Investigation into phenoxonium cations produced during the electrochemical oxidation of chroman-6-ol and dihydrobenzofuran-5-ol substituted compounds

Article abstract of DOI:10.1021/jo702415q

(Chemical Equation Presented) A series of chroman-6-ol and dihydrobenzofuran-5-ol based compounds with structures similar to vitamin E were examined by cyclic voltammetry and controlled potential electrolysis. The compounds displayed characteristic voltammetric features that enabled their electrochemical behavior to be interpreted in relation to the oxidation mechanism for vitamin E. The electrochemical experiments indicated the presence of several oxidized species: cation radicals, phenoxyl radicals, phenoxonium ions, hemiketals, and p-quinones, whose lifetimes varied depending on the extent of methylation of the aromatic ring (R1, R2, R3) and the nature of substituents R4 and R5.

Full text of DOI:10.1021/jo702415q

Investigation into Phenoxonium Cations Produced during the
Electrochemical Oxidation of Chroman-6-ol and
Dihydrobenzofuran-5-ol Substituted Compounds
Hong Mei Peng and Richard D. Webster*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological UniVersity, Singapore 637371
webster@ntu.edu.sg
ReceiVed NoVember 9, 2007
A series of chroman-6-ol and dihydrobenzofuran-5-ol based compounds with structures similar to vitamin
E were examined by cyclic voltammetry and controlled potential electrolysis. The compounds displayed
characteristic voltammetric features that enabled their electrochemical behavior to be interpreted in relation
to the oxidation mechanism for vitamin E. The electrochemical experiments indicated the presence of
several oxidized species: cation radicals, phenoxyl radicals, phenoxonium ions, hemiketals, and p-quinones,
whose lifetimes varied depending on the extent of methylation of the aromatic ring (R1, R2, R3) and the
nature of substituents R4 and R5.
1. Introduction
There currently exist only a few examples of phenoxonium
cations whose lifetimes are long enough to enable detailed
characterization by electrochemical or spectroscopic methods.3-7
Phenoxonium cations (1) are thought to be involved as key
intermediates during the oxidation of phenols, although evidence
for their existence is most often based on proposed mechanistic
pathways,1 trapping experiments,2a-d or the detection of UV-
vis spectra of transients from laser flash photolysis experiments.2e
(3) Dimroth, K.; Umbach, W.; Thomas, H. Chem. Ber. 1967, 100, 132-
141.
(4) (a) Speiser, B.; Rieker, A. J. Chem. Res. (S) 1977, 314-315. (b)
Speiser, B.; Rieker, A. J. Electroanal. Chem. 1979, 102, 373-395. (c)
Speiser, B.; Rieker, A. J. Electroanal. Chem. 1980, 110, 231-246.
(5) Vigalok, A.; Rybtchinski, B.; Gozin, Y.; Koblenz, T. S.; Ben-David,
Y.; Rozenberg, H.; Milstein, D. J. Am. Chem. Soc. 2003, 125, 15692-
15693.
(6) (a) Parker, V. D. J. Am. Chem. Soc. 1969, 91, 5380-5381. (b)
Svanholm, U.; Bechgaard, K.; Parker, V. D. J. Am. Chem. Soc. 1974, 96,
2409-2413.
(7) (a) Webster, R. D. Electrochem. Commun. 1999, 1, 581-584. (b)
Williams, L. L.; Webster, R. D. J. Am. Chem. Soc. 2004, 126, 12441-
12450. (c) Lee, S. B.; Lin, C. Y.; Gill, P. M. W.; Webster, R. D. J. Org.
Chem. 2005, 70, 10466-10473. (d) Wilson, G. J.; Lin, C. Y.; Webster, R.
D. J. Phys. Chem. B 2006, 110, 11540-11548. (e) Lee, S. B.; Willis, A.
C.; Webster, R. D. J. Am. Chem. Soc. 2006, 128, 9332-9333. (f) Webster,
R. D. Acc. Chem. Res. 2007, 40, 251-257.
(1) (a) Yoshida, K. Electrooxidation in Organic Chemistry. The Role of
Cation Radicals as Synthetic Intermediates; Wiley: New York 1983; pp
174-186. (b) Hammerich, O.; Svensmark, B. In Organic Electrochemistry,
3rd ed.; Lund, H., Baizer, M. M., Eds.; Marcel Dekker: New York, 1991;
Chapter 16. (c) Rieker, A.; Beisswenger, R.; Regier, K. Tetrahedron 1991,
47, 645-654. (d) Eickhoff, H.; Jung, G.; Rieker, A. Tetrahedron 2001, 57,
353-364.
(2) (a) Novak, M.; Glover, S. A. J. Am. Chem. Soc. 2004, 126, 7748-
7749. (b) Novak, M.; Glover, S. A. J. Am. Chem. Soc. 2005, 127, 8090-
8097. (c) Glover, S. A.; Novak, M. Can. J. Chem. 2005, 83, 1372-1381.
(d) Novak, M.; Poturalski, M. J.; Johnson, W. L.; Jones, M. P.; Wang, Y.;
Glover, S. A. J. Org. Chem. 2006, 71, 3778-3785. (e) Wang, Y.-T.; Wang,
J.; Platz, M. S.; Novak, M. J. Am. Chem. Soc. 2007, 129, 14566-14567.
10.1021/jo702415q CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/16/2008
J. Org. Chem. 2008, 73, 2169-2175
2169

Peng and Webster
SCHEME 1. One Resonance Structure Is Displayed for
Each Phenoxonium Cation
SCHEME 2. Structures and Atomic Numbering System of
the Tocopherol Forms of Vitamin E
Reports of phenols that form stable phenoxonium ions include
two organic compounds with bulky groups in the 2- and
6-positions and an aromatic group in the 4-position (2),3,4 and
a metal stabilized phenoxonium complex (3), also with bulky
groups in the 2- and 6-positions (Scheme 1).5
There exists one interesting class of phenoxonium cations
that are formed by oxidation of the natural 6-chromanol
compounds comprising vitamin E (TOH) (Scheme 2), which
have recently been extensively electrochemically and spectro-
scopically characterized.6,7 The phenoxonium cation derived
from the R-tocopherol (R-TOH) model compound was particu-
larly stable, even enabling X-ray structures to be determined
from salts crystallized with non-nucleophilic [B(C6F5)4]- and
(CB11H6Br6)- anions.7e Due to the scarcity of long-lived
phenoxonium cations, it is a remarkable observation that one
obtained from a natural compound is stable (especially in light
of the number of new non-antioxidant functions recently
discovered that have been assigned specifically to the R-TOH
vitamer8), and raises questions as to whether the cation has any
biological importance.7d,7f
FIGURE 1. Cyclic voltammograms of 2.0 mM substrates in CH3CN
with 0.2 M n-Bu4NPF6 recorded at a 1 mm diameter Pt electrode at a
scan rate of 0.1 V s-1 at T ) 293 K.
behavior examined by cyclic voltammetry (CV) and controlled
potential electrolysis (CPE).
2. Results and Discussion
2.1. Cyclic Voltammetry. Cyclic voltammograms (CVs) of
solutions containing a variety of phenols are given in Figure 1.
The tocopherols have previously been extensively studied in
CH3CN and CH2Cl2 and their electrochemical behavior is well-
understood,6,7,9 enabling CV to be used as a means of assessing
the lifetimes of oxidized species. For example, the CV of the
model compound of R-TOH with a methyl group in position 1′
(Scheme 2), [(CH3)R-TOH], shows an oxidation process with
an anodic peak (Epox) at approximately +0.5 V vs Fc/Fc+, and
a reverse reduction process with a cathodic peak (Epred) at
approximately +0.2 V vs Fc/Fc+ when the scan direction is
switched (Figure 1). The voltammetric processes are associated
with two chemically reversible heterogeneous one-electron
transfers and a homogeneous chemically reversible proton
transfer (an ECE mechanism, where E represents an electron
transfer and C a chemical step) (Scheme 3).
This study is devoted to determining what aspects of the
structure of vitamin E and structurally related chroman-6-ol and
dihydrobenzofuran-5-ol based compounds (phenols) are impor-
tant in increasing the lifetime of their related phenoxonium
cations. It has already been determined that the phenoxonium
ion of the most fully methylated form of vitamin E, R-tocopherol
(R-TO+), has the longest lifetime in solution.7d In dry CH3CN
or CH2Cl2, R-TO+ has a lifetime of at least several hours, â-TO+
persists for a few minutes, while γ-TO+ and δ-TO+ have
lifetimes <1 s.7d In this study, a number of phenols with similar
structures to vitamin E were prepared and their electrochemical
(8) (a) Boscoboinik, D.; Szewczyk, A.; Hensey, C.; Azzi, A. J. Biol.
Chem. 1991, 266, 6188-6194. (b) Tasinato, A.; Boscoboinik, D.; Bartoli,
G. M.; Maroni, P.; Azzi, A. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 12190-
12194. (c) Azzi, A.; Stocker, A. Prog. Lipid Res. 2000, 39, 231-255. (d)
Ricciarelli, R.; Zingg, J.-M.; Azzi, A. Biol. Chem. 2002, 383, 457-465.
(e) Azzi, A.; Ricciarelli, R.; Zingg J.-M. FEBS Lett. 2002, 519, 8-10.
(9) (a) Nanni, E. J., Jr.; Stallings, M. D.; Sawyer, D. T. J. Am. Chem.
Soc. 1980, 102, 4481-4485.
2170 J. Org. Chem., Vol. 73, No. 6, 2008

Lifetimes of Phenoxonium Cations
SCHEME 3. Electrochemical Oxidation Mechanism for
Tocopherols in CH3CN or CH2Cl2
SCHEME 4. Electrochemical Oxidation Mechanism for
Hydroquinones, Such as Dopamine, in Acidic Aqueous
Conditions
7,a
group in the para-position) cannot form quinones without
breaking an oxygen-carbon bond, which decreases the likeli-
hood of chemical reversibility on the CV time scale. Therefore,
the detection of a reverse (reductive) peak during CV experi-
ments on phenols that undergo two-electron oxidation (and only
contain one hydroxy group) is good evidence for the presence
of persistent phenoxonium cations.
a One resonance structure is displayed for each compound. R1, R2, R3 )
H or Me. R4 ) alkyl.
Thus, the forward oxidative process for (CH3)R-TOH in
Figure 1 is associated with two one-electron oxidations and one
proton loss to form the phenoxonium cation (CH3)R-TO+, while
the reductive process detected when the scan direction is
reversed is associated with the reverse reaction to regenerate
the starting phenol. The anodic to cathodic peak-to-peak
separation (∆Epp) for the CV of (CH3)R-TOH is much wider
than expected for a two-electron electrochemically reversible
transfer, because of the presence of the chemically reversible
deprotonation/protonation step shifting the Epox and Epred peaks.7f
The phenoxyl radicals (TO•) can also be produced by one-
electron oxidation of the phenolate anions (that can be prepared
by adding base to a solution of the phenols).7a,b,9 However, for
the conditions used in this study, the phenoxyl radicals only
have a short lifetime in solution: either being immediately
further oxidized to form the phenoxonium cations, or undergoing
protonation then being reduced back to the phenols, depending
on the applied potential.7
The chemically reversible nature of the two one-electron and
one-proton process is unusual compared to what is observed
for most phenols, which generally undergo chemically irrevers-
ible oxidations to form reaction products that are not readily
converted back to the starting material. Therefore, CVs per-
formed on phenols do not usually display a reverse cathodic
peak when the scan directions are reversed.7b Some exceptions
are (i) hydroquinones that can reversibly form quinones during
oxidation/reduction cycling, via a two-electron, two-proton
process,1b (ii) phenols with amine groups adjacent to the
hydroxyl group that undergo a chemically reversible proton
coupled one-electron transfer,10 and (iii) in organic solvents
containing strong acids some phenol cation radicals can be
stabilized against deprotonation resulting in chemically revers-
ible one-electron transfer.11
The electrochemical responses observed for the compounds
in Figure 1 can be interpreted based on the mechanism in
Scheme 3, with the lifetime of the phenoxonium cations
determining whether reverse cathodic peaks are detected within
0.3-0.4 V of the oxidation process. The degree of chemical
reversibility of the oxidation process in Scheme 3 can be
estimated by the anodic (ipox) to cathodic (ipred) peak current
ratio (ipox/ipred). For compounds where the oxidized forms are
red
stable (within the time scale of the CV), the ipox/ip ratio
approaches unity (although this relationship is complicated and
strictly depends upon the equilibrium constant for the proton-
transfer reaction).7f Compounds 4-10 show only very small
reverse cathodic peaks when the scan directions are reversed
red
(at a scan rate of 100 mV s-1), therefore, their ipox/ip ratios
are .1, indicating that their associated phenoxonium cations
are relatively short-lived and decompose/react before they can
be reduced back to the starting material. Many of the compounds
also displayed a small cathodic peak at ca. -0.2 to -0.4 V vs
Fc/Fc+ that was evident only when the scan direction was
reversed after the main oxidation process at ca. +0.5 V. The
peak at ca. -0.2 to -0.4 V vs Fc/Fc+ is due to a secondary
reaction product (but not the phenoxonium cations which occur
at ca. +0.2 V vs Fc/Fc+) and will be discussed in section 2.2.
The secondary reaction product does not show a reverse
oxidative peak when the scan direction is applied in the positive
potential direction (i.e., when the CV is conducted over three
scans), indicating that its reduced form is short-lived.
The conclusion that the observation of only a small reverse
peak (Epred) at potentials 0.3-0.4 V less positive than the
oxidation peak (Epox) for compounds 4-10 is because their
phenoxonium cations are short-lived is supported by variable
scan rate studies. For example, Figure 2 shows variable scan
rate CVs of compound 7 between ν ) 0.1 and 5 V s-1. As the
scan rate is progressively increased, the cathodic peak at ca.
+0.2 V becomes bigger, so that at a scan rate of 5 V s-1, the
CV of 7 has a very similar appearance to that observed for
(CH3)R-TOH at ν ) 0.1 V s-1 (compare Figures 1 and 2). The
close similarity in the voltammetry supports the presence of
the phenoxonium cation of 7 (albeit with a lesser lifetime
compared to (CH3)R-TO+). Concomitantly to the reductive peak
in Figure 2 at ca. +0.2 V vs Fc/Fc+ increasing with increasing
scan rate, the reductive peak at ca. -0.2 V becomes smaller
due to the faster scan rates outrunning the formation of the
secondary oxidized product. Similar variable scan rate results
were obtained for compounds 8 and 9 (the model compounds
of γ-TOH and δ-TOH), with the reverse reductive peaks at ca.
+0.2-0.3 V vs Fc/Fc+ increasing in size as the scan rate was
increased, so that at a scan rate of 10 V s-1, the voltammograms
The observation of a reverse reductive peak detected during
CV experiments, within 0.3-0.4 V of the oxidation process,
appears to be characteristic of the existence of phenoxonium
cations, as observed for R-TOH and â-TOH at ν ) 0.1 V s-1
and γ-TOH and δ-TOH at ν ) 10 V s-1 (ν ) scan rate).7d The
wide separation between the forward and reverse peaks is similar
to that observed during CV experiments on hydroquinones, such
as dopamine (a two-electron and two-proton process) (Scheme
4).12 However, phenols with one hydroxy group (and an ether
(10) (a) Costentin, C.; Robert, M.; Save´ant, J. M. J. Am. Chem. Soc.
2006, 128, 4552-4553. (b) Rhile, I. J.; Markle, T. F.; Nagao, H.;
DiPasquale, A. G.; Lam, O. P.; Lockwood, M. A.; Rotter, K.; Mayer, J. M.
J. Am. Chem. Soc. 2006, 128, 6075-6088.
(11) (a) Hammerich, O.; Parker, V. D.; Ronla´n, A. Acta Chem. Scand.
B 1976, 30, 89-90. (b) Hammerich, O.; Parker, V. D. Acta Chem. Scand.
B 1982, 36, 63-64.
(12) (a) Hawley, M. D.; Tatawawadi, S. V.; Pierkarski, S.; Adams, R.
N. J. Am. Chem. Soc. 1967, 89, 447-450. (b) Sternson, A. W.; McCreery,
R.; Feinberg, B.; Adams, R. N. J. Electroanal. Chem. 1973, 46, 313-321.
J. Org. Chem, Vol. 73, No. 6, 2008 2171

Peng and Webster
longer time scales (minutes), controlled potential electrolysis
(CPE) experiments were performed and the reaction solutions
monitored with CV. It was found that the compounds could be
divided into two classes based on their behavior under CPE
conditions. Class 1 systems were compounds where their
associated phenoxonium cations were detectable during bulk
electrolysis experiments indicating that they were stable for at
least several minutes. Class 2 compounds were those where their
phenoxonium cations were undetectable after electrolysis indi-
cating that they were unstable or reactive. Both of these classes
of compounds showed voltammetric evidence of an additional
secondary oxidized compound (not the phenoxonium cation)
that could be partly reduced back to the starting material under
electrolysis conditions. It is difficult to provide accurate kinetic
data for the stability of the cations since most were continually
decaying during the time scale of the electrolysis. One factor
that greatly decreases the lifetime of the cations is the presence
of water. Ultra-dry conditions are difficult to achieve under CPE
conditions because of the requirement of multicompartment cells
to separate the different electrodes. However, since the elec-
trolysis experiments were all performed under identical condi-
tions, the relative stabilities and subsequent division into Class
1 and Class 2 systems is valid.
FIGURE 2. Cyclic voltammograms of 2.0 mM 7 in CH3CN with 0.2
M n-Bu4NPF6 recorded at a 1 mm diameter Pt electrode at T ) 293 K.
The current data were scaled by multiplying by ν-0.5 (ν ) scan rate/V
s-1).
of 8 and 9 appeared similar to that of (CH3)R-TOH at a slow
scan rate of 0.1 V s-1
.
2.2.1. Class 1 Compounds. Figure 3 shows CV and cou-
lometry data obtained during CPE experiments on 11. Com-
pounds 11-15, (CH3)R-TOH,6,7c-e R-TOH,7 and â-TOH7d are
examples of Class 1 compounds. All CPE experiments were
performed at -20 °C in order to improve the stability of the
phenoxonium cations, which are known to have longer lifetimes
at lower temperatures (likely due to slowing down the reaction
with trace water that is usually present in mM levels in organic
solvents).7 The black line in Figure 3a is the CV of 11 prior to
the CPE, the red line is the CV obtained of the oxidized solution
at the completion of the CPE at +0.6 V vs Fc/Fc+ (after the
transfer of 2 electrons per molecule), and the dashed line is the
CV obtained after the oxidized species had been reduced back
to the starting material under CPE conditions at 0.0 V vs Fc/
Fc+.
In contrast to 7-9, variable scan rate studies on 4-6 up to
ν ) 200 V s-1 showed no evidence of chemical reversibility of
the oxidation processes, indicating that the phenoxonium cations
of 4-6 were considerably less stable than 7-9 (variable scan
rate CVs are provided in the Supporting Information).
The voltammetry and peak shapes of the dihydrobenzofuran-
5-ol substituted compounds containing a five-membered ring
(compounds 11-14) at a scan rate of 0.1 V s-1 were also
examined and showed similar electrochemical behavior to that
observed for (CH3)R-TOH (Figure 1) at the same scan rate,
indicating that their phenoxonium cations were stable for at least
several seconds (compound 11 reportedly has antioxidant
properties that exceed those of R-TOH13). Compounds 12 and
13, with hydrogen atom(s) bonded to the R-carbons adjacent to
the ether oxygen (the equivalent of position 2 in Scheme 2),
also showed chemically reversible voltammetry, indicating that
carbon atoms in positions 1′ and 2a (Scheme 2) are not essential
for the formation of long-lived phenoxonium cations. Compound
14, with the least methyl groups (of compounds 11-14) in the
aromatic ring, displayed a smaller reverse reductive peak close
to the oxidation process suggesting that its phenoxonium cation
was less stable than the other dihydrobenzofuran-5-ol based
compounds.
Panels b and c of Figure 3 are the current (black line) and
coulometry data (red line) (plotted as the number of electrons
transferred per molecule) for the forward oxidation and reverse
reduction processes, respectively. The total experiment time was
around 2100 s (35 min) excluding the time to run the CVs,
with the electrochemical data confirming that the phenoxonium
cation of 11 was stable for at least several minutes in CH3CN.
There is a small shift in potential between the first scan (solid
black line) and final scan (dashed line) possibly due to a change
in solution composition during the electrolysis affecting the
equilibrium of the homogeneous proton-transfer reaction (a
similar effect is observed during the electrolysis of R-TOH7b).
The ipox-value recorded in the CV of the final product (dashed
line) was approximately 80% of the initial ipox-value in the CV
recorded prior to the electrolysis (black line), indicating that
∼20% of the phenoxonium cation was lost during the reaction,
which is supported by the coulometry data which indicated the
transfer of ∼1.6 electrons for the reverse reduction reaction
(Figure 3c). A small reductive peak was evident at ca. -0.4 V
vs Fc/Fc+ that was due to a secondary oxidation product. All
compounds showed a reductive peak at ca. -0.4 V after their
exhaustive oxidative electrolysis, which became progressively
larger in relation to the phenoxonium cation peak as the systems
changed from Class 1 to Class 2 systems. Class 2 systems only
Compound 15 displayed voltammetric behavior similar to
(CH3)R-TOH indicating the reversible formation of its phe-
noxonium ion, while 16 and 17 displayed chemically irreversible
voltammetry indicating that their oxidized states were unstable.
Compounds 16 and 17 showed no evidence for the formation
of the phenoxonium cations at scan rates up to 200 V s-1
.
(Compound 17 is included to illustrate the typical oxidative
behavior of phenols, which generally display chemically ir-
reversible cyclic voltammograms.)
2.2. Electrolysis Experiments. CV experiments performed
in isolation only provide mechanistic information about oxidized
or reduced species that have lifetimes on the time scale of the
experiment (usually less than a few seconds). In order to gain
information about the lifetime of the oxidized compounds over
(13) Burton, G. W.; Ingold, K. U. Acc. Chem. Res. 1986, 19, 194-201.
2172 J. Org. Chem., Vol. 73, No. 6, 2008

Lifetimes of Phenoxonium Cations
TABLE 1. Calculated Number of Electrons Transferred Per
Molecule (n-values) Obtained during the Controlled Potential
Oxidation of Phenols, and in Some Cases the Reverse Reduction of
Their Associated Phenoxonium Cations
n-valuea
n-valuea
compd
(oxidation)b
(reduction)c
classd
(CH3)R-TOH
1.9
1.9
1.8
1.8
1.8
1.9
1.9
2.1
1.9
1.9
1.6
2.5
2.1
1.9
2.2
-1.5
1
2
2
2
2
2
2
2
1
1
1
1
1
2
2
4
e
5
6
7
8
e
e
e
e
e
e
9
10
11
12
13
14
15
16
17
-1.7
-1.2
-0.5
-0.3
-1.4
e
e
a Calculated from coulometry data by using the equation n ) Q/NF,
where Q is the charge passed (coulombs), N is the number of moles, and
F is the Faraday constant (96485 C mol-1). b Applied potential is +0.1 V
past oxidation peak potential (Epox) of the phenol (see Figure 1). c Applied
potential is -0.1 V past reduction potential of the phenoxonium cation (see
Figure 1). d Class 1 systems are where the phenoxonium cations are
voltammetrically detectable for several minutes, and Class 2 systems are
where the phenoxonium cations cannot be detected after electrolysis
(lifetimes < a few seconds). e Not measurable under present conditions.
the Supporting Information). In order for the phenol (7) to be
regenerated, the reaction product at -0.4 V vs Fc/Fc+ cannot
be too dissimilar from the starting material, thus a ring-opened
form is unlikely. Therefore, the species at -0.4 V vs Fc/Fc+
has been assigned as the hemiketal chromenol (Figure 4a(ii)),
which are known oxidation products of tocopherols that
subsequently convert into the ring-opened p-quinones (Scheme
5).14a-c Also evident in Figure 4a(ii) (red line) is a reductive
peak at -1.0 V vs Fc/Fc+ that has been assigned to the
p-quinone (7a) by comparison with the voltammetry of an
authentic sample synthesized by chemical oxidation of the
phenol.14c (CVs of several p-quinones are provided in the
Supporting Information section showing their voltammetric
behavior that typically involves chemically reversible one-
electron reduction processes.)
FIGURE 3. Voltammetric and coulometric data obtained at 253 K
during the controlled potential electrolysis of 5 mM 11 in CH3CN with
0.2 M Bu4NPF6. (a) Cyclic voltammograms recorded at a scan rate of
0.1 V s-1 with a 1.0 mm diameter Pt electrode: (black line) prior to
the bulk oxidation of 11; (red line) after the exhaustive oxidation of
11; (dashed line) after the exhaustive reduction of the oxidized product.
(b) Current/coulometry vs time data obtained during the exhaustive
oxidation of 11 at +0.6 V vs Fc/Fc+. (c) Current/coulometry vs time
data obtained during the reverse exhaustive reduction of the oxidized
product at 0.0 V vs Fc/Fc+.
The hemiketal evident in the CVs at -0.4 V vs Fc/Fc+ is
stable at 253 K for several hours but when the solution is
warmed to 293 K, it quickly reacts further to form a species
with a reduction potential peak (Epred) close to -1.0 V vs Fc/
Fc+ (Figure 4a(iii)), which has been assigned to the p-quinone
(7a). The voltammetric peak shape of the p-quinone is different
when it is present in a pure solution of CH3CN (Figure 4a(i))
because the presence of acid liberated during the oxidation
effects the chemical reversibility of the reduction process. When
a standard sample of 7a is added to the solution, the peak at
-1.0 V increases in size, supporting the assignment of the
p-quinone in partial yield (Figure 4a(iv)). It is likely that other
oxidation products also form at room temperature because the
long-term oxidation products of phenols are usually complicated
with one product seldom formed in 100% yield.1,14,15
showed the peak at ca. -0.4 V at the completion of the
electrolysis. A summary of the data from CPE experiments is
given in Table 1.
2.2.2. Class 2 Compounds. Figure 4 shows CV and CPE
data obtained during the electrolysis of 7, a Class 2 compound.
Figure 4a(ii) (black line) shows the CV of 7 prior to the
electrolysis and (red line) immediately after the exhaustive
transfer of 1.8 electrons per molecule. The red line CV in Figure
4a(ii) shows a reductive peak at ca. -0.4 V vs Fc/Fc+, due to
the reduction of the main oxidation product of the electrolysis.
The reductive peak at -0.4 V vs Fc/Fc+ is substantially shifted
from where the phenoxonium ion peak occurs (+0.2 to +0.4
V) and is therefore due to a secondary oxidized compound.
When the oxidized solution was reduced at -0.5 V vs Fc/
Fc+ under CPE conditions, CV experiments indicated that the
starting material could be partly regenerated in ∼50% yield (see
(14) (a) Du¨rckheimer, W.; Cohen, L. A. J. Am. Chem. Soc. 1964, 86,
4388-4393. (b) Marcus, M. F.; Hawley, M. D. J. Org. Chem. 1970, 35,
2185-2190. (c) Patel, A.; Netscher, T.; Gille, L.; Mereiter, K.; Rosenau,
T. Tetrahedron 2007, 63, 5312-5318. (d) Rosenau, T.; Klosner, E.; Gille,
L.; Mazzini, F.; Netscher, T. J. Org. Chem. 2007, 72, 3268-3281. (e)
Bowry, V. W.; Ingold, K. U. J. Org. Chem. 1995, 60, 5456-5467.
J. Org. Chem, Vol. 73, No. 6, 2008 2173

Peng and Webster
methide, which subsequently undergoes a bimolecular reaction
to form the spiro-dimer.14d It is unknown whether quinone
methides can form directly from phenoxonium cations, which
theoretically would also lead to the formation of spiro-dimers.7f
However, it is unlikely that the species detected at -0.4 V vs
Fc/Fc+ could be a complicated product such as a dimer, because
the CPE experiments indicated that the reaction is at least
partially chemically reversible, while the formation of a spiro-
dimer is a chemically irreversible process under the mild
conditions used in this study.
The oxidation reaction occurs in two steps under electrolysis
conditions: initial one-electron oxidation (and one-proton loss)
to form the phenoxyl radical, followed by further one-electron
oxidation to form the phenoxonium cation (Scheme 3). How-
ever, reactions that are performed with chemical oxidants will
not necessarily undergo the same mechanism as the electro-
chemical oxidation reported in this study, because chemical
oxidation reactions can result in higher concentrations of the
phenoxyl radicals, especially when hydrogen atom abstracting
agents are used.14c-e,15 Under electrochemical conditions, the
phenoxyl radicals will always undergo immediate further
oxidation to the phenoxonium cations. Thus, the conditions used
in this study favor the formation of the phenoxonium cations
in high yields. It is reasonable to expect the cationic compounds
to be highly reactive with nucleophiles present in the solvent;
therefore, the formation of hemiketals via reaction with low
levels of water is consistent with the present data, but may not
mimic the yields of the final products formed by chemical
oxidation experiments.14,15
Compounds 4-6, 8-10, 16, and 17 behaved similarly under
electrolysis conditions to 7 and so can also be considered Class
2 systems. A summary of the data from controlled potential
electrolysis experiments is given in Table 1 and current-time
and charge-time plots from the CPE experiments are provided
in the Supporting Information. The coulometry data confirmed
the transfer of close to two electrons per molecule over
electrolysis time scales (Table 1), which is supportive of the
initial oxidation product being the phenoxonium cations in each
case.
FIGURE 4. Voltammetric and coulometric data obtained in CH3CN
with 0.2 M Bu4NPF6. (a) Cyclic voltammograms recorded at a scan
rate of 0.1 V s-1 with a 1.0 mm diameter Pt electrode: (i) 2 mM of 7a
at 293 K; (ii) (black line) prior to the bulk oxidation of 5 mM 7 at 253
K and (red line) after the exhaustive oxidation of 5 mM 7 at 253 K;
(iii) after the electrolyzed solution of 7 had warmed to 293 K; (iv)
after 7a was added to the oxidized solution of 7 at 293 K. (b) Current/
coulometry vs time data obtained during the exhaustive oxidation of 7
at 0.8 V vs Fc/Fc+.
3. Conclusions
A number of new compounds have been identified that form
phenoxonium cations upon electrochemical oxidation in CH3-
CN. By comparing the variable scan rate CV and CPE data
obtained for the compounds in Figure 1, it is possible to make
some observations about the lifetimes of the phenoxonium
cations based on their structures. Both chroman-6-ol and
dihydrobenzofuran-5-ol substituted compounds are able to form
detectable phenoxonium cations upon oxidation in CH3CN,
several with lifetimes of at least a few seconds. In general, the
lifetime of the phenoxonium cations increases with increasing
methylation of the aromatic ring. The increased lifetime of the
phenoxonium cations with increasing methylation can be
rationalized by improved steric shielding from nucleophilic
attack, and by the electron donating ability of the methyl groups
aiding in stabilizing the increased positive charge.
Previously, results from 13C NMR experiments and data from
theoretical calculations indicated that the positive charge in the
phenoxonium cation of R-TOH (R-TO+) was, surprisingly,
mainly located on the quaternary carbon in the chromanol ring
(position 2 in Scheme 2), with lesser delocalization into the
aromatic ring.7c Therefore, it would be expected that the
SCHEME 5. Conversion of Phenoxonium Cation into
Hemiketals (chromenols) and Further Conversion into
p-Quinones
A spiro-dimer has been identified as a common product
formed via chemical oxidation of R-tocopherol in solvents with
low dielectric constants such as benzene and chlorobenzene.14d,e
R-Tocopherol is thought to be initially chemically oxidized to
the phenoxyl radical, which further reacts to form the o-quinone
(15) Parkhurst, R. M.; Skinner, W. A. Chromans and Tocopherols. In
Chemistry of Heterocyclic Compounds; Ellis, G. P., Lockhart, I. M., Eds.;
Wiley: New York, 1981; Vol. 36, Chapter 3.
2174 J. Org. Chem., Vol. 73, No. 6, 2008

Lifetimes of Phenoxonium Cations
commercial sources, except 7a, which is a new compound prepared
by a standard method.14c
properties of the group bonded to position 2 (positions 1′ and
2a in Scheme 2) would have a pronounced affect on the lifetimes
of the phenoxonium cations. Thus it was found that for the
chroman-6-ol compounds with fully methylated aromatic rings
and methyl groups in position 2a [(CH3)R-TOH, 4-7], the
lifetime of their phenoxonium cations followed the order Me
. CH2OH ≈ COOEt . OMe ≈ OEt for the groups in position
1′.
The presence of a carbon atom or heteroatom in positions 1′
or 2a (Scheme 2) is not a prerequisite for the stability of the
phenoxonium cations. It was found that compounds 12 and 13
with hydrogen atom(s) bound to position 2 formed persistent
phenoxonium cations upon electrochemical oxidation. Further-
more, compound 11, containing a 5-membered ring, formed a
phenoxonium cation upon oxidation whose lifetime in solution
was as high as that of the 6-membered ring naturally occurring
analogue, R-TO+.
7a: FeCl3 hexahydrate (762 mg, 2.8 mmol) was added to a
methanol/water/diethyl ether (40 mL, v/v/v ) 19: 1: 20) solution
of ethyl 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-
2-carboxylate (150 mg, 0.68 mmol) in an ice bath, and the resulting
solution was stirred for 2 h. Water (20 mL) was added and the
mixture was extracted with ether. The organic layer was washed
with water and brine and dried over sodium sulfate. The residue
was separated by column chromatography to give yellow oil product
(125 mg, 76%). 1H NMR (CDCl3, 400 MHz) δ 4.33-4.23 (m, 2H),
3.31 (s, 1H), 2.65-2.58 (m, 1H), 2.43-2.35 (m, 1H), 2.02 (s, 3H),
2.00 (s, 6H), 1.88-181 (m, 1H), 1.74-1.67 (m, 1H), 1.42 (s, 3H),
1.34 (t, J ) 7.1 Hz, 3H); 13C {1H} NMR (CDCl3, 400 MHz) δ
187.6, 186.9, 176.9, 143.4, 140.6, 140.5, 140.4, 74.1, 62.1, 38.3,
26.0, 21.1, 14.2, 12.3, 12.2, 11.9.
4.2. General Experimental Methods. Procedures for all elec-
trochemical experiments are provided in previous publications.7
Acknowledgment. This work was supported by a Nanyang
Technological University research grant (SUG42/06). The
authors thank Professor Keith U. Ingold for suggesting elec-
trochemical experiments on the dihydrobenzofuran-5-ol based
compounds.
4. Experimental Section
4.1. Chemicals. (CH3)R-TOH,16 4,17 5,18 6,19 7,17 8,20 9,21 10,22
11,23,24 12,25 13,25 14,23a 15,24 15a,24 16,24 and 1814c were prepared
by literature methods. Other compounds and reagents were from
Supporting Information Available: Compound characterization
data (1H, 13C NMR, and HRMS) and electrochemical data from
cyclic voltammetry and controlled potential electrolysis experiments.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Smith, L. I.; Ungnade, H. E.; Hoehn, H. H.; Wawzonek, S. J. Org.
Chem. 1939, 4, 311-317.
(17) Ramachandran, U.; Mital, A.; Bharatam, P. V.; Khanna, S.; Rao,
P. R.; Srinivasan, K.; Kumar, R.; Chawla, H. P. S.; Kaul, C. L.; Raichurd,
S.; Chakrabartid, R. Bioorg. Med. Chem. 2004, 12, 655-662.
(18) Cossy, J.; Rakotoarisoa, H.; Kahn, P.; Desmurs, J.-R. Tetrahedron
Lett. 2000, 41, 7203-7205 and references cited therein.
(19) Cohen, N.; Schaer, B.; Saucy, G.; Borer, R.; Todaro, R.; Chiu, A.
M. J. Org. Chem. 1989, 54, 3282-3292 and references cited therein.
(20) Smith, L. I.; Tess, R. W. H. J. Am. Chem. Soc. 1944, 66, 1523-
1525.
(21) (a) Lien, E. J.; Ren, S. J.; Bui, H. Y. H.; Wang. R. B. Free Radical
Biol. Med. 1999, 26, 285-294. (b) Wright, J. S.; Johnson, E. R.; DiLabio,
G. A. J. Am. Chem. Soc. 2001, 123, 1173-1183.
(22) (a) Wang, Q.; She, X.; Ren, X.; Ma, J.; Pan, X. Tetrahedron:
Asymmetry 2004, 15, 29-34. (b) Ismail, F. M. D.; Hilton, M. J.; Stefinovic,
M. Tetrahedron Lett. 1992, 33, 3795-3796 and references cited therein.
JO702415Q
(23) (a) Lars, J.; Nilsson, G.; Selander, H.; Sievertsson, H; Skjanberg, I.
Tetrahedron 1970, 26, 879-886. (b) Burton, G. W.; Doba, T.; Gabe, E. J.;
Hughes, L.; Lee, F. L.; Prasad, L.; Ingold, K. U. J. Am. Chem. Soc. 1985,
107, 7053-7065.
(24) Nova´k, L.; Kova´cs, P.; Pirok, G.; Kolonits, P.; Szabo´, E.; Fekete,
J.; Weiszfeiler, V.; Sza´ntay, C. Synthesis, 1995, 693-698.
(25) Nova´k, L.; Kova´cs, P.; Kolonits, P.; Sza´ntay, C. Heterocycles 1994,
38, 177-179.
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