Electrogenerated superoxide anion induced oxidative amidation of benzoin

Article abstract of DOI:10.1016/j.electacta.2017.09.135

Amide function is very important in both organic and medicinal chemistry. Benzamides can be obtained in good to high yields by reaction of benzoin, primary or secondary amines, molecular oxygen and electrogenerated superoxide anion (obtained with galvanos

Full text of DOI:10.1016/j.electacta.2017.09.135

Accepted Manuscript
Title: Electrogenerated superoxide anion induced oxidative
amidation of benzoin
Authors: Fabiana Pandolfi, Isabella Chiarotto, Daniele Rocco,
Marta Feroci
PII:
S0013-4686(17)32006-6
DOI:
Reference:
http://dx.doi.org/10.1016/j.electacta.2017.09.135
EA 30334
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14-9-2017
22-9-2017
Please cite this article as: Fabiana Pandolfi, Isabella Chiarotto, Daniele Rocco, Marta
Feroci, Electrogenerated superoxide anion induced oxidative amidation of benzoin,
Electrochimica Actahttp://dx.doi.org/10.1016/j.electacta.2017.09.135
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Electrogenerated superoxide anion induced oxidative amidation
of benzoin
a
a
a
a
Fabiana Pandolfi, Isabella Chiarotto, Daniele Rocco, and Marta Feroci *
a
Dept. Scienze di Base e Applicate per l'Ingegneria (SBAI), Sapienza University of Rome, via Castro Laurenziano, 7,
0
0161 Rome, Italy
Phone: +39 06 49766563; fax: +39 06 49766749; e-mail: marta.feroci@uniroma1.it
Graphical abstract
O2
Pt cathode
+
e
O2
X
O
O
R2
R2
HN
O2 / O2
N
+
R1
R1
OH
X
X
up to 89%
Highlights
-
-
-
-
the reaction between electrogenerated superoxide anion, benzoin and amine yelded benzamides
the voltammetric analysis gave information on this reaction
a reaction mechanism was hypothesized based on experimental results
benzamides can be obtained starting from deoxybenzoin, benzoin or benzil
Abstract. Amide function is very important in both organic and medicinal chemistry. Benzamides can be obtained in good
to high yields by reaction of benzoin, primary or secondary amines, molecular oxygen and electrogenerated superoxide
anion (obtained with galvanostatic method). The advantage of using electrogenerated superoxide anion is related to its
counterion, the tetraethylammonium cation, which is not tightly bound to the anion and thus renders superoxide highly
reactive also in the absence of additives (necessary when using KO
2
). The reaction conditions are very mild and only 0.5
1

F/mol are necessary to obtain good yields in benzamides. This work points out that benzamides can be obtained also
starting from deoxybenzoin and benzil, via C-C bond cleavage, with yields which depend on the charge amount.
A mechanistic hypothesis (in part supported by the literature and by voltammetric studies) is reported, which allows to
explain the formation of byproducts and to define the role of oxygen and superoxide anion.
Keywords: electrogenerated superoxide anion; electrochemistry; benzoin; benzamides; C-C bond cleavage
1
. Introduction
Amide is a widespread functional group, encountered in a large variety of natural and synthetic molecules [1].
Therefore, amide bond formation is a very important chemical reaction. Moreover, Dunetz and coworkers
report that "Amide bonds are very frequently incorporated into active pharmaceutical ingredients. In fact,
amide bond formation is one of the most prevalent transformations in the pharmaceutical industry, accounting
for 16% of all reactions carried out in medicinal chemistry laboratories" [2]. A 2006 study of three leading
pharmaceutical companies reported that acylation of amines to amides accounted for 66% of all acylation
reactions carried out in preparation of drug candidate molecules [3].
In particular, benzamides are a class of molecules with noteworthy biological activity. For example, they are
used in neuropsychiatry as dopamine antagonists [4], they are antiemetics [5], histone deacetylase inhibitors in
cancer treatment [6], analgetics and anaesthetics [7].
Amides are classically synthesized by amination of acyl chlorides, anhydrides, esters or carboxylic acids,
using stoichiometric amounts of coupling reagents [2,8]. Recently, benzamides were synthesized by the copper-
catalysed aerobic C-C bond cleavage of 1,2-diarylethan-1-one (deoxybenzoin) and reaction with an amine
(
Scheme 1) [9]. Deoxybenzoin was used in excess (2:1 mole ratio with amine) and the aldehyde was obtained
in yields higher than amide ones. The authors excluded the formation of benzil as an intermediate.
Scheme 1.
Previously, Wang reported the synthesis of benzamides starting from diaryl-alpha-diketones (benzils)
avoiding the use of transition metals and using tert-butyl hydroperoxide (TBHP) as oxidant (Scheme 2) [10]. A
radical mechanism was proposed by the authors.
Spurred by the research reported in these two last papers, we initially tried to verify if the synthesis of
benzamides from deoxybenzoin could be obtained avoiding the use of metal catalysts and under milder
conditions. In particular, we were interested in the possible use of electrogenerated superoxide ion in such a
synthesis.
Scheme 2.
2

In fact, the generation of highly reactive superoxide ion by cathodic reduction of molecular oxygen is carried
out under mild conditions, at room temperature and using the electron as reagent.
The cathodic reduction of molecular oxygen is a monoelectronic process yielding superoxide ion (Scheme 3)
[
11-13].
Scheme 3.
The main difference between electrogenerated superoxide ion and chemically generated (as KO ) is its counter-
2
+
ion. Infact, the bond between K and O
2
in KO is so strong in aprotic dipolar solvents that in order to
2
enhance superoxide reactivity a crown ether is usually necessary [14]. When carrying out the cathodic reduction
of O in an aprotic dipolar solvent (as MeCN or DMF) in the presence of a tetraalkylammonium salt as
2
supporting electrolyte, the counter-ion of superoxide anion is the tetraalkylammonium cation, not coordinated,
which renders superoxide a "naked" anion, and thus highly reactive and soluble.
Superoxide anion can give a variety of reactions: oxidations (in the presence of molecular oxygen),
reductions, deprotonations, nucleophilic additions, depending on the reaction partner [15].
2
. Experimental
2.1 Voltammetric analysis
Voltammetric measurements were performed using an Amel 552 potentiostat equipped with an Amel 566
function generator and an Amel 563 multipurpose unit in a three-electrode cell; the curves were displayed on an
Amel 863 recorder; acquisition software was a CorrWare for windows version 2.8d1 Scribner, elaboration
software was a CorrView for windows version 2.8d1 Scribner. A 492/GC/3 Amel microelectrode was
employed, using a Pt wire counter electrode and modified saturated calomel electrode as reference electrode
-1
[
16]. The scan rate was  = 0.2 V s . All cyclic voltammetries were recorded on 5 mL of DMF-0.1 M Et
4
NBF
4
at 25°C.
2.2 Electrolyses
Constant current electrolyses were performed at 25°C, using an Amel Model 552 potentiostat equipped with an
Amel Model 731 integrator. All the experiments were carried out in a divided glass cell separated through a
porous glass plug filled up with a layer of gel (i.e., methyl cellulose 0.5% vol dissolved in DMF-Et
4
NBF
0.1 mol dm-3
was used as solvent-supporting electrolyte system (catholyte: 10 cm ; anolyte: 5 cm ). The current density was
4
1.0
-3
2
mol dm ); Pt spirals (apparent area 0.8 cm ) were used as both cathode and anode. DMF-Et
4
NBF
4
3
3
-
2
2
0 mA cm .
In the catholyte 0.5 mmol of benzoin (or deoxybenzoin, or benzil) and 1.0 mmol of amine were present, with
continuous O bubbling. The electrolysis was stopped after a prefixed charge (see Tables 1-4), the oxygen
2
3

bubbling was stopped and the catholyte was kept under stirring at rT for 12 hours. Usual workup gave the
benzamides reported in Tables 1-4.
All the isolated benzamides gave spectral data identical to those reported in the literature. Products spectral
characterisation is reported in the Supporting Information.
3
. Results and Discussion
Insights into the reactivity of electrogenerated superoxide anion towards various substrates can be obtained by
studies of cyclic voltammetry.
The cyclic voltammetry, on a glassy carbon (GC) electrode at room temperature, of a DMF-0.1 M Et
4
NBF
4
-2
solution of deoxybenzoin (1·10 M) shows a first reduction peak (- - - - C1) at a potential of - 1.95 V vs
modified saturated calomel electrode (mSCE [16]), Figure 1. The cyclic voltammetry (under the same
experimental conditions) of a molecular oxygen saturated DMF-0.1 M Et
4
NBF
4
solution shows a first reduction
peak (_____ C1) at a potential of - 0.96 V vs mSCE (Figure 1), partially reversible (_____ A1). Oxygen
-3
concentration in these experimental conditions is about 2·10 M [17].
This first cathodic peak (_____ C1) corresponds to the monoelectronic reduction of oxygen to superoxide
anion (Scheme 3). It is thus possible to generate superoxide anion in the presence of deoxybenzoin. Moreover,
the literature reports that the reaction between superoxide anion and a cyclic aliphatic ketone leads to the
formation of the corresponding alcohol and adipic acid (due to ring opening and oxidation reaction),
highlighting the reactivity of superoxide as both reductant and oxidant (in the presence of O ) [18].
2
Figure 1.
It is possible that the interaction between electrogenerated superoxide anion and deoxybenzoin yields the
cleavage of the C-C bond in the alpha position to the carbonyl group and the formation of the corresponding
benzoic acid.
The addition of deoxybenzoin to an oxygen saturated DMF-0.1 M Et
modification of the cyclic voltammetry (Figure 2). In particular, the oxidation peak (_____ A1 vs - - - - A1) at -
.68 V of molecular oxygen decreases, indicating a consumption of superoxide anion generated in the direct
4
NBF
4
solution leads to a
0
scan (no more available for the oxidation on the electrode).
The decrease of the oxidation peak current of oxygen is proportional to deoxybenzoin concentration. The
voltammetric analysis thus confirms a chemical interaction between superoxide ion and deoxybenzoin.
3.1 N-Benzylbenzamide synthesis from deoxybenzoin
4

As the scope of this work was the synthesis of benzamides (Scheme 4), we carried out a first electrolysis on a
DMF-0.1 M Et NBF solution containing deoxybenzoin and benzylamine in a 1:1 mole ratio and saturated with
molecular oxygen. Due to the large difference of the values of the reduction potentials of the involved species
see Figure 1; benzylamine is not electroactive under our experimental conditions), we carried out the
4
4
(
electrolysis under galvanostatic conditions, reducing oxygen to superoxide anion in the presence of
deoxybenzoin and benzylamine.
Figure 2.
This electrolysis configuration allows to avoid the use of a reference electrode and it is thus greatly
preferred. The electrolysis was stopped after the consumption of 2 F/mol of deoxybenzoin and the catholyte
was kept under stirring at room temperature for 12 hours, without oxygen bubbling.
Scheme 4.
Usual workup of the catholyte gave the corresponding N-benzylbenzamide in 22% yield (Table 1, entry 1). In
order to obtain higher yields in benzamide, various reaction parameters must be optimized. Due to the
formation of benzoic acid as byproduct, the first choice was to increase the benzylamine amount, to neutralise
the acid. The use of two equivalents of amine led to the formation of benzamide in 64%, while a further
increase hindered the reaction (Table 1, entries 2 and 3). Also the amount of superoxide anion (i.e., the amount
of charge, in Faradays per mole) has an important role in this reaction, and the higher yields were obtained with
two equivalents of superoxide anion. Higher amounts led to benzoic acid as main product, while using a lower
amount starting material was recovered (Table 1, entries 2 and 4-6). Last, a change of solvent, from DMF to
MeCN, lowered again the yield, probably due to the proton donor ability of acetonitrile (Table 1, entries 2 and
-2
7
). A change of current density (10 mA cm , Table 1 entry 8) or the use of potentiostatic conditions (Table 1
entry 9) led to lower yields, perhaps due to the longer reaction time. As usual, we carried out control reactions
in the absence of current (Table 1, entry 10) and in the presence of a strong organic base (DBU, Table 1, entry
11) and in both cases unsatisfactory results were obtained, confirming that the role of superoxide anion is not
only as a base.
The best reaction parameters set is thus reported in entry 2 (Table 1). In many of the reactions reported in Table
1, three byproducts were isolated, in variable yields (Figure 3).
Figure 3.
In order to understand if benzoin and benzil (deoxybenzoin oxidation products) are reaction intermediates
or only byproducts, we carried out a voltammetric analysis and electrolyses starting from these two products.
3.2 N-Benzylbenzamide synthesis from benzoin
5

The cyclic voltammetry, on a glassy carbon (GC) electrode at room temperature, of a DMF-0.1 M Et
4
NBF
solution of benzoin (1·10 M) shows a first reduction peak (- - - - C1) at a potential of - 1.84 V vs mSCE
Figure 4). As seen before, the cyclic voltammetry (Figure 1) of molecular oxygen shows a first reduction peak
(_____
C1) at a potential of - 0.96 V vs mSCE. It is thus possible to generate superoxide anion in the presence of
4
-2
(
benzoin. With such a difference in the reduction potentials, it is unlikely that an electron transfer between
superoxide anion and benzoin takes place. The confirmation of a chemical interaction between benzoin and
superoxide anion came from the voltammetric analysis of a solution containing molecular oxygen and benzoin
(
Figure 5). In fact, albeit the peak current relative to the first reduction of oxygen did not modify in the
presence of benzoin (thus excluding an electron transfer, _____ C1 vs - - - - C1), the disappearance of the
corresponding anodic current (_____ A1) demonstrated the consumption of superoxide anion. We thus carried out
electrolyses of DMF solutions of benzoin, benzylamine and molecular oxygen (Scheme 5).
Scheme 5.
The benzoin:benzylamine mole ratio was kept 1:2, in order to neutralise benzoic acid. We decided to use a
lower amount of charge (i.e., of superoxide anion), as benzoin is more oxidised than deoxybenzoin. The results
are reported in Table 2.
Figure 4.
Figure 5.
When using a stoichiometric amount of superoxide anion (1 F/mol, assuming a 100% current efficiency, Table
2, entry 1), only 30% of N-benzylbenzamide was obtained, while lowering the amount of charge, the yields
were higher (65-66% with 0.3-.06 F/mol, Table 2, entries 2-3). A lower current density (Table 2, entry 4) did
not enhance sensibly the yield (68%), while extending the reaction time. Also the use of potentiostatic
conditions, thus ensuring the selective reduction of molecular oxygen, led to the same result (Table 2, entry 5).
The control reaction in the absence of current did not lead to the formation of the amide (Table 2, entry 4),
while the use of a strong chemical base (DBU, entry 5) allowed to isolate amide in 48% yield. In this case it is
clear that superoxide anion acts mainly as a base and an excess of this anion leads to overoxidation products
(
benzoic acid). It should be underlined that the reaction of benzoin and molecular oxygen leads to the formation
of benzil (Table 2, entry 4) and that the reaction between benzoin and superoxide anion is reported to yield
benzil [19].
The same study was carried out starting from benzil.
3.3 N-Benzylbenzamide synthesis from benzil
6

The cyclic voltammetry, on a glassy carbon (GC) electrode at room temperature, of a DMF-0.1 M Et
4
NBF
4
-2
solution of benzil (2·10 M) shows a first reduction peak (- - - - C1) at a potential of - 1.20 V vs mSCE, close
to the reduction peak potential of molecular oxygen (_____ C1, 0.96 V, Figure 6). It is thus unlikely to reduce
selectively oxygen in the presence of benzil. Moreover, with such a small difference in the reduction potentials,
it is possible an electron transfer (ET) between superoxide anion and benzil. The confirmation of a chemical
interaction between benzil and superoxide anion came from the voltammetric analysis of a solution containing
molecular oxygen and benzil (Figure 7). In fact, the peak current relative to the first reduction of oxygen (_____
C1) increased in the presence of benzil (+37%), suggesting an interaction with benzil regenerating molecular
oxygen on the electrode surface (ET or disproportionation). It is well known [15] that in the presence of acidic
substrates superoxide anion can deprotonate them in a disproportionation reaction (Scheme 6), regenerating
molecular oxygen. In our case, benzil has no acidic proton, thus excluding this last reaction.
Figure 6.
Figure 7.
Moreover, Boujlel and Simonet reported [20] that there is an ET interaction between benzil and superoxide
anion to yield two molecules of benzoic acid. In order to study this superoxide-benzil interaction, we carried
out electrolyses of DMF solutions of benzil, benzylamine and molecular oxygen (Scheme 7) and the results are
reported in Table 3.
Scheme 6.
Scheme 7.
As can be seen from Table 3, the yields in N-benzylbenzamide seem to be not dependent on the charge
amount, being 40-43% using 0.3-1.0 F/mol (Table 3, entries 1-3). Moreover, the same result is obtained with
DBU (Table 3, entry 5). It seems thus evident that in this case superoxide anion acts solely as a base and, in
fact, this reaction is not effective in the absence of base (control experiment, Table 3, entry 4). It is possible that
the lower yields in N-benzylbenzamide obtained from benzil (in comparison with those obtained from benzoin)
are due to a co-reduction of benzil during the synthesis of superoxide anion, as the two reduction potentials are
very close.
After all these experiments, we can assert that N-benzylbenzamide can be obtained by interaction of the
superoxide anion/molecular oxygen system with deoxybenzoin, benzoin and benzil, in the presence of
benzylamine. The higest yields are obtained starting from deoxybenzoin (64 %, 2.0 F/mol) and benzoin (66 %,
0.3 F/mol). As benzoins are more readily available than deoxybenzoins, and the reaction from benzoin needs
less energy (0.3 vs 2.0 F/mol), we decided to study the scope of this reaction starting from benzoin.
7

3.4 Benzamides synthesis from benzoin
Electrolyses of molecular oxygen in the presence of benzoin and an amine were carried out under the best
experimental conditions, i.e. using a benzoin:amine mole ratio of 1:2 and 0.5 F/mol (the reaction yields are
identical using 0.3 and 0.6 F/mol, Table 2, entries 2 and 3). The results are reported in Table 4.
Good to high yields in benzamides were obtained starting from primary (Table 4, entries 1-2, 7-10) and
secondary (Table 4, entries 4-6) aliphatic amines, while p-anisidine gave a very lower yield (Table 4, entry 3).
The substituents on the aromatic ring of benzoin have a noteworthy effect. In fact, electron withdrawing
groups led to the formation of benzamide in high yields (Table 4, entries 11 and 12), while an electron donating
group inhibited the reaction (Table 4, entry 13).
3.5 Mechanistic insights
In order to try to understand the possible mechanism of this reaction, we have carried out some experiments,
starting from the premises that:
-
benzoin and benzil were isolated from reaction of deoxybenzoin: they thus could be byproducts or
intermediates;
-
-
benzoin is oxidised to benzil by oxygen (Table 2, entry 4);
N-benzylbenzamide was obtained starting from deoxybenzoin, or benzoin or benzil, demonstrating that they
are intermediates;
benzamides were obtained in high yields from both primary and secondary aliphatic amines, rendering
-
unlikely the corresponding imine/iminium ion as intermediate (imine and iminium ion should have different
reactivity, one being uncharged and the other positively charged);
-
the reaction of deoxybenzoin, benzoin and benzil and superoxide ion could yield benzaldehyde, which could
be an intermediate of benzamide synthesis (we had p-CH
3
O-benzaldehyde as byproduct starting from p-CH O-
3
benzoin).
At first we have carried out the reaction on benzaldehyde and pyrrolidine (1.0 F/mol), in order to
confirm/exclude benzaldehyde (or the iminium ion) as intermediate (Scheme 8).
Scheme 8.
The corresponding benzamide was obtained in 11%, too low a yield to confirm benzaldehyde/iminium
cation as intermediates.
Then the same reaction was carried out starting from the imine derived from benzaldehyde and benzylamine
(
1.0 F/mol); no amide could be isolated, demonstrating that imine is not an intermediate starting from primary
amines (Scheme 9).
Scheme 9.
8

In order to explain the presence, as byproduct, of the ester reported in Figure 3, we carried out two
chemical reactions between benzoin, benzil and molecular oxygen, in the presence and in the absence of a base
(
DBU), obtaining the synthesis of the ester only in the presence of the base and confirming benzil as the
acylating agent (Scheme 10). It is not to be excluded that benzoin itself generates the acylating agent; in fact,
the reaction between benzoin and molecular oxygen yields benzil (Table 2, entry 6).
Scheme 10.
We have also tried to understand the role of the amine, reporting the yields in benzamide in function of the
pKa values of the corresponding ammonium cation (in DMSO, when known). The graph is reported in Figure
8. The graph shows a quite linear correlation between yields and pKa, indicating the importance of the amine as
base and as nucleophile.
Figure 8.
Last, we carried out the reaction between deoxybenzoin, superoxide anion and an amine starting from an
unsymmetrical deoxybenzoin (Scheme 11), under the experimental conditions reported in Table 1, entry 2.
Scheme 11.
As can be seen from Scheme 11, the mole ratio between the two possible benzamides in each experiment
is near to 1:1 in both cases, showing that the intermediate of this reaction is likely to be symmetrical (i.e.,
benzil).
Considering the information obtained from all these experiments, we suggest the possible reaction mechanism
reported in Schemes 12-14.
Scheme 12.
Scheme 13.
Scheme 14.
The first interaction between deoxybenzoin and superoxide anion could be the deoxybenzoin deprotonation via
superoxide disproportionation (Scheme 12), thus regenerating molecular oxygen, but the amount of base is not
stoichiometric, the peroxide intermediate acting as base towards deoxybenzoin. This reaction could justify the
increase in the cathodic current of molecular oxygen when in the presence of deoxybenzoin (Figure 2), increase
which is not stoichiometric.
9

Then benzoin is oxidised to benzil (as reported by Singh and Misra [19], Scheme 13) by interaction with
superoxide anion, in a reaction which does not regenerate molecular oxygen (as reported in the voltammetric
analysis, Figure 5). It should be underlined that benzoin oxidation to benzil is efficient also in the absence of
superoxide anion (but in the presence of molecular oxygen), as reported in Table 2, entry 4.
Last, benzil in the presence of amine is transformed into the corresponding benzamide by action of hydrogen
peroxide (Scheme 14), generated from superoxide anion (Schemes 12 and 13). The amine acts as both
nucleophile and base, and thus the yields of benzamides are related to the pKa values (Figure 8). As a
confirmation of the reaction depicted in Scheme 14, we carried out a chemical reaction between commercial
hydrogen peroxide, benzil and benzylamine in DMF, and N-benzylbenzamide was obtained in 46% yield (not
optimized).
4
. Conclusion
In this paper it has been demonstrated that it is possible to obtain benzamides by reaction of deoxybenzoin, or
benzoin, or benzil, with an amine (primary or secondary), molecular oxygen and electrogenerated superoxide
anion, under very mild experimental conditions. The most efficient reagent is benzoin, and benzamides are
obtained in good to high yields using only 0.5 F/mol of charge starting from benzoin by C-C bond cleavage.
The byproduct is benzoic acid, which is neutralised by the excess of amine (used in twofold amount with
respect to benzoin).
The main advantage of using electrogenerated superoxide anion resides in its counterion, the
tetraethylammonium cation, which is not tightly bound to the anion and thus renders superoxide highly reactive.
Moreover, the voltammetric analysis allowed to state the possibility to carry out this reaction under
galvanostatic conditions, much preferred with respect to the potentiostatic ones.
The isolation of byproducts and experiments purposely carried out allowed to suggest a hypothesis of
mechanism (in part supported by literature), in which superoxide anion (in the presence of molecular oxygen) is
able to oxidise deoxybenzoin to benzoin, and this last to benzil, which in turn is converted into benzamide.
Acknowledgements
The authors acknowledge Sapienza University of Rome for financial support, Mr Marco Di Pilato for his help
with the voltammetric analysis, and Prof. Achille Inesi for the stimulating discussions.
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Chem. 3 (2005) 3971-3978.
SCHEMES
CuCl 2H O (10 mol %)
2
2
1
,10-phenanthroline H O
2
O
O
O
R1
R2
(20 mol %)
R1
R2
Ar2
+
HN
Ar1
Ar1
N
+
Ar2
H
MeCN, air, reflux, 24 h
Scheme 1. Copper an phenanthroline catalysed synthesis of benzamides from deoxybenzoins and amines.
TBHP (400 mol %)
K CO (100 mol%)
O
O
O
R1
R1
2
3
Ar
+ HN
+
Ar
O
Ar
R2
Ar
N
R2
THF, 80°C, 12 h
O
Scheme 2. tert-Butyl hydroperoxide (TBHP) catalysed synthesis of benzamides from benzils and amines.
O + e
2
O2
Scheme 3. Electrochemical reduction of molecular oxygen.
O
O
O
O2 / O2
Ph +
H N
2
Ph
+
Ph Ph
Ph
Ph
N
OH
H
1
2

Scheme 4. Synthesis of N-benzylbenzamide from deoxybenzoin, benzylamine and superoxide anion.
O
O
O
O2 / O2
Ph +
2
H N
2
Ph
+
Ph Ph
Ph
Ph
N
O H N
Ph
3
H
OH
Scheme 5. Synthesis of N-benzylbenzamide from benzoin, benzylamine and superoxide anion.
2
O2 + RH
O + HO + R
2 2
Scheme 6. Disproportionation of superoxide anion in the presence of acidic substrate.
O
O
O
O2 / O2
Ph +
2
H N
2
Ph
+
Ph Ph
Ph
Ph
N
O H N
Ph
3
H
O
Scheme 7. Synthesis of N-benzylbenzamide from benzil, benzylamine and superoxide anion.
O
O
O2 / O2
+
HN
11 %
Ph
H
Ph
N
1
3

Scheme 8. Synthesis of pyrrolidinylbenzamide from benzaldehyde and pyrrolidine.
O
Ph
O2 / O2
N
Ph
Ph
N
Ph
H
H
Scheme 9. Reaction between imine and superoxide anion.
O
O
O
DMF, rt
+
O
OH
O
O
DBU, DMF, rt
30 %
Scheme 10. Chemical reaction between benzoin and benzil in the absence or in the presence of DBU.
1
4

O
O
N
NH2
O2 / O2
H
+
Y
Cl
32 %, Y: Cl / Y: H = 45 / 55
O
N
O
O2 / O2
+
Y
N
Cl
H
4
6 %, Y: Cl / Y: H = 55 / 45
Scheme 11. Reaction between unsymmetrical deoxybenzoin, amine and superoxide anion.
O2 + e
O2
O
O
Ph
Ph
Ph
O + HO2
+
+
2 O2
2
Ph
Ph
O
O
Ph
+ O2
Ph
Ph
O
O
O
O
O
O
Ph
O
+
Ph
Ph
Ph
+
Ph
Ph
Ph
Ph
O
O
OH
O
O
Ph
Ph
Ph
Ph
O
OH
OH
Scheme 12. Reaction mechanism hypothesis: from deoxybenzoin to benzoin.
1
5

O
O
O
O
Ph
Ph
Ph
Ph
+
O2
Ph
Ph
Ph
+ HO2
+ H O
2 2
Ph
OH
O
O
O
O
Ph
+
O2
+ O2
Ph
O
Scheme 13. Reaction mechanism hypothesis: from benzoin to benzil, as reported in reference 19.
OH
O
O
O
O
+
HO2
Ph
Ph + RNH2
Ph
Ph
Ph
Ph
NHR
NHR
HO
HO
O
OH
O
O
O
O
Ph
Ph
R
Ph
O
H NR +
+ HO
3
Ph
N
NHR
O
H
H
RNH2
Scheme 14. Reaction mechanism hypothesis: from benzil to benzamide.
1
6

FIGURES
-
2
-3
Figure 1. Superimposed cyclic voltammetries of deoxybenzoin (1·10 M) and molecular oxygen (about 2·10 M). DMF-
-
1
0
.1 M Et
4 4
NBF solution, GC electrode (3 mm diameter), rT; reference electrode: mSCE. : 0.2 V s . Scan potential: 0.0 to
-2.7 to +1.6 to 0.0 V.
1
7

Figure 2. Superimposed cyclic voltammetries of molecular oxygen (about 2·10-3 M) and of a solution containing
molecular oxygen and deoxybenzoin (1·10-2 M). DMF-0.1 M Et
NBF solution, GC electrode (3 mm diameter), rT;
4
4
-
1
reference electrode: mSCE. : 0.2 V s . Scan potential: 0.0 to -2.1 to +1.6 to 0.0 V.
O
O
O
Ph
O
Ph
Ph
Ph
Ph
Ph
O
Ph
OH
benzoin
Figure 3. Byproducts in the synthesis of N-benzylbenzamide from deoxybenzoin.
O
benzil
2-oxo-1,2-diphenylethyl benzoate
1
8

-
2
-3
Figure 4. Superimposed cyclic voltammetries of benzoin (1·10 M) and molecular oxygen (about 2·10 M). DMF-0.1 M
-
1
Et
4 4
NBF solution, GC electrode (3 mm diameter), rT; reference electrode: mSCE. : 0.2 V s . Scan potential: 0.0 to -2.7 to
+
1.6 to 0.0 V.
1
9

Figure 5. Superimposed cyclic voltammetries of molecular oxygen (about 2·10-3 M) and of a solution containing
-
2
molecular oxygen and benzoin (2·10 M). DMF-0.1 M Et
4 4
NBF solution, GC electrode (3 mm diameter), rT; reference
-
1
electrode: mSCE. : 0.2 V s . Scan potential: 0.0 to -2.7 to +1.6 to 0.0 V.
2
0

-
2
-3
Figure 6. Superimposed cyclic voltammetries of benzil (2·10 M) and molecular oxygen (about 2·10 M). DMF-0.1 M
-
1
Et
4 4
NBF solution, GC electrode (3 mm diameter), rT; reference electrode: mSCE. : 0.2 V s . Scan potential: 0.0 to -2.7 to
+
1.6 to 0.0 V.
2
1

Figure 7. Superimposed cyclic voltammetries of molecular oxygen (about 2·10-3 M) and of a solution containing
molecular oxygen and benzil (4·10-2 M). DMF-0.1 M Et
NBF solution, GC electrode (3 mm diameter), rT; reference
electrode: mSCE. : 0.2 V s . Scan potential: 0.0 to -2.7 to +1.6 to 0.0 V.
4
4
-
1
2
2

Figure 8. Yields of benzamides (Table 4) versus pKa of ammonium cation in DMSO.[21]
2
3

Table 1. Synthesis of N-benzylbenzamide from benzylamine, deoxybenzoin, oxygen and superoxide anion (Scheme 4).
Reaction parameters optimization.a)
Entry Benzylamine,
eq.
F/molb)
Benzamide,
yieldc)
1
1
2
3
2
2
2
2
2
2
2
2
2
2
2.0
22 %
64 %
31 %
26 %
41 %
64 %
37 %
64 %
26 %
44%
39%
-
2
2.0
3
2.0
4
1.0
5
1.5
2d)
2.0
6
3.0
2d)
7e)
8f)
9
2.0
2.0
2.0
2.0
1
0g)
-
1
1
DBU, 2 eq.h)
5 %
a)
-2
Electrolysis conditions: divided cell, platinum electrodes, rT, galvanostatic conditions (I = 20 mA cm ). Catholyte: 10
mL of DMF-0.1 M Et
4
NBF containing 0.5 mmol deoxybenzoin, benzylamine as in Table, and saturated with molecular
4
oxygen. At the end of electrolysis (charge as in Table), 12 h at rT, then usual workup. b) With respect to deoxybenzoin. c)
Isolated yields with respect to starting deoxybenzoin. In the majority of these experiments byproducts described in Figure
3
were obtained in variable yields. d) Entry 2 was reported thrice for a better comparison. e) MeCN as solvent. f) I = 10 mA
cm . Electrolysis carried out under potentiostatic conditions, E = -1.2 V vs mSCE. h) In the absence of current. DBU:
-2 g)
1
,8-diazabicyclo5.4.0undec-7-ene.
Table 2. Synthesis of N-benzylbenzamide from benzylamine, benzoin and oxygen under chemical and electrochemical
conditions (Scheme 5).a)
Entry
F/molb)
Benzamide, yieldc)
1
2
3
4
5
6
1.0
30 %
65 %
66 %
68% d)
66% e)
-f)
0.6
0.3
0.3
0.3
-
7
DBU, 2 eq.f)
48 %
a)
-2
Electrolysis conditions: divided cell, platinum electrodes, rT, galvanostatic conditions (I = 20 mA cm ). Catholyte: 10
NBF containing 0.5 mmol benzoin, 1.0 mmol benzylamine, and saturated with molecular oxygen.
At the end of electrolysis (charge as in Table), 12 h at rT, then usual workup. b) With respect to benzoin. c) Isolated yields
mL of DMF-0.1 M Et
4
4
2
4

with respect to starting benzoin. d) I = 10 mA cm-2. e) Electrolysis carried out under potentiostatic conditions, E = -1.2 V vs
f)
f)
mSCE.
A mixture of benzoin/benzil in 38/62 ratio was obtained.
In the absence of current. DBU: 1,8-
diazabicyclo5.4.0undec-7-ene.
Table 3. Synthesis of N-benzylbenzamide from benzylamine, benzil and oxygen under chemical and electrochemical
conditions (Scheme 7).a)
Entry
F/molb)
Benzamide, yieldc)
1
2
3
4
1.0
40 %
43 %
42 %
-
0.6
0.3
-
5
DBU, 2 eq.d)
36 %
a)
-2
Electrolysis conditions: divided cell, platinum electrodes, rT, galvanostatic conditions (I = 20 mA cm ). Catholyte: 10
mL of DMF-0.1 M Et
4
NBF containing 0.5 mmol benzil, 1.0 mmol benzylamine, and saturated with molecular oxygen. At
4
the end of electrolysis (charge as in Table), 12 h at rT, then usual workup. b) With respect to benzil. c) Isolated yields with
respect to starting benzil. d) In the absence of current. DBU: 1,8-diazabicyclo5.4.0undec-7-ene.
Table 4. Synthesis of benzamides from amines, benzoins, oxygen and superoxide anion.a)
X
O
O
R2
R2
R1
O2 / O2
N
+
HN
R1
OH
X
X
Entry
X
Amine
Benzamide
Yieldb)
66%
O
1c)
H
H
H
H N
2
Ph
Ph
Ph
N
Ph
H
O
Ph
Ph
2
70%
8%
N
H N
2
H
O
O
O
O
3
H N
2
Ph
Ph
N
H
4
H
HN
N
7
9%
2
5

O
O
HN
HN
Ph
Ph
N
N
5
H
82%
51%
O
6
7
H
H
O
O
O
H2N c-C6H11
Ph
Ph
HN c-C H
6 11
8
8
9%
3%
8
H
H N
c-C H
6 11
N
H
c-C6H11
2
O
O
9
1
H
H
68%
77%
H N
Ph
Ph
N
H
2
0
1
H N
2
N
H
O
1
1
F
HN
HN
4
-F-Ph
N
8
8
9%
1%
O
2
Br
4
-Br-Ph
N
O
HN
4-CH O-Ph
N
3
1
3
CH
3
O
43%
a)
-2
Electrolysis conditions: divided cell, platinum electrodes, rT, galvanostatic conditions (I = 20 mA cm ). Catholyte: 10
mL of DMF-0.1 M Et
4
NBF containing 0.5 mmol benzoin, 1.0 mmol amine, and saturated with molecular oxygen. At the
4
end of electrolysis (25 C, 0.5 F/mol), 12 h at rT, then usual workup. b) Isolated yields with respect to starting benzoin. c)
Same experiment reported in Table 2, entry 3.
2
6