Experimental and theoretical studies of the redox potentials of cyclic nitroxides

Article abstract of DOI:10.1021/jo801099w

(Chemical Equation Presented) The redox potentials of 25 cyclic nitroxides from four different structural classes (pyrrolidine, piperidine, isoindoline, and azaphenalene) were determined experimentally by cyclic voltammetry in acetonitrile, and also via high-level ab initio molecular orbital calculations. It is shown that the potentials are influenced by the type of ring system, ring substituents and/or groups surrounding the radical moiety. For the pyrrolidine, piperidine, and isoindolines there is excellent agreement (mean absolute deviation of 0.05 V) between the calculated and experimental oxidation potentials; for the azaphenalenes, however, there is an extraordinary discrepancy (mean absolute deviation of 0.60 V), implying that their one-electron oxidation might involve additional processes not considered in the theoretical calculations. This recently developed azaphenalene class of nitroxide represents a new variant of a nitroxide ring fused to an aromatic system and details of the synthesis of five derivatives involving differing aryl substitution are also presented.

Full text of DOI:10.1021/jo801099w

Experimental and Theoretical Studies of the Redox Potentials of
Cyclic Nitroxides
James P. Blinco,†,‡ Jennifer L. Hodgson,†,§ Benjamin J. Morrow,†,‡ James R. Walker,†,‡
Geoffrey D. Will,‡ Michelle L. Coote,†,§ and Steven E. Bottle*,†,‡
Australian Research Council Centre of Excellence for Free Radical Chemistry and Biotechnology, School
of Physical and Chemical Sciences, Queensland UniVersity of Technology, GPO Box 2434,
Brisbane, Queensland, 4001, Australia, and Research School of Chemistry, Australian National UniVersity,
Canberra, ACT, 0200, Australia
s.bottle@qut.edu.au
ReceiVed May 20, 2008
The redox potentials of 25 cyclic nitroxides from four different structural classes (pyrrolidine, piperidine,
isoindoline, and azaphenalene) were determined experimentally by cyclic voltammetry in acetonitrile,
and also via high-level ab initio molecular orbital calculations. It is shown that the potentials are influenced
by the type of ring system, ring substituents and/or groups surrounding the radical moiety. For the
pyrrolidine, piperidine, and isoindolines there is excellent agreement (mean absolute deviation of 0.05
V) between the calculated and experimental oxidation potentials; for the azaphenalenes, however, there
is an extraordinary discrepancy (mean absolute deviation of 0.60 V), implying that their one-electron
oxidation might involve additional processes not considered in the theoretical calculations. This recently
developed azaphenalene class of nitroxide represents a new variant of a nitroxide ring fused to an aromatic
system and details of the synthesis of five derivatives involving differing aryl substitution are also presented.
Introduction
sulfur-, and phosphorus-centered radicals, as well as interact
with oxygen-centered radicals via one-electron redox processes.
Reactive free radicals may play a detrimental role in biologi-
cal systems with evidence they contribute toward aging,
ischemia, inflammatory and autoimmune diseases, as well as
atherosclerosis.1 The general conditions under which these
reactions take place have been termed “oxidative stress” and
this refers to a situation of cellular damage resulting from
accumulation of reactive oxygen species (ROS). ROS and other
free radicals are constantly formed in the human body as a part
of normal metabolic processes. However, when produced in
excess, these ROS can lead to tissue injury and even cell death.
Nitroxides, which are persistent, kinetically stable free radicals,
have been widely studied as potential antioxidants against such
reactive species due to their unique ability to trap carbon-,
Oxidation and reduction processes involving nitroxides are
of particular interest as both appear to be biologically relevant.
Mitchell et al.2,3 showed that the nitroxide 2-ethyl-2,5,5-
trimethyl-3-oxazolidin-1-oxyl was able to protect mammalian
cell lines against superoxide (O2•-) by acting as a superoxide
dismutase mimic. This result was rationalized by the proposal
that the nitroxide was first reduced by superoxide to a hydroxy-
lamine and subsequently reoxidised to regenerate the nitroxide
in a catalytic cycle yielding O2 and H2O2 (mechanism 1, Scheme
1). Other piperidine-based nitroxides such as 2,2,6,6-tetram-
ethylpiperidin-1-yloxyl and 4-hydroxy-2,2,6,6-tetramethylpip-
eridin-1-yloxyl have been shown to catalyze the dismutation
of superoxide in a process thought to involve the nitroxide
* Corresponding author. Phone: +61-7-3138-1356. Fax: +61-7-3138-1804.
† Australian Research Council Centre of Excellence for Free Radical
Chemistry and Biotechnology.
(2) Mitchell, J. B.; Samuni, A.; Krishna, M. C.; DeGraff, W.; Ahn, M. S.;
Samuni, U.; Russo, A. Biochemistry 1990, 29, 2802.
(3) Samuni, A.; Krishna, M. C.; Mitchell, J. B.; Collins, C. R.; Russo, A.
Free Radical Res. Commun. 1990, 9, 241.
‡ Queensland University of Technology.
§ Australian National University.
(1) Gutteridge, J. M. Free Radical Res. Commun. 1993, 19, 141.
10.1021/jo801099w CCC: $40.75
Published on Web 08/07/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6763–6771 6763

Blinco et al.
SCHEME 1. SOD Mechanisms of Cyclic Nitroxides
experimental results, of the 54 compounds assessed computa-
tionally, only 7 aliphatic derivatives were able to be directly
compared with literature data. In this study we report oxidation
and, where possible, reduction potentials of 25 nitroxides (shown
in Scheme 2) measured via cyclic voltammetry (Table 1). The
data are then compared with those of high-level ab initio
molecular orbitals for the same compounds under the experi-
mental conditions of the present work, thereby providing an
opportunity to test the theory underpinning the ab initio
calculations.
Synthetic Results
The treatment of 2-benzyl-1,1,3,3-tetramethyl-2,3-dihydro-
2-azaphenalene (3a′, designated as ′ to indicate its precursor
relationship to the nitroxide 3a) with HNO3 in the presence of
H2SO4 selectively nitrates the 6 position of the azaphenalene
ring in high yield. This nitration is highly dependent on the
reaction temperature. When the reaction is carried out at room
temperature, quantitative mononitration can be achieved in 150
min. Raising the reaction temperature to 60 °C results in double
nitration of the azaphenalene ring, yielding the 6,7-dinitroamine
3c′. No nitration of the benzyl ring was observed under these
conditions. Both the mono- and dinitro analogues were able to
be debenzylated and oxidized to the corresponding nitroxides,
3b and 3c, in one step with use of mCPBA.
Hydrogenation of 3b in the presence of Pd/C catalyst followed
by treatment with PbO2 to partially reoxidize the resultant
aminohydroxylamine to the nitroxide yielded the amino ana-
logue 3d. Although this compound is stable in air after
preparation, when stored, even in an inert environment at low
temperatures, a small amount of highly colored degradation
product is formed. A more stable dimethylamino analogue 3e
could be synthesized from this compound via a basic methy-
lation by using methyl iodide in a sealed vessel. Attempts to
reduce the dinitro compound 3c under similar conditions to those
used for 3b to give the 6,7-diamino analogue failed as the
product formed during hydrogenation rapidly decomposed on
workup.
TABLE 1. Experimental Redox Potentials (V) of the Nitroxides
Studieda
oxidation
reduction
Epc Epa
0.94 -1.450
1.10 -2.335 -0.455
0.92 -1.518
b
c
compd
Epa
0.753
0.631
0.692
0.649
Epc Eo
Epa - Epc ipa/ipc
1
0.651
0.522
0.608
0.557
0.702
0.577
0.65
0.102
0.109
0.084
0.092
0.109
0.079
0.088
0.077
0.065
0.076
0.103
0.08
0.082
0.094
0.103
0.085
0.106
0.085
0.099
0.109
0.13
2a
2b
2c
2d
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4f
0.603
0.789
0.736
0.822
0.902
0.829
0.908
0.771
0.821
0.849
0.749
0.757
0.733
0.825
0.857
0.817
0.875
0.717
0.729
1.027
0.816
0.793
0.91 -1.592
0.55 -2.079
0.843(0.698)d 0.734
0.775
0.866
0.94
0.696
0.778
0.863
0.85 -1.672 -0.910
0.93 -2.432
0.86 -1.915
0.861(0.654)d 0.796
0.53 -1.787
0.946(0.722)d 0.87
0.822
0.861
0.89
0.796
0.808
0.775
0.878
0.899
0.866
0.929
0.55 -1.898
0.719
0.781
0.808
0.702
0.705
0.69
1.05 -2.192 -0.911
0.99 -1.279
0.93 -0.996
0.92 -1.562
0.83 -2.153
1.02
4g
4h
4i
0.772
0.814
0.767
0.82
0.98 -2.160 -0.633
0.95 -2.149 -0.718
0.98 -1.966 -0.778
0.88
4j
4k
5a
5b
6
0.782(1.357)d 0.652
0.91 -2.128 -0.783
0.777
1.069
0.858
0.837
0.68
0.097
0.085
0.085
0.088
0.89 -2.262
0.984
0.773
0.749
0.83 -1.638
0.83 -2.048
7
0.93 -1.948 -1.136
a 0.1 M TBAF in acetonitrile, Pt electrode, Ag/AgCl electrode, sweep
rate 0.15 (Epc [(ipa)0/ipc] +
V
s-1 b Eo Epa)/2. c (ipa/ipc)
.
)
+
)
The synthetic route to nitroxides 4e and 4f (Scheme 4) was
developed from the established procedures for methanolysis by
Capdevielle and Maumy.6 Starting with 4g it was possible to
carry out copper(I)-catalyzed aryl bromide substitution by
methoxide ion to form the methylaryl ether 4e in good yield.
Analogous synthesis of the dimethoxy compound 4f from the
nitroxide 4h proved troublesome. However, the methanolysis
could be carried out on the secondary amine analogue 4h′, which
subsequently could then be oxidized to the nitroxide 4f with
mCPBA.
[0.485(isp)0/ipc] + 0.086, where (ipa)0 is the uncorrected anodic current
and (isp)0 is the current at the switching potential.8 d Secondary oxidation
not related to the nitroxide moiety.
oxidizing to the oxammonium cation.4 The oxammonium cation
is then reduced back to the nitroxide also yielding O2 and H2O2
(mechanism 2). The exact nature of the mechanism involved
in this dismutation may be dependent on the nature of the redox
pairs involved in the process. In this regard, cyclic voltammetry
measurements of the redox potentials of the nitroxides may
provide insight into the factors that govern this dismutation and
could provide insight into the mechanism of action of nitroxides
in vivo. The ability to predict the redox potentials of differently
substituted and various ring classes of nitroxides would also be
of value to help define the best synthetic targets for potential
biologically relevant antioxidants.
Compounds 4d and 4i were synthesized via a diazonium
cation intermediate that was prepared in situ from 4k and NaNO2
in an acidic aqueous environment.
The phenol 4d was generated by simple heating of the
aqueous solution once sufficient time had been allowed for the
diazotation to take place (Scheme 5). The yield of the reaction
was moderate (41%) though alternative procedures with H2SO4
instead of HCl as the mineral acid did not improve the outcome.
The synthesis of 4i requires quenching the diazonium solution
with an aqueous solution of KI and CuI. On a small scale (<100
mg) the addition of the diazonium salt to the iodide solution or
vice versa did not affect the yield significantly. On larger scales
Previously, we were able to predict the redox potentials for
54 cyclic nitroxides using high-level ab initio calculations.5
Although these calculations correlated well with the available
(4) Krishna, M. C.; Grahame, D. A.; Samuni, A.; Mitchell, J. B.; Russo, A.
Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 5537.
(5) Hodgson, J. L.; Namazian, M.; Bottle, S. E.; Coote, M. L. J. Phys. Chem.
A 2007, 111, 13595.
(6) Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34, 1007.
6764 J. Org. Chem. Vol. 73, No. 17, 2008

Redox Potentials of Cyclic Nitroxides
SCHEME 2. Nitroxides Investigated in Cyclic Voltammetry and Theoretical Studies
SCHEME 3. Synthesis of Azaphenalene Derivatives 3b-e
FIGURE 1. Cyclic voltammograms of the nitroxide/N-oxoammonium
couple of 2a (---) and 4a (s).
examples of the observed waves are shown in Figure 1. In all
cases the nitroxides underwent a one-electron oxidation that
corresponds to the formation of the N-oxoammonium cation.
The redox potentials, Eo, of the oxidation of the nitroxide were
estimated as half the sum of the anodic (Epa) and cathodic (Epc)
peak potentials. The peak separation, Epa - Epc, ranged from
65 to 109 mV. These values are approaching the theoretical
Nernstian value of 59 mV indicating kinetic reversibility in the
oxidations. The ipa/ipc for the oxidation wave was approaching
unity in all cases (except when an amino functionality was
present) showing the nitroxide/oxoammonium cation couple is
also thermodynamically reversible. The robustness of the
nitroxides was also tested by cycling the unsubstituted parent
structures 2a, 3a, and 4a more than 100 times each resulting in
no change to the intensity of the ipa values or shifting the Epa/
Epc values.
Compounds 2d, 3d, 3e, and 4k displayed another oxidation
wave that in all cases was irreversible (shown in parentheses in
Table 1). This is believed to arise from oxidation of the amino
functionality present on the aromatic ring. This functional group
has been shown to undergo oxidation under similar conditions.7
On the basis of the experimental results, it can be seen that
for the unsubstituted ring systems, the order of oxidation from
(∼1 g), however, it was determined that it was essential that
the diazonium salt be added to the iodide solution to avoid
significant yield variations (70% cf. 41%). This variation may
arise from competition between the radical mechanism com-
monly proposed for this reaction and the alternate cationic
mechanism. While the nitroxide is a potent scavenger of carbon-
centered radicals, by adding the nitroxide diazonium salt to the
aqueous iodide solution, the desired product is rapidly formed,
and precipitates from the solution thereby become unavailable
to react with any incoming diazonium salt. On a smaller scale
this effect may not be as significant as the two solutions can be
transferred and mixed quickly and concentrations are lower.
Cyclic Voltammetry
The redox potentials of the nitroxides shown in Scheme 2
were determined by cyclic voltammetry in acetonitrile with use
of a platinum electrode and are listed in Table 1. Typical
(7) Korbi, B. H.; Tapsoba, I.; Benkhoud, M. L.; Boujlel, K. J. Electroanal.
Chem. 2004, 571, 241.
(8) Nicholson, R. S. Anal. Chem. 1965, 37, 1351.
J. Org. Chem. Vol. 73, No. 17, 2008 6765

Blinco et al.
SCHEME 4. Synthesis of Isoindoline Derivatives 4e and 4f
SCHEME 5. Synthesis of Isoindoline Derivatives 4d and 4i
theory and experiment (the mean absolute deviation (MAD) of
theory from experiment is just 50 mV or 4.8 kJ mol-1) for the
other classes of nitroxide studied, for the azaphenalenes there
is a level of error (MAD 600 mV) that is unprecedented for the
high level of theory used in the present work. This discrepancy
will be discussed in more detail below, but could indicate that
some additional factor (such as complex formation), not
considered in the theoretical calculations, is contributing to the
experimental results.
Functionalization of the aromatic ring systems has a small
but predictable effect on the oxidation potentials, even if this
occurs in a position quite remote from the nitroxide moiety.
This is most obvious when oxidation potentials of monosub-
stituted isoindoline nitroxides are plotted against the Hammet
parameters, σp, an empirical constant based on the electronic
effect of the subsistent12 (see Figure 3), and is consistent with
our earlier theoretical observations. During preparation of this
article, a paper by Manda et al. was published that showed a
similar substituent-activity effect for the 5-membered pyrrolidine
ring class.13
It is also observed that changing the R groups surrounding
the nitroxide moiety of the isoindoline can affect the oxidation
potential of the compounds, as seen in Figure 4. By replacing
the methyl groups surrounding the nitroxide with ethyl groups
there is a slightly lower oxidation potential, as the electron-
donating ethyl groups can more effectively stabilize the positive
charge on the cation. However, when replaced by phenyl groups,
a substantially higher oxidation potential is observed. This may
be the result of increased steric hindrance impacting on the ease
of planarization of the cation.
The electrochemical reductions of the nitroxides were also
measured by cyclic voltammetry, where possible. Typical
examples are shown in Figure 5. In most cases a broad,
irreversible cathodic peak is observed in an area where the
solvent is also undergoing electrochemical change. This corre-
sponds to the reduction of the nitroxide moiety to a hydroxy-
lamine, initially formed as the nonprotonated anion. If reoxi-
dation does occur, it is generally observed at a much higher
potential than for the initial reduction (ca. 1-1.5 V) probably
reflecting the oxidation of the hydroxylamine rather than the
exact reversal of the reduction. When these reductions are
cycled, the original nitroxide does appear to reform, based on
the similarity of the subsequent reduction wave. This is
consistent with the hydroxylamine oxidizing to reform the
nitroxide, but may also reflect simple mass transport of new
material to the electrode. The added complexity of the reductions
most easily oxidized to least easily oxidized is piperidine (2a,
0.577 V) . azaphenalene (3a, 0.736 V) > isoindoline (4a, 0.771
V). As described previously,5 the 6-membered piperidine and
azaphenalene derivatives are more easily oxidized than the
5-membered isoindoline derivatives. This probably arises from
the greater flexibility of the 6-membered ring, which allows the
nitrogen center to planarize more easily on oxidation (and
pyramidalize more easily upon reduction). However, the dif-
ferences between the piperidine and azaphenalene derivatives
are more difficult to explain, as structural studies9-11 suggest
that the piperidine and azaphenalene rings may have similar
flexibilities at nitrogen. In our previous theoretical study of
nitroxides in water,5 it was found that azaphenalenes were
actually more easily oxidized than the piperidine derivatives, a
result that we attributed to the ability of the aromatic ring of
the azaphenalene to stabilize the cation, by helping to delocalize
the positive charge. As seen in Figure 2, calculations indicated
a significant interaction between the aromatic rings of the
azaphenalene and the nitrogen center in the cation, but not in
the reactant radical, giving the expectation of a net stabilizing
effect on the oxidation potential of the azaphenalenes. Similar
results are presented here for the calculation of the oxidation
potentials of these species in this case solvated in acetonitrile
(Table 2). While there is again excellent agreement between
(9) Bolton, R.; Gillies, D. G.; Sutcliffe, L. H.; Wu, X. J. Chem. Soc., Perkin
Trans. 2 1993, 2049.
(10) Shen, J.; Bottle, S.; Khan, N.; Grinberg, O.; Reid, D.; Micallef, A.;
Swartz, H. Appl. Magn. Reson. 2002, 22, 357.
(11) Blinco, J. P.; McMurtrie, J. C.; Bottle, S. E. Eur. J. Org. Chem. 2007,
4638.
(12) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(13) Manda, S.; Nakanishi, I.; Ohkubo, K.; Yakamura, H.; Matsumoto, K.;
Ozawa, T.; Ikota, N.; Fukuzumi, S.; Anzai, K. Org. Biomol. Chem. 2007, 5,
3951.
6766 J. Org. Chem. Vol. 73, No. 17, 2008

Redox Potentials of Cyclic Nitroxides
FIGURE 2. B3LYP/6-311+G(3df,2p) orbital diagrams showing the singly occupied molecular orbital (SOMO) of the parent nitroxide radicals and
the highest occupied molecular orbital (HOMO) of the oxidized species.
made estimating Eo values for these measurements impractical
and as such only the Epc and Epa (where applicable) are quoted.
RT
F
RT
F
Er1e⁄2v ) Eo -
ln K K +
ln K K + K H + H
+
+ 2
[
]
[
]
(
)
(
)
1
2
1
2
1
(1)
Theoretical Calculations
where K1 and K2 are the acid dissociation constants of the
hydroxylamine and protonated hydroxyl amine, respectively, R is
the universal gas constant, F is the Faraday constant, and T is the
temperature. These corrections to the formal reduction potential
are significant: in our previous study of nitroxides in water we
found the calculated half-wave potentials in water differed from
the calculated formal reduction potentials by over 1.65 V, with the
former showing excellent agreement (within 0.04 V) with the
corresponding experimental values.5 Unfortunately, there is cur-
rently no published formula describing the calculation of irreversible
half-wave potentials for nitroxides in acetonitrile, and we are thus
unable to make the same comparisons in the present work.
From Table 2, it is seen that the correlation between the
theoretical calculations and experimental data is very high for the
pyrroline, piperidine, and isoindoline ring classes. As noted above,
for these species the mean absolute deviation of theory from
experiment is 50 mV. The only significant outlier is the calculation
for compound 2d (where the error is 268 mV). In this case, the
experimental results indicate that the irreversible oxidation of the
amine substituent, not considered in the theoretical calculations, is
affecting the results. However, as foreshadowed above, there is an
enormous and relatively systematic deviation of 600 mV between
the calculated results and experiment for the azaphenalene class
We previously identified a computational method for calculating
electrode potentials of nitroxide species and showed that it compared
well to experimental values in an aqueous medium.5 Recalculating
the oxidation potentials of some of the previously studied nitroxides
in aceonitrile and calculating some additional species allowed us
to compare a greater number of calculated species with experimental
oxidation potentials. The experimental and theoretical results for
the oxidation potentials are shown in Table 2. As discussed in our
previous theoretical study,5 the reduction reaction is more compli-
cated due to protonation of the reduced species. As a result, the
formal one-electron reduction potentials obtained via our calcula-
tions are not directly comparable with the irreversible half-wave
potentials obtained via cyclic voltammetry, and have to be corrected
for the additional chemical reactions that take place on reduction.
For the one-electron reduction of nitroxides in water, eq 1 describes
the relationship between the formal one-electron reduction potentials
rev
(Eo) and the half-wave potentials (E ) for pH 7 in water at 298
1/2
K.14,15
(14) Kato, Y.; Shimizu, Y.; Yijing, L.; Unoura, K.; Utsumi, H.; Ogata, T.
Electrochem. Acta 1995, 40, 2799.
(15) Israeli, A.; Patt, M.; Oron, M.; Samuni, A.; Kohen, R.; Goldstein, S.
Free Radical Bio. Med. 2005, 38, 317.
J. Org. Chem. Vol. 73, No. 17, 2008 6767

Blinco et al.
TABLE 2. Comparison of Experimental and Theoretical
Oxidation Potentials (V) of the Studied Nitroxides
compd
exptl Eo
corrected to SHE
calcd Ea
exptl - calcd
1
0.702
0.577
0.65
0.976
0.850
0.924
0.877
1.063
1.010
1.096
1.175
1.102
1.182
1.045
1.095
1.123
1.023
1.030
1.007
1.099
1.130
1.091
1.148
0.990
1.003
1.301
1.091
1.067
0.971
0.807
0.895
0.836
0.005
-0.043
-0.029
-0.041
-0.268
-0.536
-0.524
-0.470
-0.761
-0.708
-0.046
-0.015
0.044
2a
2b
2c
2d
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4f
0.603
0.789
0.736
0.822
0.902
0.829
0.908
0.771
0.821
0.849
0.749
0.757
0.733
0.825
0.857
0.817
0.875
0.717
0.729
1.027
0.816
0.793
0.795
0.474
0.572b
0.705b
0.341b
0.474b
0.999
1.080b
1.167b
0.980b
0.972b
0.957b
1.061b
1.112b
-0.043
-0.058
-0.050
-0.038
-0.018
4g
4h
4i
FIGURE 4. Cyclic voltammograms of the nitroxide/N-oxoammonium
couple of 5a (---), 4a (s), and 5b (- -).
4j
1.142b
0.920b
0.972b
-0.006
-0.070
-0.031
4k
5a
5b
6
0.967b
1.042a
-0.124
-0.025
7
a Calculated by using gas-phase species optimized at the G3(MP2)-RAD
level with B3-LYP/6-31G(d) optimized geometries. Solvation energies were
calculated by using PCM at the B3-LYP/6-31G(d) level of theory, using the
SCFVAC keyword in GAUSSIAN. b ONIOM calculations found by using
core systems calculated at G3(MP2)-RAD, with the full system
calculated at RMP2/6-311+G(3df,2p); using as core systems the parent
(H-substituted) nitroxides.
FIGURE 5. Cyclic voltammograms of the nitroxide/hydroxylamine
couple of 2a and 4a.
The level of error observed for the azaphenalenes in the present
work is thus almost unprecedented for this high level of theory,
and inconsistent with the generally good agreement between theory
and experiment for the other classes of nitroxide. This would seem
to suggest that the error does not arise in the electronic structure
calculations themselves, but rather in some additional factor that
is affecting the experimental oxidation of the azaphenalenes but is
not being taken into account in the theoretical calculations. For
example, as noted above, we have previously shown the reduction
potentials of the nitroxides in water are strongly affected by
protonation of the reduced speciessonce this reaction is taken into
account, the reduction potentials change by over 1.65 V and show
excellent agreement with the available experimental data.5 Proto-
nation is clearly not the cause of the discrepancy in the oxidation
potentials; however, some other physical or chemical interaction
may be occurring. For example, if the azaphenalenes were to form
complexes through π-stacking, this could lead to the experimentally
observed oxidation potential being higher than the calculated formal
one-electron oxidation potential as this would limit the concentration
of free nitroxide available for oxidation. The azaphenalene nitrox-
ides have only recently been synthesized11 and experimental data
on their properties is limited; however, the discrepancy between
theory and measurement is noteworthy. Further studies to explore
the origin of this intriguing result are currently underway.
FIGURE 3. Oxidation potentials of monosubstituted isoindoline ni-
troxides plotted with respect to the Hammett constant of the functional
group (σp).
with the theoretical calculations. This level of error is an order of
magnitude higher than that observed for the other species, both in
the present work and our previous theoretical study of nitroxides
in water, and also in other studies of one- and two-electron oxidation
and reduction potentials.16 More generally, the G3 family of
computational methods has been shown to deliver “kcal accuracy”
when assessed against large test sets of experimental data.17
(16) See for example: (a) Namazian, M.; Coote, M. L. J. Phys. Chem. A
2007, 111, 7227. (b) Namazian, M.; Siahrostami, S.; Coote, M. L. J. Fluorine
Chem. 2007, 129, 222–225. (c) Namazian, M.; Zare, H. R.; Coote, M. L. Biophys.
Chem. 2008, 132, 64.
(17) See for example: (a) Henry, D. J.; Sullivan, M. B.; Radom, L. J. Chem.
Phys. 2003, 118, 4849. (b) Curtiss, L. A.; Raghavachari, K. Theor. Chem. Acc.
2002, 108, 61.
6768 J. Org. Chem. Vol. 73, No. 17, 2008

Redox Potentials of Cyclic Nitroxides
yielding 2-benzyl-1,1,3,3-tetramethyl-6-nitro-2,3-dihydro-2-azaphe-
nalene, 3b′, as a bright orange crystalline solid (226 mg, 99%).
Recrystallization from EtOH gave bright orange prisms (mp
Conclusions
Redox potentials determined by cyclic voltammetry were
compared with calculated potentials derived by using high-level
ab initio molecular orbitals theory for 25 cyclic nitroxides.
Favorable comparisons were found between theoretical and
experimental potentials for pyrroline, piperidine, and isoindoline
ring classes. Substitutions on the nitroxide rings were correctly
calculated to have a small yet predictable effect on the potentials.
The redox potentials of the novel azaphenalene nitroxides
were underestimated by the calculations in all cases by at least
a factor of 2. This level of error is unprecedented for the level
of theory and inconsistent with the good agreement obtained
for the other nitroxide classes measured. This suggests that other,
as yet unknown, influences on the redox potentials of the
azaphenalene ring class are not being taken into account by the
theoretical model.
1
145-147 °C). H NMR (400 MHz, CDCl3) δ 1.58 (12H, d, J )
2.3 Hz), 4.29 (2H, s), 7.18 (1H, m), 7.28 (2H, m), 7.44 (2H, d, J
) 7.1 Hz), 7.51 (1H, d, J ) 8.2 Hz), 7.61 (2H, dd, J ) 7.6, 1.2
Hz), 7.73 (1H, dd, J ) 7.6, 8.2 Hz), 8.23 (1H, d, J ) 8.2 Hz), 8.50
(1H, d, J ) 8.8, 1.2 Hz); 13C NMR (75 MHz, CDCl3) δ 48.4, 58.7,
119.9, 120.9, 122.9, 123.6, 125.3, 126.0, 126.1, 126.5, 128.1, 128.9,
144.0, 144.7, 150.6. HRMS (EI) m/z 359.1175 (0.1 ppm from the
calculated value for C23H23N2O2 (molecular ion - H))
Synthesis of 1,1,3,3-Tetramethyl-6-nitro-2,3-dihydro-2-azaphe-
nalene-2-yloxyl (3b). The benzylated amine 3b′ (120 mg, 0.33
mmol) was dissolved in 25 mL of dichloromethane (CH2Cl2). To
this was added 50% m-chloroperbenzoic acid (228 mg, 1.32 mmol)
with stirring at room temperature under a normal atmosphere. The
solution was then stirred for 24 h, replacing any dichloromethane
lost to evaporation. After 24 h the reaction mixture was washed
with 50 mL of saturated sodium bicarbonate solution, followed by
25 mL of brine, then dried over sodium sulfate, next the solvent
was evaporated to produce an orange oil. Purification by flash
column chromatography (silica gel, 100% CH2Cl2) afforded 170
mg of 1,1,3,3-tetramethyl-6-nitro-2,3-dihydro-2-azaphenalene-2-
yloxyl, 3b, as a orange/red solid (90% yield) (mp 171-173 °C).
NMR gave a broad amorphous spectrum typical of paramagnetically
broadened nitroxide. HRMS (EI) m/z 285.1238 (-0.4 ppm from
the calculated value for C16H17N2O3). Found: C, 71.89; H, 7.09:
N, 9.76. C16H17N2O3 requires: C, 71.81; H, 7.09: N 9.85.
Experimental Section
Nitroxides 1a and 2a-d were purchased from commercial
suppliers and used as received. Nitroxides 3a, 4a, 4b, 4g, 4h, 4i,
4j, 4k, 5a, and 5b and precursors 3a′ and 4h′ were synthesized via
published procedures.10,11,18-21 The complete synthetic details for
the nitroxides 4c, 6, and 7 will be published in an article currently
under preparation.
The electrochemical experiments were conducted in a sealed,
three-electrode glass cell, controlled by a Princeton Applied
Instruments 273A Potentiostat galvanostat. A platinum wire and
solid Ag/Ag+ electrode were used as a counter and reference
electrode, respectively. A platinum electrode with a disk radius of
1 mm was used as the working electrode. Redox potentials were
measured in MeCN, which was refluxed over CaH and distilled
under argon prior to use. The concentration of nitroxides used for
the experiments was 1-5 mM. The supporting electrolyte was 0.1
M tetrabutylammonium tetrafluoroborate (TBAF). TBAF had been
recrystallized and dried under vacuum prior to use. Before collecting
the cyclic voltammograms, molecular sieves were added to the cell
to minimize water present and the solution bubbled for 15 min with
UHP argon to remove oxygen. The cyclic voltammograms were
collected at room temperature at potential sweep rates of 0.05, 0.1,
0.15, 0.2, and 0.25 V s-1 for the oxidation potentials and 0.2 V s-1
for the reduction potentials. The ferrocene/ferrocenium redox couple
was Eo ) 0.350 V vs this reference electrode and was used as a
calibration standard. Potentials corrected to SHE were calculated
by using conversion constants listed by Pavlishchuk et al.22
Synthesis of 2-Benzyl-1,1,3,3-tetramethyl-6-nitro-2,3-dihydro-
2-azaphenalene (3b′). The protected amine 2-benzyl-1,1,3,3-tet-
ramethyl-2,3-dihydro-2-azaphenalene 3a′ (200 mg, 0.64 mmol) was
dissolved in glacial AcOH (ca. 10 mL) and the mixture was stirred.
This solution was immersed in an ice/water bath and 98% H2SO4
(2 mL) was added slowly, but at a rate sufficient to prevent the
liquid from freezing. HNO3 (0.5 mL, 70%) was then added slowly
and the solution was allowed to stir in the ice/water bath for ca. 10
min. The mixture was then stirred at room temperature for ca. 2.5 h.
The reaction was worked up by its slow addition (with stirring) to
cold 10% NaOH (250 mL) immersed in an ice bath. The resulting
suspension was extracted with Et2O. The combined extracts were
washed with brine, dried with Na2SO4, and evaporated to dryness
Synthesis of 2-Benzyl-1,1,3,3-tetramethyl-6,7-dinitro-2,3-dihy-
dro-2-azaphenalene (3c′). The protected amine 3a′ (400 mg, 1.27
mmol) was dissolved in glacial AcOH (ca. 10 mL) and stirred. The
solution was immersed in an ice/water bath and 98% H2SO4 (8
mL) was added slowly, but at a rate sufficient to prevent the liquid
from freezing. HNO3 (2 mL, 70%) was then added slowly and the
solution was stirred in the ice/water bath for ca. 10 min. The mixture
was then stirred at 60 °C for ca. 6 h. The reaction was worked up
by its slow addition (with stirring) to cold 10% NaOH (250 mL)
immersed in an ice bath. The resulting suspension was extracted
with Et2O. The combined extracts were washed with brine, dried
with Na2SO4, and evaporated to dryness. This was then subjected
to flash column chromatography (silica gel, 100% toluene) yielding
the monosubstituted 3b′ as a bright orange crystalline solid (146
mg, 32%) and the disubstituted 2-benzyl-1,1,3,3-tetramethyl-6,7-
dinitro-2,3-dihydro-2-azaphenalene, 3c′ (185 mg, 36%). Recrys-
tallization from EtOH gave bright orange prisms of 3c′ (mp
1
229-230 °C). H NMR (400 MHz, CDCl3) δ 1.61 (12H, s), 4.29
(2H, s), 7.20 (1H, m), 7.29 (2H, m), 7.41 (2H, m), 7.68 (2H, d, J
) 8.2 Hz), 8.30 (2H, d, J ) 8.2 Hz); 13C NMR (75 MHz, CDCl3)
δ 48.3, 59.1, 116.9, 122.1, 126.2, 126.25, 126.4, 127.2, 128.2,
143.89, 143.93, 150.2; HRMS (EI) m/z 404.1613 (0.7 ppm from
the calculated value for C23H22N3O4 (molecular ion - H)).
Synthesis of 1,1,3,3-Tetramethyl-6,7-dinitro-2,3-dihydro-2-aza-
phenalene-2-yloxyl (3c). The amine 3c′ (140 mg, 0.592 mmol) was
dissolved in 25 mL of CH2Cl2. To this was added 50% m-
chloroperbenzoic acid (408 mg, 2.37 mmol, 4 equiv) with stirring
at room temperature under a normal atmosphere. The solution was
then stirred for 24 h, replacing any dichloromethane lost to
evaporation. After 24 h the reaction mixture was washed with
saturated sodium bicarbonate solution and dried over Na2SO4, then
the solvent was evaporated to produce a red solid. Purification by
flash column chromatography (silica gel, 100% CH2Cl2) afforded
74 mg of 1,1,3,3-tetramethyl-6,7-dinitro-2,3-dihydro-2-azaphe-
nalene-2-yloxyl, 3c, as a deep red crystalline solid. Recrystallization
from EtOH gave ruby red cubes (74 mg, 65% yield) (mp 202-203
°C dec). NMR gave a broad amorphous spectrum. HRMS (EI) m/z
330.1092 (0.6 ppm from the calculated value for C16H16N3O5).
Found: C, 57.89; H, 4.75; N, 12.60. C16H16N3O5 requires: C, 58.18;
H, 4.88; N, 12.72.
(18) (a) Micallef, A. S.; Bott, R. C.; Bottle, S. E.; Smith, G.; White, J. M.;
Mastuda, K.; Iwamura, H. J. Chem. Soc., Perkin Trans. 2 1999, 65. (b) Griffiths,
P. G.; Moad, G.; Rizzardo, E.; Solomon, D. H. Aust. J. Chem. 1983, 36, 397.
(19) Reid, D. A.; Bottle, S. E.; Micallef, A. S. Chem. Commun. 1998, 1907.
(20) Sato, H.; Kathirvelu, V.; Fielding, A.; Blinco, J. P.; Micallef, A. S.;
Bottle, S. E.; Eaton, S. S.; Eaton, G. R. Mol. Phys. 2007, 105, 2137.
(21) Fairfull-Smith, K. E.; Blinco, J. P.; Keddie, D. J.; George, G. A.; Bottle,
S. E. Macromolecules 2007, 41, 1577.
(22) Pavlishchuk, V. V.; Addison, A. W. Inorg. Chim. Acta 2000, 298, 97.
J. Org. Chem. Vol. 73, No. 17, 2008 6769

Blinco et al.
Synthesis of 1,1,3,3-Tetramethyl-6-amino-2,3-dihydro-2-aza-
phenalene-2-yloxyl (3d). The nitroxide 3b (170 mg, 0.60 mmol)
was dissolved in EtOH (50 mL) and hydrogenated at ca. 20 psi H2
over 10% Pd/C (50 mg) in a Parr hydrogenator for 2 h. PbO2 (50
mg, 2.1 mmol) was added and the suspension swas tirred vigorously
in air for ca. 15 min before being filtered. Evaporation of the solvent
yielded 1,1,3,3-tetramethyl-6-amino-2,3-dihydro-2-azaphenalene-
2-yloxy,l 3d, as a orange crystalline solid (120 mg, 79%).
Recrystallization from MeOH gave orange needles (mp 112-114
°C dec). NMR gave a broad amorphous spectrum. HRMS (EI) m/z
255.1495 (-0.9 ppm from the calculated value for
C16H19N2O).(Found: C, 75. 05; H, 7.49; N, 10.85. C16H19N2O
requires: C, 75.26; H, 7.50; N, 10.97.
Synthesis of 6-(Dimethylamino)-1,1,3,3-tetramethyl-2,3-dihydro-
2-azaphenalene-2-yloxyl (3e). The amine nitroxide 3d (150 mg, 0.59
mmol), NaH (125 mg, 5.2 mmol), and MeI (20 mL) were combined
in a sealed reaction vessel and the mixture was stirred at 65 °C for
96 h, protected from the light. The mixture was then cooled and
water was added carefully with continuous stirring to consume
excess NaH (Caution: violent reaction). Additional water (ca. 50
mL) and CHCl3 (50 mL) were then added, the mixture was shaken,
and the organic phase was separated. The solution was washed with
25 mL of brine and dried over sodium sulfate, then the solvent
was evaporated to produce a brown solid. Purification by flash
column chromatography (silica gel, 100% CH2Cl2) afforded 6-(dim-
ethylamino)-1,1,3,3-tetramethyl-3-dihydro-2-azaphenalene-2-ylox-
yl, 3e, as a golden crystalline solid (164 mg, 98%) (mp 122-123
°C). HRMS (EI) m/z 283.1810 (-0.1 ppm from the calculated value
for C18H23N2O). Found: C, 76.28; H, 8.33; N, 9.82. C18H23N2O
requires: C, 76.29; H, 8.18; N, 9.89.
Synthesis of 5-Methoxy-1,1,3,3-tetramethylisoindolin-2-yloxyl
(4e). Nitroxide 4g (1.5 g, 5.6 mmol) and copper iodide (0.218 g,
1.1 mmol) were added to a solution of MeONa/MeOH (5 M, 7.5
mL) and ethyl acetate (0.327 mL, 3.3 mmol). This mixture was
refluxed for 14 h, allowed to return to room temperature, and then
poured onto ice. Extraction of the aqueous phase was performed
with Et2O, then the organics were separated, washed with brine,
and dried over Na2SO4. After evaporation of the solvent under
reduced pressure, the product was purified by column chromatog-
raphy (silica gel, 100% CHCl3) to give a yellow solid (0.877 g,
71%). Recrystallization from hexane produced fine yellow needles
of 5-methoxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (mp 95-97
°C). HRMS (EI) m/z 220.1340 (1.1 ppm from the calculated value
for C13H18NO2). Found: C, 70.86; H, 8.18; N, 6.36. C13H18NO2
requires: C, 70.88; H, 8.24; N, 6.36.
was recrystallized from hexane (152 mg, 79%) (mp 201-203 °C
dec). HRMS (EI) m/z 250.1453 (3.9 ppm from the calculated value
for C14H20NO3). Found: C 67.15, H 8.19, N 5.47. Calcd for
C13H18NO2: C 67.18, H 8.05, N 5.60.
Synthesis of 5-Hydroxy-1,1,3,3-tetramethylisoindolin-2-yloxyl
(4d). The nitroxide 5-amino-1,1,3,3-tetramethylisoindolin-2-yloxyl
(4k) (100 mg, 0.488 mmol) was dissolved in H2O (0.6 mL) and
HCl (11 M, 0.4 mL) and the mixture was cooled to 0 °C. To this
was added NaNO2 (37 mg, 0.536 mmol, 1.1 equiv) in H2O (2.5
mL) over 30 min and the reaction was then stirred for a further 10
min. The reaction mixture was then diluted with H2O to ca. 40 mL
and refluxed for 1 h. The resultant solution was cooled and extracted
with Et2O. The organic phase was dried with Na2SO4 and the
solvent was removed yielding a yellowish oil. This was then
subjected to column chromatography (silica gel, 50:50 EtOAc:
hexane), which yielded 5-hydroxy-1,1,3,3-tetramethylisoindolin-
2-yloxyl, 4d, as a pale yellow powder (41 mg, 41%) (mp 235 °C
dec). HRMS (EI) m/z 206.1189 (0.8 ppm from the calculated value
for C12H16NO2). Found: C 69.69, H 7.96, N 6.75. Calcd for
C12H16NO2: C 69.88, H 7.82, N 6.79.
Synthesis of 5-Iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl (4i). A
solution of 4k (800 mg, 3.9 mmol) in HCl (3.2 mL) and H2O (4.8
mL) was cooled to 0 °C. To this was added NaNO2 (374 mg, 5.42
mmol, 1.4 equiv) in H2O (21 mL) over a period of 10 min and the
subsequent solution was allowed to stir for a further 15 min, after
which time it was added beneath the surface of a vigorously stirred
cold solution of KI (3.15 g, 19 mmol, ∼5 equiv) and CuI (74 mg,
0.39 mmol, 10 mol %) in H2O (120 mL). The reaction mixture
was transferred to a hot water bath and stirred at 40-50 °C for 20
min. The mixture was then basified and treated with Na2S2O3 and
extracted with CHCl3. The organic layer was further washed with
a basic thiosulfate solution and dried with Na2SO4, then the solvent
was removed under reduced pressure to yield a brown oil. This
was subjected to column chromatography (silica gel, 30:70 EtOAc:
hexane) yielding 5-iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl (4i)
(864 mg, 70%) as a bright yellow solid (mp 132-134 °C) in
agreement with literature (lit.21 mp 132-135 °C).
Computational Procedures. Standard ab initio molecular orbital23
and density functional24 calculations in this work were carried out
with use of GAUSSIAN 0325 and MOLPRO 2000.6.26 Geometries
of all species were optimized at the B3-LYP/6-31G(d) level of
theory. Frequency calculations were also carried out at the B3-
LYP/6-31G(d) level and scaled via the appropriate factors.27
Significant effort was taken to ensure that the optimized structure
was the global (rather than merely the local) minimum energy
structure by performing extensive conformational searches at the
Synthesis of 5,6-Dimethoxy-1,1,3,3-tetramethylisoindoline (4f′).
A solution of 4h′ (300 mg, 0.9 mmol) in anhydrous N,N-
dimethylformamide (1.0 mL) was added to a solution of MeONa/
MeOH (5 M, 2 mL). To this solution was added copper iodide (20
mg, 0.1 mmol) and the mixture was heated at 85 °C for 24 h. The
reaction was then allowed to return to room temperature and was
subsequently poured onto ice. The aqueous phase was extracted
with Et2O, then the organics were combined and washed with H2O
and brine and dried over Na2SO4. The solvent was removed under
reduced pressure to give a crystalline white solid 4f′ (187 mg, 88%).
This material had limited stability, but was shown to be of sufficient
(23) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986.
(24) Koch, W.; Holthausen, M. C. A. Chemist’s Guide to Density Functional
Theory; Wiley-VCH: Weinheim, Germany, 2000.
(25) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian,
H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala,
P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul,
A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision
B.03; Gaussian, Inc.: Pittsburgh, PA, 2003.
(26) Werner, H.-J.; Knowles, P. J.; Amos, R. D.; Bernhardsson, A.; Berning,
A.; Celani, P.; Cooper, D. L.; Deegan, M. J. O.; Dobbyn, A. J.; Eckert, F.;
Hampel, C.; Hetzer, G.; Korona, T.; Lindh, R.; Lloyd, A. W.; McNicholas, S. J.;
Manby, F. R.; Meyer, W.; Mura, M. E.; Nicklass, A.; Palmieri, P.; Pitzer, R.;
Rauhut, G.; Schu¨tz, M.; Stoll, H.; Stone, A. J.; Tarroni, R.; Thorsteinsson, T.
MOLPRO 200.6; University of Birmingham: Birmingham, UK, 1999.
(27) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502.
1
purity by NMR for the subsequent oxidation step. H NMR (400
MHz, CDCl3) δ 1.46 (12H, s, CH3), 1.77 (1H, br, NH), 3.91 (6H,
s, OCH3), 6.62 (2H, s, 7-H and 4-H); 13C NMR (75 MHz, CDCl3)
δ 32.0, 56.1, 62.9, 104.3, 140.3, 148.8.
Synthesis of 5,6-Dimethoxy-1,1,3,3-tetramethylisoindolin-2-
yloxyl (4f). The precursor secondary amine 4f′ (180 mg, 0.76 mmol)
was dissolved in CH2Cl2 (8 mL) and cooled to 0 °C. To this was
added m-chloroperbenzoic acid (77%, 223 mg, 1.3 equiv) and the
solution was stirred for 20 min at 0 °C. The reaction was then
allowed to warm to room temperature, H2O was added, and the
CH2Cl2 layer was washed with 2 M NaOH. The organic phase was
then washed with brine and dried over Na2SO4. Evaporation of the
solvent under reduced pressure afforded a yellow solid, 4f, which
6770 J. Org. Chem. Vol. 73, No. 17, 2008

Redox Potentials of Cyclic Nitroxides
same level. It should also be noted that all radicals and all closed-
shell species considered in this study were true (local) minimum
energy structures (i.e. having no imaginary frequencies). Improved
gas phase energies were obtained via G3(MP2)-RAD calculations
on the B3-LYP optimized structures. An ONIOM approximation
that combined G3(MP2)-RAD calculations for the core (unsubsti-
tuted parent nitroxide) and ROMP2/6-311+G(3df,2p) calculations
for the full system was used for larger systems. The solvation
energies of each species were calculated by using the polarized
continuum model PCM at the B3-LYP/6-31G(d) level, using an
SCFVAC keyword in the GAUSSIAN calculation,28 and added to
the gas phase free energies to give the total Gibbs energies of the
species. The oxidation and reduction potentials were found from
the Gibbs free energies of species by using the procedure detailed
in our previous work,5 using the value of 4.52 V for the standard
hydrogen electrode (SHE) potential in acetonitrile found recently
with use of Boltzmann statistics.29 Molecular orbital diagrams
showing the singly occupied molecular orbital of the parent
nitroxide and the highest occupied molecular orbital of the
corresponding oxidized species were calculated by using a NBO
population analysis performed in GAUSSIAN at the B3-LYP/6-
311+G(3df,2p) level. Theoretical calculations were not performed
for compounds 4i and 5b as, owing to their size, it was not possible
to treat them with the same degree of accuracy as the other
compounds in the study.
Acknowledgment. We would like to acknowledge the
support of the Australian Research Council under the ARC
Centres of Excellence program, CE0561607. M.L.C. and J.L.H.
gratefully acknowledge generous allocations of computing time
from the Australian Partnership for Advanced Computing and
the Australian National University Supercomputing Facility, and
the award (to J.L.H.) of an Australian Postgraduate Award.
Supporting Information Available: 1H and 13C NMR
spectra of non-nitroxide intermediates, B3-LYP/6-31G(d) op-
timized geometries in the form of GAUSSIAN archive entries,
and corresponding total energies. This material is available free
of charge via the Internet at http://pubs.acs.org.
(28) Frisch, A.; Frisch, M. J.; Trucks, G. W. Gaussian 03 User’s Reference;
Gaussian, Inc.: Wallingford, CT, 2003.
(29) Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2007, 111,
408.
JO801099W
J. Org. Chem. Vol. 73, No. 17, 2008 6771