Synthesis and electrochemical properties of substituted para-benzoquinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.03.007

A facile transformation of pentasubstituted tribromophenol derivatives to the corresponding alkyl-substituted dibromo-p-benzoquinones has been achieved using PbO₂ as oxidizing agent in combination with 60% aq HClO₄ in acetone in 70-72% yields. The electrochemical properties of these quinones were studied by means of cyclic voltammetry and compared with p-benzoquinone (BQ) and 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) recorded under identical experimental conditions.

Full text of DOI:10.1016/j.tetlet.2010.03.007

Tetrahedron Letters 51 (2010) 2541–2544
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journal homepage: www.elsevier.com/locate/tetlet
Synthesis and electrochemical properties of substituted para-benzoquinone
derivatives
*
Faiz Ahmed Khan , Sumit Choudhury
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile transformation of pentasubstituted tribromophenol derivatives to the corresponding alkyl-
substituted dibromo-p-benzoquinones has been achieved using PbO2 as oxidizing agent in combination
with 60% aq HClO4 in acetone in 70–72% yields. The electrochemical properties of these quinones were
studied by means of cyclic voltammetry and compared with p-benzoquinone (BQ) and 2,3-dichloro-
5,6-dicyano-benzoquinone (DDQ) recorded under identical experimental conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 22 December 2009
Revised 1 March 2010
Accepted 2 March 2010
Available online 4 March 2010
Synthesis and chemistry of quinones continue to draw the
attention of chemists as they are important intermediates in
organic synthesis1,2 and are among the most abundant substruc-
tures found in numerous naturally occurring bioactive molecules.3
Quinones constitute a large group of natural pigments,1 exhibit
interesting photochemistry,4 function as intermediates in the bio-
synthesis of important antibiotics like tetracyclines,5 display a
broad spectrum of biological activities including antioxidative,6
cytotoxic,7 anticancer,8 antidiabetic9 and enzyme inhibitory activ-
ities.10 They find applications in charge-transfer complexes11 and
chemical sensors.12 The ease of reduction to hydroquinones and
their re-oxidation enable them to play a vital role in the redox
processes occurring in the living organisms. They act as electron-
proton carriers in biochemical processes.5 Besides, substituted qui-
nones are used as oxidants and dehydrogenating agents13 and as
precursors for the synthesis of polycyclic compounds utilizing their
inherent dienophilic character in the Diels–Alder reaction.14 The
versatility of quinones as useful building blocks in the synthesis
of natural products and their biological activity led to the develop-
ment of many synthetic methods.15
Although a large number of reagents16,17 are known to oxidize
phenols to quinones, our initial attempts with 2 revealed the task
to be arduous and required optimization. For this purpose, we first
selected compound 2a as the model substrate for carrying out the
reaction employing few of the known oxidizing agents as depicted
in Table 1. While [(diacetoxy)iodo]benzene (DAIB) and ceric ammo-
nium nitrate (CAN) were able to convert 2a to the corresponding
p-quinone derivative 3a albeit in low yields, other reagents such as
lead tetraacetate (LTA) and [bis(triflouroacetoxy)iodo]benzene
(BTIB) showed a deleterious effect on the yield of the reaction as
trace amount of product was observed. On the other hand, PbO2 in
combination with 60% aq HClO4 furnished 3a in moderate yield.
Reducing the amount of PbO2 from 4 to 2 equiv improved the yield
of 3a to 72%.19 Further decrease of PbO2 to 1.2 equiv was fruitless
as longer reaction time diminished the product yield with incom-
plete conversion of starting material. The reaction was also found
to be sensitive to the amount of HClO4 used. A systematic study in
which the amount of HClO4 was varied, keeping PbO2 constant
(2 equiv), revealed that 0.1 mL of 60% aq HClO4 for 0.07 mmol of sub-
strate gave the best results.
Benzoquinones are commonly prepared by oxidation of phe-
nols16 and alkoxybenzene derivatives17 using a variety of oxidants.
Earlier we had developed an easy access to highly substituted trib-
romophenol derivatives 2, starting from Diels–Alder adducts 1
derived from 1,2,3,4-tetrabromo-5,5-dimethoxycyclopentadiene
and b-substituted vinyl acetates using a three- step hydrolysis-oxi-
dation-fragmentation strategy in high overall yield (Scheme 1).18 It
occurred to us that tribromophenols 2 could serve as excellent pre-
cursors to substituted benzoquinone derivatives. Herein we wish
to report the synthesis of alkyl-substituted dibromo-p-benzoqui-
none derivatives from tribromophenols 2 and their electrochemi-
cal properties as exhibited by cyclic voltammetric studies.
The reaction was also screened to determine the best solvent to
obtain 3a employing PbO2 and 60% aq HClO4 according to the opti-
mized stoichiometry mentioned above. Almost all the commonly
used solvents were found to furnish 3a in varying yields except
MeOH and benzene. Solvents such as AcOH, CH2Cl2, CHCl3, CH3CN,
OH
MeO
Br
OMe
Br
Br
Br
R
H
3 steps
H
CO2Me
Br
Ref 18
R = Alkyl/Aryl
Br
R
OAc
Br
2
1
* Corresponding author. Tel.: +91 512 2597864; fax: +91 512 2597436.
E-mail address: faiz@iitk.ac.in (F.A. Khan).
Scheme 1. Synthesis of substituted tribromophenols.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.007

2542
F. A. Khan, S. Choudhury / Tetrahedron Letters 51 (2010) 2541–2544
Table 1
Screening of oxidizing agents for conversion of 2a to 3aa
O
O
OH
Br
Br
Br
Br
Oxidising agent
rt
CO2Me
CO2Me
Br
3a
2a
Entry
Oxidizing agent
Equivalents
Solvent
Time (h)
Yieldb
1
2
3
4
5
6
7
8
Pb(OAc)4
PhI(OCOCF3)2
PhI(OAc)2
(NH4)2Ce(NO3)6
PbO2, 60% aq HClO4
PbO2, 60% aq HClO4
PbO2, 60% aq HClO4
PbO2, 60% aq HClO4
2
2.2
3
3
4
2.5
2
1.2
Benzene
CH3CN/H2O (2:1)
TFA/AcOH (3:2):cat. H2O
CH3CN/H2O (7:3)
Acetone
Acetone
Acetone
Acetone
10
12
3.5
2.5
2
2
2
4
Tracec
Tracec
30%
40%
60%
70%
72%
47%d
a
b
c
All the reactions were carried out using 0.1 mmol of substrate.
Isolated yield after column chromatography.
On the basis of TLC monitoring against authentic product.
Yield calculated on the basis of recovered starting material.
d
Et2O and dioxane furnished 3a in 38–45% yield in 3 h at room tem-
perature. On the other hand, in THF, DMSO and DMF, reaction did
not proceed to completion even after 16 h to furnish, respectively,
54%, 42% and 50% of 3a (80–95% conversion). DME and acetone
gave the best results (67% and 72% in 3.5 and 2 h, respectively).
Thus acetone emerged as the solvent of choice for the reaction.
Efforts to improve the yield further were not successful perhaps
because of various competitive side reactions arising from the spe-
cies produced under strongly acidic medium during the reaction.
The reactions were deliberately carried out under dilute conditions
(0.025 M) to minimize the competitive side reactions, mainly the
coupling reactions which are common in quinone chemistry.16e
Prolonging the reaction resulted in a proportionate increase in
complexity of the reaction mixture and consequent decrease in
the yield of the product.
All subsequent reactions were carried out using 2 equiv of PbO2,
0.1 ml of 60% aq HClO4 for 0.07 mmol of phenol derivatives 2 in
acetone, maintaining a concentration of 0.025 M. For tribromophe-
nols 2b–d, reactions were completed within 2 h at room tempera-
ture, giving p-benzoquinone derivatives 3b–d in 70–72% yields as
the only isolable products,19 with no indication of the formation
of corresponding o-benzoquinones (Scheme 2).
We then applied the optimized condition to few representative
phenols 4a–c to obtain quinones 5a–c in 62%, 58% and 51% yields,
respectively, as shown in Scheme 3.16e
After successfully synthesizing the p-benzoquinone derivatives
3a–d, our next task was to examine their electrochemical behavior
as quinone–hydroquinone couples have been known to have been
studied extensively over the years as the prototypical examples of
organic redox systems.20 The electrochemical properties of the qui-
nones 3a–d were evaluated by cyclic voltammetry (CV) in dry
CH2Cl2 with 0.1 M tetra-n-butylammonium hexafluorophosphate
O
O
OH
R1
R1
R2
PbO2, 60% aq. HClO4
acetone, rt, 0.5-1 h
R4
R4
R2
R3
4a, R1, R2, R4 = H; R3 = Br
4b, R1, R3 = H; R2, R4 = Me
4c, R1, R2 = Me; R3, R4 = H
5a, 62%
5b, 58%
5c, 51%
Scheme 3. Oxidation of representative phenols 4a–c to quinones 5a–c.
(nBu4NPF6) as the supporting electrolyte.21 The CV curves exhibited
typically two cathodic polarographic waves corresponding to two
single electron reductions to give semiquinone radical anion
(QÅÀ) and hydroquinone dianion (Q2À), respectively, in all the cases
(Fig. 1). Cathodic to anodic peak separations were 140–260 mV for
the first reduction waves (
second reduction waves (
D
D
E1) and about 150–250 mV for the
E2) (Table 2). Although benzoqui-
none–hydroquinone redox couple is one of the known reversible
electrochemical systems but the electrochemical reductions of qui-
nones 3a–d to first semiquinone radical anions (QÅÀ) and then to
behave quasi-reversibly as the
potential differences between cathodic and anodic peaks ( E1,
E2) are in between 140 and 260 mV which are higher than the va-
hydroquinone dianions (Q2À
)
D
D
lue for a reversible process. Furthermore, the ratios between the
cathodic and anodic peak currents of these electrochemical species
range from 1.0 to1.04 for the first reduction potentials (i.e., Q–QÅÀ
)
establishing that the electro- generated species (i.e., semiquinone
radical anions, QÅÀ) are stable in CV time scale and the concentra-
tion of oxidized and reduced species are the same suggesting
reversible nature of the electrochemical response during the con-
version of quinones 3 to corresponding semiquinone radical
anions. On the other hand, in the second reduction process (i.e.,
QÅÀ to Q2À), the corresponding ratios between the cathodic and
anodic peak currents vary from 1.0 to 1.3 showing depletion of
reduced species before the reverse scan suggesting chemical insta-
bility of the reduced species (i.e., hydroquinone dianions, Q2À) in
CV time scale.
O
OH
Br
Br
Br
Br
( )
( )
PbO2, 60% aq. HClO4
acetone, rt, 2h
n
n
CO2Me
CO2Me
O
Br
2b, n=3
3b, 70%
3c
2c
2d
, n=4
, n=5
, 70%
3d, 72%
To visualize the electrochemical effect of the substituents
present in the aforementioned quinones 3, the cyclic voltammo-
grams were compared with that of two known 1,4-quinone
Scheme 2. Oxidation of tribromophenols 2b–d to p-benzoquinone derivatives 3b–d.

F. A. Khan, S. Choudhury / Tetrahedron Letters 51 (2010) 2541–2544
2543
Table 2
Electrochemical parameters: reductions of quinones 3a–d, BQ and DDQ
(1)
(2)
Entry
Quinone
D
E1 (mV)
ÀE1/2 (V)
D
E2 (mV)
ÀE1/2 (V)
À
DE1/2 (V)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
BQ (5a)
DDQ
5b
260
220
160
140
320
80
0.18
0.18
0.19
0.18
0.52
0.31
0.67
0.66
250
220
170
150
320
220
260
250
0.95
0.95
0.95
0.93
1.19
0.97
1.26
1.16
0.77
0.78
0.77
0.75
0.67
0.66
0.59
0.50
220
210
5c
r
Half wave or formal potential E1/2 = (Epr + Epo)/2, Epr = Reduction peak potential, Epo = Oxidation peak potential. Potential separation
and second reductions, respectively. E1/2 = Separation in formal potentials.
D
E = (Ep À Epo). (1) and (2) stand for first
D
values are found to be very much lower with respect to that of BQ
(E1/2(1) = À0.52 V, E1/2(2) = À1.19 V) suggesting easy two- step
reduction of quinones 3a–d to corresponding hydroquinones com-
pared to that of BQ (Fig. 1(i), Table 2). Moreover, in spite of the sec-
ond reduction potentials being almost comparable to that of DDQ
(2)
(2)
(E1/2
values
for
3a–d = À0.95 ? À0.93 V;
E1/2
for
DDQ = À0.97 V), the much lower first reduction potentials of 3a–
d (E1/2(1) = À0.18 ? À0.19 V) in comparison to that of DDQ (E1/
(1) = À0.31 V) indicate quinones 3 as comparable or relatively bet-
2
ter electron acceptors than DDQ (Fig. 1(i), Table 2). These results
may be explained on the basis of electronic environment around
the benzoquinone skeleton. The combined electron- withdrawing
effects of the ester (COOMe) as well as two bromine substituents
generate an overall electron pump away from benzoquinone core
making their reduction easier. With increasing number of carbons
in the alkyl substituent (C3?C6, 3a–d), electron- donating property
does not change significantly. As a result, no appreciable alteration
in the reduction potentials was observed.
Cyclic voltammograms of quinones 5, obtained from the com-
mercially available phenols 4 (Scheme 3) were also recorded and
compared with that of quinones 3 (Fig. 1(ii)). Quinones 5 exhibited
distinctly different voltammograms with respect to quinones 3. It
is clear from the voltammograms (Fig. 1(ii), Table 2) that both the
first and second reduction potentials of 5 are higher than that of 3.
In conclusion, synthesis of alkyl-substituted dibromo-p-benzo-
quinones has been accomplished from pentasubstituted tribrom-
ophenol derivatives using PbO2 as oxidizing agent in combination
with 60% aq HClO4 in acetone in 70–72% yields. A detailed optimi-
zation study revealed a major dependency of the outcome of the
reaction on solvent, stoichiometry of the oxidant and the amount
of acid used. Title compounds exhibited interesting electrochemi-
cal properties as revealed from cyclic voltammetric studies.
Acknowledgments
We thank the Council of Scientific & Industrial Research (CSIR),
New Delhi, for financial assistance. S.C. thanks CSIR for
fellowship.
a
Figure 1. Comparison of cyclic voltammograms of 3a–d with (i) BQ and DDQ and
(ii) 5a (BQ), 5b and 5c in dry CH2Cl2 with nBu4NPF6 (0.1 M) as the supporting
electrolyte at a scan rate of 100 mVsÀ1. The reference electrode was Ag/AgCl.
References and notes
systems, p-benzoquinone (BQ) and 2,3-dichloro-5,6-dicyano-
benzoquinone (DDQ) recorded under identical experimental condi-
tions. All the electrochemical parameters associated with the cyclic
voltammograms are tabulated in Table 2.
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(1) = À0.18 ? À0.19 V, E1/2(2) = À0.93 ? À0.95 V) indicating elec-
2
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3.
Methyl
4,5-dibromo-3,6-dioxo-2-propylcyclohexa-1,4-
dienecarboxylate 3a: To a magnetically stirred heterogeneous mixture of PbO2
(98 mg, 0.41 mmol, 2 equiv) in acetone (2.6 mL) was added dropwise a solution
of 60% aq HClO4 (0.3 mL) followed by a solution of 2a (88 mg, 0.2 mmol) in
acetone (5.4 mL) over a period of 10 min at room temperature and the resulting
mixture was stirred for 2 h. After disappearance of the starting material (as
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quinone derivative 3a. Rf = 0.5 (5% EtOAc in hexane); yield: 53 mg; 72%, yellow
oil. 1HNMR(400 MHz, CDCl3):d3.86 (s, 3H, COOMe), 2.40 (t, J = 7.7 Hz, 2H), 1.52–
1.42 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 177.1 (C@O),
174.6 (C@O), 163.5 (C@O of COOMe), 146.1, 139.8, 138.8, 136.9, 53.1, 30.9, 22.7,
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1080 cmÀ1. ESI-HRMS: m/z calcd for C11H11Br2O4 (M+H)+: 364.9024, found:
364.9023. Methyl 4,5-dibromo-2-butyl-3,6-dioxocyclohexa-1,4-dienecarboxylate
3b: Rf = 0.5 (5% EtOAc in hexane); yield: 70% from 2b, yellow oil. 1H NMR
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2H), 1.34–1.25 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
177.1 (C@O), 174.6 (C@O), 163.5 (C@O of COOMe), 146.4, 139.8, 138.8, 136.7,
53.1, 31.3, 28.7, 22.8, 13.6; IR (neat): 2900, 1720 (C@O), 1660 (C@O), 1560, 1420,
1220, 1120, 1080 cmÀ1. ESI-HRMS: m/z calcd for C12H13Br2O4 (M+H)+: 378.9181,
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Chem. Commun. 1991, 31–33; (k) Tomatsu, A.; Takemura, S.; Hashimoto, K.;
Nakata, M. Synlett 1999, 9, 1474–1476; (l) Saladino, R.; Neri, V.; Minicione, E.;
Filippone, P. Tetrahedron 2002, 58, 8493–8500; (m) Felpin, F.-X. Tetrahedron
Lett. 2007, 48, 409–412; (n) Tohma, H.; Morioka, H.; Harayama, Y.; Hashizume,
M.; Kita, Y. Tetrahedron Lett. 2001, 42, 6899–6902; (o) Kato, N.; Sugaya, T.;
Mimura, T.; Ikuta, M.; Kuge, Y.; Tomioka, S.; Kasai, M. Synthesis 1997, 625–627;
(p) Perumal, P. T.; Bhatt, M. V. Synthesis 1979, 205–206; (q) Murahashi, S.-I.;
Naota, T.; Miyaguchi, N.; Noda, S. J. Am. Chem. Soc. 1996, 118, 2509–2510; (r)
found:
378.9185.
Methyl
4,5-dibromo-3,6-dioxo-2-pentylcyclohexa-1,4-
dienecarboxylate 3c: Rf = 0.5 (5% EtOAc in hexane); yield: 70% from 2c, yellow
oil. 1HNMR (500 MHz, CDCl3):d3.91(s, 3H, COOMe), 2.46 (t, J = 7.9 Hz, 2H), 1.49–
1.46 (m, 2H), 1.32–1.29 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d 177.2 (C@O), 174.8 (C@O), 163.6 (C@O of COOMe), 146.5, 139.9, 138.9,
136.8, 53.2, 31.9, 29.0, 28.9, 22.2, 13.9; IR (neat): 2900, 1720 (C@O), 1660 (C@O),
1560, 1420, 1220, 1120, 1080 cmÀ1. ESI-HRMS: m/z calcd for C13H15Br2O4
(M+H)+: 392.9337, found: 392.9335. Methyl 4,5-dibromo-3,6-dioxo-2-
hexylcyclohexa-1,4-dienecarboxylate 3d: Rf = 0.5 (5% EtOAc in hexane); yield:
72% from 2d, yellow oil. 1H NMR (500 MHz, CDCl3): d 3.92 (s, 3H, COOMe), 2.47 (t,
J = 7.9 Hz, 2H), 1.49–1.44 (m, 2H), 1.36–1.24 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H); 13C
NMR (125 MHz, CDCl3): d 177.1 (C@O), 174.6 (C@O), 163.5 (C@O of COOMe),
146.4, 139.7, 138.8, 136.6, 53.1, 31.2, 29.4, 29.2, 29.0, 22.4, 13.9; IR (neat): 2900,
1720 (C@O), 1660 (C@O), 1560, 1420, 1220, 1140, 1080 cmÀ1. ESI-HRMS: m/z
calcd for C14H17Br2O4 (M+H)+: 406.9494, found: 406.9490.
20. (a) Chambers, J. Q. In The Chemistry of the Quinonoid Compounds; Patai, S., Ed.;
John Wiley and Sons: London, 1974; pp 737–791. Chapter 14; (b) Shaidarova, L.
G.; Gedmina, A. V.; Budnikov, G. K. J. Anal. Chem. 2003, 58, 171–175; (c) Tang,
Y.; Wu, Y.; Wang, Z. J. Electrochem. Soc. 2001, 148, 133–138; (d) Gupta, N.;
Linschitz, H. J. Am. Chem. Soc. 1997, 119, 6384–6391; (e) Sasaki, K.; Kashimura,
T.; Ohura, M.; Ohsaki, Y.; Ohta, N. J. Electrochem. Soc. 1990, 137, 2437–2443.
21. Cyclic voltammetric studies were performed on a BAS Epsilon electrochemical
workstation in dichloromethane using 0.1 M nBu4NPF6 as the supporting
electrolyte. The reference electrode was Ag/AgCl and the concentrations of the
compounds were used in the order of 10À3 M. The ferrocene/ferrocenium
couple occurs at E1/2 = +0.45 (65)
experimental conditions.
V versus Ag/AgCl under the same