Scope and mechanism of the electrochemical Reformatsky reaction of α-haloesters on a graphite powder cathode in aqueous anolyte

Article abstract of DOI:10.1016/j.electacta.2014.03.118

Six α-haloesters and eighteen carbonyl compounds were submitted to electrochemical coupling on a graphite powder cathode using aqueous anolyte free of organic solvents. Preparative yields of coupling products could be obtained with ethyl 2-bromoisobutyrate and aromatic aldehydes. Ethyl 2-bromopropionate was much less efficient. Extensive variation of applied potential, electrolyte composition, stoichiometry, catalyst, leaving halogen and activating substituents on the carbonyl compound led to the conclusion that the reaction mechanism in most cases proceeds via a radical intermediate generated from the halide reduction. Ethyl chloroacetate produced only trace amounts of coupling product, most probably by a carbanionic mechanism.

Full text of DOI:10.1016/j.electacta.2014.03.118

Electrochimica Acta 132 (2014) 118–126
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Electrochimica Acta
journal homepage: www.elsevier.com/locate/electacta
Scope and mechanism of the electrochemical Reformatsky reaction of
␣-haloesters on a graphite powder cathode in aqueous anolyte
Carlos A. de Souzaa, Marcelo Navarrob, Lothar W. Bieberb, Madalena C.C. Areiasb,∗
a Unidade Acadêmica de Serra Talhada, UAST, Universidade Federal Rural de Pernambuco, Serra Talhada, PE, Brazil
b Departamento de Química Fundamental, CCEN, Universidade Federal de Pernambuco, 50670-901 Recife, PE, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Six ␣-haloesters and eighteen carbonyl compounds were submitted to electrochemical coupling on
a graphite powder cathode using aqueous anolyte free of organic solvents. Preparative yields of
coupling products could be obtained with ethyl 2-bromoisobutyrate and aromatic aldehydes. Ethyl
2-bromopropionate was much less efficient. Extensive variation of applied potential, electrolyte com-
position, stoichiometry, catalyst, leaving halogen and activating substituents on the carbonyl compound
led to the conclusion that the reaction mechanism in most cases proceeds via a radical intermediate gen-
erated from the halide reduction. Ethyl chloroacetate produced only trace amounts of coupling product,
most probably by a carbanionic mechanism.
Received 20 January 2014
Received in revised form 14 March 2014
Accepted 17 March 2014
Available online 2 April 2014
Keywords:
Reformatsky
␣-haloesters
Carbonyl compounds
Cavity cell
© 2014 Published by Elsevier Ltd.
Graphite powder cathode
1. Introduction
aqueous medium between ethyl 2-bromoisobutyrate (1) and benz-
aldehyde (2) to give ␤-hydroxyester 3, Scheme 1, was conducted
The Reformatsky reaction [1] to obtain ˇ-hydroxy esters from
alkyl ␣-bromoalkanoates and aldehydes or ketones is initiated by
an organometallic generated by the insertion of zinc in the carbon-
halogen bond [2].
The activation of the zinc is the main problem related to use
this methodology, because the acidic condition conducts a highly
exothermic process of difficult control [3]. The association of Zn-
Ag [4] and Zn-Cu [5,6] or many other metals like a Mg, Cd, Ni,
Ce, Mn and In, have been tested to minimize the problem without
advantages [7–12].
Alternatively to the classic chemical reactions, electrochemical
methodologies in undivided cell, with Mg, Al, Zn and Fe as sacrifi-
cial anodes, were used for the preparation of some organometallic
intermediates with good results [13–20]. The yields were increased
by the use of sub-stoichiometric amounts of [NiII(bipy)Br2] along
with a Zn anode [21,22].
in a metal free electrochemical condition with the potential main-
tained constant during the electrolysis [24]. In this methodology,
the zinc was replaced by carbon fiber electrode of large surface,
as electron source excluding any participation of organometallic
species.
In 2008, to improve the moderate yield [25], the same reaction
was conducted with compacted graphite powder cell to provide
a higher active surface. The cell is comparable to a thin-layer cell
where the species are adsorbed at the cathode surface and also
confined in a thin liquid layer between the grains interstices pro-
viding short diffusion pathways [26]. In the following years, the
same cell has been successfully applied to the coupling of benzal-
dehyde with allyl [27], prenyl [28] and benzylhalides [29] as well
as with ␣-haloketones [30]. In all these reactions the mechanism
showed characteristics of both radical and carbanionic processes,
depending on the halide and reaction conditions.
Bieber and co-workers described in 1997 the Reformatsky reac-
tion in aqueous medium with zinc powder for some aromatic and
aliphatic aldehydes and primary, secondary and tertiary ␣-halo-
esters, catalyzed by dibenzoyl peroxide, (BzO)2, postulating an
evidence of radical mechanism [23]. This proposal of radical mecha-
nism became once again evident, when the Reformatsky reaction in
In the present work we describe the effects of an extensive vari-
ation of structural and experimental parameters on the coupling of
different ␣-haloesters and carbonyl compounds aiming at a better
evaluation of the synthetic scope and the mechanistic aspects of
the reaction.
2. Experimental
∗
All chemicals were of reagent grade and used without fur-
ther purification. Distilled water was employed in all experiments.
Corresponding author.
E-mail address: areias.madalena@gmail.com (M.C.C. Areias).
http://dx.doi.org/10.1016/j.electacta.2014.03.118
0013-4686/© 2014 Published by Elsevier Ltd.

C.A. de Souza et al. / Electrochimica Acta 132 (2014) 118–126
119
CHO
O
O
OH
O
e-/KBr/H2O
Br
+
OEt
+
OEt
OEt
graphite
powder
3
4
2
1
Scheme 1. Electrochemical coupling of ethyl 2-bromoisobutyrate (1) with benzaldehyde (2) [24].
The cathode materials were graphite Timrex KS44 (9 m2 g−1:GT)
from Timcal Group pure as received or mixed with 5 mg of silver
sulfate. Voltammetry and controlled-potential electrolyses were
carried out using Autolab PGSTAT 30 potentiostat/galvanostat and a
home-made three-electrode undivided cell described in a previous
work [25]. The cathodic compartment was prepared compressing
150 mg of graphite powder (pure or mixed with silver sulfate under
1.9 kg cm−2 during 10 min). In all experiments the organic reagents
or their mixtures were impregnated dropwise, without any solvent,
on the compressed graphite powder, which was then protected by
a filter paper. The anodic compartment was filled with 10 mL of
aqueous 0.1 mol L−1 KBr. A platinum anode was used and all poten-
tials are referred to the reference electrode Ag/AgCl, KCl (sat’d).
The electrolyses were performed at controlled potential over a
period of 1 − 4 h until transfer of around 1.7 times the theoreti-
cal charge. The aqueous electrolyte was decanted and the cathode
cavity was extracted with 5.0 mL of CHCl3 containing 0.1 mmol of
1,3,5-trimethoxybenzene (TMB) as internal quantitative standard.
Graphite powder was filtered off and the crude extracts were ana-
lyzed by 1H NMR (Varian Unity-Plus-300) and GC/MS (QP 5050
Shimadzu). All experiments were performed at 25 ◦C. The reaction
products were identified by comparison of their 1H NMR and EIMS
spectra with published data.
three-electron reduction. Similar effects have been observed in ear-
lier reports with benzylic, allylic and alkylic halides on electrodes
of pure silver [31–33] or silver doped graphite powder [27,29].
After this voltammetric exploration, a mixture of 0.2 mmol of
aldehyde 2 and 0.4 mmol of bromoester 5a was submitted to elec-
trolyses at constant potentials between −0.6 V and −1.4 V in the
absence and presence of catalytic silver (Table 1). The uncatalyzed
reaction at the least negative potential (−0.6 V) was extremely slow
and most of both reagents remained unchanged; only 6.2% of the
expected hydroxyester 6 and 24.3% of ethyl propionate (7) were
detected in the crude extract (Table 1, entry 1). At a potential of
−0.8 V, the halide 5a was completely consumed and 38.1% of cou-
pling product 6 were obtained (entry 2). More negative potentials
of −1.0 V and −1.2 V caused a weak drop in the yields to 35.5%
and 33.2%, respectively (entries 3 and 4). Finally, at −1.4 V cor-
responding to the peak potential of aldehyde 2, only 11.2% of 6
was formed and 1,2-diphenyl ethan-1,2-diol (8) became the main
product (52.1%, entry 5).
As could be expected from the increased current in the voltam-
metric experiments, all silver catalyzed electrolyses occurred much
faster. At −0.6 V all starting halide 5a was consumed, but only 13.3%
of coupling product 6 was obtained (entry 6). Also at potentials
between −0.8 V and −1.2 V (entries 7 − 9), this yield was always
lower than that obtained in the uncatalyzed reaction. At the most
negative potential,–1.4 V, both reactions produced almost the same
low yield of 6 and, once more, 8 was the main product (entry 10).
In all reactions described so far, the electrolyte was nearly neu-
tral before the electrolysis (pH 5.8), but became weakly acidic at
the end (pH 4.0–4.3). This finding can be explained by the different
processes occurring at the electrodes. At the anode, both reduc-
tion processes to 6 and 7 consume two electrons and one proton;
the formation of 8 demands two electrons and two protons, but
occurred only at −1.4 V. On the other hand, the only oxidation
process at the anode abstracts two electrons from two bromide
3. Results and discussion
In our first communication with a compacted graphite powder
cell [25], excellent yields of coupling product 3 had already been
obtained with the tertiary halide 1 and benzaldehyde (2), whereas
its secondary lower homologue, ethyl 2-bromopropionate (5a), had
shown only moderate reactivity (Scheme 2). For this reason, the lat-
ter halide was chosen to initiate a systematic study of the influence
of several experimental parameters on the coupling reaction.
Voltammetric analysis at very slow scan rate was performed
with the pure reagents and their mixture in the same cavity cell
used in previous work. Pure 5a produced a reduction peak at
−0.96 V with a peak current of −9.9 mA (Fig. 1a); the total charge
of 31.1 C is situated closer to a two-electron than to a one-electron
reaction (theoretical charge for 1 electron: 19.3 C). Under the same
conditions, 2 showed a more cathodic peak at −1.31 V and a lower
peak current of −7.8 mA; the total charge of 21 C corresponds very
well to a one-electron process (Fig. 1b). These peak potentials
showed only weak shifts to −0.9 V and −1.32 V, respectively, when
an equimolar mixture of both reagents was analyzed (Fig. 1c). At
the same time, however, a considerable decrease of the peak cur-
rent to −6.1 mA and −6.8 mA, respectively, was observed and the
separation of both maxima was much less pronounced. The total
charge of 43.3 C consumed by the mixture is about 8 C lower than
the sum of the values of the pure reagents, indicating a different
reduction process.
b
0
d
c
-2
a = 5a
a
- 0.90 V
-4
-6
b = 2
c = 5a + 2
d = 5a + 2 + Ag
- 1.32 V
- 1.31 V
-8
- 0.57 V
-10
- 1.27 V
- 0.96 V
When the voltammetry of the mixture was repeated using sil-
ver doped graphite powder (Fig. 1, line d), a pronounced shift of
the first peak from −0.9 V to −0.57 V was observed, whereas the
second one was only moved from −1.32 V to −1.27 V; the peak
currents increased to −8.2 mA and −9.2 mA, respectively, and the
total charge reached 57.6 C, almost exactly the value expected for a
-1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0
E vs sat (Ag/AgCl)/V
Fig. 1. Voltammograms recorded at 0.1 mV s−1 on pure graphite powder of: (a)
0.2 mmol 5a, (b) 0.2 mmol of 2, (c) 0.2 mmol of 5a and 0.2 mmol of 2 and (d) 0.2 mmol
of 5a and 0.2 mmol of 2 on silver doped graphite powder (3.4%).

120
C.A. de Souza et al. / Electrochimica Acta 132 (2014) 118–126
CHO
O
OH
O
OH
O
e-/KBr/H2O
X
+
+
+
OEt
OEt
OEt
graphite
powder
OH
5a (X: Br)
5b (X: Cl)
5c (X: I)
2
6
7
8
Scheme 2. Electrochemical coupling of ethyl 2-halopropionates 5a-c with benzaldehyde (2).
ions, producing bromine which hydrolyses partially to bromide
and hypobromide generating two protons. As 6 and 7 are the pre-
dominant products in all experiments, except in entries 5 and
10, the overall reaction produces more protons than it consumes
and turns the electrolyte more acidic. Based on these preliminary
considerations, we decided to examine alternative electrolytes of
different pH values and buffering capacity under the general con-
ditions of experiment 3 (entries 11–19). As a first result, none of
the basic or acidic additives to the aqueous potassium bromide
solution improved the yield of 6, but basic compounds (entries
11 − 15) produced results very close to the reference reaction (entry
3). The same additives, but in the absence of potassium bromide,
brought even lower yields of 6 (entries 16 and 17). In all these
cases, the electrolysis started at pH values between 7.3 and 12.7
and finished under neutral or weakly basic conditions. On the other
hand, addition of acetic acid had a more adverse effect, but this
can be explained also by the incomplete conversion of halide 5a
(entry 18). At −1.4 V (entry 19), the negative effect of potassium
carbonate, was even more pronounced reducing the yield of 6 to
one fourth when compared with entry 5. We conclude from this
series of experiments, that any additive or alternative electrolyte
decreases the efficiency of the coupling reaction and that the over-
all pH control is not decisive. Most probably, the local basicity at
the hydrophobic cathode is maintained by the cathodic reactions
till the total consumption of starting materials.
In the next step, the influence of stoichiometry was examined
using a 4-fold excess of halide 5a. A small, but consistent increase
to 40.9 − 43.3% of coupling product 6 was observed at potentials
between −1.0 V and −1.3 V (entries 20 − 22).
In the following experiments, the influence of the leaving
halogen was studied beginning with a voltammetric comparison
of ethyl 2-chloro- and iodopropionate (5b,c) and the bromo-
compound 5a, all in the presence of benzaldehyde (2) (Fig. 2).
Based on literature data for alkyl halides [32], we expected a less
Table 1
Electrochemical coupling of ethyl 2-halopropionate 5a,b,c and acetate 9a,b with benzaldehyde (2)a.
Entry
Halide
E(V)
Conditions
Product
composition/yield (%)b
2
6
7
8c
1
2
3
4
5
6
7
8
5a
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
-0.6
-0.8
-1.0
-1.2
-1.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.0
“
“
“
“
“
“
“
-1.4
-1.0
-1.2
-1.3
-0.8
-1.0
-1.3
-1.3
-1.3
0.1 mol L−1 KBr
“
“
“
88.8
57.6
45.6
40.8
1.7
6.2
24.3
44
22.2
6.3
0
49.7
22.4
39.2
47.5
0
0
0
0
0
52.1
0
0
0
0
32.8
0
0
0
0
0
0
0
0
38.1
35.5
33.7
11.2
13.3
8.5
23.1
23.6
11.5
36
35.5
29.8
35.7
33.6
31.1
30.5
26.9
3.2
43.4
40.9
43.2
32.7
5
“
Ag, 0.1 mol L−1 KBr
72
“
“
“
50.4
69.6
52.8
1.4
48.7
49.1
40.8
48
41.2
48
33.6
45.6d
1.4
17.5
32
39
23.4
69
2.5
9
10
11
12
13
14
15
16
17
18
19
20e
21e
22e
23
24
25
26
27
“
0.05 mol L−1 KBr, 0.05 mol L−1 KOH
21
0.1 mol L−1 KBr, 0.2 mol L−1 K3PO4
24.3
21.6
12
21.1
6.4
14.5
28.5
0
81.5
22.6
24.3
27.6
10
0.1 mol L−1 KBr, 0.2 mol L−1 K2HPO4
0.1 mol L−1 KBr, 0.2 mol L−1 K2CO3
0.05 mol L−1 KBr, 0.05 mol L−1 NaOAc
0.1 mol L−1 KOH
0.1 mol L−1 K2CO3
“
“
“
“
0.05 mol L−1 KBr, 0.05 mol L−1 HOAc
0.05 mol L−1 KBr, 0.1 mol L−1 K2CO3
92.3
0
0
0
0
0.1 mol L−1 KBr
“
“
“
“
“
“
“
“
5c
5b
5b
5a
5c
0
8.3
25.3
12.4
7
0
0
27.2
9.1
0.6
6,5
2
2
10
11
8
28
29
30
31
9a
9a
9b
9b
-0,8
-1.0
-1.0
-1.0
Ag, 0.1 mol L−1 KBr
Ag, 0.1 mol L−1 KBr
0.1 mol L−1 KBr
73.4
71.2
62.4
91.5
5.6
4
2
0
0
0
0
0
0
0
0
Ag, 0.1 mol L−1 KBr
0.4
aGeneral procedure: 0.4 mmol of haloester and 0.2 mmol of 2 impregnated on 150 mg of graphite powder
bDetermined by GC and 1H NMR relative to internal standard
cMixture of meso and d,l
d25.8% of 5a remained also unreacted
eOnly 0.1 mmol of 2 were applied

C.A. de Souza et al. / Electrochimica Acta 132 (2014) 118–126
121
0
0
-2
c
a
b
-2
a
-4
-0.90 V
-4
a = 5a + 2
b
b = 5b + 2
-6
a = 1 + 2
b = 1 + 2 + Ag
c = 5c + 2
-6
-8
-0.90 V
-0.86 V
-8
-1.32 V
- 1.32 V
- 1.26 V
- 1.29 V
- 0.57 V
-10
-12
-14
-10
-12
-1.35 V
- 0.91 V
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
E vs sat (Ag/AgCl)/V
E vs sat (Ag/AgCl)/V
Fig. 2. Voltammograms recorded at 0.1 mV s−1 on pure graphite powder of: (a)
0.2 mmol of 5a and 0.2 mmol of 2, (b) 0.2 mmol of 5b and 0.2 mmol of 2 and (c)
0.2 mmol of 5c and 0.2 mmol of 2.
Fig. 3. Voltammograms of a mixture of 0.2 mmol of 1 and 0.2 mmol of 2 on graphite
powder recorded at 0.1 mV s−1: (a) in the absence and (b) in the presence of silver
(3.4%).
Table 2
value in the same range of the other haloesters studied so far, but
a more negative peak at −1.11 V for the chloride 9a (entry 1); the
peak currents were also comparable with those of 5a,b. On silver
doped cathode material, both peak potentials became less negative
and more intense (entries 2 and 4), but these effects were more
pronounced in the case of the chloride 9a (entry 1).
As could be expected, the electrolysis of 9a in the presence of
2 on pure graphite at −0.8 V and −1.0 V proceeded with very low
charge and conversion rate and produced no trace of the coupling
product 10. In the presence of catalytic silver, however, complete
conversion even at −0.8 V and 5.6% of coupling to 10 were achieved
(Scheme 3, Table 1, entry 28) which decreased to 4% at −1.0 V
(Table 1, entry 29). At the latter potential on pure graphite, the bro-
mide 9b produced only 2% of 10 (Table 1, entry 30); silver catalysis
had no positive effect and reduced the yield to nearly undetectable
0.4% (Table 1, entry 31).
In contrast to all other haloesters described so far, we observed
in the case of ethyl 2-chloroacetate (9a) for the first time a beneficial
effect of silver catalysis and higher yields for the chloride than for
the bromide. In this aspect, 9a showed a behavior very similar to
allyl [27] and benzylchlorides [29] and this can be related to the
primary structure of these three halides.
The experiments described so far confirmed our previous find-
ings that the excellent coupling results with the tertiary bromide
1 cannot be obtained with its secondary and primary analogues
even under modified experimental conditions. For this reason, our
attention returned to the tertiary bromoester 1 in order to explore
its reactivity and synthetic utility with a wide range of structurally
and electronically different carbonyl compounds. Once more, we
began with a comparative voltammetric assay in the absence and
presence of catalytic silver (Fig. 3).The mixture of 1 and 2 on pure
graphite reproduced very well the curve published in our previ-
ous paper [25] with maxima at −1.26 and −0.91 V. The latter peak,
attributed to 1, was shifted by 0.34 V to less cathodic values when
Voltamographic data of ethyl chloro- and bromoacetate (9a,b) recorded on pure
graphite and on silver doped graphite (3.4%) at 0.1 mV s−1
.
Entry
Compound
X
Catalyst
Ep(V)
Ip(mA)
1
2
3
4
9a
9a
9b
9b
Cl
Cl
Br
Br
−
−1.11
−0.88
−0.98
−0.77
4.7
13.7
4.2
Ag
−
Ag
5.4
negative reduction potential in the order Cl > Br > I. This tendency
was not observed in the case of the halopropionates examined
here, for all three compounds exhibited almost the same peak
potential between −0.86 V and −0.90 V on pure graphite. The peak
current, however, increased significantly from chloride to bromide
and iodide.
Accordingly, all electrolytic coupling experiments with the chlo-
ride 5b proceeded at a very slow rate and no coupling product at
all could be detected at −0.8 V. By contrast, at the same potential,
the iodide 5c produced 32.7% of 6 (entry 23), only 5% less than
the bromide 5a (entry 2). At more negative potentials, −1.0 and
−1.3 V, 5b still produced very modest coupling yields (5 and 8.3%,
entries 24 and 25), far away from the results obtained with the bro-
mide 5a (entry 3 and 26); also the iodide 5c gave only 12.4% of 6 at
−1.3 V (entry 27). Again, at the latter potentials, pinacol 8 was also
observed (entries 25 − 27).
From the results presented so far we can deduce that bromoester
5a has the highest coupling power of all three halides, especially
at −0.8 V. The electrolyte composition and the reagent ratio have
restricted influence.
After the extensive investigation with 2-halopropionates under
different conditions, we turned our attention to the primary halides
ethyl 2-chloro and 2-bromoacetate (9a,b, Scheme 3).
Preliminary voltammetric evaluation showed a peak potential
for the bromide 9b of −0.98 V (Table 2, entry 3) on pure graphite, a
CHO
O
OH
O
O
e-/KBr/H2O
X
+
+
OEt
OEt
OEt
graphite
powder
9a (X: Cl)
9b (X: Br)
2
10
11
Scheme 3. Electrochemical coupling of ethyl cloro-, and bromoacetate (9a,b) with benzaldehyde (2).

122
C.A. de Souza et al. / Electrochimica Acta 132 (2014) 118–126
Scheme 4. Electrochemical coupling of ethyl 2-bromoisobutyrate (1) with aromatic and heteroaromatic aldehydes 2,12a-i.
silver doped graphite was used, whereas the peak attributed to 2
showed a weak opposite effect. Another striking difference was
observed in the relative peak currents: in the absence of catalyst
the peak current of 1 was much higher than that of 2 and in the
presence of silver the opposite relation was found.
benzaldehyde. In the case of an electrochemical coupling, the
voltammetric behavior had to be analyzed first. The mixture of 15a
and 1 on pure graphite produced a main reduction peak at −1.23 V
with shoulders at −1.40 and −1.07 V (Fig. 4).
This broad peak became resolved in three separate maxima at
−1.41, −1.17 and −0.63 V when silver doped graphite was used.
This proximity or partial superposition of reduction peaks allow
no prediction of the coupling behavior. Indeed, a first experiment
under the standard conditions of entry 1, gave not only a very
satisfying yield of 83% of the expected coupling product 16a, but
also two minor products (Scheme 5, entry 12). The first one can
be explained by an electroreductive dimerization of 15a to 17a, as
already reported in the literature [34,35]. The second side prod-
uct was the dimeric ester 14 obtained already in entry 2. These
two homocoupling products became much more important on
silver catalysis and decreased once more the desired heterocou-
pling to 16a (entry 13). Introduction of a 2-methoxy group in
the aromatic ring (15b) or of a methyl group in ␣ to the car-
bonyl group of the aldehyde (15c) resulted in lower yields of
adducts 16b,c, but also in the absence of side products 14 or 17b,c
(entries 14 and 15).
These effects in the voltammetric analysis can be related to the
behavior in the electrolyses at −1.0 V. In the uncatalysed reaction,
86% of coupling product 3 was obtained, reproducing our previous
results [25] (Scheme 4, Table 3, entry 1). However, in the presence
of silver, the yield of 3 decreased considerably and an important
sideproduct was formed, identified as the diester 14 previously
detected in our first coupling experiments on carbon fiber [9], but
not observed so far in the graphite powder cell (entry 2). Conse-
quently, all following reactions were carried out on pure graphite
powder under the conditions of entry 1. Benzaldehydes substi-
tuted in position 4 by F or Br gave even higher coupling yields
of 96.3 and 93%, respectively, than the unsubstituted parent com-
pound 2 (entries 3 and 4). On the other hand, the electron donating
thiomethyl group in 12c caused a net decrease to 65.7% of cou-
pling product 13c (entry 5). A similar negative effect was observed
in the case of a 3-acetyl group (12d, 61.5%, entry 6), whereas 4-
phenylbenzaldehyde (12e, 80%, entry 7) and 2-naphthaldehyde
(12f, 83.1%, entry 8) gave results very close to that of entry 1.
Three heterocyclic aldehydes 12g-i gave also interesting yields in
the range of 65% (entries 9 − 11).
Further decrease in the coupling ability was expected for 3-
methyl-2-butenal (18) which showed a peak potential of −1.41 V
and very low peak current (2 mA) in the voltammetric analysis. In
fact, under standard conditions at −1.0 V, only 14.3% of coupling
product 19 were observed (Scheme 6a, entry 16). Change of the
constant potential to −1.4 V doubled the yield of 19 to 29.3% (entry
17), but silver catalysis reduced it once more and favored instead
reductive dimerization to 14 (entry 18).
The reactivity of cinnamaldehyde (15a) in traditional nucle-
ophilic carbonyl addition is expected to be comparable to
As an example of an unconjugated aldehyde we chose 3-
phenylpropanal (20) because of its low volatility and weak
tendency to undergo spontaneous aldol-type reactions. Submitted
to voltammetry, this compound showed no peak before the reduc-
tion of water. Electrolysis in the presence of 2 at −1.0 V produced
10.2% of the expected coupling product 21, but aldolic condensation
to 22 [36,37] was an important side-reaction (Scheme 6b, entry 19).
Silver catalysis depressed the heterocoupling severely, had little
influence on the condensation and favored reductive dimerization
of the halide to the dimeric ester 14 as the major product (entry 20).
Also a more cathodic potential of −1.3 V in the absence of silver did
not improve the results (entry 21).
Finally, acetophenone (23a)–one of the most reactive ketones in
nucleophilic additions–was tested in the coupling reaction with 1a
(Scheme 6c). Under standard conditions only 1.2% of the expected
product 24a could be detected (entry 22). A very limited improve-
ment of this extremely low yield was achieved by introduction of
F–substituents in the methyl group (23b, 1.5%, entry 23) or–more
efficiently–in the aromatic ring (23c, 3.1%, entry 24).
0
a
b
-2
- 1.41 V
a = 2 + 15a
b = 2 + 15a + Ag
-4
-6
- 1.40 V
- 1.07 V
-8
- 0.63 V
- 1.23 V
-10
- 1.17 V
-12
-1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2
E vs sat (Ag/AgCl)/V
0.0
Fig. 4. Voltammograms of a mixture of 0.2 mmol of 1 and 0.2 mmol of 15a on
graphite powder recorded at 0.1 mV s−1: (a) in the absence and (b) in the presence
of silver (3.4%).

C.A. de Souza et al. / Electrochimica Acta 132 (2014) 118–126
123
Scheme 5. Electrochemical coupling of ethyl 2-bromoisobutyrate (1) with cinnamaldehydes 15a-c.
Summarizing all results reported here, we conclude that only
ethyl 2-bromoisobutyrate (1) adds efficiently to aromatic and
heteroaromatic aldehydes, as well as to cinnamaldehyde (15a).
The same substrates react with ethyl 2-bromopropionate (5a)
only in moderate yields. Ethyl chloro- and bromoacetate (9a,b)
produce only trace amounts of coupling products. Other ␣,␤-
unsaturated and saturated aldehydes and aromatic ketones are
not sufficiently reactive for preparative purposes even with
1.
The first possibility is a transfer of a single electron to a halide A
producing a radical C, most probably in a concerted process [38,39].
A second electron transfer to C, still adsorbed on the graphite sur-
face, will generate a carbanion D, a powerful nucleophile which
will attack adsorbed aldehyde B and, after protonation, give the
final product F.
In the second alternative, radical C adds to B forming another
radical intermediate E which can receive a second electron and a
proton to produce the same coupling product F.
On the other hand, the effects of experimental and structural
parameters observed in the described experiments allow important
conclusions on the possible mechanisms involved in the electro-
chemical Reformatsky reaction. In principle, the cathodic coupling
reaction can involve neutral molecules, radicals, radical anions and
carbanions and three general pathways can be formulated with
these species (Scheme 7).
The third pathway starts with a first electron transfer to alde-
hyde B producing initially radical anion G, and, after protonation,
radical H. The latter can combine with a radical C, generated from
halide A, and also give F.
The sub-products I and J, observed in several experiments, result
from dimerization of radicals H and C, and K arises from protonation
of D.
Table 3
Electrochemical coupling of ethyl 2-bromoisobutyrate (1) with different carbonyl compoundsa.
Entry
Carbonyl compound
E(V)
Conditions
Product
composition/yield (%)b
2
3
4
8
14
1
2
2
2
−1.0
0.1 mol L−1 KBr
9.5
28.5
86
34
47.3
70.2
0
0
0
17.1
“
Ag, 0.1 mol L−1 KBr
12
13
4
14
3
12a
12b
12c
12d
12e
12f
12 g
12 h
12i
“
“
“
“
“
“
“
“
“
0.1 mol L−1 KBr
4.8
4.7
96.3
93
65.8
61.5
80
83.1
68.2
62.3
65.1
47.1
59.2
46.3
64.9
59
52.3
54.6
35.4
42.3
0
0
0
5.6
0
0
0
0
0
4c
5
“
“
“
“
“
“
“
“
34.2
9.7
12.3
13.4
11.5
20
6c
7c
8c
9
10
11
3.6
15
16
4
17a
14
12
13
14
15
15a
15a
15b
15c
“
“
“
“
“
12.7
46.2
34.4
43
83
46
52.3
47
31.6
66
66.7
47.3
1.8
8.2
1.6
14.5
0
Ag, 0.1 mol L−1 KBr
0.1 mol L−1 KBr
“
0
19
4
14
16
17
18
18
18
18
−1.0
−1.4
−1.4
“
14.3
29.6
9.2
66.2
37.5
45.3
0
0
12.6
“
Ag, 0.1 mol L−1 KBr
20
21
4
22
14
19
20
21
20
20
20
−1.0
−1.0
−1.3
0.1 mol L−1 KBr
Ag, 0.1 mol L−1 KBr
0.1 mol L−1 KBr
55.8
55.6
49.1
10.2
0.7
9
96.3
43.3
87.2
5.1
5.2
5.3
0
30.2
0.6
23
24
4
14
22
23
24
23a
23b
23c
−1.0
0.1 mol L−1 KBr
“
“
95.8
21.7
95.8
1.2
1.5
3.1
86.3
93.5
97.1
0
0
0
“
“
aGeneral procedure: 0.4 mmol of haloester and 0.2 mmol of carbonyl compound impregnated on 150 mg of graphite powder
bDetermined by GC and 1H NMR relative to internal standard
cOnly 0.1 mmol of carbonyl compound were applied

124
C.A. de Souza et al. / Electrochimica Acta 132 (2014) 118–126
Scheme 6. Electrochemical coupling of ethyl 2-bromoisobutyrate (1) with less reactive carbonyl compounds 18, 20, 23a-c.
In the following analysis we will try to decide between these
in the coupling reaction, but the most stable radical C can, com-
bining either directly with the aldehyde B or with the radical
H.
three possibilities and the reactive intermediates involved on the
basis of thirteen different observations made in the experiments
described before (Table 4).
2. All halides used in this work are reduced at less negative poten-
tials than the carbonyl substrates and the most efficient halide
1 exhibits also a much higher peak current. These differences
in the voltammetric data suggest that the first electron transfer
occurs to the halide (A) and turn an initial formation of radicals
G and H improbable.
3. Although there was only a single peak in the voltammograms of
all halides used, a reduction by a single electron to C is expected
to be favored by a less negative potential and a two − electron
transfer to D or a reduction of B at more negative values. The
1. The first and most striking observation, already mentioned in
our previous publication [23,25] is the sharp decrease of cou-
pling reactivity from the tertiary bromoester 1 to its secondary
and primary homologues 5a and 9b. This order corresponds
exactly to the stability of radicals of type C and is opposite
to that of carbanions D and their reactivity towards carbonyl
addition. In other words, the most basic and less nucleophilic
tertiary carbanion D cannot be responsible for the best results
Scheme 7. General mechanism of the cathodic coupling of halide with aldehydes.

C.A. de Souza et al. / Electrochimica Acta 132 (2014) 118–126
125
Table 4
support a carbanionic intermediate D. However, the effect is
less pronounced than in other nucleophilic additions and a
similar stabilization of radicals E, G and H cannot be excluded.
9. The reactivity of the carbonyl substrates used in this work fol-
lows the order generally observed in nucleophilic additions,
decreasing from aromatic aldehydes 12a-i to cinnamaldehy-
des 15a-c, 3-methyl-2-butenal (18), 3-phenylpropanal (20) and
acetophenones 23a-c, and thus supports an intermediate D.
However, as in the foregoing point, a similar order can be
attributed to decreasing stability of radical intermediates and
no preference for one of the three mechanisms is given here.
10. Pinacol formation (I) is not an important side reaction except
at potentials close to the reduction peak of benzaldehyde. This
makes a pathway via radicals G and H improbable for the cou-
pling reaction to F and supports both mechanisms starting with
A.
11. On pure graphite, reductive dimerization of A to J is observed
only with the tertiary bromide 1 in a few reactions with less
reactive carbonyl compounds such as 12d, 15a and 20. This is
probably due to the high stability of a tertiary radical C, whose
homocoupling cannot compete with the addition to more reac-
tive aldehydes. This observation is another strong argument in
favor of a radical mechanism via C. On silver doped graphite,
higher amounts of dimeric ester J were also found in several
experiments and probably cannot be explained by a carbanionic
intermediate D as postulated in point 4. The reason is rather a
special surface effect as found previously in the zinc-promoted
dimerization of organic halides [41]. A mechanism via radicals
G and H can also be excluded because in no case both dimers I
and J were detected in the same experiment.
Compatibility of experimental observations and possible reactive intermediates.
Entry Intermediates
C + E
D
H + C
1
Reactivity order tertiary > secondary > primary
+
−
+
+
2
Reduction potentials of halide and carbonyl substrate
Applied potential
+
−
3
+
−
−
−
+
−
4
Silver catalysis in 1 and 5a
+
−
5
Electrolyte composition
+
−
6
Excess of halide
+
+
7
Leaving halogen in 5a,b,c
+
−
+
−
8
Substituents in the aromatic ring
Reactivity of carbonyl substrates
Absence of pinacol formation
Reductive dimerization of haloester
+/−
+/−
+
+/−
+/−
−
9
+
10
11
+
+
−
−
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
Leaving halogen in 9a,b
−
−
+
+
−
−
13
Silver catalysis in 9a
best results with halides 1 and 5a were all obtained at −0.8 or
−1.0 V and more negative potentials resulted in lower yields of
F and increasing formation of pinacol I. This gives additional
support to the pathway via C and E.
4. The presence of catalytic silver on the cathode turns the peak
potentials of organic halides less negative, thus making a selec-
tive one-electron transfer more difficult and favoring the direct
formation of D. This should enhance the coupling by a carban-
ionic mechanism as observed recently in the case of allylic and
benzylic halides [27,29]. However, in the case of bromoesters
1 and 5a, the effect of silver catalysis was clearly adverse in all
experiments, indicating that no carbanion D is involved in the
absence of silver, but rather a radical C. Intermediates G and H
are also improbable because no effect of silver was observed in
the voltammograms.
5. The rather weak effect of changes in the electrolyte composition
points also in the direction of radical C. Especially the addition
of acetic acid should affect severely a process based on highly
basic carbanions such as D. On the other hand, formation of
radical H and pinacol I even should be favored by acid, but this
was not observed.
Summarizing these arguments (Table 4), we can conclude that
all experimental observations are best conciliated with a pre-
dominant mechanism via radicals C and E, because none of the
eleven points is found contrary to it and only two can be con-
sidered ambiguous. A carbanionic intermediate D is compatible
only with five points, but incompatible with six. A pathway start-
ing from B via radicals G and H is even less supported with only
two points compatible, two ambiguous and seven incompatible.
It must be emphasized that this analysis refers essentially to the
results with the tertiary bromoester 1 and its less reactive sec-
ondary homologue 5a. The very low yielding primary halides 9a,b
provided some contradictory results which have to be discussed
separately.
12. In sharp contrast to 5a,b, the chloroacetate 9a gives better
yields than the bromo compound 9b. This cannot be accounted
to an easier formation of radical C because the voltammetric
data show that the C–Br bond is cleaved at a less negative poten-
tial and with a much higher peak current. On the other hand,
chlorides are reported to undergo directly a two − electron
reduction to carbanion D, whereas bromides can stop at the rad-
ical stage C [40]. Therefore, the higher reactivity of the chloride
9a can be explained by preferential formation of a carbanion D
and the low stability of a primary radical C. This interpretation
is reinforced by the better stabilization and lower basicity of
primary enolates in comparison to secondary or tertiary ones.
13. In the same direction points the now beneficial effect of sil-
ver catalysis with the chloride 9a. As already stated before, in
the presence of silver the reduction potential is shifted to less
cathodic values and the peak current increases significantly,
thus favoring the carbanion D.
6. Higher excess of halide as in entries 20 − 22 caused some
improvement in the yield of F, but this can be expected for
all three mechanisms because of the participation of interme-
diates derived from A.
7. The superiority of bromo- and iodoesters 5a and 5c over their
chloro-analogue 5b can be explained by their higher peak cur-
rent and less negative peak potential. This means that the
cathodic cleavage of the C–Cl bond is more difficult to occur,
but also to stop at the radical C. C–Br and C–I bonds have a bet-
ter chance for a monoelectronic process producing the radical C
[40]. A mechanism starting with the radicals G and H should not
be affected by the leaving halogen of A and can also be rejected.
8. Our coupling experiments with 1 and substituted benzalde-
hydes 12a-f show exactly the trend expected for nucleophilic
additions: increase of reactivity by electronegative substituents
and decrease by electron donors. Also the activating effect
of F − substituents observed in acetophenones 23a-c can be
attributed to increased electrophilicity. Both trends seem to
From the last two observations we must conclude that haloac-
etates 9a,b prefer an anionic mechanism in the coupling reaction
with benzaldehyde. Although this contrasts with the radical

126
C.A. de Souza et al. / Electrochimica Acta 132 (2014) 118–126
process found for the secondary and tertiary homologues, there is
a striking parallel with the behavior of benzylic [29] and allylic [27]
halides and haloketones [30] which also show higher reactivity
of the chlorides, especially in the presence of catalytic silver. All
four types of halides have some common characteristics: their pri-
mary structure facilitates the formation of a resonance-stabilized
carbanion D which is less basic–and therefore more stable in
aqueous medium–than secondary or tertiary analogues.
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The electrochemical Reformatsky reaction of structurally dif-
ferent haloesters and carbonyl substrates can be performed on a
graphite powder cathode in aqueous medium and in the absence
of reactive metals and organic solvents. The preparative interest
is restricted to tertiary bromoesters which add in high yield to
aromatic aldehydes and cinnamaldehydes. Secondary bromoesters
are less efficient and produce only moderate yields. Mechanistic
evaluation of the experimental data suggests a radical pathway
starting with a one-electron reduction of the halide. By contrast,
haloacetates produce only trace amounts of coupling product with
benzaldehyde, but probably react via a carbanionic species.
[25] M.C.C. Areias, M. Navarro, L.W. Bieber, F.B. Diniz, E. Leonel, C. Cachet-Vivier,
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The authors thank Brazilian granting authorities CNPq, CAPES
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