Electrochemical/chemical oxidation of bisphenol A in a four-electron/two- proton process in aprotic organic solvents

Article abstract of DOI:10.1016/j.electacta.2013.08.181

The electrochemical behavior of bisphenol A (BPA) was examined using cyclic voltammetry, bulk electrolysis and chemical oxidation in aprotic organic solvents. It was found that BPA undergoes a chemically irreversible voltammetric oxidation process to form compounds that cannot be electrochemically converted back to the starting materials on the voltammetric timescale. To overcome the effects of electrode fouling during controlled potential electrolysis experiments, NO⁺ was used as a one-electron chemical oxidant. A new product, hydroxylated bisdienone was isolated from the chemical oxidation of BPA with 4 mol equiv of NO⁺SbF₆^- in low water content CH₃CN. The structure of the cation intermediate species was deduced and it was proposed that BPA is oxidized in a four-electron/two-proton process to form a relatively unstable dication which reacts quickly in the presence of water in acetonitrile (in a mechanism that is similar to phenols in general). However, as the water content of the solvent increased it was found that the chemical oxidation mechanism produced a nitration product in high yield. The findings from this study provide useful insights into the reactions that can occur during oxidative metabolism of BPA and highlight the possibility of the role of a bisdienone cation as a reactive metabolite in biological systems.

Full text of DOI:10.1016/j.electacta.2013.08.181

Accepted Manuscript
Title: Electrochemical/Chemical Oxidation of Bisphenol A in
a Four-Electron/Two-Proton Process in Aprotic Organic
Solvents
Author: Ya Yun Chan Yanni Yue Yongxin Li Richard D.
Webster<ce:footnote id="fn1"><ce:note-para
id="npar0005">ISE Member</ce:note-para></ce:footnote>
PII:
S0013-4686(13)01712-X
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.electacta.2013.08.181
EA 21207
To appear in:
Electrochimica Acta
Received date:
Revised date:
Accepted date:
8-7-2013
23-8-2013
27-8-2013
Please cite this article as: Y.Y. Chan, Y. Yue, Y. Li, R.D. Webster,
Electrochemical/Chemical Oxidation of Bisphenol A in a Four-Electron/Two-
Proton Process in Aprotic Organic Solvents, Electrochimica Acta (2013),
http://dx.doi.org/10.1016/j.electacta.2013.08.181
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Highlights
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Bisphenol A undergoes a chemically irreversible voltammetric oxidation process.
Chemical oxidation was performed to overcome adsorption effects that cause
electrode fouling.
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A new product was isolated from chemical oxidation with 4 mol equiv. of the one-
electron oxidant, NO+.
The oxidative mechanism was proposed to be a four-electron/two-proton process.
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Electrochemical/Chemical Oxidation of Bisphenol A in
a Four-Electron/Two-Proton Process in Aprotic Organic
Solvents
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Ya Yun Chan,a,b Yanni Yue,a Yongxin Lia and Richard D. Webstera,b,1
*
aDivision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371
bNEWRI-ECMG, Nanyang Environment & Water Research Institute, 1 Cleantech Loop, CleanTech
One, #06-08, Singapore 637141, Singapore
*E-mail: webster@ntu.edu.sg, Telephone: +65 6316 8793; Fax: +65 6791 1961
1ISE Member
TITLE RUNNING HEAD: Oxidation mechanism of bisphenol A
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ABSTRACT
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The electrochemical behavior of bisphenol A (BPA) was examined using cyclic voltammetry, bulk
electrolysis and chemical oxidation in aprotic organic solvents. It was found that BPA undergoes a
chemically irreversible voltammetric oxidation process to form compounds that cannot be
electrochemically converted back to the starting materials on the voltammetric timescale. To overcome
the effects of electrode fouling during controlled potential electrolysis experiments, NO+ was used as a
one-electron chemical oxidant. A new product, hydroxylated bisdienone was isolated from the chemical
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oxidation of BPA with 4 mol equiv of NO+SbF6 in low water content CH3CN. The structure of the
cation intermediate species was deduced and it was proposed that BPA is oxidized in a four-
electron/two-proton process to form a relatively unstable dication which reacts quickly in the presence
of water in acetonitrile (in a mechanism that is similar to phenols in general). However, as the water
content of the solvent increased it was found that the chemical oxidation mechanism produced a
nitration product in high yield. The findings from this study provide useful insights into the reactions
that can occur during oxidative metabolism of BPA and highlight the possibility of the role of a
bisdienone cation as a reactive metabolite in biological systems.
Keywords: Proton-coupled electron transfer (PCET), hydrogen bonding, trace water, phenol oxidation
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1. Introduction
BPA is a synthetic industrial chemical that contains two phenol functional groups connected by a
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bridge containing two methyl groups. It has been widely used as a monomer in the production of
polycarbonate and polysulfone plastics (used in food contact materials such as baby feeding bottles,
microwave ovenware and plastic water containers) and epoxy resins (used as epoxy protective linings
for canned food and beverages). There are increasing concerns regarding the potential toxicity and
hormonal activities of bisphenol A (BPA) because of emerging evidence of adverse health effects
reported in laboratory animal studies as well as the widespread human exposure to the compound. This
potentially toxic pollutant was first banned in 2010 by Canada, followed by countries in Europe and in
July 2012, the Food and Drug Administration (FDA) outlawed the use of BPA in baby bottles but not in
other general consumer products. Substantial amounts of the compound have been detected in human
biological fluid samples which are likely ingested through food and water due to BPA leaching [1-3] as
well as in surface waters and sediments [4-6]. BPA is a known endocrine disruptor which mimics
hormones and disrupts normal hormonal functions. Animal studies on rats, aquatic organisms and
wildlife have shown evidence of reproductive and developmental toxicity especially in the early
postnatal stages but further studies are needed to translate the findings from animal studies to potential
toxic effects on human health [1,2,6,7].
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There are very few reports providing mechanistic information on the electrochemical oxidation
of BPA in aprotic organic solvents, which are useful media for stabilizing reactive intermediates [8] and
are closer in properties to the natural lipophilic environment where BPA undergoes oxidative metabolic
reactions. Most electrochemical studies on BPA are conducted in buffered aqueous solutions to explore
electrochemical methods for the treatment of contaminated water [9-17] or chemical modification of
electrodes for a fast and sensitive detection of BPA [18-30]. In aqueous systems, hydroxyl radicals can
be generated at the electrode surface, which then proceed to bring about BPA degradation. In organic
solvents, electrochemical oxidation does not generate hydroxyl radicals and hence, it is possible that
BPA and its potential metabolites react differently in organic and aqueous solvents. The aim of this
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study is to use electrochemical methods to investigate redox reaction mechanisms of BPA in aprotic
organic solvents as a model for oxidative reactions that can occur within low water content biological
(lipophilic) systems.
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Electrochemical studies have been performed on the oxidation of BPA in aqueous buffered
solutions at unmodified electrode surfaces such as platinum [15], glassy carbon [31] and boron-doped
diamond [32]. A large number of studies on a wide range of modified electrodes incorporating
nanomaterials such as carbon nanotubes (CNTs) [18-20], carbon nanohorns (CNHs) [21], quantum dots
[22], chitosan-Fe3O4 nanocomposite [23] and gold nanoparticles [24], as well as reactions mediated by
ruthenium (II) complexes at an indium tin oxide (ITO) electrode [25] and carbon electrodes modified
with stacked graphene nanofibers/gold nanoparticle composites [26], Mg-Al-CO3 layered double
hydroxides [27], fullerenes [17], non-covalently modified ionic liquid-based -cyclodextrine [28],
cobalt phthalocyanine [29] and tyrosinase enzymes [30].
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Unmodified metallic electrodes reportedly give poor selectivity and sensitivity due to a fouling
effect. Electrode modification can potentially decrease the oxidation overpotential and improvements in
the stability of the electrode and current responses have been achieved. However, a fouling phenomenon
– adsorption of polymeric films of BPA was often still observed on the modified electrode surfaces in
aqueous solutions [12,23,25,27,29]. The adsorption processes that occur during electrochemical
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oxidation result in diminishing oxidative peak currents (ip ) with repetitive scanning. It was proposed
that the polymeric film was due to electrochemical polymerization. BPA could be electrochemically
oxidized via a ‒ 2e-/‒ 2H+ process to produce phenoxyl radicals which first combined to form dimers
and then are further oxidized to new diradicals that couple randomly among themselves to form
polymers that vary in structure [12,14,16,22,23,27]. For the water soluble products, it was suggested that
BPA was oxidized via a two-electron and two-proton process [12,18-22,24,27-29] and the oxidized
product was proposed to be bisdienone, whereby the two phenolic groups on BPA were oxidized to
carbonyl groups [18-21,28,29]. There is also a study by Niu et al. [26] who reported a four-electron and
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four-proton process and proposed the formation of dihydroxybenzene at each phenolic group on BPA,
which was then oxidized to four carbonyl groups.
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In this work we have examined the electrochemical oxidation mechanism of BPA in several
organic solvents in order to identify whether the reaction mechanism is the similar to that observed for
other phenols. Phenolic compounds can have important functions in biological processes and knowledge
of the oxidative properties of BPA will be helpful in the investigation of toxicity at the molecular level.
Electrochemical methods are useful for examining electron transfer reactions of phenolic compounds;
giving information on the number of electrons involved and the order of electron transfer which is
critical in identifying intermediates that are likely to exist, and aiding understanding the potential
pathways of biological/chemical conversions [8].
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2. Experimental Section
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2.1. Chemicals
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BPA (≥99%) was obtained from Sigma-Aldrich. Nitrosonium hexafluoroantimonate, NOSbF6
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(99.9%) used for chemical oxidation experiments was obtained from Sigma-Aldrich and stored in a
glovebox in a nitrogen atmosphere. The supporting electrolyte used was tetra-n-butylammonium
hexafluorophosphate (n-Bu4NPF6) prepared according to a literature procedure [33] by reacting equal
molar amounts of aqueous solutions of tetra-n-butylammonium hydroxide, n-Bu4NOH (40% in water,
Alfa Aesar) and hexafluorophosphoric acid, HPF6 (65% in water, Fluka), washing the precipitate and
recrystallising from hot ethanol followed by drying under the vacuum at 160oC for 24 h and storing
under vacuum. Acetonitrile, CH3CN (ACI labscan), dichloromethane, CH2Cl2 (Tedia), N,N-
dimethylformamide, DMF (Tedia) and dimethyl sulfoxide, DMSO (Tedia) were analytical grade and
used directly from the bottles. Ultrapure water with a resistivity of 18.2 MΩ.cm was obtained freshly
from ELGA Purelab Option-Q water purification system. Trifluoroacetic acid, CF3COOH (˃ 99%)was
obtained from Tokyo Chemical Industry (TCI).
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2.2. Electrochemical Procedures
Cyclic voltammetry (CV) experiments were conducted with a computer controlled Eco Chemie
Autolab PGSTAT302N potentiostat in a three-electrode cell under an argon atmosphere. The working
electrode was a 1 mm diameter planar glassy carbon (GC) disk (Cypress Systems), used in conjunction
with a platinum wire (Pt) auxiliary electrode (Metrohm) and a silver (Ag) wire miniature reference
electrode (Cypress Systems) connected to the test solution via a salt bridge containing 0.5 M n-Bu4NPF6
in CH3CN. Accurate potentials were obtained using ferrocene (Fc) as an internal standard that was
added to the test solution at the end of the measurements. Ferrocene is oxidized at approximately +0.64
V vs. SHE (standard hydrogen electrode) in CH3CN [34]. Controlled potential electrolysis (CPE)
experiments were performed in a two-compartment electrolysis cell separated with a porosity no. 5 (1.0
– 1.7 m) sintered glass frit [35]. A GC rod was used as the working electrode and a Pt mesh as the
auxiliary electrode, both arranged with respect to each other with an Ag wire (isolated from the working
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electrode compartment by a salt bridge) as the reference electrode. The number of electrons transferred
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during the bulk electrolysis process (n) was calculated from
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N = Q/nF
(1)
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where N is the no. of moles of starting material, Q is charge in coulombs and F is the Faraday constant
(96485 C mol-1).
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2.3. Chemical Oxidation Experiments
NOSbF6 (4 equiv) was added to a solution of BPA (200 mg, 0.175 mol) in 5 mL of CH3CN at 22
± 2 °C. The solution became black immediately and was stirred for another 15 minutes before checking
with thin layer chromatography (TLC) for complete reaction. The solvent was then removed under
vacuum and the residue was separated by column chromatography and then preparative thin layer
chromatography to give a solid (1), 4,4'-(propane-2,2-diyl)diphenol (20 mg, 9%). mp 101 – 102 °C. IR:
3283, 1659, 1603, 1582 cm-1.1H NMR (CDCl3, 400 MHz) δ: 7.91 (d, 4H, J = 8.8 Hz), 7.17 (s, 2H, OH),
6.93 (d, 4H, J = 8.4 Hz), 2.58 (s, 6H). 13C {1H} NMR (CDCl3, 400 MHz) δ: 198.2, 161.0, 131.1, 129.8,
115.5, 26.3. DEPT NMR (CDCl3, 400 MHz) δ: 131.2, 115.5, 26.3. HRMS (ESI) calcd for C15H16O4:
261.1127. Found: 261.1131.
Repeating the experiment yielded a mixture of product 1 (3 mg, 1%) and a yellow solid (2), 4-
nitrophenol [36] (6 mg, 5%). mp 112 – 114 °C. 1H NMR (CDCl3, 400 MHz) δ: 8.18 (d, 2H, J = 9.2 Hz),
6.91 (d, 2H, J = 8.8 Hz), 5.92 (s, 1H, OH), 7.07 (d, 2H, J = 8.8 Hz), 1.70 (s, 6H). 13C {1H} NMR
(CDCl3, 400 MHz) δ: 161.2, 141.8, 126.3, 115.7. DEPT NMR (CDCl3, 400 MHz) δ: 126.3, 115.7.
The chemical oxidation experiment was later repeated with 10% water in CH3CN solution to
give a yellow solid (3), 4,4'-(propane-2,2-diyl)bis(2-nitrophenol) (195 mg, 70%). mp 135 – 138 °C. IR:
3422, 1630, 1537, 1323 cm-1. UV-vis: 359 nm. 1H NMR (CDCl3, 400 MHz) δ: 10.53 (s, 2H, OH), 8.04
(d, 2H, J = 2.4 Hz), 7.33 (dd, 2H, J = 8.8 and 2.4 Hz), 7.07 (d, 2H, J = 8.8 Hz), 1.70 (s, 6H). 13C {1H}
NMR (CDCl3, 400 MHz) δ: 153.7, 141.7, 136.8, 133.0, 121.8, 120.2, 42.0, 30.3. DEPT NMR (CDCl3,
400 MHz) δ: 136.8, 121.8, 120.3, 30.3. HRMS (ESI) calcd for C15H14N2O6: 319.0930. Found: 319.0929.
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1H, 13C and distortionless enhancement by polarization transfer (DEPT) nuclear magnetic
resonance NMR spectroscopy, high resolution mass spectrometry (HRMS), Fourier transform infrared
(FTIR) spectroscopy and ultraviolet-visible (UV-vis) spectroscopy of compounds obtained from
chemical oxidation experiments using NOSbF6 in CH3CN are provided in the Appendix section, along
with the X-ray crystal structure data of compound 3.
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3. Results and Discussion
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3.1. Cyclic Voltammetry
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Previous electrochemical studies on BPA in water showed an oxidative process on the forward
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scan and no reductive peak when the scan direction was reversed [12,15,17-22,24,25,27-29,31,32].
Because adsorption effects can impede the study drastically, the electrochemical behavior of BPA was
first tested in four aprotic organic solvents namely CH3CN, CH2Cl2, DMF and DMSO and a mixture of
80% CH3CN: 20% H2O solution to determine an optimal solvent composition to work with. The cyclic
voltammograms obtained for BPA in all solvents tested in this study showed only one anodic oxidation
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ox
process with oxidation peak potentials (Ep ) between +0.60 V to +1.00 V vs. Fc/Fc+, with no evidence
of a reverse cathodic (Epred) peak (Figure 1). Thus, it can be concluded that in organic solvents BPA
undergoes a chemically irreversible voltammetric oxidation process to form compounds that cannot be
electrochemically converted back to the starting materials (at least on the CV timescale of a few
seconds), which is similar to the results obtained in water. The intermediate oxidized form of BPA is
chemically short lived, likely undergoing a follow up homogenous chemical reaction(s) after the initial
heterogeneous electron transfer oxidation step(s).
Adsorption phenomena were observed during the CV experiments in organic media such that the
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oxidative peak currents (ip ) decreased noticeably during the second scans in all solvents tested (Figure
1a). The decrease in the ipox for the second scan however, became less pronounced in Figure 1b when the
potentials were cycled to more negative potentials, and it appears that the adsorbed species can be
reduced and at least partially stripped off the electrode by applying sufficiently negative potentials.
The appearance of the voltammograms obtained for BPA in DMF and DMSO were somewhat
different from those obtained in CH3CN and CH2Cl2 solutions (Figure 1). CVs obtained for BPA in
DMF and DMSO solutions showed two closely spaced oxidative peaks during the forward oxidative
process whereas the latter showed one oxidative peak, although the CVs obtained in CH2Cl2 displayed a
particularly broad peak, suggesting overlapping voltammetric processes. Since the voltammetric
process(es) appear chemically irreversible (show no reverse peak when the scan direction is reversed) in
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all solvents, the second process that is detected at more positive potentials in DMSO and DMF is
associated with the oxidation of a product of the initial electron(s) transfer/homogenous chemical
reaction. It is possible that these new oxidized products of BPA are themselves oxidized at different
potentials in DMSO and DMF than observed in CH3CN or CH2Cl2, due to specific solvent-substrate
interactions, therefore, are not observable within the same potential range. An alternative explanation is
that the oxidation pathway does not go by exactly the same route in DMF/DMSO compared to in
CH3CN or CH2Cl2, so different reaction products are produced.
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The ipox values for the oxidation process were also much lower in DMF and DMSO compared to
those recorded in CH3CN and CH2Cl2 (Figure 1). The lower peak currents can partly be explained by the
smaller diffusion coefficient values in the more viscous solvents DMF and DMSO. A further
observation was that BPA is more easily oxidized at less positive potentials in DMF and DMSO
compared to in CH3CN and CH2Cl2.
3.2. Controlled Potential Electrolysis
The oxidation of BPA showed the least adsorption effects in DMF and DMSO as elucidated
from the shapes of the voltammograms, with the second scan more closely overlapping the first scan
compared to CH3CN and CH2Cl2 (Figure 1). Therefore, to minimize adsorption effects, DMSO was
chosen as the solvent to perform controlled potential electrolysis experiments, and also because BPA
oxidizes more easily in DMSO, thus a complete bulk oxidation may be achieved more readily.
Bulk controlled potential electrolysis and coulometry experiments were performed to determine
the number of electrons transferred as well as to gain information on the identity of the intermediates
and long-term electrolysis products. The potential applied during the CPE experiments was +1.55 V vs.
Ag wire (0.5 M n-Bu4NPF6 in CH3CN), which was approximately 150 mV more positive than the first
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Ep -value obtained by CV experiments in DMSO. The applied potential was theoretically sufficiently
positive to bring about the complete oxidation of the analyte. Attempts were made to overcome the
problem of electrode fouling from the adsorption of oxidized products of BPA on the electrode surface
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as the electrolysis proceeded, by periodically applying a negative potential to strip adsorbed species off
the electrode. Pulsed stripping was performed at a potential of 1.00 V for approximately 30 - 60
seconds when the electrolysis current was observed to drop below 1 mA at the large Pt mesh working
electrode (which was used as a gauge that the electrode had fouled; minimal current was passing and
further bulk oxidation was extremely slow). Cyclic voltammograms performed at the beginning and
after electrolysis (incorporating pulsed stripping by alternating several cycles of oxidative electrolysis
and pulsed stripping steps) which took over 3 hours at 22 ± 2 °C are shown in Figure 2. While
performing pulsed stripping at a negative potential of 1.00 V vs. Ag wire (0.5 M n-Bu4NPF6 in
CH3CN) seemed to be effective in regenerating the electrode for the short time-scale cyclic
voltammetric experiments (obtained over several seconds), it did not work for exhaustive long time-
scale controlled potential oxidative electrolysis (obtained over minutes to hours). The CV obtained at
the end of the electrolysis [Figure 2a (bold line)] showed no obvious change from that of the starting
material [Figure 2a (dashed line)] with a transfer of 0.36 electrons (n value) per molecule. The reason is
likely due to a larger amount of the oxidized product adsorbing on the working electrode surface, which
makes it more difficult to strip off by applying a negative potential.
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Previous studies by Murugananthan et al. [9] indicated that it was possible to remove the fouling
layer on the electrode by anodic polarization at the potential region of water decomposition > 2.30 V vs.
saturated calomel electrode (SCE). It was suggested that the adsorbed polymeric film can be oxidized
into smaller un-adsorbed molecules by hydroxyl radicals generated during decomposition of water. It
was not possible to study the electrochemical behavior of BPA at potential greater than +1.70 V vs. Ag
wire (0.5 M n-Bu4NPF6 in CH3CN) during cyclic voltammetric experiments because the solvent begins
to undergo oxidation at that potential. DMSO has a small solvent window of approximately 2.30 V to
+1.70 V. The CPE experiment was nevertheless repeated with the pulsed stripping performed at +2.00 V
vs. Ag but the attempt to oxidize BPA completely was also not successful despite performing the
electrolysis over a duration of more than 3 hours. The CV obtained at the end of the electrolysis [Figure
2b (bold line)] showed little change from that of the starting material [Figure 2b (dashed line)]. It is
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likely that the bulk of the electrons transferred (apparent n ~ 0.93) comes from the solvent being
oxidized at the positive potentials and any reaction that converts the adsorbed species to un-adsorbed
forms is unlikely. The adsorption effects were clearly blocking the electrodes and further electrolysis
was not possible.
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3.3. Chemical Oxidation with NOSbF6 in CH3CN
A fast and straightforward method for oxidizing phenols was previously achieved with the use of
NOSbF6 as a one-electron chemical oxidant, which closely mimicked the results of electrochemical
oxidation experiments [37]. The procedure simply involves adding a weighed quantity of NOSbF6 in the
desired stoichiometric amount to a solution containing the phenolic compound and stirring the mixture
at room temperature for approximately 30 minutes. Chemical oxidation experiments were conducted on
BPA because it was not possible to use electrolysis due to electrode fouling from the adsorption effects.
Another advantage of using chemical oxidation is that it occurs considerably faster than electrochemical
oxidation and avoids the use of the supporting electrolyte which can be difficult to remove when trying
to isolate the oxidized products. Furthermore in the case of NOSbF6, the byproduct, NO● (reduced form
of NO+) exists as a gaseous product and can be removed easily from the solution [38]. Chemical
oxidation experiments were performed on BPA using NOSbF6 in the solvent CH3CN, since it has a
much lower boiling point than DMSO and is easier to remove during the product work-up stages.
The chemical oxidation of BPA with varying molar equivalents of NO+ was first analyzed in
conjunction with cyclic voltammetry, in order to determine the equivalents of NO+ required to achieve
complete oxidation, and hence to calculate the number of electrons transferred during the process. It was
found that the main oxidation peak of BPA at Epox = +1.00 V vs. Fc/Fc+ shifted and reduced in size after
the addition of the 1st and 2nd mol equiv. of NO+ respectively, but the exact changes in the shapes of the
voltammograms are difficult to explain due to the complicated homogeneous reactions (likely proton
transfers) that are also occurring following the electron transfer steps (Figure 3). The wave belonging to
the starting material (BPA) disappears completely and a new product is formed at a more positive
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potential at +1.30 V vs. Fc/Fc+ after the addition of 4 mol equiv. of NO+, indicating the transfer of 4
electrons for exhaustive oxidation. The recorded voltammogram of the product remained similar with
the addition of a 5th equivalent and it was hence confirmed that a total of 4 electrons were involved in
the oxidation of BPA. Some unknown compounds, likely a mixture of products were also formed
concomitantly to the addition of NO+ and were detected voltammetrically at the negative potentials (~
1.00 V vs. Fc/Fc+), which increased proportionally with increasing additions of the oxidant up until the
4th equivalent (Figure 3).
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The reductive wave observed at ~ 1.00 V vs. Fc/Fc+ did not increase in size when the 5th
equivalent of NO+ was added, which indicates that the wave was most likely due to intermediate species
or products formed during the oxidation of BPA with 4 equivalents of NO+. The possibility of the wave
belonging to the H+ released during oxidation was ruled out. The mechanism for the oxidation of BPA,
which is discussed in detail below, was proposed to involve the release of 4H+ ions. The cyclic
voltammogram of 8 mM trifluoroacetic acid, CF3COOH (4 equivalents) was recorded in acetonitrile
solution to test the CV response for H+ ions, but the addition of acid did not lead to a reductive peak at ~
1.00 V vs. Fc/Fc+. It is also unlikely that the wave was related to the NO+ (or NO•) present in excess
since the reductive process at 1.00 V vs. Fc/Fc+ shown in Figure 3 did not increase in size as more NO+
were added after the reaction was complete (after the addition of 4 equivalents of NO+). The cyclic
voltammogram of 8 mM NOSbF6 (4 equivalents) however, showed a reduction peak at ~ 2.00 V vs.
Fc/Fc+ which suggested the presence of some NO+/NO• in solution. The cyclic voltammograms of
CF3COOH and NOSbF6 are provided in the Appendix section.
Synthetic scale oxidation experiments were conducted by reacting 0.175 M of BPA with 4 mol
equiv. of NOSbF6 in CH3CN at 22 ± 2 °C. TLC analysis of the reaction mixture indicated a large
number of products. One product successfully isolated from the reaction mixture and purified was the
hydroxylated bisdienone (1) which was identified by NMR (1H and 13C) and high resolution mass
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spectrometry (HRMS). Compound 1 has not previously been identified as a reaction product of BPA,
possibly because the reaction conditions previously employed favored more highly oxidized products.
It is reasonable to propose, based on the knowledge of the identity of 1, that a mechanism for the
oxidation of BPA is through the formation of a bisdienone cation via two ECE steps (where E represents
an electron transfer and C a chemical step). The overall electrochemical mechanism for the oxidation of
BPA can be considered to be similar to the oxidation of phenols in general. A generic oxidative
mechanism for phenols is known to occur via three steps as illustrated in Scheme 1: initial one electron
oxidation to form the phenol cation radical, deprotonation of the cation radical to form neutral radical
and a further one electron oxidation of the neutral radical to form the dienone cation (there is some
uncertainty as to whether the reactions occur consecutively as shown in Scheme 1 or whether the proton
transfer step can occur concertedly with the electron transfer step).
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An oxidation mechanism for BPA to form compound 1 can be proposed based on the existing
general pathway for phenols [39,40], via a four-electron/two-proton process (‒ 4e-/‒ 2H+) as shown in
Scheme 2. Furthermore, the four-electron transfer, which was confirmed earlier during the cyclic
voltammetric monitoring of the chemical oxidation, is also in agreement with the proposed route to the
formation of 1. However, the exact sequence of the steps occurring during the two ECE mechanisms is
complicated because of the presence of the two phenolic groups. Thus, the order of the electron transfer,
proton transfer and hydrolysis steps may not proceed by exactly the route in Scheme 2. There is also the
possibility of disproportionation reactions occurring where one oxidized compound undergoes
homogeneous electron transfer with the starting material (which will also result in the same number of
electrons transferring and the same final product). The adsorption effects observed during the CV
experiments make it very difficult to deduce the exact sequence of proton and electron transfers via
digital simulation modeling techniques.
Even though the overall oxidation involves the transfer of four electrons, only one broad anodic
peak was detected. This is likely because the electron transfer steps that occur after the initial electron
transfer step occur at lower potentials, which is also observed for other phenolic compounds [8,37]. The
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phenoxonium cation (1+) or dication (1++) produced during the oxidation are very unstable in the
presence of nucleophiles and react immediately with moisture/water to form 1, which is one likely
reason why a chemically irreversible oxidation process was observed for BPA. Phenoxonium cations are
highly reactive and are commonly known to undergo hydration or self reactions like dimerization or
dealkylation [37]. Voltammetric scans performed up to 20 V s-1 did not lead to any chemical
reversibility in the oxidation process.
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Figure 4 compares the cyclic voltammogram obtained for 2 mM of the chemically isolated
compound 1 with the cyclic voltammogram recorded during the monitoring of the oxidation reaction as
the oxidant was injected directly into the CV cell containing BPA. Both CVs have the main oxidation
peak at the same potential, ~ +1.30 V vs. Fc/Fc+, indicating that they are likely associated with the
oxidation of the same compound (1). The smaller peak current observed at +1.30 V for the product
formed during the electrochemical monitoring experiment was expected since the yield for compound 1
via chemical oxidation was substantially <100%. However, the large difference in concentration
between the electrochemical experiments and chemical oxidation experiments could result in some
different products being formed between the two oxidation methods. Nevertheless, electrochemical
monitoring offers a fast and efficient method in investigating the electrochemical behavior of the
products and their intermediate species while chemical oxidation experiments aid in the isolation of the
products for identification.
The lifetime of the phenoxonium cations (Scheme 2, 1+ or 1++) is partly determined by how
reactive they are with nucleophiles such as water in the solvent [38]. In the low water content
electrolysis conditions compound 1 was obtained in up to 9% yield. Therefore, it was thought that
increasing the percentage of water in the reaction mixture would give 1 in a higher yield. However,
when the water content was increased to 10%, a nitration product (3) was obtained in very high yield
(70%), with no evidence of compound 1. Therefore, it would appear the formation of 1 is highly
sensitive to moisture levels that are present in the solvent. The relatively low yield of 1 that was isolated
after chemical oxidation of BPA is likely to be a result of the high reactivity of all the intermediate
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species in Scheme 2 (cations, cation radicals and neutral radicals), which are able to undergo other non-
hydrolysis reactions. TLC indicated that there were a number of unidentified products produced which
were not easily separated from the reaction medium.
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The mechanism for the formation of compound 3 in the presence of high percentages of water
(Scheme 3) can be proposed based on an earlier report by Kim et al. [41] who reacted other phenolic
compounds with NO+ and suggested that the nitrosonium cation was reduced first, followed by a
conversion to nitric oxide in the presence of oxygen for nitration to occur. Another nitration product (4-
nitrophenol, 2) was also obtained in low yield in low-water content solutions, likely formed by
undergoing a cleavage at the methyl bridge and then reacting through the same oxidative aromatic
nitration mechanism. It is also possible that the water aids the nitration reaction through hydrogen-
bonding reactions with the phenolic hydrogen atom changing the reactivity of the molecule. Recently,
experiments conducted to study the effect of water on the electrochemical behavior of quinones and
phenols have shown that these compounds can undergo substantial hydrogen-bonding interactions with
water (even in small amounts) in organic solvents which in some cases aids in stabilization of the
oxidized molecules [42,43]. The cyclic voltammograms of compounds 2 and 3 are provided in the
Appendix section.
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4. Conclusions
The one-electron chemical oxidant NO+ has been demonstrated to be a useful alternative to
electrochemical oxidation at solid electrodes for phenolic compounds that adsorb strongly on electrode
surfaces for reactions conducted in organic solvents. Nevertheless, the chemical oxidation process is
strongly influenced by the amount of water in the organic solvent. At low water concentrations, the
oxidation process appears to occur directly via homogeneous electron transfer, while at higher
concentrations of water, the chemical oxidant is able to take part in nitration reactions in the ortho-
position to the phenolic group. The isolation of the hydroxylated bisdienone product 1 led to the
proposed identity of the cationic intermediate species and this highlights the possibility of the role of the
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bisdienone cation as a reactive metabolite during BPA oxidation in biological systems (in low water
content environments).
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One complication with comparing the results of cyclic voltammetry and chemical oxidation
experiments is that the CV experiments are performed at low concentrations while the chemical
oxidation experiments are performed at high concentrations to enable the products of the reactions to be
separated and purified. However, since we have now identified several products of the oxidation of
BPA, it is now possible to perform chemical oxidations at low mM levels of BPA and determine the
yields of the species produced using a chromatographic technique. Future studies will also involve
quantifying how the product distribution varies as the organic solvent and the water content of the
organic solvent varies.
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Acknowledgements
This work was supported by an A*Star SERC Public Sector Funding (PSF) Grant (112 120
2006) and a Singapore Ministry of Education Tier 1 research grant (RG 61/11).
Appendix A. Supplementary data
Compound characterization data of compounds 1 - 3; 1H, 13C and DEPT NMR, HRMS, FTIR
and UV-vis spectra from synthetic experiments and X-ray crystallographic data of 3. Cyclic
voltammograms of compound 1 – 3 in CH3CN with 0.2 M n-Bu4NPF6 at a 1 mm glassy carbon
electrode recorded at a scan rate of 0.1 V s-1.
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Quinones in Organic Solvents are Strongly Influenced by Hydrogen-Bonding with Water, J.
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[43] Y. S. Tan, S. Chen, W. M. Hong, J. M. Kan, E. S. H. Kwek, S. Y. Lim, Z. H. Lim, M. E.
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oxidation of [small alpha]-tocopherol (vitamin E) and other phenols in acetonitrile, Phys. Chem.
Chem. Phys. 13 (2011) 12745-12754.
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Fig. 1. Cyclic voltammograms of two consecutive scans of 2 mM BPA recorded at a scan rate of 0.1 V
s-1 in a range of solutions with 0.2 M n-Bu4NPF6 at a 1 mm glassy carbon electrode over (a) shorter
potential range, and (b) longer potential range. (―) First scan. (---) Second scan.
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Fig. 2. Cyclic voltammograms recorded at a scan rate of 0.1 V s-1 with a 1.0 mm diameter glassy carbon
electrode during the controlled potential electrolysis of 5 mM BPA in DMSO with 0.2 M n-Bu4NPF6 at
22 ± 2 °C. The controlled potential electrolysis experiment was performed by incorporating a pulsed
stripping step in between oxidative electrolysis runs in attempts to overcome electrode fouling. (a)
Pulsed stripping at -1.0 V for 30 – 60 seconds. (b) Pulsed stripping at 2.0 V vs. Ag wire (0.5 M n-
Bu4NPF6 in CH3CN) for up to 900 seconds. n is the apparent number of electrons transferred during
electrolysis; (---) before the bulk oxidation of BPA, (―) after bulk oxidation conducted for over 3 hours.
Fig. 3. Cyclic voltammograms of 2 mM BPA with the addition of 1 – 5 molar equivalents of NOSbF6
(one-electron chemical oxidant) recorded at a scan rate of 0.1 V s-1 in CH3CN with 0.2 M n-Bu4NPF6 at
a 1 mm glassy carbon electrode.
Fig. 4. Cyclic voltammograms of the products of the oxidation of 2 mM BPA with 4 molar equivalents
of NOSbF6 in CH3CN with 0.2 M n-Bu4NPF6 at a 1 mm glassy carbon electrode recorded at a scan rate
of 0.1 V s-1. (---) Electrochemically monitoring of oxidation reaction in CV cell. (―) Isolated compound
1.
Scheme 1. General mechanism for electrochemical oxidation of phenols
Scheme 2. Proposed oxidative mechanism (2 × ECE) for chemical oxidation of BPA with 4 NOSbF6 in
CH3CN, consisting of four one-electron steps (E) and two-proton transfers (C). One resonance structure
is displayed for each compound. The counterions for the charged ions are the chemical oxidant anion
-
[SbF6 ] and the “H+” ions exist coordinated to the organic solvent or with trace water.
Scheme 3. Oxidative aromatic nitration mechanism for nitration of BPA with 2 NOSbF6 in CH3CN
modified based on an earlier report [37].
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Fig. 1.
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Fig. 2.
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Fig. 3.
Fig. 4.
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Scheme 1.
Scheme 2.
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Scheme 3.
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