Journal of Electroanalytical Chemistry 507 (2001) 275 286

www.elsevier.com/locate/jelechem

Electrochemical aspects of the reduction of biologically active

2-hydroxy-3-alkyl-1,4-naphthoquinones
Patrcia A.L. Ferraz a, Fabiane C. de Abreu a,b, Antonio V. Pinto c, Victor Glezer d,
Josealdo Tonholo a, Marlia O.F. Goulart a,*
a

Departamento de Qumica, CCEN, Campus A.C. Simoes, Uni6ersidade Federal de Alagoas, Tabuleiro dos Martins, 57072 970 Maceio,
Alagoas, Brazil
b
Departamento de Qumica Fundamental, UFPE, Recife, Pernambuco, Brazil
c
Nucleo de Pesquisas de Produtos Naturais, UFRJ, Rio de Janeiro, Rio de Janeiro, Brazil
d
Laboratory of En6ironmental Chemistry, The Hebrew Uni6ersity of Jerusalem, Jerusalem, Israel
Received 6 September 2000; received in revised form 20 December 2000; accepted 23 February 2001

Abstract
A series of natural and synthetic 2-hydroxy-3-alkylnaphthoquinones, several of them with relevant biological activities, showed
typical voltammograms, on Hg and glassy carbon electrodes, in aprotic medium (DMF 0.1 mol l 1 TBAP). Two main pairs of
peaks, the first one corresponding to irreversible and the second one to quasi-reversible processes, were observed. Intermediate
shoulders were also present. They showed strong dependence on scan rate, concentration and pKa of added proton sources.
Lapachol was chosen for detailed investigations, on Hg and glassy carbon electrodes. A self-protonation mechanism and
hydrogen-bonded intermediates explain the nature of the first peaks and shoulders. The last pair of peaks is related to the
quasi-reversible two-electronic reduction of the respective anion of the 2-hydroxynaphthoquinones (NQOH). Addition of proton
sources of different strength caused pKa-dependent modifications of voltammograms. Electrochemical effects are demonstrated
over the full reduction range, from protonation of unreduced quinones to hydrogen-bonding of reduced dianions. Strong acids
like trifluoroacetic acid cause protonation of the original quinone and consequent easier reduction. Benzoic acid is strong enough
to cause the merging of the waves into one pair of irreversible waves. Phenol is able to modify only the more basic
electrogenerated intermediates.
Some OH-free derivatives were prepared and their voltammetric behavior observed. They showed the expected quinone
reduction pattern. 2001 Elsevier Science B.V. All rights reserved.
Keywords: 2-Hydroxy-3-alkylnaphthoquinones; Lapachol; Cyclic voltammetry; Electrolysis; Proton effects; Self-protonation

1. Introduction
Numerous quinones play vital roles in the biochemistry of living cells and exert relevant biological activities. Their cytostatic and antimicrobial activities emerge
due to their ability to act as potent inhibitors of electron transport [1], as uncouplers of oxidative phosphorylation [2], as intercalating agents in the DNA double
helix [3], as bioreductive alkylating agents of
biomolecules [4] and as producers of reactive oxygen
radicals, by redox cycling, under aerobic conditions [5].
* Corresponding author. Tel./fax: + 55-82-214-1389.
E-mail address: mofg@qui.ufal.br (M.O.F. Goulart).

In all these cases, the mechanism of action, in vivo,

requires the bioreduction of the quinones as the first
activating step. Other potential mechanisms of action
of quinones, not based on electron transfer include
sulfhydryl arylation [6], or topoisomerase involvement
[7].
More specifically, lapachol (1) and its analogues are
known to possess antitumor, antibiotic, antimalarial,
anti-inflammatory and antiulceric activities [8]. Lapachol has been shown to be bioactivated by P450 reductase to reactive species, which promote DNA scission
through the redox cycling-based generation of superoxide anion radical [9]. Recent results revealed strong
molluscicidal [10,11] and trypanocidal activities [10,12]
for lapachol and its derivatives and analogues.

0022-0728/01/$ - see front matter 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 0 7 2 8 ( 0 1 ) 0 0 4 3 9 - 9

276

P.A.L. Ferraz et al. / Journal of Electroanalytical Chemistry 507 (2001) 275286

In the specific case of hydroxyquinones, the possibility of stabilization of the electrogenerated anion radical
by intramolecular hydrogen-bonding causes the shift of
the reduction potentials to less negative values [13,14], a
fact that in some cases can be fundamental for biological activity [13]. The necessity of the hydroxyl groups in
the quinone moiety for the occurrence of peroxidation,
in the presence of oxygen, was also emphasized [15].
References to hydrogen-bonding effects in quinone redox chemistry are remarkably sparse [16,17] and, only
very recently, has systematic research been conducted,
clarifying the differences between protonation and hydrogen-bonding [18].
Despite the vast knowledge of electrochemical data
concerning quinones and the intensive research performed at the beginning of the twentieth century [19],
the electrochemistry of 2-hydroxy-1,4-naphthoquinones
is poorly described [16]. Earlier studies on the electrochemistry of lawsone and lapachol (1), on a Pt electrode, in DMSOTEAP suggested that the first and
second irreversible reduction steps could be related to
hydroxyl group reduction to H2 of ortho- (12) and
para-quinone (1) tautomeric forms [20,21]. However,
no comments were made about the possible influence of
intra- or intermolecular hydrogen-bonding; either the
reason why the aforementioned reduction is so easy,
compared to the reduction of carboxylic acids under
the same conditions or why such a large potential
difference for the reduction of the isomeric forms (1
and 12) (Eppara Eportho =0.620 V) is observed, was

discussed. The proposed peculiarities of the 2-hydroxy1,4-naphthoquinone reduction mechanism, on Hg, due
to the very large overpotential for proton reduction,
sound quite improbable.
So, the present paper aims to clarify the electrodic
mechanism of this important class of biologically active
NQOH (1 6) (Fig. 1), under various conditions, using
Hg and glassy carbon electrodes, in an attempt to
understand the role of hydroxyl and quinone carbonyl
interaction, during electrochemical reduction.

2. Experimental

2.1. Chemicals
The NQOHs used in this work were commercial (5),
isolated from natural sources and kindly supplied by
Produtos Vegetais do Piau (PVP, Parnaba, Piau,
Brazil) (1) or synthesized as described elsewhere, (2)
[22], (3) [23], (4) [24]. The lapachol derivatives (710)
were obtained by usual methods: methylation with generated diazomethane (8), acetylation with acetic anhydride and pyridine (9), catalytic hydrogenation using
PtO2, in EtOH (7) and reductive acetylation (10) (as
described here). The potassium salt of lapachol was
prepared by reaction with ethanolic KOH [10].
Tetrabutylammonium hydroxide (TBAOH, 0.1
mol l 1 in MeOH, Aldrich), phenol (PhOH, Merck)
and benzoic acid (BA, Aldrich) were used without
further purification. Trifluoroacetic acid (TFA, Merck)
was kept in P2O5 for 1 h and distilled under N2. Acetic
anhydride (Aldrich) was used after distillation.
Lapachol (1) was studied by UVvis spectrometry in
DMF 0.1 mol l 1 TBAP and based on the literature
[25,26], the observed bands are suggestive of the presence in solution of a hydrogen-bonding associated lapachol dimer (11) and of its ortho-isomer (12), in a
diminute amount. UV (DMFTBAP 0.1 mol l 1) umax
(abs.) (nm): 269 (0.53) (quinoid), 320 (sh.) (quinoid),
336 (0.96) (benzenoid), 480 (o-quinoid) (0.3).

2.2. Sol6ents, electrolytes and solutions

Fig. 1. Structures of the quinones studied.

DMF (Merck, Uvasol Grade) was treated with anhydrous cupric sulphate, filtered and distilled at reduced
pressure through a glass Vigreux column (12 cm).
Tetra-n-butylammonium perchlorate (TBAP) was prepared from the corresponding bromide (Aldrich or
Lancaster synthesis) and perchloric acid 70% (Aldrich).
The resulting salt was washed with cold water until
neutral pH, recrystallized from ethyl acetate and thoroughly dried before use (2 days, 70C, under high
vacuum). Test solutions of the quinones (c=2
mmol l 1) were prepared just before electrochemical
experiments and the dissolved oxygen eliminated by

P.A.L. Ferraz et al. / Journal of Electroanalytical Chemistry 507 (2001) 275286

277

Table 1
Electrolyses of 1 under different conditions
Entry

1/mmol, electrophile (c/mmol)

Eap/V

Charge/mol electrons mol1

Chemical yield (%)

1a
2a

1 (0.5)
1 (0.5)
Ac2O (53)
1 (0.173)
1 (0.173)
Ac2O (10.5)
1 (0.5)
PhOH (5)
1 (0.08)
BA (0.08)
1 (0.166)
TBAOH (0.2)

1.4
1.7

2
2

Recovery of 1
10 (90)

0.7
0.7

2
2

9 (80)
10 (90)

1.4

Recovery of 1

1.4

2.7

Recovery of 1

1.7

2.3

Recovery of 1

3 a,b
4a
5a
6a
7a

a
b

(Hg, DMF0.1 mmol l1 TBAP), controlled potential, divided cell.

Work-up with Ac2O (10.5 mmol), followed by addition of water.

bubbling the solution with dry nitrogen. During the

experiments the cell was kept in a dark Faraday cage to
minimize photoreactions and external electric fields.

2.3. Electrochemical measurements

Cyclic voltammetry (CV) was performed using a
PAR model 273 A/PAR EG&G potentiostat galvanostat equipped with an HP 7090A measuring plotter
system. A PS 486-IBM PC controlled the whole system.
An SMDE 303 A/EG&G PARC hanging mercury electrode (area 0.0097 cm2) and a glassy carbon electrode
BAS (3 mm) were used as the working electrode, together with a platinum counter-electrode and a homebuilt Ag  AgCl  NaCl (0.1 M) Luggin reference
electrode, isolated from the solution by a Vycor rod.
The scan rate was in the range 0.020 35 V s 1. Three
sets of experiments were performed with a glassy carbon electrode: from the anodic to the cathodic arm
(0 1.8 V, back to 2.0 and 0 V), from the cathodic to
anodic arm (0 to 2.0 V, back to 1.8 and 0 V) and
some experiments were held using Ei =1.4 V.

2.4. Reductions
The electrolysis of lapachol (1) was carried out on a
potentiostatgalvanostat 371/PAR EG&G (Table 1).
The current was integrated electronically. Conventional
glass cells (50 ml) were used with the anode and
cathode compartments separated by medium porosity
sintered glass. The electrolyte was pre-electrolyzed at
2.0 V until the background current reached a low
steady value.
The following description is typical for electrolysis
procedures and methods for work-up and isolation of
products. Lapachol (1) (0.042 g, 0.173 mmol), dissolved
in 20 ml of DMFTBAP (0.1 mol l 1) was electrolyzed
at a Hg pool cathode held at 0.75 V, in the presence

of 1 ml of acetic anhydride (10.6 mmol). After consumption of 2 mol electrons mol 1, the cell current
reached a residual current (less than 2% from Ii). Addition of water, followed by ether extraction and washing
with Na2CO3 (5%) and HCl (10%) gave a light yellow
mixture of compounds that was submitted to column
chromatography (hexaneethyl acetate 9:1). The triacetylated-reduced derivative (10) [10] was obtained,
with a yield of 90% (Table 1). The same procedure was
performed with 1 at the potential of the second wave.
After reaching the residual current, with exact consumption of 2 electrons per molecule, the catholyte was
separated and worked up, furnishing, after silica gel
column fractionation, 10 as the main product (90%)
[10] (Table 1). The proton sources were added with
variable concentration. See Table 1 for the respective
amounts.

2.5. CV + electrolysis
Electrolysis of 1, in DMF 0.1 mol l 1 TBAP, followed by CV was performed in a special cell, equipped
with two working electrodes; the first one for larger
electrolyses was a mercury pool (area= 12.5 cm2) and
the second, a GCE (BAS, 3 mm), for running CVS.
Platinum was used as the auxiliary electrode. A homebuilt Ag  AgCl  NaCl (0.1 M) Luggin reference electrode, isolated from the solution by a Vycor rod was
the reference electrode for both processes. The electrolysis was initiated at a potential close to wave IIc (0.8
V) and interrupted after consumption of 0.54 mol
electrons mol 1, without reaching the residual current.
A CV was obtained and the potential was altered to
values close to the cathodic region IIIc (1.2 V), with
additional consumption of 0.33 mol electrons mol 1.
The combined charge (0.87 mol electrons mol 1) suggests a consumption of 1 mol electrons mol 1 for the
initial wave reduction, since the residual current was

P.A.L. Ferraz et al. / Journal of Electroanalytical Chemistry 507 (2001) 275286

278

not reached, due to the longer time required to attain

that point. At this stage, a sample of the solution was
collected, diluted in DMSO to give a solution of 1
mmol l 1 and a UV vis spectra was obtained. At the
potential of wave IV, the current does not decrease.
Continuous generation of an electroactive compound
occurs. Interruption of electrolysis, addition of water,
followed by ether extraction gave an unstable mixture
of compounds that, on air, oxidized back to the starting
quinone 1, quite exclusively.
3. Results and discussion
A series of natural and synthetic 2-hydroxy-3-alkyl1,4-naphthoquinones (1 7) (Fig. 1), several of them
with relevant biological activities, showed typical
voltammograms, on Hg, in aprotic medium (DMF+
TBAP 0.1 mol l 1) (Fig. 2). They are represented by
two main pairs of peaks, the first cathodic one, designated IIc, with a related anodic peak (IIa), and the
second pair, IVc (cathodic) and IVa (anodic), the processes having irreversible and quasi-reversible natures,
respectively. Several initial (peak Ic) and intermediate
shoulders (IIIc1 and IIIc2) are also present (Fig. 2).
Table 2 reports the main electrochemical parameters
measured with scan rates of 0.020, 0.100, 1 and 20
V s 1 and cNQOH of 2 mmol l 1. The observed differences in potential, not addressed in the present work,
are probably related to the OH acidic strength.
This behavior is totally different from the very characteristic feature of non-hydroxylated quinones and
compared to peri-OH-substituted anthraquinones
[13,16,27] or furanquinones [14], it also shows significant differences. Based on data presented in Table 2,
the ease of reduction, represented by the potential of
the first well-defined wave (EpIIc), at w =0.100 V s 1, is
expressed as: 2\ 6\ 3\ 4 5 1  7.

Detailed investigations were carried out with lapachol (1), which would be better represented by 11, with
a minor structural contribution of the tautomer 12. The
tautomer 1 (para-form) is more stable than the tautomer 12 (ortho-form) and the dimeric form 11 predominates over the monomeric form at concentrations
higher than approximately 10 4 M, which, in turn,
decreases the fraction of 12 [26]. For reasons of simplicity, structure 1 is generally used.
Experiments using a glassy carbon electrode were
performed in order to investigate the electrooxidizable
groups and to complete the information in the presence
of proton sources. Additional oxidation waves are
discernible.

3.1. Lapachol
The CV, on Hg and on GCE, showed a strong
dependence on scan rate, concentration and pKa of
added proton sources.

3.1.1. Effect of scan rate

At slow scan rates, the voltammogram of 1 (Fig. 2) is
composed of four cathodic regions. The first wave,
named Ic, is ill defined and observed only at wB0.100
V s 1. The second wave, IIc, is broad. Two close
shoulders, with variable height, represent the region
named IIIc according to w. The fourth wave, IVc, is
well defined. Two anodic waves are evident, the first
one (IIa) is related to peak IIc and the second (IVa),
corresponds to peak IVc, as is shown by adequate
reversal of potentials.
The first waves (IIc, IIa) and shoulders (IIIc) correspond to irreversible reduction processes. The welldefined wave IIc is diffusion controlled, (Ipc 8 w 1/2). The
poor definition of the shoulders and wave IVc precludes
accurate wave height measurements. Despite this, waves

Fig. 2. Cyclic voltammograms of 1 in DMF 0.1 mol l 1 TBAP, Hg, c1 =2 mmol l 1. Effect of scan rate.

P.A.L. Ferraz et al. / Journal of Electroanalytical Chemistry 507 (2001) 275286

279

Table 2
Main electrochemical parameters for 2-hydroxy-3-alkyl-1,4-naphthoquinones
Quinones
1

w/V s1

Elec.

EpIIc/V

EpIIa/V

EpIVc/V

EpIVa/V

EpVa/V

0.020

Hg
GCE
Hg
GCE
Hg
GCE
Hg
GCE

0.699
0.648
0.715
0.666
0.756
0.718
0.828
0.903

0.398
0.180
0.392
0.150
0.365
0.068
0.286
0.126

1.465
1.446
1.522
1.470
1.536
1.528
1.633
1.736

1.392
1.350
1.420
1.350
1.402
1.310
1.318
Broad

1.224

1.260

1.348

1.659

0.100
1
20
2

0.020
0.100
1
20

0.438
0.438
0.436
0.420

0.360
0.372
0.362
0.301

1.452
1.470
1.492
1.561

1.368
1.368
1.346
1.274

0.020
0.100
1
20

0.576
0.580
0.598
0.721

0.300
0.288
0.254
0.196

1.344
1.368
1.402
1.456

1.260
1.248
1.220
1.113

0.020
0.100
1
20

0.696
0.708
0.730
0.790

0.384
0.366
0.338
0.273

1.542
1.560
1.576
1.638

1.476
1.470
1.454
1.365

0.020
0.100
1
20

0.696
0.713
0.748
0.805

0.396
0.390
0.368
0.294

1.452
1.470
1.498
1.575

1.380
1.374
1.364
1.260

0.020
0.100
1
20

0.519
0.503
0.497
0.500

0.438
0.438
0.446
0.385

1.498
1.528
1.546
1.604

1.428
1.428
1.412
1.358

0.100

0.720

0.412

1.418

1.333

IVc and IVa can be considered a quasi-reversible system, by considering the separation between cathodic
and anodic peaks, not the significant shifts of EpIVc and
(DE(p p/2)) with w. As w increases (Fig. 2), wave Ic
disappears and negative shifts for all the cathodic waves
and positive shifts for the anodic ones are observed.
The Epc dependence on w is indicative of the presence
of coupled chemical reactions. The analysis of the
normalized current shows that IpIIc and IpIIa are quite
constant, while IpIIIc and IpIVc are reduced as w increases. At intermediate w (1 BwB 5 V s 1), the ratio
(IpIVc +IpIIIc)/IpIIc 2. For w=20 V s 1, IpIVc/IpIIc is
1.34. It is possible to predict that at w faster than 35
V s 1, the voltammogram could be represented exclusively by the two main pairs of irreversible/quasi-reversible waves with almost the same current.

3.1.2. Effect of concentration

The voltammetric features change with concentration
(Fig. 3). At w = 0.100 V s 1, c1 =5.38 10 5 mol l 1,
only two well-defined cathodic waves are discernible,
the first one enlarged, with a related tiny anodic counterpart (IIa) and a second reversible one (IVc), coupled

with IVa (figure not shown). By doubling the concentration, some modifications occur: two waves are now
discernible in the first cathodic region, the intermediate
shoulders begin to appear and the wave IVc remains
unaffected. As the concentration increases, the separation of the first waves increases as well as the current of
the shoulders in the region IIIc. With a further concentration increase (c1 ] 4.5 mmol l 1) (Fig. 3), IpIc increases at the expense of IpIIc. The following peaks (IIIc
and IVc) suffered larger current increases, which suggest adsorption effects. The graph of IpIIc versus concentration is not linear. The same pattern is observed
with higher scan rates (figure not shown).

3.1.3. Effect of electrode nature

On a glassy carbon electrode, with an initial cathodic
run (Fig. 4), the electrochemical behavior is practically
the same as in Hg (Table 2, entry 1), except for the
presence of an additional irreversible anodic wave
(EpVa), with a current similar to the sum of the cathodic
waves. At high scan rates (1.0 V s 1), reversal of
potential after IIc shows this wave has IIa and an
additional one Ia as its anodic counterparts (Fig. 4).

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P.A.L. Ferraz et al. / Journal of Electroanalytical Chemistry 507 (2001) 275286

Fig. 3. Cyclic voltammograms of 1 in DMF 0.1 mol l 1 TBAP, Hg, w =0.100 V s 1. Effect of concentration.

Fig. 4. Cyclic voltammograms of 1 in DMF 0.1 mol l 1 TBAP, GCE, c1 =2 mmol l 1. (- - -) Initial potential =0 V; ( ) initial potential =1.4
V, Eu after IIc and Ic.

With an initial positive potential (Ei =1.4 V), the difference is related to the appearance of an additional wave,
in the region Ic (Fig. 4). IIc is related to IIa and to Ia
(as shown before) and Ic is related to Ia (Fig. 4).

3.1.4. Effect of added proton source

In the presence of a proton source, the electrodic
mechanism is affected according to the concentration
and nature of added proton sources. The pKa values of
the added acids and 1 [28] in DMSO and the calculated
values in DMF [29] are included in Table 3.
3.1.4.1. Trifluoroacetic acid. On Hg, at w=0.100 V s ,
with cTFA 10 times lower than c1, new cathodic waves
(Ac1 and Ac2) at higher potentials begin to appear. As
cTFA increases, they grow and their intensities vary. For
cTFA 1 mmol l 1, IpIIc and EpIIc remain unchanged,
except for the appearance of a shoulder, which soon
disappears. The wave IIa decreases until it disappears
1

completely (Fig. 5A). The waves IIIc, IVc and IVa also
disappear at cTFA two times higher than c1.
Studies conducted on glassy carbon electrodes allowed the observation of the anodic arm. The behavior
is similar to that described and at cTFA two times higher
than c1, the combined pair of waves appears at 0.578
V (Ac) and 0.198 V (Aa) (Fig. 5B). No significant
differences are observed with different scan rates.
Table 3
Reported pKa values of the acids used in different media
Acids

H2O

DMSO

DMF

Benzoic acid (BA)

Trifluoroacetic acid
Phenol (PhOH)
H2O
Lapachol (1)

4.25
0.2
11.0
15.7
5.02

11.1
3.45
18.0
32

12.32; 12.22 a
4.87 a
16.4; 18.84 a
32.28 a

a
Calculated
following
0.96pK DMSO
[29].
a

the

expression:

pK DMF
= 1.56+
a

P.A.L. Ferraz et al. / Journal of Electroanalytical Chemistry 507 (2001) 275286

281

Fig. 5. Cyclic voltammogram of 1 in DMF0.1 mol l 1 TBAP, c1 =2 mmol l 1, w =0.100 V s 1: (A) effect of added TFA (pK DMF
4.87), Hg;
a
(B) effect of added TFA, GCE; (C) effect of added BA (pK DMF
12.22), Hg; (D) effect of added BA, GCE; (E) effect of added PhOH (pK DMF
a
a
18.84) Hg; (F) effect of added PhOH, GCE.

3.1.4.2. Benzoic acid. The voltammetric analysis was

performed at two main scan rates. At slow w (0.020
0.100 V s 1), a pre-wave, similar to Ic in the CV of 1,
appears and increases slightly, following the increase of
cBA (Fig. 5C). As w increases, this pre-wave vanishes
completely.
Mixtures of BA and 1 in DMF exhibit a classical
pattern of voltammograms [30]; the first reduction wave
grows (IIcf) at the expense of the others as BA is added
in increasing concentrations. EpcIIa does not change,
except by a strong increase in its current (Fig. 5C). The
same behavior is observed at a GCE (Fig. 5D).
3.1.4.3. Phenol. At slow w, waves IIc and IIa remain
practically unaltered, independent of cPhOH. For the
other waves, as cPhOH increases, the voltammetric features change, but in a way completely different from
that verified in the presence of the two acids discussed
above (Fig. 5). For w= 0.100 V s 1 (Fig. 5E) and cPhOH
of 0.2 mmol l 1 (1/10 c1), wave IVc loses its reversibility, suffers a positive shift and is divided into two
waves. The Epc of the larger one is similar to EpIIIc2.
Wave IIIc1 remains. In the anodic portion, wave IVa
disappears and multiple anodic peaks (IVaf) are now
visible, at potentials more negative than IIa. When the
cPhOH (2 mmol l 1) is similar to that of c1, there is a
sequential shift of wave IVc and IIIc2 and now they
become superimposible on wave IIIc1. The new combined wave is designated IVcf (Fig. 5E). For cPhOH of
40 mmol l 1 (20 times higher than c1), IIc and IIa
remain as before and IVcf suffers an additional positive

shift. The recently produced anodic waves become better defined, two main waves being distinguished (Fig.
5E).
At faster w (1 and 10 V s 1) and low cPhOH, the
pattern concerning waves IIc and IIa is kept (figure not
shown). The behavior of the other waves is similar to
that already shown, except for the fact that the fusion
of waves occurs at smaller cPhOH.
Two possible situations can be suggested:
At slower w and high cPhOH, the first pair of waves
(IIc and IIa) remains and Epc of the new cathodic one
undergoes an anodic shift of 270 mV, in relation to
the original one.
At high w and high cPhOH, the voltammogram is
represented by two pairs of irreversible waves, IIc
and IIa, which remain unchanged and the new combined pair (IVcf and IVaf).
Phenol affects only wave IVc and IVa. Similar behavior
is observed at a GCE (Fig. 5F).

3.1.4.4. Effect of added base (TBAOH). The cathodic

waves, in the presence of TBAOH, are well behaved,
but the anodic waves are disturbed in a manner highly
reminiscent of behavior ascribed to streaming effects
[27] (Fig. 6). It is evident that the effect on the quinone
reduction of removing the phenolic hydrogen is considerable. When cTBAOH is twice that of c1, a unique and
reversible pair of peaks, at a potential slightly negative
to the original one, with peak heights twice its original
size, remained. A negative shift of 0.81 V, along with
the disappearance of the shoulders and the first pair of

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P.A.L. Ferraz et al. / Journal of Electroanalytical Chemistry 507 (2001) 275286

peaks, shows the influence of the hydroxyl proton on

the electrodic reduction mechanism [31]. The same result is obtained after consecutive electrolyses in cathodic regions IIc and IIIc (see Section 2). The
reversibility is evident also on a GCE (Fig. 7). An
anodic peak at a less positive potential, named Va%, at
0.727 V compared to Va (Fig. 4, Table 2, entry 1), is
evident and is related to the oxidation of the electrogenerated enolate (NQO) (Fig. 7). NQO was prepared
chemically and its CV is similar to the one shown in
Fig. 7, except for the broader shape of wave Va% (figure
not shown). Wave IVc is related to a reversible electron
transfer and is diffusion-controlled.

3.1.4.5. Effect of substitution of the hydroxyl proton by

methyl and acetyl groups. The CV of the lapachol
derivatives, 8 and 9, showed the typical behavior of
quinones, with the presence of two pairs of waves,
reversible and diffusion-controlled, in the case of 8

(EpIc = 0.768 V, EpIa = 0.696 V, EpIIc = 1.320 V,

EpIIa = 1.236 V) and less reversible (EpIc = 0.660
V, EpIa = 0.582 V, EpIIc = 1.206 V, EpIIa = 1.036
V), in the case of 9 (figures not shown). Comparison of
the voltammetric data showed the strong influence exerted by the hydroxylic proton. In its absence, simpler
voltammograms are obtained with the predictable effect
of the substituents. 9 is reduced more easily than 8, as
expected.

3.1.4.6. Electrolyses. Electrolysis of quinones, in the

absence of electrophiles furnished unstable hydroquinones that are converted back, quite regularly to
the starting materials, by air oxidation. The same result
was obtained with 1. The electrolyses were followed by
CV and after reaching the residual current at a potential close to EpcIII, a voltammogram very similar to the
one in the presence of TBAOH is obtained (Fig. 7
versus Fig. 6). Spectroscopic analysis of this electrolysis

Fig. 6. Cyclic voltammogram of 1 in DMF0.1 mol l 1 TBAP, c1 =2 mmol l 1, Hg, w = 0.100 V s 1. Effect of added TBAOH.

Fig. 7. Cyclic voltammograms of 1 in DMF 0.1 mol l 1 TBAP, GCE, w =0.100 V s 1, after electrolysis on Hg held initially at EpIIc and followed
by electrolysis at EpIIIc1, c1 = 2 mmol l 1.

P.A.L. Ferraz et al. / Journal of Electroanalytical Chemistry 507 (2001) 275286

product is identical to the one already reported [21],

with the presence of a well-defined absorption band
close to 500 nm. Usual work-up led to the recovery of
the initial quinone. In the final electrolyses at 1.7 V,
the current did not decrease and the reaction was
interrupted. Electrolyses were also run in the presence
of PhOH, BA and TBAOH, with charges of 2, 2.7 and
2.3 mol electrons mol 1 (Table 1) and recovery of 1
[31].
Besides the preparative scale electrolyses for establishing a reaction mechanism, electrochemical transformations were performed for the selective synthesis of
phenol derivatives for screening of their biological activities [10]. In this case, the use of electrophiles was
imperative. Co-electrolyses of 1 with acetic anhydride,
using Pt or Hg, at the potentials of wave IIc (0.7 V)
or IVc ( 1.4 V), using 2 mol electrons mol 1 in
both cases, yield 1,2,4-triacetoxy-3-(g,g-dimethylallyl)naphthalene (10) (90%) [10,31]. Addition of acetic anhydride only during the work-up (Table 1, entry 3) led
to 9. This result is a consequence of the basicity of the
medium, generated in the course of reduction, which
leads to the enolate of 1, which reacts with the acylating
agent.

3.2. Mechanistic rationalization

Earlier electrochemical studies on lapachol and lawsone proposed reduction of hydroxyl groups to H2,
leading to the corresponding anions [20,21]. In the
present case, using Hg, this mechanism sounds
improbable.
The results of electrolyses (Table 1) were informative.
In the absence of an electrophile, recovery of the substrate is the pathway of choice. This fact would not
shed any light on the mechanistic explanation, so the
use of an electroinactive electrophile is fundamental.
Co-electrolysis with acetic anhydride, at EpIIc, furnished 10 in high yield (Table 1), without any evidence
of H2. This result accounts clearly for the reduction, at
EpIIc of the quinone to the semiquinone, which suffers
disproportionation, giving back the original substrate
and a modified catechol dianion, which is nucleophilic
enough to react with acetic anhydride, furnishing 10 in
high yield (Table 1, entries 1 4).
Acidbase equilibria are the most frequently encountered type of chemical reaction preceding or following
electron transfer. In addition, electron attachment onto
reducible compounds also bearing acidic functions is
expected to lead, in aprotic medium, to the well-known
self-protonation mechanism, in which the actual proton
source for the electrogenerated base is the starting
compound itself [32,33]. So, since this class of compounds carries an acidic enolic proton, the reduction of
1, as a model, at such high potential is more likely to be
explained by two kinds of effects that surely depend on

283

concentration: self-protonation (intermolecular proton

transfer) [32,33] and stabilization of electron-generated
species by intramolecular/intermolecular hydrogenbonding [13,14,17].
Dimer formation upon proton source addition will
also be expected, most commonly with basic samples
and with proton sources whose conjugate bases have
strengths comparable to that of the sample. Studies on
weak acids with their conjugate bases and with other
bases in non-aqueous solvents, with formation of heteroconjugate or homoconjugate acidbase dimers, were
held mainly in ACN and DMSO but the properties of
DMF are sufficiently similar to anticipate the formation
of acidbase dimers [27].
For all systems involving acidbase equilibria, it has
been proved that the acid form is reduced at more
positive potentials, i.e. more easily, than the conjugate
base. For oxidation, the reverse is true: the conjugate
base is the more reactive species and is oxidized at more
negative potentials [34].
In the electrochemistry of quinones in neutral aprotic
solvents, the effect of hydrogen-bonding can be distinguished clearly from that of protonation by consideration of appropriate pKa values and the characteristics
of the cyclic voltammogram itself. A continuous positive shift in potential with no change in wave height,
reversibility, or appearance of new waves indicates hydrogen-bonding of reduction products. Even if the first
wave increases in height at the expense of the second,
hydrogen-bonding is not excluded, since a disproportionation mechanism assisted by hydrogen-bonding
may be responsible [18].
The comparison of the above facts with the literature, along with the analysis of Fig. 8, on a GCE,
allows the reduction of NQOH to be described qualitatively. The analysis of the current shows that the sum is
the same in all cases and together with the coulometric
experiments, seems to equal 2 mol electrons mol 1. A
complete mechanistic analysis is not possible at the
present stage, due to the complexity of the system.
In the absence of protons (Fig. 6 versus Fig. 8, Table
1, entry 7), the mechanism of cathodic reduction becomes simpler. The electrochemical behavior is associated with the anion of 1 (NQO), as is proven by
similar electrochemical results concerning the product
generated after electrolysis performed at the potential
of waves IIIc (Fig. 7), and the CV of chemically generated NQO. It is also similar to that reported
[20,21,27]. The reduction of NQO proceeds reversibly
through an apparent bielectronic step, especially after
exhaustive electrolysis, when the proton source decreases. Evidence that the actual number of transferred
electrons is two comes from analysis of Fig. 6: the
height of the wave after complete removal of protons
increases and corresponds to the sum of all the initial
waves. As the new system is a substituted naphthalene,

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P.A.L. Ferraz et al. / Journal of Electroanalytical Chemistry 507 (2001) 275286

Fig. 8. Cyclic voltammograms of 1 in DMF 0.1 mol l 1 TBAP, c1 =2 mmol l 1. Comparison of behavior after the addition of different proton
sources. w = 0.100 V s 1, GCE. Attribution of the waves to the redox behavior of the species. The wave at 0.520 V is due to the reduction of
oxidized phenol.

the dispersion of the charge is possible through

resonance.
In the case of the chemically generated NQO, the
electrochemical behavior is less reversible, the oxidation
wave IVa is broader and a protonation intermediate
step can be included to explain the different CV feature,
according to the studies by Piljac and Murray [27].
In the presence of external protons, the mechanism
changes, once they replace the substrate as the source
of protons (Fig. 8). Despite not being proved by spectroscopic methods, the electrochemical behavior of
NQOH could be considered similar to precedent examples [27,35].
When the proton source is very strong as in the case
of TFA (Fig. 5A and B), the monoprotonation of the
starting quinone is possible, making the reduction easier, so that is the reason for the appearance of additional peaks at more positive potentials. Two peaks are
evident due to the possible tautomerism. The oxidation
wave at 0.198 V (Aa) (GCE) (0.100 V s 1) is related to
the oxidation of NQOH3. The anodic wave Va (on
GCE) remains unaltered.
In the case of BA (Fig. 5C and D), the chemical step
of the ECE reaction occurring at the first reduction
wave (protonation of the electrogenerated anion radical
by BA) appears to be essentially quantitative, as cBA/
cNQOH =10.
The resulting wave (Epcf = 0.770 V) is related to
the uptake of two electrons and one proton. In the
anodic counterpart, a wave (Epa = 0.415 V), related
to the oxidation of NQOH
2 is discernible. The ratio
Ipa/Ipc =0.70 (w= 0.100 V s 1) is dependent on the
sweep rate.
Proton sources too weak to cause the ECE reaction
for a substance reduced in two one-electron steps are

without effect on the first wave but often produce a

shift of the second wave to less negative potentials. This
effect is usually interpreted as a post-electron transfer
protonation of the product of the second reduction step
[34]. Such behavior is observed upon addition of phenol
to solutions of 1, at w= 0.100 V s 1, with the added
feature that the second main wave (IVc) is shifted
positively (DE = 0.14 V), upon addition of phenol
(cPhOH = 2 mmol) and an additional positive shift occurs (DE =0.20 V), with an increased concentration of
phenol. Coincidentally, the two new peaks have the
same Epc as the intermediate shoulders IIIc1 and IIIc2
(Fig. 5E and F).
These results suggest that in the presence of phenol,
equilibrium between NQO and another species is established. The new species could be their heteroconjugate acidbase dimer (Eq. (1)) [27].
PhOH + NQO X PhOHNQO

(1)

The formation of homoconjugate dimers with the

added phenol explains the necessity of larger amounts
of phenol.
Although much further experimentation will be required to characterize completely the role of acidbase
dimer formation in the electroreduction of 1, dimer
formation upon proton source addition is possible, due
to the close similarity between the acidbase properties
of the generated conjugate base and those of the proton
source.
Secondly, it is known that the reduction potential for
a sample involved in dimerization would lie between the
reduction potentials of the completely protonated and
non-protonated forms of the sample [27], which occurs,
in the present case.

P.A.L. Ferraz et al. / Journal of Electroanalytical Chemistry 507 (2001) 275286

The explanation of the reduction of 1, which is by

far, the most difficult, should take account of the
presence of the dimer 11 (the tautomer is not shown,
but this explains the broadness of the waves) and
differences between proton transfer and hydrogenbonding formation. The behavior in the presence of BA
helps in the understanding of the region IIc IIa. The
analysis of the addition of TFA and phenol allows the
characterization of waves Ic, Aa and the shoulders IIIc1
and IIIc2, respectively.
After the uptake of the first electron, generating
NQOH, a self-protonation, which generates NQOH2
and NQO occurs. NQOH2 receives a second electron
(no distinction between homogeneous or heterogeneous
electron transfers), forming the related anion (NQOH
2 ),
which suffers a second self-protonation leading to the
electroinactive NQOH3 (visible only at a GCE, wave Ia
(Fig. 4)), together with NQO. The oxidation of the
generated species occurs at a more positive potential
due to a lesser electronic density caused by the protonation. That is the reason for the separation of waves IIc
and IIa.
Alternatively, the generated radical suffers disproportionation, yielding the original quinone and the anion
that can form acid base homoconjugated dimers. The
hydrogen-bonded complex is then reduced at the region
of the shoulders, by uptake of one electron.
The conjugated base, produced in several instances,
suffers an ECE process, at the potential of wave IVc.
The reduction of NQO in the wave IVc is accompanied by a quantitative monoprotonation step, due to
the higher basicity of the generated species [27]. That is
the reason for the broad anodic wave IVa. The proton
source is the medium. In the presence of base, as
already shown (Figs. 7 and 8), and after electrolysis at
EpcIII, the wave becomes more reversible, owing to a
lesser amount of protons or residual water, and the
mechanism is probably an EE mechanism.
In intermediate sweep rates, the grandfather grandson reaction predominates, i.e. the protonated radical
(NQOH), generated from the first self-protonation
step, receives one electron and a second proton, also
from the starting quinone (Eq. (2)) [32,33] so the ratio
(IpcIII + IpcIV/IpcII) tends to 2.
3NQOH +2e 2NQO +NQOH3

(2)

4. Conclusions
The voltammetric behavior of
aprotic medium and on Hg and
trodes is very typical and differs
pattern of hydroxy-free or
naphthoquinones.

several NQOHs, in
glassy carbon elecfrom the reduction
peri-OH-substituted

285

The electrodic mechanism just proposed differs from

reported ones, where no self-protonation effects were
suggested to explain the electrochemical pathway. In
the present case, the self-protonation mechanism is
included to justify the dependence of CV on concentration and also the higher reduction potential value presented by this class of compounds compared to
non-substituted quinones. Spectroscopic investigations
of all the possible intermediates are presently being
conducted in our laboratory.

Acknowledgements
We thank Prof. Ota vio L. Bottecchia (Departamento
de Qumica, UFU, Uberla ndia, MG, Brazil) and Prof.
D.H. Evans (Department of Chemistry and Biochemistry, Newark, USA) for fruitful discussions and Produtos Vegetais do Piau (PVP, Parnaba, Piau, Brazil) for
the kind gift of lapachol. We are grateful to CNPq,
RHAE/CNPq, CAPES and FAPEAL for financial support and fellowships and Prof. Jose Dias de Sousa
Filho (Departamento de Qumica, UFMG, Belo Horizone, MG, Brazil) for running NMR spectra of the
lapachol derivatives.

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