Preparation and spectroscopic, magnetic, and electrochemical studies of mono-/biradical TEMPO derivatives

Article abstract of DOI:10.1021/jo400845m

A comparison set of mono-/biradical TEMPO derivatives was prepared, novel compounds were fully characterized, and their physicochemical properties were determined. Cyclic voltammetry revealed reversible redox behavior for all studied nitroxides. Moreover, the electron-withdrawing substituents increased the oxidation potential of the respective nitroxides in comparison to electron-donating groups. While EPR spectra of monoradicals in dichloromethane at 295 K reveal the expected three-line signal, spectra of biradicals show more complex features. DFT and MP2 calculations indicate that the EPR splitting pattern of dinitroxide 7 could be explained by its interactions with solvent molecules. In the solid state, mononitroxides 4 and 5 behave as a Heisenberg antiferromagnetic chain, whereas dinitroxides 6-8 are almost isolated paramagnetic diradicals coupled in an antiferromagnetic manner.

Full text of DOI:10.1021/jo400845m

Article
pubs.acs.org/joc
Preparation and Spectroscopic, Magnetic, and Electrochemical
Studies of Mono-/Biradical TEMPO Derivatives
Miroslav Kavala,† Roman Boca,‡ Lubomír Dlhan,‡ Vlasta Brezova,§ Martin Breza,§ Jozef Kozísek,§
̌
́
̌
́
̌
̌
§
§
∥
,†
̌
Marek Fronc, Peter Herich, Lubomír Svorc, and Peter Szolcsanyi*
́
†Department of Organic Chemistry, Department of Inorganic Chemistry, §Department of Physical Chemistry, and ∥Department of
‡
́
Analytical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinskeho 9,
SK-812 37 Bratislava, Slovakia
S
* Supporting Information
ABSTRACT: A comparison set of mono-/biradical TEMPO
derivatives was prepared, novel compounds were fully
characterized, and their physicochemical properties were
determined. Cyclic voltammetry revealed reversible redox
behavior for all studied nitroxides. Moreover, the electron-
withdrawing substituents increased the oxidation potential of
the respective nitroxides in comparison to electron-donating
groups. While EPR spectra of monoradicals in dichloromethane at 295 K reveal the expected three-line signal, spectra of
biradicals show more complex features. DFT and MP2 calculations indicate that the EPR splitting pattern of dinitroxide 7 could
be explained by its interactions with solvent molecules. In the solid state, mononitroxides 4 and 5 behave as a Heisenberg
antiferromagnetic chain, whereas dinitroxides 6−8 are almost isolated paramagnetic diradicals coupled in an antiferromagnetic
manner.
influence on the spectroscopic, magnetic, and electrochemical
properties.
INTRODUCTION
■
Nitroxides as stable organic radicals1 represent an interesting
class of molecules that form the basis of novel and/or emerging
functional materials as radical batteries,2 spin probes,3 polariz-
ing agents for DNP-NMR,4,5 antioxidants,6 magneto-active
materials,7 and radiation protective agents.8 Arguably, the most
prominent representative of nitroxide-type radicals is TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxyl).9,10 Its 4-oxo derivative
1 (oxo-TEMPO) is used as a polymerization catalyst,11 the 4-
hydroxy derivative 2 (TEMPOL) shows antihypertensive
effects,12 and 4-amino-TEMPO 3 (Figure 1) was recently
Figure 2. Mono-/biradical TEMPO derivatives 5−8 used in this study.
RESULTS AND DISCUSSION
■
Synthesis. While TEMPO and its derivatives 1−4 are
commercially available, nitroxides 5−8 were prepared by
standard synthetic protocols. Thus, the sulfonamide 5 was
accessed by a two-step procedure starting from 4-amino-2,2,6,6-
tetramethylpiperidine via its quantitative mesylation and
subsequent oxidation of the hydrochloride salt 9 in 85% overall
yield (Scheme 1).
Figure 1. TEMPO and its known C(4)-heteroatom-substituted
derivatives 1−4.
Next, biradicals 6 and 7 were prepared by reductive
amination17 of oxo-TEMPO 1 with amino-PROXYL 10 (for
6: 46%) or with 4-amino-TEMPO 3 (for 7: 64%) using sodium
cyanoborohydride in acidic methanol under nonoptimized
reaction conditions (Scheme 2). The following mesylation of
biradical 7 toward the sulfonamide 8 proved to be unexpectedly
identified as a new target for neuro-drug discovery.13 From a
methodological point of view, not only are compounds 1−3
useful oxidants in organic synthesis14 but they also serve as
optimal substrates for the preparation of novel nitroxide
analogues.
Thus, we have prepared the known monoradical15 5 and
biradical16 7, as well as novel biradicals 6 and 8 bearing the
TEMPO moiety (Figure 2), and investigated their structural
Received: April 23, 2013
© XXXX American Chemical Society
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Scheme 1. Preparation of Nitroxide 5
Table 1. Experimental Redox Potentials and Current
Responses of Nitroxide/N-Oxoammonium Cation Redox
a
Couples
nitroxide
Epa (mV)
Epc (mV)
E1/2 (mV)
ΔE (mV)
ipa/ipc
TEMPO
462
614
538
600
558
549
574
644
340
520
410
494
450
449
466
490
401
616
474
547
504
499
520
567
122
94
1.1
4.5
1.1
1.1
1.2
1.2
1.2
1.1
difficult. While the use of excess of methanesulfonyl chloride in
combination with various bases (triethylamine, N,N-diisopro-
pylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, imidazole,
1,8-bis(dimethylamino)naphthalene, sodium hydroxide, and
potassium carbonate) in various solvents (dichloromethane,
1,4-dioxane, toluene, and diethyl ether) afforded 8 up to only
15% yield, the use of a 5-fold molar excess of methanesulfonyl
anhydride delivered the desired sulfonamide 8 in 35% yield
(Scheme 2).
With the desired mono-/biradicals 5−8 in hand, we
investigated their spectroscopic (EPR), magnetic (SQUID),
and electrochemical (CV) properties. We have also performed
single-crystal X-ray analyses of compounds 4−8 and elucidated
their solid state structures.
Cyclic Voltammetry. The redox potentials of the nitroxides
1, 2, and 4−8 were determined by cyclic voltammetry (CV) in
phosphate buffer solution (PBS, pH 7.0), using a paraffin-
impregnated graphite electrode (PIGE). In general, stable cyclic
nitroxides undergo one-electron oxidation, reflecting the
formation of the corresponding N-oxoammonium cations.18
Cyclic voltammograms of 1, 2, and 4−8 reveal that all of the
studied compounds undergo a one-electron transfer process
with half-wave potentials (E1/2) in the range of 401−616 mV vs
Ag/AgCl electrode (Table 1). In all cases except for 1, the
anodic and cathodic peak currents are approximately equal, and
thus it may be concluded that nitroxides 2 and 4−8 are
reversibly oxidized to their corresponding N-oxoammonium
cations (Figures S9−S13 in the Supporting Information).
However, the intensities of the anodic and cathodic currents
were far from equal for oxo-TEMPO 1, indicating a loss of the
kinetic reversibility19 (Figure S8 in Supporting Information).
On the other hand and in comparison, the half-wave potential
(E1/2) values of TEMPO and mononitroxide 2 corresponded
well with those previously reported.20−22 Due to the different
1
2
4
5
6
7
8
128
106
108
100
108
154
a
Definitions: Epa = anodic peak potential, Epc = cathodic peak
potential, E1/2 = (Epa + Epc)/2, ΔE = Epa − Epc, ipa = anodic peak
current, ipc = cathodic peak current.
natures of the carbonaceous electrode surfaces used (PIGE vs
GCE), there is an almost constant increment of potential, being
approximately 130 mV for both nitroxides TEMPO (401 vs
522 mV) and 2 (474 vs 611 mV).
The experimentally determined values of redox potentials of
nitroxides 1, 2, and 4−8 are summarized in Table 1.
The results indicate an emerging trend that the electron-
withdrawing substituents (OMs, HNMs) tend to increase the
oxidation potential of a nitroxide in comparison to electron-
donating groups (OH, NH2; cf 2 vs 1 and 4 and 7 vs 8; Figure
3). Thus, our empirical observations verify the recently
postulated influence of the nature of ring substituents on the
one-electron-oxidation potential of cyclic nitroxide radicals.23
Interestingly, the shapes of cyclic voltammograms of mono-
nitroxides 1, 2, 4, and 5 and dinitroxides 6−8 are analogous
throughout the series (Figures S5−S13 in Supporting
Information), thus indicating that electrochemical oxidation
of biradicals 6−8 likely involves simultaneous one-electron
transfer to both radical centers rather than a stepwise process.
In addition, we have observed a noteworthy anodic potential
of biradical 8 (Epa = 644 mV) that is higher than the
corresponding value for 4-oxo-TEMPO 1 (Epa = 614 mV). The
Scheme 2. Preparation of Dinitroxides 6−8
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Figure 3. Comparison of ring substituent influence on the oxidation potential of nitroxides.
Figure 4. (left) Cyclic voltammogram of the nitroxide/N-oxoammonium couple of 8 (blue) vs control (pink): scan rate 100 mV s−1, concentration 1
× 10−4 mol L−1 in PBS at pH 7.0 on a PIGE electrode. (right) Influence of scan rate on current response in the CV of biradical 8: concentration 1 ×
10−4 mol L−1 in PBS at pH 7.0 on a PIGE electrode. Scan rates: (a) 50, (b) 100, (c) 250, (d) 500, (e) 750, and (f) 1000 mV s−1. Inset: dependence
of anodic peak current on the square root of the scan rate.
peak separation values are higher (ΔE = 94−128 mV) in
comparison to the theoretical Nernstian value (59 mV);
however, the electrode reactions of the studied nitroxides are
considered to be kinetically reversible. Moreover, biradical 8
provides the largest separation of respective redox potentials
(ΔE = 154 mV; Figure 4).
Useful information on the mechanism of the electrode
process (rate-determining step) can be obtained from the
relationship between the peak current and scan rate (v). As an
illustrative example, Figure 4 displays the effect of scan rate on
the current response of biradical 8 within the range 50−1000
mV s−1. It was found that the oxidation (inset of Figure 4) and
reduction currents of biradical 8 increased linearly with the
square root of scan rate. This dependence of the oxidation
process can be expressed by eq 1:
attributed to the hydrogen nuclei of two equatorial and two
axial methyl groups, along with equatorial and axial ring
hydrogens (Table 2). In contrast, these interactions are
negligible in the EPR spectra24 of oxo-TEMPO 1 and,
moreover, 13C satellites are visible here (Table 2).
EPR spectra of dinitroxides 6−8 were analyzed by applying
an exchange-coupled spin Hamiltonian, where exchange
coupling between two electrons is defined via the exchange
coupling constant J.4,17,25−29 Figure 5 illustrates the EPR
spectrum of derivative 6 in DCM, representing a five-line signal
characteristic for dinitroxide structures with J values signifi-
cantly higher than the nitrogen nuclei hyperfine coupling
constant (J ≫ AN). The derivative 6 possesses two different
nitroxide moieties, in good agreement with the nonequivalent
nitrogen splittings elucidated from the simulated spectra (AN1
=
1.592 mT and AN2 = 1.460 mT); simultaneously, small
differences in g values were found (Table 2). Surprisingly,
similar results were obtained for dinitroxide 7 in DCM, as the
simulation analysis of experimental EPR spectra (Figure 5)
revealed an asymmetry of nitroxide groups with AN1 = 1.528
mT and AN2 = 1.640 mT (Table 2). However, nearly equivalent
values of AN1 and AN2 were obtained from EPR spectra of
dinitroxide 7 in the nonpolar solvent n-heptane (AN1 = 1.501
mT and AN2 = 1.548 mT). Such an observation raises the
question whether this asymmetry resulted from different
dinitroxide conformations or from the interactions of particular
nitroxide moieties with the solvent molecules (see below).
The EPR spectrum of dinitroxide 8 is more complex (Figure
5), demonstrating a restriction in the exchange coupling (J >
AN), and the best simulation fit was obtained using J ≈ 13 mT
(Table 2). In comparison to 7, the presence of a sulfonamide
I(A) = −[8.056( 0.102)] × 10−7 + [1.012( 0.014)]
× 10−5v1/2 mV s−1 R2 = 0.998
(1)
The high linearity and low intercept value suggest that
diffusion is the rate-determining step in the electrode process of
biradical 8 and that the rate-limiting adsorption and/or specific
interactions on the PIGE electrode are thus negligible. A similar
phenomenon was also observed in the case of all other studied
nitroxides 1−7.
EPR Spectroscopy and DFT Calculations. The room-
temperature X-band EPR spectra of mononitroxides 1, 2, 4, and
5 in DCM revealed a three-line signal corresponding to the
dominant hyperfine coupling of unpaired electron with the
nitrogen nucleus (Figure S14 in the Supporting Information).
Further analyzed hyperfine coupling constants (Hfcc) were
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temperature only two conformers (7a,b) are present in relevant
concentrations and their relative abundance depends on the
solvent used. Nevertheless, N−O spin densities and AN values
practically do not depend on the mutual ring positions (H4−
C4−C4′−H4′ dihedral angles; Table 3).
In the next step, we tried to change a single piperidine ring
conformation in the most stable 7a conformer. According to
our results, the system with an axial N−O bond is unstable and
the same holds for its boat conformation according to the N1−
C4 axis. We have found only one stable boat conformation, 7d,
according to a C2−C5 axis (Figure S15 in Supporting
Information) with two significantly different AN values, but its
energy is too high, and this implies its negligible concentration
in solution (Table 3).
Finally, we tried to approximate the solvent effects by
dichloromethane and propane molecules located near the N−O
group (models 7e−h). As can be seen, >N−O···H−CHCl2
hydrogen bonds significantly affect the N−O spin density
distribution, which implies higher AN values in comparison to
the >N−O···Cl−CH2Cl values. The difference between both
DFT calculated AN values is ca. 3 times lower in comparison to
experimental data (cf. Table 2), because DFT methods
underestimate weak interactions. Our results indicate a
comparable abundance of the symmetric 7e0 model with two
hydrogen bonds (Figure S16 in the Supporting Information)
and the asymmetric 7f0 model with a single hydrogen bond in a
dichloromethane solution (the energy of the 7g0 model
without hydrogen bonds is too high). On the other hand, the
large energy difference between analogous adducts of 2 with
dichloromethane (2b0 and 2c0 models) implies the dominant
abundance of the 2b0 model with the hydrogen bond (see
Table 3).
MP2 calculations on 2b0, 2c0 and 7e0−7g0 model systems
confirmed the above DFT results on their relative abundance in
dichloromethane solutions (Table 3). On the other hand, the
MP2 method produces overly high AN values, despite the fact
that their differences are very close to the experimental
differences.
As expected, the DFT method used (especially without
inclusion of solvent effects) produces lower AN values in
comparison to experimental data, whereas the MP2 values are
overestimated. Nevertheless, our results indicate that the
asymmetry in experimental EPR spectra of 7 in dichloro-
methane cannot be explained by the existence of its various
conformers in solution but rather by the differences between
>N−O···H−CHCl2 and >N−O···Cl−CH2Cl interactions.
Table 2. Spin Hamiltonian Parameters Elucidated from the
Simulation of Experimental EPR Spectra of Mono-/
Dinitroxide Derivatives 1, 2, and 4−8 Measured in
Dichloromethane at 295 K
hyperfine coupling
constant (mT)
exchange
coupling
constant
nitroxide
ANO
A
g
(cm−1
)
1
1.484
0.544 (13C), 0.554 (13C)
0.520 (13C), 0.543 (13C)
0.574 (13C), 0.535 (13C)
0.045 (6H), 0.033 (6H)
0.039 (2H), 0.001 (2H)
0.043 (6H), 0.032 (6H)
0.035 (2H), 0.004 (2H)
0.052 (6H), 0.037 (6H)
0.017 (2H), 0.003 (2H)
2.0061
2
4
5
6
7
8
1.581
1.571
1.578
2.0062
2.0063
2.0060
1.592
1.460
1.528
1.640
1.623
1.536
2.0064
2.0061
2.0065
2.0063
2.0065
2.0063
∼0.024
∼0.065
∼0.012
spacer in 8 has a noticeable effect on the exchange between two
nitroxide units, as summarized in Table 2.
Next, DFT calculations were performed with the aim of
obtaining detailed information about the origin of the
asymmetry of EPR spectra of 7 in dichloromethane solutions.
In the first step, we have varied the mutual orientations of both
piperidine rings in 7 with chair conformations of both rings
(according to N1−C4 axes) with equatorial N−O bonds. Three
stable conformations of this type (characterized by H4−C4−
C4′−H4′ dihedral angles in Table 3) have been found by the
geometry optimization of 7 in triplet (spin multiplicity MS = 3)
and “broken-symmetry” singlet (MS = 1) spin states in vacuum
as well as in dichloromethane and n-heptane solutions using a
CPCM treatment. As there are only vanishing differences
between both spin states (except different signs for spin
densities), only data for the triplet spin state are presented. As
can be seen from Table 3, N−O spin densities (as well as the
corresponding AN values) do not depend on mutual ring
orientations. This might be a consequence of no spin density at
the central amine nitrogen. Energy data indicate that at room
Figure 5. Experimental (black ) and simulated (red ) X-band EPR spectra of dinitroxides 6−8 obtained at 295 K in dichloromethane: magnetic
field sweep 6 mT; dinitroxide concentration 0.1 mM. Spin Hamiltonian parameters elucidated from simulations are summarized in Table 2.
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Table 3. Model System Notations, Mutual Ring Orientations, Relative Free Energies at 298 K (ΔG298), NO Spin Densities (ρN
and ρO), Corresponding Hyperfine Coupling Constants (AN), and Relative Abundances (Nrel)
H4−C4−C4′−H4′
ΔG298
nitroxide
MS
solvent
model
angle (deg)
(kJ/mol)
ρN
ρO
AN (mT)
1.521
Nrel
B3LYP Method
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
2a0
2a1
2a2
2b0
2c0
7a0
7b0
7c0
0.432
0.524
CH2Cl2
n-C7H16
0.460
0.497
1.583
0.446
0.511
1.539
a
a
b
b
b
b
d
d
d
d
e
a
a
b
b
b
b
d
d
d
d
e
2···H−CHCl2
2···Cl−CClH2
0.00
10.71
0.00
0.465
0.485
1.585
1.000
0.013
1.000
0.098
0.006
0.001
1.000
1.892
0.022
0.004
1.000
0.214
0.007
0.002
1.000
0.257
0.001
0.441
0.509
1.539
7
81.8
25.1
166.8
12.5
81.2
28.5
167.1
10.8
82.8
26.2
166.8
13.6
80.0
83.0
77.5
81.4
0.431
0.524
1.523
7
5.78
0.430
0.524
1.526
7
12.76
17.56
0.00
0.430
0.524
1.526
c
7
7d0
0.430, 0.450
0.460
0.521, 0.524
0.497
1.529, 1.275
1.578
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
n-C7H16
n-C7H16
n-C7H16
n-C7H16
7a1
7b1
7c1
7
−1.58
9.45
0.459
0.460
1.591
7
0.459
0.497
1.587
c
7
7d1
19.43
0.00
0.460, 0.480
0.445
0.492, 0.497
0.511
1.589, 1.368
1.550
7
7a2
7b2
7c2
e
e
7
3.81
0.444
0.510
1.555
e
e
7
12.21
20.69
0.00
0.443
0.512
1.565
c
e
e
7
7d2
0.444, 0.465
0.463
0.507, 0.511
0.488
1.557, 1.330
1.573
f
f
Cl2HC−H···7···H−CHCl2
Cl2HC−H···7···Cl−CH2Cl
ClH2C−Cl···7···Cl−CH2Cl
C3H8···7···H8C3
7e0
7f0
f
f
3.36
0.440, 0.462
0.440
0.510, 0.491
0.511
1.538, 1.564
1.531
f
f
7g0
7h0
16.38
0.439
0.513
1.532
MP2 Method
a
a
f
a
a
f
2···H−CHCl2
2···Cl−CClH2
Cl2HC−H···7···H−CHCl2
Cl2HC−H···7···Cl−CH2Cl
ClH2C−Cl···7···Cl−CH2Cl
2
2
3
3
3
2b0
2c0
7e0
7f0
0.00
12.09
0.00
0.604
0.380
2.295
1.000
0.008
0.606
0.382
2.381
0.602
0.382
2.286
1.000
f
f
0.94
0.605, 0.597
0.382, 0.388
0.393
2.370, 2.232
0.683
f
f
7g0
22.51
0.597
2.342
<0.001
a
b
c
d
e
Related to the 2b0 model. Related to the 7a0 model. Different chair conformations of both rings. Related to the 7a1 model. Related to the 7a2
f
model. Related to the 7e0 model.
X-ray Diffraction Studies. To get a detailed insight into
the molecular and bulk structures of the studied nitroxides in
the solid phase, the X-ray analyses of single crystals of 4−8
were performed (Table 4 and the Supporting Information).
The crystal structures of nitroxides 4−8 are depicted in
Figures 6−10 (for their ORTEP drawings and/or packing
diagrams see Figures S17−S21 in the Supporting Information).
As expected, the piperidine rings in all of these compounds
exhibit a chair conformation, while the pyrrolidine ring in 6 has
an envelope conformation. Due to the presence of a
methanesulfonyl group, molecules of nitroxide 4 (Figure 6)
in the packing are linked in chains through weak interactions
between O4 and H10A with an interatomic distance of 2.326 Å.
Similarly, and due to the presence of a sulfonamide group in the
nitroxide 5, there are two intermolecular hydrogen bonds
(Figure 7) formed by sulfonyl O3 and amino H2A from one
molecule and the same pair of the atoms from the second
molecule at a distance of 2.43 Å (symmetry code −x + 2, −y,
−z + 1). On the other hand, nitroxide 6 features an
intermolecular hydrogen bond (Figure 8) between the
PROXYL nitroxyl O2 and amino H1A at a distance of 2.26
H1 and acetyl O2 at a distance of 1.789 Å. Finally, molecules of
nitroxide 8 in the packing are linked in a chain (Figure 10)
through a weak stabilization interaction between nitroxyl O1
and methanesulfonyl H19A (interatomic distance of 2.573 Å
with symmetry codes x, y, 1 + z and x, y, −1 + z). Moreover,
the crystal structures of all studied nitroxides 4−8 possess two
common characteristic features: (a) oxygen atoms of N−O
radical sites are located close to methyl and/or methylene H
atoms at β positions of adjacent molecules with intermolecular
O···H distances close to the sum of van der Waals radii (2.6
Å)30 (Table S2 in the Supporting Information); (b) N1−O1
distances of the nitroxyl moieties are shortened in comparison
to those in TEMPO31 (Table 5).
Magnetic Measurements. The solid state of nitroxide 4
consists of monoradical species. The effective magnetic
moment refers to a Curie paramagnet: μeff < 2 μB (Figure
11). Low-temperature susceptibility and its inverse indicate a
presence of a maximum (minimum) that is a fingerprint of the
chainlike behavior. The fitting procedure to the model of a
1
regular S = /2 Heisenberg chain gave g = 2.001, isotropic
exchange coupling constant J/hc = −2.15 cm−1, temperature-
independent magnetism χTIM = −2.73 × 10−9 m3 mol−1,
molecular-field correction (zj)/hc = −1.24 cm−1, and
discrepancy factor for the susceptibility R(χ) = 0.0091. It can
be seen that the fit is almost perfect for the magnetic
susceptibility and/or its inverse. However, the magnetization
stays unfitted, since there are neither closed formulas nor a
1
Å (symmetry code −x + 1, y + /2, −z). Due to the poor
crystallinity of nitroxide 7, the molecular structure was
determined by a single-crystal X-ray analysis of its ammonium
salt 7′ in the form of acetate (Figure 9), prepared by slow
evaporation of a DCM/AcOEt solution of 7 at room
temperature. There is a hydrogen bond formed by the amino
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Table 4. Crystallographic Data from Single-Crystal X-ray Analyses of Nitroxides 4−8
4
5
6
7′
C20H39N3O4
8
empirical formula
formula wt
temp, K
C10H20NO4S
250.33
C10H21N2O3S
249.35
C17H33N3O2
C19H37N3O4S
403.58
311.46
385.29
293(2)
1.54184
293(2)
293(2)
293(2)
100(2)
wavelength, Å
cryst syst; space group
a, Å
0.71073
0.71073
0.71073
0.71073
monoclinic; P21/c
12.9484(6)
9.9797(3)
11.1310(4)
113.437(5)
1319.69(9)
monoclinic; P21/c
6.3108(3)
21.6752(8)
11.2066(5)
119.167(3)
1338.6(1)
4; 1.237
monoclinic; P21
7.8821(8)
11.6183(7)
10.8273(8)
111.061(1)
925.3(1)
tetragonal; P4n2
orthorhombic; Fdd2
41.422(1)
̅
11.8431(1)
11.8431(1)
19.1284(4)
b, Å
21.0998(6)
c, Å
10.1443(3)
β, deg
V, Å−3
2682.93(6)
8; 0.954
8866.1(4)
16; 1.209
0.174
Z; calcd density, Mg m−3 4; 1.260
2; 1.118
abs coeff, mm−1
0.245
0.238
0.073
0.531
F(000)
540
540
344
848
3520
cryst size, mm−3
0.420 × 0.477 × 0.853
3.66−29.56
0.686 × 0.903 × 1.104
4.11−26.37
0.257 × 0.303 × 0.481
4.34−26.37
0.663 × 0.127 × 0.115
4.39−76.03
0.95 × 0.70 × 0.46
2.67−28.18
θ range for data
collection, deg
no. of collected/unique
rflns
21523/3391 (R(int) =
0.0193)
19947/2716 (R(int) =
0.0171)
14911/3774 (R(int) =
0.0207)
58185/2804 (R(int) =
0.0438)
44036/5160 [(R(int) =
0.0399)
completeness to 2θ =
25.00, %
99.8
99.6
99.4
100
99.9
abs cor
analytical
refinement method
full-matrix least squares
on F2
no. of data/restraints/
params
GOF on F2
3391/0/146
2716/0/145
1.185
3774/1/202
1.046
2804/1/129
1.095
5160/1/244
1.043
1.030
final R indices (I > 2σ(I)) R1 = 0.0405, wR2 =
R1 = 0.0383, wR2 =
0.1241
R1 = 0.0386, wR2 =
0.1015
R1 = 0.0370, wR2 =
0.1086
R1 = 0.0351, wR2 =
0.0961
0.1059
R indices (all data)
R1 = 0.0508, wR2 =
0.1126
R1 = 0.0412, wR2 =
0.1269
R1 = 0.0427, wR2 =
0.1046
R1 = 0.0397, wR2 =
0.1114
R1 = 0.0357, wR2 =
0.0967
Δρmax and Δρmin, e, Å−3 0.254 and −0.415
0.407 and −0.359
0.152 and −0.134
0.085 and −0.083
0.227 and −0.208
Figure 7. ORTEP drawing of nitroxide 5 and its intermolecular
hydrogen bonds.
1
regular S = /2 Heisenberg chain gave g = 2.041, J/hc = −3.05
cm−1, χTIM = −1.86 × 10−9 m3 mol−1, (zj)/hc = −0.141 cm−1,
and R(χ) = 0.0036.
Figure 6. Weak intermolecular interactions between molecules of
nitroxide 4.
The solid state of nitroxide 6 exhibits features of a biradical
(Figure 12) constituted of [S1, S2] = [1/2, 1/2] spins: the room-
temperature effective magnetic moment is μeff = 2.32 μB, which
matches the value for two uncoupled spins (2.45 for g = 2).
When the temperature is lowered, the susceptibility passes
through a maximum and then decreases. However, at very low
temperature a contamination with uncoupled magnetic centers
is visible. The magnetization data reflect a presence of that
paramagnetic impurity. The fitting procedure for a model of
rigorous approach for an infinite system at our disposal. The
only way is to mimic the chainlike properties by a finite ring
approximation with even and odd members at finite temper-
ature.29 The solid state of nitroxide 5 consists of monoradical
species as well. The effective magnetic moment refers to a
Curie paramagnet: μeff < 2 μB (Figure 11). Low-temperature
susceptibility and its inverse indicate the presence of a
maximum (minimum) that is a fingerprint of the antiferro-
magnetic chain. The magnetization per formula unit does not
saturate at B = 7 T and T = 2.0 K; this again indicates a
chainlike behavior. The fitting procedure to the model of a
̂
̂
ex
⃗
⃗
exchange interaction between two spins with H = −J(S1·S2)
gave the following: exchange coupling constant J/hc = −8.68
cm−1, g = 1.93, mole fraction of the paramagnetic impurity xPI =
F
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Table 5. Comparison of N−O Bond Lengths Obtained from
X-ray Analyses
nitroxide
N−O bond length (Å)
TEMPO
1.294(4)
1.280(2)
1.277(2)
1.277(2)
1.285(2)
1.285(2)
4
5
6
7′
8
Owing to the small value of the exchange coupling constant, a
maximum at the susceptibility curve is not seen until the lowest
temperature reached during the data acquisition.
Finally, the solid state of nitroxide 8 refers to the biradical
[S1, S2] = [1/2, 1/2] (Figure 12). The effective magnetic
moment on cooling behaves like a Curie paramagnet with some
temperature-independent magnetism χTIM (negative, owing to
uncompensated diamagnetism of the specimen). Since no
maximum at the susceptibility curve is visible down to T = 2.0
K, the exchange coupling constant should be small and
negative. The magnetization per formula unit nearly saturates at
B = 7 T and T = 2.0 K to the value of M1 = 2 μB; this supports
the model of a isolated biradical. The fitting procedure gave the
following: J/hc = −1.50 cm−1, g = 2.00, χTIM = −5.81 × 10−9 m3
mol−1, (zj)/hc = −0.069 cm−1, R(χ) = 0.029, R(M) = 0.030.
Only a weak intermolecular interaction of an antiferromagnetic
nature is detected.
Figure 8. ORTEP drawing of nitroxide 6 and its weak bimolecular
interaction.
CONCLUSIONS
■
In conclusion, a comparison set of five mono-/biradical
TEMPO derivatives 4−8 was prepared. All compounds were
fully characterized and their structures determined by single-
crystal X-ray analyses. The spin, magnetic, and redox properties
of novel compounds were studied by means of EPR
spectroscopy, SQUID magnetometry, and cyclic voltammetry.
Regarding CV, all studied nitroxides undergo a reversible one-
electron-transfer process with half-wave potentials in the range
of 401−616 mV. The results indicate an emerging trend that
the electron-withdrawing substituents tend to increase the
oxidation potential of a nitroxide in comparison to electron-
donating groups. While EPR spectra of monoradicals 1, 2, 4,
and 5 in DCM revealed the expected three-line signal, spectra
of biradicals 6−8 showed more complex features. Interestingly,
symmetric biradicals 7 and 8 exhibit five-line spectra analogous
to the that of the nonsymmetric 6. Results of DFT and MP2
Figure 9. ORTEP drawing of nitroxide 7′. Labels are given for
independent atoms only. Acetate anion and voids (for water molecule)
are omitted for clarity.
0.127, χTIM = −0.93 × 10−9 m3 mol−1, (zj)/hc = −0.879 cm−1,
R(χ) = 0.011, R(M) = 0.090. Only a weak intermolecular
interaction of an antiferromagnetic nature is detected.
The solid state of nitroxide 7 represents a biradical system as
well (Figure 12). The final set of magnetic parameters is as
follows: J/hc = −2.23 cm−1, g = 2.00, χTIM = −2.91 × 10−9 m3
mol−1, (zj)/hc = −0.164 cm−1, R(χ) = 0.046, R(M) = 0.097.
Figure 10. Packing diagram of nitroxide 8 and its weak bimolecular interactions.
G
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Figure 11. Magnetic data for nitroxides 4 and 5: (left) temperature dependence of the effective magnetic moment; (center) field dependence of the
magnetization; (right) inverse susceptibility. Circles denote experimental data, and solid lines are fitted with a model of an S = 1/2 regular Heisenberg
chain.32,33
flow 1.5 mL/min). HRMS spectra were recorded on a TOF-Q
instrument and evaluated using Compass DataAnalysis 4.0 software.
Elemental analysis was carried out at the Department of Inorganic
Chemistry, Slovak University of Technology.
calculations indicate that the EPR splitting patterns of 7 in
DCM could be explained by differences between the >N−
O···H−CHCl2 and >N−O···Cl−CH2Cl interactions with
solvent molecules. In the solid state, mononitroxides 4 and 5
behave as a Heisenberg antiferromagnetic chain, whereas
dinitroxides 6−8 are almost isolated paramagnetic diradicals
coupled in an antiferromagnetic manner. Moreover, the crystal
structures of all studied nitroxides 4−8 possess two common
characteristic features: (a) oxygen atoms of N−O radical sites
are located close to methyl and/or methylene H atoms at β
positions of adjacent molecules with intermolecular O···H
distances close to the sum of van der Waals radii (2.6 Å); (b)
N1−O1 distances of the nitroxyl moieties are shortened in
comparison to those in TEMPO.
2,2,6,6-Tetramethyl-4-(methylsulfonyloxy)piperidine N-
Oxide (4). Triethylamine (6.663 g, 4.50 mL, 58.17 mmol) was
added to a cooled (ice bath) solution of 4-hydroxy-TEMPO 2 (5.000
g, 29.08 mmol) in DCM (80 mL) under Ar. After 5 min,
methanesulfonyl chloride (5.885 g, 8.06 mL, 58.17 mmol) was
added dropwise with stirring and the reaction temperature
continuously rised to 20 °C. After 2 h of stirring at room temperature,
the DCM solution was washed with water (2 × 80 mL) and a
saturated aqueous NaHCO3 solution (35 mL), and the separated
organic layer was dried over anhydrous MgSO4. The filtration of solids,
evaporation of volatiles in vacuo, addition of ethyl acetate (5 mL), and
final filtration of the solution through a short pad of silica gel (0.5 × 2
cm, eluting with EtOAc) afforded mesylate 4 (5.857 g, 80%) as a deep
red crystalline solid. Slow evaporation from its DCM or EtOAc
solution afforded deep red crystals of 4 suitable for X-ray analysis
(Figure S17, Supporting Information).
EXPERIMENTAL SECTION
■
General Considerations. Commercially available TEMPO and
nitroxides 1−3 were purchased. All solvents of p.a. purity were dried
over 4 Å molecular sieves. All reagents were purchased and used as
received without further purification. Thin-layer chromatography
(TLC) was performed on aluminum plates precoated with 0.2 mm
silica gel 60 F254. Flash column liquid chromatography (FLC) was
performed on Kieselgel 60 (40−63 μm). Infrared (IR) spectra were
recorded on a FTIR spectrometer as films on a diamond sampler
(ATR). Melting points were determined on a capillary apparatus and
are uncorrected. Liquid chromatography−mass spectrometry (LC-
MS) analyses were performed on an instrument equipped with a
multimode MS detector using the MM ESI/APCI ionization method
(column Zorbax SB C-8 12.5 2.1 mm, particle size 5 μm, eluent water/
MeOH with 0.1% HCO2H, gradient 0−100% of MeOH for 2.5 min,
Data for 4: Rf = 0.32 (EtOAc/toluene 1/3); mp 94−95 °C (lit.34
mp 94 °C); IR (ATR): νmax 3033, 2981, 2941, 1468, 1346, 1339, 1169,
933, 870, 828, 525, 501 cm−1; MS (m/z) 251.3 [M + 1]+. Anal. Calcd
for C10H20NO4S• (250.34): C, 47.98; H, 8.05; N, 5.60; S, 12.81.
Found: C, 47.71; H, 7.93; N, 5.52; S, 12.79.
2,2,6,6-Tetramethyl-4-(methylsulfonylamino)piperidine N-
Oxide (5). In a modification of the previously described procedure,15
compound 5 was prepared via the following two-step protocol. Thus,
4-amino-2,2,6,6-tetramethylpiperidine (500 mg, 556 μL, 3.20 mmol)
was dissolved in DCM (30 mL) and methanesulfonyl chloride (367
mg, 248 μL, 3.20 mmol) was added dropwise with stirring at room
temperature. After 1 h, the precipitated solids were filtered off, washed
H
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Figure 12. Magnetic data for nitroxides 6−8: (left) temperature dependence of the effective magnetic moment; (center) field dependence of the
magnetization; (right) inverse susceptibility. Circles denote experimental data, and solid lines are fitted with a model of isolated biradicals [S1, S2] =
1
[1/2, /2].
with DCM (10 mL), and dried in vacuo to give the mesylated product
as the hydrochloride 9 (859 mg). This salt was dissolved in MeOH/
H2O (10 + 5 mL), and a saturated aqueous NaHCO3 solution (4 mL)
was added. Next, Na2WO4·2H2O (211 mg, 0.64 mmol) and 30%
aqueous H2O2 solution (983 μL, 32 mmol, 10 equiv) were added
sequentially to the resulting solution. The reaction mixture was stirred
at room temperature for 4 h. Then, water (30 mL) and DCM (30 mL)
were added, the mixture was stirred for 5 min, and the separated water
layer was re-extracted with DCM (20 mL). The combined organic
extracts were dried over anhydrous MgSO4, filtered, and evaporated in
vacuo. The obtained crude product was purified by FLC (SiO2,
gradient elution with hexanes/AcOEt from 1/0 to 1/1) to afford the
light orange solid product 5 (676 mg, 85%). Slow crystallization from
its EtOAc/hexanes solution (1/1) afforded red crystals of 5 suitable
for X-ray analysis (Figure 7).
Data for 5: Rf = 0.21 (EtOAc/hexanes 1/1); mp 141−143 °C (lit.15
mp 141−143 °C); IR (ATR) νmax 3275, 2979, 2941, 1436, 1361, 1330,
1318, 1299, 1153, 1067, 985, 767, 523, 485 cm−1; MS (m/z) 250.2 [M
+ 1]+. Anal. Calcd for C10H21N2O3S• (249.35): C, 48.17; H, 8.49; N,
11.23; S, 12.86. Found: C, 48.31; H, 8.47; N, 11.23; S, 12.68.
N-(1-Oxido-2,2,6,6-tetramethylpiperidin-4-yl)-N-(1-oxido-
2,2,5,5-tetramethylpyrolidin-3-yl)amine (6). A solution of 3-
amino-PROXYL (100 mg, 0.64 mmol) and 4-oxo-TEMPO (108 mg,
0.64 mmol) in MeOH (2 mL) was acidified with 3 drops of glacial
AcOH in a pressure tube under Ar. After the mixture was stirred for 20
min, NaBH3CN (80 mg, 1.27 mmol) was added and the reaction
vessel was heated in an oil bath at 80 °C for 24 h. The solution was
cooled to room temperature, and water (2 mL) and DCM (2 mL)
were added. The organic layer was separated, and the water phase was
extracted with DCM (2 × 2 mL). The combined organic layers were
I
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Article
dried over anhydrous MgSO4 and filtered, and the solvent was
evaporated in vacuo. The crude product was purified by FLC (SiO2,
gradient elution with DCM/MeOH from 1/0 to 9/1) to give biradical
6 (91 mg, 46%) as a yellow-orange crystalline solid. Slow
crystallization from an EtOAc/hexanes mixture via the diffusion
method afforded deep orange crystals of 6 suitable for X-ray analysis
(Figure 8).
Electrochemical Measurements. The cyclic voltammetry (CV)
measurements were performed using a PGSTAT-302N potentiostat/
galvanostat equipped with a USB electrochemical interface connected
to a three-electrode single-compartment glass cell and personal
computer for data storage and processing. NOVA 1.8 software was
employed for elaboration and evaluation of all CV voltammograms.
The glass electrochemical cell consisted of Ag/AgCl (3 mol L−1 KCl)
and Pt wire as reference and counter electrodes, respectively. A
paraffin-impregnated graphite electrode (PIGE) with a diameter of 5
mm was used as the working electrode. The PIGE was polished with
aluminum oxide (grain size 0.3 μm) and rinsed with deionized water
to obtain a fresh electrode surface before each experiment. The pH
value of PBS was monitored with a pH meter with a combined glass
electrode, which was regularly calibrated with standard buffer
solutions. All of the half-wave potentials (E1/2) are given against Ag/
AgCl (3 mol L−1 KCl) at an ambient temperature of 25 1 °C. A 20
mL portion of the supporting electrolyte containing an appropriate
amount of the studied compound was added to the glass electro-
chemical cell. Before each measurement, ultrapure N2 (O2 <2 ppm)
was used to degas the solutions (10 min) and to provide an inert
atmosphere inside the electrochemical cell. CV voltammograms were
recorded in a potential range from −1.5 to +1 V and from 0 to +1 V,
respectively. The optimized instrumental CV parameters were as
follows: scan rate of 100 mV s−1, step potential of 5 mV, and interval
time of 0.05 s. At the beginning, the current response for a blank (PBS
at pH 7 without any compound) was measured to check the
electrochemical background of the system. CV voltammograms of
each studied species were carried out 5-fold (n = 5), and the average
scan was considered for the evaluation of E1/2 and construction of the
CV figures.
Data for 6: Rf = 0.59 (EtOAc); mp 161−163 °C; IR (ATR) νmax
3294, 2974, 2938, 2868, 1462, 1359, 1174, 1129, 801, 769, 530 cm−1;
MS (m/z) 312.3 [M+1]+. Anal. Calcd for C17H33N3O2•• (311.46): C,
65.56; H, 10.68; N, 13.49. Found: C, 65.73; H, 10.55; N, 13.47.
N,N-Bis(1-oxido-2,2,6,6-tetramethylpiperidin-4-yl)amine (7).
4-Oxo-TEMPO 1 (496 mg, 2.92 mmol) was added to a solution of 4-
amino-TEMPO (500 mg, 2.92 mmol) in anhydrous MeOH (12 mL)
under Ar. After the mixture was stirred for 5 min, acetic acid (5 drops)
was added and the resulting solution was stirred for 20 min. Next,
sodium borohydride (366 mg, 5.84 mmol) was added at once and the
mixture was refluxed for 50 h. The reaction mixture was then diluted
with DCM (20 mL), and saturated aqueous NaHCO3 solution (10
mL) with water (10 mL) was added. The separated water layer was
extracted with DCM (20 mL). The combined organic phases were
dried over anhydrous MgSO4, the solids were filtered off, the volatiles
were evaporated in vacuo, and the residue was purified by FLC (SiO2,
gradient elution with hexanes/EtOAc from 4/1 to 1/0) to furnish 7
(608 mg, 64%) as a red-orange solid. Slow evaporation from a DCM/
EtOAc solution (1/2) afforded bright red crystals of the ammonium
salt 7′ suitable for X-ray analysis (Figure 9).
Data for 7: Rf = 0.58 (CHCl3/EtOAc/MeOH 7/3/1); mp 154−156
°C (lit.17 mp 156−158 °C); IR (ATR) νmax 3435, 3298, 2972, 2932,
2866, 1666, 1457, 1375, 1358, 1242, 1180, 1116, 700, 567, 558, 497
Electron Paramagnetic Resonance. The stock solutions of all
nitroxides were prepared in dichloromethane (maximum 0.004%
H2O). EPR spectra were measured with freshly diluted solutions (c ≈
0.1 mM) carefully saturated with Ar and immediately transferred to a
small quartz flat cell optimized for the TE102 cavity. The X-band
spectra were recorded using an EPR spectrometer at a temperature of
295 K. The experimental g values were determined using a built-in
magnetometer. Typical EPR spectrometer settings were as follows:
microwave frequency 9.428 GHz; microwave power 10.53 mW; center
field 335.8 mT; sweep width 6−10 mT; gain 5 × 103; modulation
amplitude 0.02 mT; scan 82 s; time constant 10.24 ms; number of
scans 5. The experimental EPR spectra were analyzed and simulated
using the WinEPR and SimFonia, Winsim2002 software.36 The
simulated spectra of dinitroxides were calculated with the EasySpin
software package25 using the fitting function pepper suitable for the
••
cm−1; MS (m/z) 326.3 [M + 1]+; HRMS mass calcd for C18H35N3O2
[M + H]+ 326.2808, found 326.2565, [M + Na]+ calcd 348.2627,
found 348.2621. Anal. Calcd for C18H35N3O2•• (325.49): C, 66.42; H,
10.84; N, 12.91. Found: C, 66.74; H, 10.71; N, 12.87.
Methanesulfonyl-N,N-bis(1-oxido-2,2,6,6-tetramethylpiperi-
din-4-yl)amide (8). Diisopropylethylamine (401 mg, 541 mL, 3.07
mmol) was added to a solution of 7 (100 mg, 0.31 mmol) in
anhydrous DCM (4 mL) at 0 °C (ice bath) under Ar in a sealable
tube. After the mixture was stirred for 5 min, methanesulfonic acid
anhydride (268 mg, 1.54 mmol) was added portionwise at 0 °C over a
period of 5 min and the reaction temperature continuously rose to 20
°C for 2 h. After the solution was stirred for an additional 16 h at 60
°C, the reaction was stopped by addition of water (2 mL). DCM (10
mL) was added, and the organic layer was washed with water (2 × 10
mL) and saturated aqueous NaHCO3 solution (5 mL) and dried over
anhydrous MgSO4. The solids were filtered off, the volatiles were
evaporated in vacuo, and the residue was purified by FLC (SiO2,
gradient elution with hexanes/EtOAc from 10/1 to 1/1) to furnish
mesylate 8 (44 mg, 35%) as an orange solid. Slow crystallization from
a hexanes/EtOAc mixture via the diffusion method afforded red
crystals of 8 suitable for X-ray analysis (Figure S21, Supporting
Information).
Data for 8: Rf = 0.64 (EtOAc/Hex 1/1); mp 192−195 °C; IR
(ATR) νmax 2978, 2937, 1734, 1471, 1322, 1199, 1152, 1019, 955, 802,
743, 517 cm−1; MS (m/z) 404.3 [M + 1]+; HRMS mass calcd for
C19H37N3O4S•• [M + Na]+ 426.2397, found 426.2693, [2M + Na]+
calcd 829.4998, found 829.4446. Anal. Calcd for C19H37N3O4S••
(403.58): C, 56.54; H, 9.24; N, 10.41; S, 7.95. Found: C, 56.63; H,
9.14; N, 10.38; S, 7.82.
Cyclic Voltammetry. Chemicals. Stock solutions of compounds
1−8 (c = 1 × 10−3 mol L−1) in H2O/MeOH (9/1 v/v) were used for
the preparation of working solutions (1 × 10−4 mol L−1) for
electrochemical measurements by dilution with aqueous phosphate
buffer (PBS) at pH 7 as supporting electrolyte. The latter was
prepared from a mixture of monosodium phosphate (NaH2PO4) and
disodium phosphate (Na2HPO4) according to the literature.35 All
chemicals (analytical-reagent grade) were used without further
purification. The aqueous solutions were made with double-distilled
deionized water with resistivity above 18 MΩ cm.
1
exchange coupling constant calculations in systems with S > /2. The
spin Hamiltonian parameters were optimized by nonlinear least-
squares methods to obtain the best agreement between experimental
and calculated spectra.
Quantum-Chemical Calculations. The geometries of the neutral
systems under study were optimized without any symmetry
restrictions at the DFT level of theory (B3LYP hybrid functional)37
and some of them also at the MP238 (with all electrons included in a
correlation calculation) level of theory using standard cc-pVDZ basis
sets39 from the GAUSSIAN03 library.40 The stability of the obtained
structures has been tested by vibrational analysis (no imaginary
vibrations). The solvent effects of dichloromethane and n-heptane
were estimated by single solvent molecules in the vicinity of NO•
groups (using propane molecules instead of the n-heptane) and
alternatively by using the polarizable conductor calculation model
(CPCM).41 The values of isotropic hyperfine coupling constants were
evaluated in terms of Fermi contact interactions.42,43 Their values for
the systems containing two unpaired electrons have been doubled.44
All calculations have been performed using the GAUSSIAN03
program package.40 Relative abundances of individual model systems
were evaluated using Boltzmann distributions and their free energy
data at room temperature.
X-ray Analyses. X-ray diffraction data were collected on a
diffractometer equipped with a ruby CCD detector and Mo Kα and
Cu Kα sealed-tube sources at room temperature. Data reduction was
J
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The Journal of Organic Chemistry
Article
performed with CrysAlis RED (version 1.171.36.20) software.45
Crystal structures were solved and refined with SHELXS97.46 The
DIAMOND program was used for the molecular graphics.47
Magnetic Measurements. The experimental data were taken
with a SQUID magnetometer using the RSO mode of detection with
ca. 20 mg of the sample encapsulated in a gelatin sample holder. The
magnetic susceptibility taken at B = 0.5 T has been corrected for the
underlying diamagnetism and converted to the effective magnetic
moment. The magnetization has been measured at two temperatures:
T = 2.0 and T = 4.6 K.
(10) Montanari, F.; Quici, S.; Henry-Riyad, H.; Tidwell, T. T. 2,2,6,6-
Tetramethylpiperidin-1-oxyl. In Encyclopedia of Reagents for Organic
Synthesis; Wiley: New York, 2005.
(11) Han, Ch. H.; Drache, M.; Baethge, H.; Schmidt-Naake, G.
Macromol. Chem. Phys. 1999, 200, 1779.
(12) Wilcox, C. S.; Pearlman, A. Pharmacol. Rev. 2008, 60, 418.
(13) Ji, J.; Kline, A. E.; Amoscato, A.; Samhan-Arias, A. K.; Sparvero,
L. J.; Tyurin, V. A.; Tyurina, Y. Y.; Fink, B.; Manole, M. D.; Puccio, A.
M.; Okonkwo, D. O.; Cheng, J. P.; Alexander, H.; Clark, R. S. B.;
Kochanek, P. M.; Wipf, P.; Kagan, V. E.; Bayır, H. Nat. Neurosci. 2012,
15, 1407.
(14) Merbouh, N.; Bobbitt, J. M.; Bruckner, Ch. Org. Prep. Proced.
Int. 2004, 36, 1.
̈
ASSOCIATED CONTENT
■
S
* Supporting Information
(15) Krishna, M. C.; DeGraff, W.; Hankovszky, O. H.; Sar
Kalai, T.; Jeko, J.; Russo, A.; Mitchell, J. B.; Hideg, K. J. Med. Chem.
1998, 41, 3477.
́
, C. P.;
Figures, tables, and CIF files giving HRMS spectra of
dinitroxides 7 and 8, CV spectra of all studied nitroxides,
EPR spectra of mononitroxides 1, 2, 4, and 5, and ORTEP
drawings and/or packing diagrams of nitroxides 4−8 and their
selected crystallographic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
́
̋
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail for P.S.: peter.szolcsanyi@stuba.sk.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the Science and Technology
Assistance Agency under Contract Nos. APVV-0202-10, APVV-
0014-11, and APVV-0797-11 and by the Scientific Grant
Agency of the Slovak Republic VEGA (Project Nos. 1/0679/
11, 1/0289/12, 1/0327/12, and 1/0051/13). We thank the
HPC center at the Slovak University of Technology in
Bratislava, which is a part of the Slovak Infrastructure of
High Performance Computing (SIVVP Project No.
26230120002, funded by the European Region Development
Funds), for computing facilities.
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DEDICATION
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Dedicated to the memory of Peter Tisovsky.
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