Mechanistic study of electrochemical oxidation of 2,5-dihydroxybenzoic acid and 3,4-dihydroxybenzaldehyde in the presence of 3-hydroxy-1H-phenalene-1-one

Article abstract of DOI:10.1248/cpb.56.513

The mechanism of the electrochemical oxidation of 2,5-dihydroxybenzoic acid and 3,4-dihydroxybenzaldehyde in the presence of 3-hydroxy-1H-phenalene-1-one as a nucleophile has been studied in water/acetonitrile (80/20 v/v) solution using cyclic voltammetry and controlled-potential coulometry methods. The results indicate that the quinones derived from oxidation of 2,5-dihydroxybenzoic acid and 3,4-dihydroxybenzaldehyde participate in Michael addition reactions with 3-hydroxy-1H-phenalene-1-one and via ECE and ECEC mechanisms convert to the different products, with good yield under controlled potential conditions, at carbon electrode.

Full text of DOI:10.1248/cpb.56.513

April 2008
Chem. Pharm. Bull. 56(4) 513—517 (2008)
513
Mechanistic Study of Electrochemical Oxidation of 2,5-Dihydroxybenzoic
Acid and 3,4-Dihydroxybenzaldehyde in the Presence of 3-Hydroxy-1H-
phenalene-1-one
Davood NEMATOLLAHI* and Amaneh AMANI
Faculty of Chemistry, Bu-Ali-Sina University; Hamadan 65174, Iran.
Received November 23, 2007; accepted January 7, 2008; published online January 9, 2008
The mechanism of the electrochemical oxidation of 2,5-dihydroxybenzoic acid and 3,4-dihydroxybenzalde-
hyde in the presence of 3-hydroxy-1H-phenalene-1-one as a nucleophile has been studied in water/acetonitrile
(80/20 v/v) solution using cyclic voltammetry and controlled-potential coulometry methods. The results indicate
that the quinones derived from oxidation of 2,5-dihydroxybenzoic acid and 3,4-dihydroxybenzaldehyde partici-
pate in Michael addition reactions with 3-hydroxy-1H-phenalene-1-one and via ECE and ECEC mechanisms
convert to the different products, with good yield under controlled potential conditions, at carbon electrode.
Key words cyclic voltammetry; 3-hydroxy-1H-phenalene-1-one; 2,5-dihydroxybenzoic acid; 3,4-dihydroxybenzaldehyde
Quinones are of considerable interest because many drugs peak (C1) was obtained, which correspond to the transforma-
such as doxorubicin, daunurobicin and mitomycin C in can- tion of 2,5-dihydroxybenzoic acid (1a) to the related p-ben-
cer chemotherapy contain quinones,1) whereas various other zoquinone 2a and vice versa within a quasi-reversible two-
quinones have found use in industry.2) Some of them also ex- electron process. A peak current ratio (IpA1/IpC1) of nearly
hibit antitumor and antimalarial activities3) and many of them unity in the cyclic voltammogram can be considered as a cri-
are also involved in enzyme inhibition and DNA cross-link- terion for a stable benzoquinone produced at the surface of
ing.4) On the other hand, in recent years, medicinal properties electrode under the experimental conditions. In other words,
of benzofuran derivatives have been investigated widely and any side reactions such as hydroxylation and/or dimerization
were shown to be effective as antitumor,5) anti-depressant,6) reactions are too slow to be observed at the time scale of
antifungal,7) anti-hypertensive, and cytotoxic.8) They are also cyclic voltammetry.17) The oxidation of 2,5-dihydroxyben-
potent and selective oxytocin antagonists,9) PDE5 inhibitor zoic acid (1a) in the presence of 3 as a nucleophile was stud-
for treatment of erectile dysfunction,10) and H3 receptor an- ied in some detail. Figure 1 (curve b) shows the cyclic
tagonists.11) In order to synthesise new quinone derivatives voltammogram obtained for a 0.5 mM solution of 1a in the
we studied the electrochemical oxidation of benzenediols in presence of 0.5 mM 3. The voltammogram exhibits one an-
the presence of a variety of nucleophiles.12,13) Also, in order odic peak A1 and two cathodic peaks (C1 and C0). The sec-
to synthesise benzofuran derivatives we investigated the elec- ond cycle in the cyclic voltammogram (Fig. 1, curve c)
trochemical oxidation of catechols in the presence of b-dike- shows that, parallel to the decrease in current of A1 and the
tones such as acetylacetone,14) dimedone,15) and dibenzoyl- shift of its potential in a positive direction, a new anodic peak
methane.16) In this connection, the electrochemical oxidation
of hydroquinones and catechols in the presence of 3-hy-
droxy-1H-phenalene-1-one (3) as a nucleophile has been re-
cently reported by us (Chart 1).17)
In the present paper, we describe the preparation of the
new polycyclic quinone derivative 6a and the new polycyclic
benzofuran derivative 8b using electrooxidation of 2,5-dihy-
droxybenzoic acid (1a) and 3,4-dihydroxybenzaldehyde (1b)
in the presence of 3-hydroxy-1H-phenalene-1-one (3) as a
nucleophile via ECE and ECEC electrochemical mechanisms
respectively.
Results and Discussion
Electrochemical Study of 2,5 Dihydroxybenzoic Acid
Cyclic voltammogram of a 0.5 mM of 2,5-dihydroxybenzoic
acid (1a) in water/acetonitrile (80/20) solution containing
0.1 M acetate buffer (pHꢀ5.5) is shown in Fig. 1 curve a. As
can be seen, one anodic (A1) and its corresponding cathodic
Fig. 1. Cyclic Voltammograms of (a) 0.50 mM 2,5-Dihydroxybenzoic Acid
(1a), (b) 0.5 mM 2,5-Dihydroxybenzoic Acid, (1a) in the Presence of 0.5 mM
3-Hydroxy-1H-phenalene-1-one (3), the First Cycle, (c) 0.5 mM 2,5-Dihy-
droxybenzoic Acid in the Presence of 0.5 mM 3, the Second Cycle and (d)
0.5 mM 3-Hydroxy-1H-phenalene-1-one (3) at a Glassy Carbon Electrode
in Water/Acetonitrile (80/20) Solution Containing 0.1 M Acetate Buffer
Chart 1
(pHꢀ5.5). Scan rate: 100 mV sꢁ1; tꢀ25ꢂ1 °C
∗ To whom correspondence should be addressed. e-mail: nemat@basu.ac.ir
© 2008 Pharmaceutical Society of Japan

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Vol. 56, No. 4
(A0) appears at less positive potential. The positive shift of containing 0.1 M acetate buffer (pHꢀ5.5) has been selected
the A1 peak in the presence of 3 is probably due to the forma- for electrochemical study and synthesis of 1a in the presence
tion of a thin film of product at the surface of the electrode, of 3.
inhibiting to a certain extent the performance of the electrode
Controlled-potential coulometry was performed in
process. On the other hand, another important difference be- water/acetonitrile (80/20) solution (60 ml) containing 0.2 M
tween these voltammograms, is related to the amounts of acetate buffer (pHꢀ5.5), 0.2 mmol of 1a and 0.2 mmol of 3
their currents at starting potential (ꢁ0.20 V versus SCE). at 0.35 V versus SCE. The electrolysis progress was moni-
The results show that the amount of current for curves a and tored using cyclic voltammetry (Fig. 2). It is shown that, pro-
b at starting potential is nearly zero, but curve c shows ca- portional to the advancement of coulometry, the anodic peak
thodic current at starting potential. This cathodic current is A1 decreases and A0 increases. Anodic peak A1 disappears
related to reduction of 6a. In this Figure, curve d is the when the charge consumption becomes about 4eꢁ per mole-
voltammogram of 3 in the same condition and in the absence cule of 1a. These observations and the mass spectra of iso-
of 1a.
lated product (m/z, 346), allow us to propose an ECE path-
Also, it is seen that proportional to the augmentation of the way in Chart 2 for the electrooxidation of 1a in the presence
potential sweep rate, parallel to the increase in the height of of 3. The existence of carboxylic group probably causes the
the C1, the height of C0 decreases. A similar situation is ob- Michael acceptor 2a to be attacked by 3 at the A (C-6), B (C-
served when the 3 to 1a concentration ratio is decreased. A 4) or C (C-3) positions to yield three types of products in
plot of peak current ratio (IpA1/IpC1) versus scan rate for a each case (Fig. 3) (Chart 2).
1
mixture of 1a and 3, appearing as an increase in the height of
In this connection, the H-NMR of product 6a indicates
the cathodic peak C1 at higher scan rates confirms the reac- that the coupling constants, J, for the two quinoneic peaks
tivity of 2a towards 3. On the other hand, the current function (7.05, 7.70 ppm) are 14 and 13 Hz respectively, which are in
for the A1 peak (IpA1/v1/2) decreases on increasing the scan
rate. In addition, electrochemical oxidation of 1a in the pres-
ence of 3 was studied at various pHs. The results indicate
that, the peak current ratio (IpC1/IpA1) increases with decreas-
ing pH. This can be related to protonation of 3 and inactiva-
tion of it towards Michael addition reaction with p-benzo-
quinone 2a. This indicates that, the rate of coupling reaction
is pH dependent and enhanced by increasing pH. On the
other hand, in basic solutions and in the absence of 3, the
peak current ratio (IpC1/IpA1) is less than unity and decreases
with increasing pH. This is related to the coupling of the an-
ionic or dianionic forms of 1a with p-benzoquinone 2a
(dimerization reaction). Therefore, in this study, solution
Chart 2
Fig. 2. Cyclic Voltammograms of 0.2 mmol 2,5-Dihydroxybenzoic Acid
(1a) in the Presence of 0.2 mmol 3-Hydroxy-1H-phenalene-1-one (3) at a
Glassy Carbon Electrode during Controlled Potential Coulometry at 0.35 V
versus SCE. After consumption of (a) 0, (b) 10, (c) 20, (d) 32, (e) 42, (f) 52,
and (g) 62 C. Scan rate: 100 mV sꢁ1
Fig. 3. The Structure of o-Benzoquinone 2a

April 2008
515
agreement with the existence of two protons in the quinone
1
ring in the ortho position.18) Therefore, according to the H-
NMR results we suggest that p-benzoquinone 2a is attacked
in the A (C-6) position by 3 leading to the formation of 6a
(path A).
According to our results, the anodic peaks of the voltam-
mograms presented in Fig. 1 (A1 and A0) pertain to the oxi-
dation of 2,5-dihydroxybenzoic acid (1a) and intermediate
5a to the p-benzoquinones 2a and 6a, respectively. Obvi-
ously, the cathodic peak C1 and C0 are corresponding to the
reduction of o-benzoquinone 2a and 6a, respectively.
In the present paper, we describe the preparation of a
highly conjugated quinone derivative 6a using electrooxida-
tion of 2,5-dihydroxybenzoic acid (1a) in the presence of 3-
hydroxy-1H-phenalene-1-one (3) as a nucleophile via an
ECE electrochemical mechanism. We think that, electron-
withdrawing effect of carboxyl group in one hand and forma-
tion of two intramolecular hydrogen bonding in intermediate
5a and final product 6a, on the other hand, causes p-benzo-
quinone 2a, which is attacked in the A (C-6) position by 3
(path A). Also, contrary to previous cases (Chart 1),17) p-ben-
zoquinone 6a (final product) is highly stabilized by two in-
tramolecular hydrogen bonding, and remained in quinone
form. The synthesis of 6a has been performed using electro-
chemical oxidation of 2,5-dihydroxybenzoic acid in the pres-
ence of 3 in water/acetonitrile (80/20) solution (pH 5.5, 0.2 M
acetate buffer) in a divided cell at a potential 0.35 V.
Fig. 4. First and Second Cyclic Voltammograms of 0.5 m
M
3,4-Dihydroxy-
benzaldehyde (1b) in the Presence of 0.5 mM 3-Hydroxy-1H-phenalene-1-
one (3) at a Glassy Carbon Electrode in Water/Acetonitrile (80/20) Solution
Containing 0.1 M Acetate Buffer (pHꢀ5.5). Scan rate: 100 mV sꢁ1
tꢀ25ꢂ1 °C
;
Electrochemical Study of 3,4-Dihydroxybenzaldehyde
Electrochemical oxidation of dihydroxybenzaldehydes has
been investigated in various solvents previously.19—21) The
electrochemical oxidation of 3,4-dihydroxybenzaldehyde
(1b) in the presence of 3, has been studied in water/acetoni-
trile (80/20) solution containing 0.10 M acetate buffer (pH
5.5). Figure 4 shows the voltammograms of 3,4-dihydroxy-
benzaldehyde (1b) in the presence of 3. The anodic (A1) and
its cathodic counterpart (C1) are corresponding to the trans-
formation of 3,4-dihydroxybenzaldehyde (1b) to the related
o-benzoquinone (2b) and vice versa within a quasi-reversible
two-electron process.19—21) Under these conditions, the ca-
thodic counterpart of A1 peak decreases. Anodic peak (A0)
which predominates at low scan rates could be indicative of
the oxidation of a new compound produced from the con-
sumption of 2b in the course of following chemical reaction
on the time scale of the experiment. This idea is supported by
the fact that the peak current ratio, (IpA1/IpC1) decreases with
increasing scan rate (Fig. 5) and the anodic current function,
(IpA1/v1/2), decreases with increasing sweep rate. The multi-
cyclic voltammetry of 1b in the presence of 3 shows that par-
Fig. 5. Typical Voltammograms of 0.5 mM 3,4-Dihydroxybenzaldehyde
(1b) in the Presence of 0.5 mM 3-Hydroxy-1H-phenalene-1-one (3) at a
Glassy Carbon Electrode (1.8 mm Diameter), in Water/Acetonitrile (80/20)
Solution Containing 0.1 M Acetate Buffer (pHꢀ5.5) and at Various Scan
Rates. Scan rates from (a) to (e) are 25, 50, 100, 250 and 500 mV sꢁ1, re-
spectively
allel to the shift of the A1 peak in a positive direction a new tional to the advancement of coulometry, the A1 anodic peak
peak (A0) appears at less positive potential in the second decreases. All anodic and cathodic peaks disappear when the
cycle (Fig. 4, 2nd. scan). Since the existence of a b-diketon charge consumption becomes about 4eꢁ per molecule of 1b.
type group, as an electrodonating group, on the catechol ring Our experiences on electrochemical oxidation of catechols in
makes its oxidation easier, this new peak (A0) is related to the presence of nucleophiles,12—17,19—21) diagnostic criteria of
electrooxidation of intermediate 5b. In this case, each mole- cyclic voltammetry, consumption of four electrons per mole-
cule of 1b in the presence of 3 converts to 8b, via inter and cule of 1b and the mass spectra of isolated product (m/z,
intramolecular Michael addition reactions.
Controlled-potential coulometry was performed in tion of 1b in the presence of 3 is ECEC (Chart 3).
water/acetonitrile (80/20) solution containing 0.2 M acetate According to our results, it seems that the Michael addi-
330), indicate that the reaction mechanism of electrooxida-
buffer (pHꢀ5.5), 0.1 mmol of 1b and 0.1 mmol of 3 at tion reaction of 3 to p-benzoquinone 1b (Chart 3, Eq. 2) is
0.45 V versus SCE. The electrolysis progress was monitored faster than other secondary reactions, leading to the interme-
using cyclic voltammetry (Fig. 6). It is shown that, propor- diate 5b. The oxidation of this compound (5b) is easier than

516
Vol. 56, No. 4
anodic oxidation of some catechols and hydroquinones in the
presence of 3-hydroxy-1H-phenalene-1-one (3).17) We ob-
served an interesting diversity in the mechanism (ECE,
ECEC) of electrochemical oxidation of 1a and 1b in the
presence of 3. In the case of 2,5-dihydroxybenzoic acid (1a),
the final product is a quinone derivative, whereas in the case
of 3,4-dihydroxybenzaldehyde (1b), the final product (8b) is
a dihydroxybenzofuran derivative that was obtained after in-
tramolecular Michael addition reaction. Nature stability of p-
quinone in comparison with o-quinone in one hand and sta-
bility of final product arising from two intramolecular hydro-
gen bonding, on the other hand, are responsible for remain-
ing the final product in a quinone form. And finally, although
the experiments were conducted on a relatively small scale,
there is little difficulty in producing larger quantities either
by using larger cells or by running several cells in series.
Experimental
Apparatus Cyclic voltammetry, controlled-potential coulometry and
preparative electrolysis were performed using an Autolab model PGSTAT 20
potentiostat/galvanostat. The working electrode used in the voltammetry ex-
periments was a glassy carbon disc (1.8 mm2 area) and a platinum wire was
used as the counter electrode. The working electrode used in controlled-po-
tential coulometry and macroscale electrolysis was an assembly of four car-
bon rods (31 cm2) and a large platinum gauze constituted the counter elec-
trode. The working electrode potentials were measured versus SCE (all elec-
trodes from AZAR Electrodes).
Reagents All chemicals (2,5-dihydroxybenzoic acid, 3,4-dihhydroxy-
benzaldehyde and 3-hydroxy-1H-phenalene-1-one) were reagent-grade ma-
terials. Sodium acetate, solvents and reagents were of pro-analysis. These
chemicals were used without further purification.
Fig. 6. Cyclic Voltammograms of 0.1 mmol 3,4-Dihydroxybenzaldehyde
(1b) in the Presence of 0.1 mmol 3-Hydroxy-1H-phenalene-1-one (3) at a
Glassy Carbon Electrode during Controlled Potential Coulometry at 0.45 V
versus SCE. After consumption of (a) 0, (b) 6, (c) 13, (d), 20 (e) 27, and (f)
35 C. Scan rate 100 mV sꢁ1. Inset: variation of peak current (IpA1) versus
charge consumed. tꢀ25ꢂ1 °C
Electro-Organic Synthesis of 6a and 8b In a typical procedure, 60 ml
of acetate buffer solution (0.2 M, pHꢀ5.5) in water/acetonitrile (80/20) was
pre-electrolyzed at 0.45 V versus SCE, then 0.20 mmol of 1a or 1b and
0.20 mmol of 3 were added to the cell. The electrolysis was terminated when
the current decayed to 5% of its original value. The process was interrupted
during the electrolysis and the carbon anode was washed in tetrahydrofuran
(THF) in order to reactivate it. At the end of the electrolysis, a few drops of
acetic acid were added to the solution and the cell was placed in refrigerator
overnight. The precipitated solid was collected by filtration and washed sev-
eral times with water. After washing, products were characterized by IR, 1H-
NMR, 13C-NMR, and MS. The Faraday yields of 6a and 8a are more than
95% and the isolated yields of 6a and 8a after washing (in the case of 6a)
and recrystallization (in the case of 8a, the crude product was purified by re-
crystallization from a mixture of THF/acetonitrile in room temperature) are
62 and 67%, respectively.
Characterization of Products 6a and 8b. (6a) (C20H10O6): mp 125—
1
127 °C. H-NMR (300 MHz, DMSO-d6) d: 7.05 (d, Jꢀ14 Hz, 1H, quinone)
and 7.70 (d, Jꢀ13 Hz, 1H, quinone), 7.80—8.00 (m, 2H, aromatic), 8.30—
8.60 (m, 4H, aromatic), 9.8 (broad, 1H, –COOH), 12.85 (broad, 1H, enol-
OH). 13C-NMR, (125 MHz, DMSO-d6) d: 112.6, 115.1, 115.7, 116.3, 119.6,
120.7, 125.4, 125.5, 127.0, 127.4, 129.1, 130.1, 132.0, 132.9, 135.3, 148.3,
151.3, 161.3, 167.5, 178.5. IR (KBr) cmꢁ1: 3408, 3062, 1690, 1630, 1608,
1550, 1460, 1418, 1379, 1226, 1105, 978, 903, 824, 779. MS (EI): m/z (rela-
tive intensity): 346 (Mꢃ·, 2.1), 330 (100), 313 (26.8), 286 (41.5).
Chart 3
the oxidation of the parent-starting molecule (1b). The in-
tramolecular reaction (Chart 3, Eq. 4), performed via a 1,6-
addition reaction, leads to the formation of the final product
8b. The reaction product 8b can also be oxidized at a lower
potential than the starting 3,4-dihydroxybenzaldehyde (1b).
However, overoxidation of 8b was circumvented during the
preparative reaction because of the insolubility of product in
(8b) (C20H10O5): mp ꢄ230 °C (dec). IR (KBr) cmꢁ1: 3484, 3421, 1710,
1627, 1587, 1525, 1451, 1426, 1368, 1343, 1255, 1195, 1076, 893, 785. 1H-
NMR, d ppm (300 MHz, DMSO-d6) d: 6.90 (s, 1H, aromatic), 7.87—8.78
(m, 6H aromatic), 9.56 (broad 1H, OH), 10.26 (broad 1H, OH), 11.33
(broad, 1H, aldehyde). MS (EI): m/z (relative intensity): 330 (Mꢃ·, 2.08),
302 (1.48), 196 (33.3), 163 (11.9), 126 (33.3), 87 (14.3), 63 (26.19), 44
the electrolysis media. The synthesis of 8b has been per- (100).
formed using electrochemical oxidation of 3,4-dihydroxy-
benzaldehyde (1b) in the presence of 3 in water/acetonitrile
Acknowledgments The authors acknowledge to Bu-Ali Sina University
Research Council and Center of Excellence in Development of Chemical
Methods (CEDCM) for supporting this work.
(80/20) solution (pH 5.5, 0.2 M acetate buffer) in a undivided
cell at a potential less than the 0.45 V.
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The present results complete the previous reports on the

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