.2010.02.092

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K. Urgin et al. / Electrochimica Acta 55 (2010) 4495–4500
Scheme 1.
optimal experimental conditions allowing to improve yield and
selectivity.
competitor of the 2,2ꢀ-bipyridine in the Ni complexes involved
in the catalytic cycle of the cross-coupling reaction.
First, we will analyze the respective electrochemical behaviors
of the starting compounds I, II and catalytic precursor NiBr2bpy
(Fig. 1).
Methyl 4-bromobenzoate I (Fig. 1, curve a) is reduced in two
steps. The first reduction can be assigned to the irreversible cleav-
age of the carbon–bromine bond. At more negative potentials, the
reduction of the ester function takes place.
2. Experimental
2.1. Chemicals
All reagents and the solvent N,N-dimethylformamide (DMF)
were purchased from commercial suppliers and used without
purification. The nickel-2,2ꢀ-bipyridine complex NiBr2bpy used as
precursor of the catalytic system was prepared according to a pub-
lished procedure [40].
Two reduction peaks were also obtained for
a solution
of 3-chloro-6-methoxypyridazine II (Fig. 1, curve b). That is
in agreement with other works about the electroreduction of
chloropyridazines [41,42]. The first step corresponds to the cleav-
age of the carbon–chlorine bond and the second process is
attributed to the reduction of the pyridazine moiety.
2.2. Instrumentation
Electrochemical measurements were carried out using [in
The electroreduction of NiBr2bpy has been described previ-
ously [40,43]. For a solution of the sole NiBr2bpy (Fig. 1, curve c1),
the voltammogram exhibits two one-electron partially reversible
reduction steps corresponding to the successive formation of
Ni(I)bpy+ and Ni(0)bpy complexes. If extra bpy is added [bpy/Ni
(mol/mol) > 2] (Fig. 1, curve c2), a quite reversible bielectronic signal
DMF (20 mL) + n-Bu4NBr (0.1 mol dm−3
)
as supporting elec-
trolyte]
a Voltalab PST006 Education potentiostat in the 3-
electrodes configuration. The working microelectrode was Au
(area = 3.1 × 10−2 cm2) while a gold wire acted as the counter
electrode. A saturated calomel electrode (SCE) was used as refer-
ence electrode and all potentials are expressed vs. this reference
system.
To avoid contamination by water, the SCE was separated
from the solution by a sintered disk compartment filled with
DMF + Bu4NBr (0.1 mol dm−3). The working electrode was polished
with Emery 3/0 prior to use, and all measurements were performed
at room temperature under an argon atmosphere.
is obtained that corresponds to a direct reduction of Ni(II)bpy2 to
2+
Ni(0)bpy2. In both cases, another peak is observed at a lower poten-
tial (−1.95 V) and is assigned to the reduction of the zerovalent
•−
Ni0(bpy)1 or 2 complex to the radical anion [Ni0bpy1 or 2
]
.
The respective peak potential’s (Epc) values measured for com-
pounds I and II and the Ni-bpy complexes are listed in Table 1.
When comparing the electrochemical behaviors of the start-
ing compounds, the divalent nickel complex, used as a catalytic
precursor, appears to be the easiest species to reduce. As a con-
sequence, we can expect that, during the electrosyntheses, the
catalytic cycle starts with a reaction between an electrogenerated
zerovalent Ni-bpy complex and the carbon–halogen bond of either
the functionalized aryl bromide I or chloropyridazine II.
Therefore, we have examined, in a second time, the electro-
chemical behavior of solutions of NiBr2bpy (without or with extra
bpy) added with either I or II.
As observed usually in the case of numerous aryl halides [40,43],
the addition of I to the solution of NiBr2bpy (Fig. 2) induces the loss
of the reversibility of the two reduction steps of the divalent nickel
due to a fast oxidative addition reaction of the carbon–halogen
bond on the zerovalent metal complex (Scheme 2, lines 1 and 2).
At lower potentials (−1.4 V), a new reduction step was observed,
its intensity raising with increasing amount of I. This phenomenon
was attributed to the reduction of the ꢀ-aryl-nickel intermediate
which will lead to the formation of biaryl Ar–Ar and the regenera-
tion of oxidized nickel, explaining the catalytic current (Scheme 2,
line 3) [43].
3. Results and discussion
We chose as a reference, a coupling reaction previously reported
[39] and presented in Scheme 1. This nickel-catalyzed electroreduc-
tive cross-coupling reaction between methyl 4-bromobenzoate I
and 3-chloro-6-methoxypyridazine II in equimolar amounts was
achieved by supplying a constant current intensity in an undi-
vided cell fitted with a sacrificial iron anode and the product III
was obtained in 57% isolated yield.
The aim of this electrochemical study is to get information
about:
(1) The electrochemical properties of each component (reactants
and catalytic precursor). The easiest species to reduce is a pri-
ori the divalent Ni-bpy. However, we wanted to prove that,
under our conditions, the reduction of nickel (II) is very selective
towards the respective electroreductions of I and II.
(2) Does the electrogenerated Ni(0)-bpy react preferentially with
compound I or II ? We made the presumption that cyclic
voltammetry (CV) can help answering the question.
(3) This synthesis involves various compounds containing the
pyridazine ring: starting material II, product III but also
methoxypyridazine, which is a likely by-product arising from
reduction–protonation of II. As mentioned above, pyridazines
are known to be potential ligands for various transition met-
als, including nickel ions [14]. Thus, we can suppose that the
pyridazine ring may also interfere as a co-ligand or even as a
Fig. 3 shows that, in presence of extra bpy [bpy/Ni (mol/mol) > 2],
the reversibility of the two-electron reduction of NiIIbpy2 is lost
2+
only when I is added in a large excess. The 18-electrons complex
Ni0bpy2 is more stable that the unsaturated Ni0bpy and the oxida-
tive addition reaction is slowing down as the amount of bpy is
getting higher [40]. The kinetic models proposed by Savéant and
Vianello [44] and by Nicholson and Shain [45] which correspond to
2nd order and pseudo-1st order conditions respectively, were used

K. Urgin et al. / Electrochimica Acta 55 (2010) 4495–4500
4497
Table 1
Electroreduction data for compounds I, II and NiBr2bpy.
Compound
Epc1 vs. SCE/V
Epc2 vs. SCE/V
−1.97
−2.35
cleavage of C–Br bond
reduction of ester function
−1.88
−2.25
cleavage of C–Cl bond
reduction of pyridazine
function
NiBr2bpy
−1.07
−1.18
Ni(II)bpy2+ + e ꢀ Ni(I)bpy+
Ni(I)bpy+ + e ꢀ Ni(0)bpy
NiBr2bpy + extra bpy
−1.23
Ni(II)bpy22+ + 2e ꢀ Ni(0)bpy2
to calculate the rate constant of the oxidative addition reaction with
I. For example, at room temperature, when the solution contains
3 mol of bpy per mol of Ni, k ≈ 5 dm3 mol−1 s−1. Consequently, the
catalytic current due to the reduction of the ꢀ-aryl-nickel complex
was observed only when the amount of bpy, comparing to that of
I, was not too high (e.g. bpy/I (mol/mol) ≤ 1/5, cf. Fig. 3, curve c).
In the presence of II, the voltammograms corresponding respec-
tively to the reduction of NiIIbpy2+ (Fig. 4) or NiIIbpy22+ (Fig. 5) were
dramatically modified. The reduction steps of Ni(II) into low-valent
Ni(I) and Ni(0) become fully irreversible, with or without extra bpy.
We concluded that, when the zerovalent Ni-bpy complex is elec-
trogenerated in the presence of equal amounts of I and II, the fastest
reaction occurs with chloropyridazine II. Subsequently, voltammo-
grams presented in Fig. 4 or Fig. 5 were not affected by adding the
aryl bromide I, even in a large excess, to the solutions.
also be supposed since complexes where nickel is bound both to
pyridyl and pyridazinyl nitrogens have already been reported [46].
When the solution contained NiBr2bpy with extra bpy (Fig. 7),
the loss of reversibility of the system NiIIbpy22+/Ni0bpy2, accom-
panied by a reduction process at −1.40 V which characterize the
ligand competition, was also observed but only if pyridazine was
added in excess with moderate amount of bpy.
Consequently, it is obvious that the pyridazine ring and bpy
can act as associated or competitive ligands for nickel metal. Since
the CV of NiBr2bpy solutions is deeply modified by the addition of
pyridazine, important changes may occur for the nickel based cat-
alytic system involved in the electrolytic coupling reaction. That is
the reason why the synthesis of III (according to Scheme 1) was
achieved in the presence of pyridazine in the starting solution.
Results presented in Table 2 show that an increasing amount of
pyridazine induces a poisoning of the catalytic system that can be
partially counterbalanced by addition of extra bpy.
The electrochemical results displayed here allow us to discuss
some mechanistic considerations. The most easily reduced species
is the complex NiIIbpy2+. The electrogenerated Ni0bpy reacts much
faster with the 3-chloro-6-methoxypyridazine II than with the
methyl 4-bromobenzoate I yielding, by oxidative addition, a ꢀ-
pyridazinyl-nickel complex MeOPyrNiIICl. The aryl halide I will be
implicated in a not yet elucidated multistep pathway involving
either MeOPyrNiIICl or (MeOPyr)2NiII and leading to the hetero-
coupling product III (Scheme 3). This proposition was based on
mechanisms proposed by Kochi who reported that reaction of an
aryl halide ArX with either a ꢀ-aryl-nickel complex ArꢀNiIIX [47] or
an aryl methyl nickel complex ArꢀNiMe [48] yield the unsymmet-
rical biaryl Ar–Arꢀ.
Considering these assumptions, the reaction(s) between the
pyridazine nickel complex(es) and the aryl bromide would cer-
tainly be promoted by an excess amount of the latter. That is why a
lot of electrosyntheses have been investigated in order to compare
the yields in coupling product obtained either from initial stoichio-
metric amounts of arylbromide and substituted chloropyridazine
or with initial ArBr in a twofold concentration. Results are collected
At least, no catalytic current was detected, even when II was
added in a large amount. Then, we can suppose that a very fast
oxidative addition reaction occurs, yielding a pyridazine nickel
complex that appears stable at the CV time scale.
CV experiments were also achieved on solutions of Nibpy2+ in
the presence of the coupling product III. When adding one molar
equivalent of III, the voltammogram becomes very similar to the
one obtained in presence of extra bpy (Fig. 1, curve c2), i.e. a quasi-
reversible two-electron process with respective peak potentials
Epc = −1.13 V and Epa = −0.94 V. This result means that the pyri-
dazine ring of III acts as ligand of nickel in our conditions.
In the course of electrolyses involving a coupling reaction
between an aryl halide and a chloropyridazine [39], side reac-
tions may form other products containing a pyridazine ring (e.g.
reduction–protonation product and substituted bipyridazine). This
is the reason why we examined the electrochemical behavior of Ni-
bpy solutions in the presence of the most simple pyridazine ring,
i.e. pyridazine itself (Fig. 6). The CV of mixed Nibpy2+/pyridazine
solutions is complex giving multiple reduction processes and no
well defined associated oxidation at the reverse scan. Actually,
the cyclic voltammograms do not depend on the pyridazine ratio
(0.5–10 molar equivalents per Nibpy+). For the first reduction step
where Ni(II) is reduced to Ni(I), the addition of pyridazine induces
only a slight shift (≈50 mV) towards more positive potentials (Fig. 6
vs. Fig. 1, curve c1), probably because of a rapid reaction between
pyridazine and either NiIIbpy2+ (CE mechanism) or NiIbpy+ (EC
mechanism). However, monovalent nickel is now reduced in two
well-separated steps (Epc = −1.16 V and −1.40 V). Each peak inten-
sity corresponds to a one-electron process involving only 50% of
initial nickel (II). We think that, under these conditions, electrogen-
erated monovalent (and presumably zerovalent) nickel involves
two complexes differing by the nature of the associated lig-
ands (pyridazine and/or bpy). We then supposed the existence of
low-valent nickel complexes associated either with bpy or with
pyridazines. The existence of bpy–pyridazine mixed complexes can
Table 2
Influence of the addition of pyridazine on the electrosynthesis of III according to
Scheme 1.
Pyridazine (molar ratio vs. NiBr2bpy)
0
1
2.5
5
5a
GC yield of III
92%
82%
37%
17%
67%
General conditions: DMF (25 mL) + Bu4NBr (0.025 mol dm−3) + I (0.2 mol dm−3) + II
(0.1 mol dm−3) + NiBr2bpy (0.01 mol dm−3) + pyridazine in various ratio. Undivided
cell, iron rod anode, nickel foam cathode, J = 6.37 mA cm−2
.
a
5 molar equivalents of pyridazine and 5 molar equivalents of bpy vs. NiBr2bpy
were added.

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K. Urgin et al. / Electrochimica Acta 55 (2010) 4495–4500
Fig. 2. CVs recorded at 0.1 V s−1 in DMF + Bu4NBr 0.1 mol dm−3 for (a) NiBr2bpy
10−2 mol dm−3, (b) NiBr2bpy 10−2 mol dm−3 + I 10−2 mol dm−3 and (c) NiBr2bpy
10−2 mol dm−3 + I 5 × 10−2 mol dm−3
.
Scheme 2.
Fig. 3. CVs recorded at 0.1 V s−1 in DMF + Bu4NBr 0.1 mol dm−3 for (a) NiBr2bpy
Fig. 1. CVs recorded at 0.1 V s−1 in DMF + Bu4NBr 0.1 mol dm−3 for (a)
I
10−2 mol dm−3 + bpy 2 × 10−2 mol dm−3
,
(b) NiBr2bpy 10−2 mol dm−3 + bpy
10−2 mol dm−3, (b) II 10−2 mol dm−3, (c1) NiBr2bpy 10−2 mol dm−3 and (c2) NiBr2bpy
2 × 10−2 mol dm−3 + I 10−2 mol dm−3 and (c) NiBr2bpy 10−2 mol dm−3 + bpy
10−2 mol dm−3 + bpy 2 × 10−2 mol dm−3
.
2 × 10−2 mol dm−3 + I 10−1 mol dm−3
.
Scheme 3.

K. Urgin et al. / Electrochimica Acta 55 (2010) 4495–4500
4499
Fig. 7. CVs recorded at 0.1 V s−1 in DMF + Bu4NBr 0.1 mol dm−3 for
(a)
NiBr2bpy
10−2 mol dm−3 + bpy
2 × 10−2 mol dm−3
,
(b)
NiBr2bpy
Fig. 4. CVs recorded at 0.1 V s−1 in DMF + Bu4NBr 0.1 mol dm−3 for (a) NiBr2bpy
10−2 mol dm−3 + bpy 2 × 10−2 mol dm−3 + pyridazine 10−2 mol dm−3 and (c)
10−2 mol dm−3, (b) NiBr2bpy 10−2 mol dm−3 + II 10−2 mol dm−3 and (c) NiBr2bpy
NiBr2bpy 10−2 mol dm−3 + bpy 9 × 10−2 mol dm−3 + pyridazine 10−1 mol dm−3
.
10−2 mol dm−3 + II 10−1 mol dm−3
.
Table 3
Influence of an excess of aryl bromide on the electrosynthesis of various
arylpyridazines.
FG
Yield % of arylpyridazine (isolated)a
R = OMe
R = Me
ArBr ratiob = 1
ArBr ratiob = 2
ArBr ratiob = 1
ArBr ratiob = 2
3-CO2Me
4-CO2Me
3-CN
4-CN
3-CF3
4-CF3
3-COMe
4-COMe
45
57
27
58
50
62
18
50
86
70
99
68
67
62
57
74
59
12
46
52
31
63
Fig. 5. CVs recorded at 0.1 V s−1 in DMF + Bu4NBr 0.1 mol dm−3 for (a) NiBr2bpy
18
30
18
50
10−2 mol dm−3 + bpy 9 × 10−2 mol dm−3
,
(b) NiBr2bpy 10−2 mol dm−3 + bpy
9 × 10−2 mol dm−3 + II 10−2 mol dm−3 and (c) NiBr2bpy 10−2 mol dm−3 + bpy
9 × 10−2 mol dm−3 + II 10−1 mol dm−3
.
a
Experimental workup procedures and characterization data of arylpyridazines
have been reported in reference [39].
b
Ratio (mol/mol) of initial ArBr vs. initial substituted chloropyridazine.
in Table 3. They show that, in most cases, yields in aryl pyridazine
were effectively increased significantly when ArBr was added in
excess.
According to our previous work [39] and the present results, we
propose now a reaction pathway for this electrochemical coupling
reaction between an aryl halide ArX and a chloropyridazine R-PyrCl.
Scheme 4 describes various plausible routes engaging Ni complexes
in a coupling reaction. For each electrosynthesis, the main way
will be strongly dependent on the respective reactivity of the cho-
sen starting molecules. We believe that the aimed cross-coupling
product will be essentially obtained following Scheme 3. The cor-
Fig. 6. CVs recorded at 0.1 V s−1 in DMF + Bu4NBr 0.1 mol dm−3 for (a) NiBr2bpy
10−2 mol dm−3, (b) NiBr2bpy 10−2 mol dm−3 + Pyr 10−2 mol dm−3 and (c) NiBr2bpy
10−2 mol dm−3 + Pyr 10−1 mol dm−3
.
Scheme 4.

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K. Urgin et al. / Electrochimica Acta 55 (2010) 4495–4500
responding route is indicated by bold lines in Scheme 4 (steps 1,
2a, 3a), where electrogenerated Ni(0) reacts rapidly, hence pref-
erentially, with R-PyrCl. After that, one or several steps involving
ArX, promoted by an excess of this compound, yield the aimed cou-
pling product. If the aryl halide is not reactive enough (no excess or
unactivated compound), the intermediate pyridazine nickel com-
plex(es) will lead to other products, for example to the pyridazinyl
dimer R-Pyr-Pyr-R (ways 2a, 3c) which is obtained in the absence
of ArX [49].
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CV experiments allowed us to obtain significant information
about the electrochemical synthesis of arylpyridazines from aryl
halides and substituted chloropyridazines.
The reaction starts with the electroreduction of
a diva-
lent Ni-bpy complex. Oxidative addition of the chloropyridazine
carbon–halogen bond to the electrogenerated Ni0bpy complex is
faster than the analogous reaction involving the aryl halide.
We proposed some mechanistic considerations which enlighten
the formation of the aimed arylpyridazine and by-products. We
showed why the success of the reaction depends strongly on the
respective reactivities and amounts of each substrate. Particu-
larly, we explained why the yield of cross-coupling product can
be improved by addition of an excess of the aryl halide.
The exact nature of Ni complex implicated in the catalytic cycle
is not fully elucidated. We proved that pyridazine rings act as co-
ligands or competitive ligands of 2,2ꢀ-bipyridine and can (at least in
the case of the pyridazine) poison the catalyst. Complement works
are on course to obtain more accurate data on this subject.
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K. Urgin thanks the Université Paris Est Créteil Val de Marne
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ANR program FOLDAPSULES for financial support.
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