Novel piperidine nitroxide derivatives: Synthesis, electrochemical and antioxidative evaluation

Article abstract of DOI:10.1002/jhet.5570450212

(Chemical Equation Presented) Novel paramagnetic materials (3a, 3b, 4a and 4b) based on heterocyclic dyes (2a and 2b) and one stable nitroxide radical (4-NH₂-TEMPO) were synthesized. EI-MS, elemental analysis and FT-IR spectral data confirmed t

Full text of DOI:10.1002/jhet.5570450212

Mar-Apr 2008
371
Novel Piperidine Nitroxide Derivatives:
Synthesis, Electrochemical and Antioxidative Evaluation
Hongli Zhao1, Juhua Wu1, Xianjiang Meng1, Shaohua Zuo1, Wentian Wang1,
Huihui Yuan2, Minbo Lan1,2*
1. Research Center of Analysis and Test, East China University of Science and Technology,
Shanghai 200237, P.R. China. 2. Key Laboratory for Ultrafine Materials of Ministry of Education,
East China University of Science and Technology, Shanghai 200237, P.R. China.
Received April 12, 2007
OHC
CHO
X
N
X
N
CHO
HAc, Ac2O
1a, X=S
1b, X=O
2a, X=S
2b, X=O
H2N
N O
X
N
N
N
O
O
N
3a, X=S
3b, X=O
NaBH4
X
N
N
H
4a, X=S
4b, X=O
Novel paramagnetic materials (3a, 3b, 4a and 4b) based on heterocyclic dyes (2a and 2b) and one stable
nitroxide radical (4-NH2-TEMPO) were synthesized. EI-MS, elemental analysis and FT-IR spectral data
confirmed the structures of the newly synthesized compounds. In addition, the cyclic voltammetry, the
antioxidant activity and reactive oxygen species (ROS) scavenging properties of these compounds are
discussed in this paper.
J. Heterocyclic Chem., 45, 371 (2008).
INTRODUCTION
improved properties. To develop more potent compounds
with enhanced free radical scavenger properties, we
designed and synthesized a series of nitroxides combined
with heterocyclic dyes and piperidine nitroxide free
radical. Polymethine dyes, which represent a special class
of charged π-electron organic compounds [15], could
improve properties such as antioxidant activity of new
nitroxides prepared. We wish to report in this paper our
research about synthesis and characterization of novel
nitroxides. The newly synthesized compounds exhibit
improved antioxidant activity, ROS scavenger's activity
and possess interesting electrochemical properties.
Furthermore, the relationship between the antioxidant
activity and electrochemical properties of the studied
compounds is also discussed.
The stable nitroxide radicals, such as 2,2,6,6-tetra-
methyl-1-piperidinyloxy (TEMPO) and its derivatives, are
widely used in various biological and pathological areas
as spin labels [1], electron paramagnetic resonance
imaging (EPRI) [2], antioxidants and anticancer drugs
[3,4,5], or synthetic studies [6,7]. Some of the chemical
properties of nitroxides favor the design of new nitroxide
compounds using in different biological and chemical
systems. Nitroxide free radicals continue to be interesting
compounds because they often exhibit a chemical
inertness quite uncharacteristic of most other free radicals
[8,9]. Now piperidine nitroxides and their derivatives are
intensively investigated because of their versatile
properties such as antioxidant and radioprotective [10,11].
They are less toxic stable free radicals and can be used in
noninvasive methods to exert superoxide dimutase (SOD)
mimic activity and scavenge reactive oxygen species
(ROS) [12,13,14] as cycle antioxidants.
RESULTS AND DISCUSSION
The studied compounds were synthesized according to
Scheme 1. Original heterocyclic dyes 2-(p-formylstyryl)-
benzothiazole (2a) and 2-(p-formylstyryl)benzoxazole (2b)
were synthesized by 2-methylbenzothiazole (1a) and 2-
methylbenzoxazole (1b) reacted with p-phthaldialde-hyde in
It is possible that organic molecular design and
synthesis will yield other superior nitroxides with

372
H. Zhao, J. Wu, X. Meng, S. Zuo, W. Wang, H. Yuan, M. Lan
Vol 45
acetic anhydride and acetic acid solutions in about 80%
yield, according to the process described by Huang, Z.L. et
al [16]. The Schiff-base derivatives N-[2-(p-vinylbenzyl-
idene)benzothiazole] 4-amino-2,2,6,6-tetra-methyl-1-piperi-
dinyloxy (3a) and N-[2-(p-vinylbenzyl-idene)benzoxazole]
4-amino-2,2,6,6-tetramethyl-1-piper-idinyloxy (3b), in turn,
were obtained by the reaction of 2a and 2b with 4-NH2-
TEMPO in alcohol solution containing a catalytic amount of
acetic acid in 80-85% yield. The N-methylamine derivatives
N-[2-(p-vinyl-benzyl)benzoxazole] 4-amino-2,2,6,6-tetra-
methyl-1-pi-peridinyloxy (4a) and N-[2-(p-vinylbenzyl)
benzoxazole] 4-amino-2,2,6,6-tetramethyl-1-piperidinyloxy
(4b) of 3a and 3b were prepared by reducing compounds 3a
and 3b with NaBH4 in alcohol solution, and the purification
were performed by silica-gel column chromatography using
the solvent system of petroleum ether/ethyl acetate/acetone
as eluent to afford 4a and 4b (35-45%) as orange crystals.
Figure 1 and 2 show typical cyclic voltammograms of all
studied compounds. Both polymethine dyes molecules 2a
and 2b indicate a little charge-transfer character, no redox
reaction (in Figure 2 a and b). Because they could be
classified as neutral streptopolymethines similar to mero-
cyanine dyes, no electrons transfer. Generally, piperidine
nitroxides show reversible redox behavior such as 4-OH-
TEMPO (Figuer 1 b), whose peak separation of cyclic
voltammogram is 68 mV (Table 1) closed to the theoretical
value (59.5 mV) based on a reversible redox reaction. When
conjugated to 4-NH2-TEMPO, the obtained compounds 3a
and 3b display typical reversible redox behavior similar to
that of the 4-OH-TEMPO. In Figure 1 a, 4-NH2-TEMPO
shows a little difference in redox signal with 4-OH-TEMPO
because of the effect of the –NH2 group. But, in the
structures of the compounds 3a and 3b, new double bonds
C=N were formed by the -NH2 group of the 4-NH2-TEMPO
reacting with the -CHO of the polymethine matrix. And the
C=N conjugates with phenyl ring, thus forming one whole
conjugated system with the polymethine molecules. This
also is the reason that the compounds 3a and 3b as Schiff
bases could exist stably. The nitrogen atom of the C=N does
not become an oxidizable center in the conjugated system
within the range of the CV experimental scan because it is
not easily oxidized, hence no electrons are transfer in this
moiety of the molecule. The compounds 3a and 3b exhibit
the typical reversible redox signals of the nitroxyl radical
and the peak separations are 64 mV and 71 mV,
respectively. The reaction followed as [17]:
Scheme 1
OHC
CHO
HAc, Ac2O
X
N
X
N
CHO
1a, X=S
1b, X=O
2a, X=S
2b, X=O
H2N
N O
X
N
N
N
N
O
O
3a, X=S
3b, X=O
Nitroxide free radical is oxidized into oxoammonium
cation at the anode by losing an electron:
NaBH4
X
N
N
H
-e
N
O
N
O
4a, X=S
4b, X=O
Oxoammonium cation is reduced into nitroxide free
radical at the cathode by obtaining an electron:
Cyclic voltammetry (CV). All the electrochemical
measurements were carried out in dry acetonitrile (AN)
solution containing 0.1 M sodium perchlorate (NaClO4.H2O)
as supporting electrolyte at a scan rate of 50mV/s with a
CHI440A Electrochemical Analyzer controlled by a personal
computer. The conventional three-electrode setup was used
with a platinum electrode as the working electrode, a
platinum wire as the counter electrode, and a saturated
calomel electrode (SCE) as the reference electrode.
+e
N
O
N O
When the C=N bonds in 3a and 3b structures were
reduced, it is interesting that the CV curves of the
compounds 4a and 4b exhibit two-electron transfers
(Figure 2). The measurement results indicate that there are
Table 1
Electrochemical parameters of the compounds.
4-OH-TEMPO
4-NH2-TEMPO
3a
4a
3b
4b
0.717
Epa/V
Epc/V
0.579
0.511
0.545
68
0.693
0.611
0.652
82
0.582
0.518
0.550
64
0.582
0.538
0.560
44
0.721
0.648
0.685
73
0.579
0.508
0.544
71
0.572
0.517
0.544
55
0.638
0.678
69
(Epa+Epc)/2,E1/2/V
Epa-Epc (mV)
Note: : Epa: anodic peak potential; Epc: cathodic peak potentials; (Epa+Epc)/2 (E1/2): the half of the sum of anodic and cathodic peak potentials;
Epa-Epc: the peak separation of cyclic voltammogram.

Mar-Apr 2008 Novel Piperidine Nitroxide Derivatives: Synthesis, Electrochemical and Antioxidative Evaluation
373
two redox reaction processes within the molecular
structures of compounds 4a and 4b. Because the cyclic
voltammograms of the heterocyclic matrix 2a and 2b
show no redox signals, and the CV curves of the
compounds 3a and 3b only give the redox signals of the
long time. To evaluate the total antioxidant activity
(TAA) of the materials, one of the most commonly used
methods is the 2,2'-azinobis(3-ethylbenzothiazoline-6-
sulfonic acid) radical cation (ABTS.+) assay. Here, we
used this method to evaluate the TAA of all our studied
a
b
Figure 1. Cyclic voltammograms of 4-NH2-TEMPO and 4-OH-TEMPO.
a
b
Figure 2. Cyclic voltammograms of the studied compounds.
nitroxyl radical (Figure 2), which suggested that none of
those two-electron transfers of the novel compounds 4a and
4b could take place on the heterocyclic units. And the C-N
bonds reduced from the C=N bonds in the molecular
structures of the Schiff bases 3a and 3b show charge-
transfer character. The new single bond C-N could be one
new oxidizable nitrogen center breaking away from the
original neutral conjugated systems, and form the two
oxidizable nitrogen centers of the compounds 4a and 4b
together with the nitroxyl radical. Novel compounds 4a and
4b exhibit two distinct oxidation stages, respectively,
corresponding to the two oxidizable centers (Figure 2 and
Table 1).
compounds. The ABTS+ radical has absorption maxima in
the near-infrared region at 645, 734 and 815 nm. The
antioxidant suppresses the A734 to an extent and on a
time scale dependent on the antioxidant activity, and tests
were carried out at 6 minutes after initial mixing because
the system had been stable at that time [18].
The 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)
(ABTS) radical was generated through reacting ABTS
with potassium persulfate in our assay according to the
method described by Roberta Re et al [18]. A 1 mL
ABTS+ solution was added to 1 mL of standard or sample
(diluted as required). The decolourisation caused by
reduction of the cation through antioxidants from the
sample was measured at 734 nm, with a UV–Vis
recording spectrophotometer, at 6 minutes after initial
The total antioxidant activity (TAA). Nitroxides have
been recognized as a class of antioxidant compounds for a

374
H. Zhao, J. Wu, X. Meng, S. Zuo, W. Wang, H. Yuan, M. Lan
Vol 45
Figure 3 The antioxidant activity of the compounds
nicotinamide adenine dinucleotide (reduced form, NADH)
(PMS-NADH) system and assayed by the reduction of NBT
according to the method described by the F. Liu, V.E.C. Ooi
and S.T. Chang [19]. And the color reaction of superoxide
radicals and NBT was detected at 560 nm with a UV–Vis
spectrophotometer. The blank sample with no PMS had no
absorbance at 560 nm. The scavenging activities for
hydroxyl radical •OH of the compounds were measured by
salicylic acid method according to the literatures [20,21]. The
hydroxyl radicals were generated in the reaction of H2O2-
FeSO4 and colored substance produced by reacting •OH with
salicylic acid had absorption at 510nm, which measured by a
UV–Vis spectrophotometer. Assays were performed with
five different concentrations per sample, and each
concentration test had 3 replicates, with a UV–Vis
recording spectrophotometer (UNICO UV-2102PC
spectrophotometer). A linear relationship between samples'
concentration and inhibition was established.
mixing. Assays were performed with five or six different
concentrations per sample, and each concentration test
had 3 replicates. Figure 3 shows the TAA of the studied
compounds. The results indicate that the polymethine
matrix have a little antioxidative activity and piperdine
nitroxides play a main role in the antioxidant action, while
the polymethine moieties in the para-position of the
nitroxyl group could influence the antioxidative effect of
the compounds. All compounds with the nitroxyl radical
exhibit high TAA.
Scavenging ROS properties of the compounds.
Synthetic nitroxide antioxidants could attenuate oxidative
damage and nitroxides are a class of more stable agents than
other traditional antioxidants [12]. As shown in Scheme 1,
because the structural modification occurs only in the
heterocycle-based part, where the S atom has been replaced
by an O atom, such a modification only leads to negligible
changes in the π-conjugated length and the characterization
of the compounds. According to the measurements, the
properties of the compounds a and b series in the cyclic
voltammetry and the total antioxidant activity are similar.
We selected the compounds a series to study the scavenging
ROS properties. The scavenging activities for superoxide
O
According to the assays, a linear relationship between
samples' concentration and inhibition could be established
with high correlation coefficients, R2>0.97. Further
according to the linear relationship, 50% inhibition
concentration (IC50) values of the scavenging ROS
activity of the compounds were obtained. Table 2 shows
the IC50 values of the studied compounds. Polymethine
matrix 2a shows very weak hydroxyl radicals scavenging
radicals
of the compounds were assayed by the reduction
2
of nitroblue tetrazolium (NBT). The superoxide radical was
generated in the N-methylphenazonium (PMS) and
Table 2
The ROS scavenging activity of the compounds (n=5)
superoxide
radical
scavenging
activity
Compound
hydroxyl radical scavenging activity IC50(mg/ml)
IC50(mg/ml)
OH-TEMPO
0.766
2.34
NH2-TEMPO
1.36
2.24
2a
3a
4a
Precipitate
Precipitate
0.271
No hydroxyl radical scavenging activity
2.44
2.57
Note: 50% inhibition concentration (IC50) values were calculated by linear relationship, R2>0.97; “Precipitate” means the assay systems were

Mar-Apr 2008 Novel Piperidine Nitroxide Derivatives: Synthesis, Electrochemical and Antioxidative Evaluation
375
O2
reaction process and the novel compounds exhibit
improved antioxidant activity and the superoxide radical
scavenging activity. Furthermore, according to the
measurements, the superoxide radical scavenging activity
of the nitroxides is related with redox property of the
compounds, and the nitroxides can be used as preferable
cycle antioxidants.
activity. And the
scavenging assay systems of the
polymethine moiety 2a and the novel compounds 3a were
unable to be measured with the UV–Vis spectrophoto-
meter because of precipitate formed. The compound 4a
exhibits high superoxide radical scavenging activity at
low concentration.
The piperidine nitroxide derivatives have an unpaired
electron on the piperidine ring, resulting in paramagnetic
properties, the antioxidant activity and scavenging ROS
properties. The different structural parameters such as
ring size and ring substituents would influence the
characterization of the compounds [12, 22]. The antioxi-
dative effects and scavenging ROS properties of the stable
nitroxides are similar to those of the SOD with a one-
electron exchange among their reduced and oxidized
states. They can be reduced to hydroxylamines or
oxidized to oxoammonium cations (Scheme 2) [23]:
EXPERIMENTAL
Melting points were determined by an X-5 micro-melting
point apparatus and uncorrected. EI-Mass spectra were obtained
on a Micromass GCT TOF GC/MS Spectrometer. Elemental
analyses were realized with an elementar vario EL III analyser.
IR spectra were measured on Nicolet AVATAR360 FT-IR
Spectrophotometer. The UV-Visible spectra were recorded on a
UNICO UV-2102PC spectrophotometer. EPR measurements
were performed at X-band, 9.85 GHz, using a Bruker EMX EPR
spectrometer and the measurement of g-factors of the
compounds was carried out in contrast to a standard g-marker
valued 1.9800 provided by Bruker Company. And the traditional
1H NMR spectra can do very limited help in detecting the final
compounds because the spectra of the nitroxide-containing
molecules are broad.
Scheme 2
R
N O
R
N
O
R
N O
e
e
Materials. 4-Amino-2,2,6,6-tetramethyl-1-piperidinyloxy (4-
NH2-TEMPO, 97%) radical used as building blocks in this study
and 4-hydroxyl-2,2,6,6-tetramethyl-1-piperidinyloxy (4-OH-
TEMPO, 99.9%) radical are commercially available and were
bought from Sigma Comp. 2,2'-azinobis(3-ethylbenzothiazoline-
6-sulfonic acid) (ABTS) nitroblue tetrazolium (NBT), N-methyl-
phenazonium (PMS) and nicotinamide adenine dinucleo-tide
(reduced form, NADH) were bought from Sinopharm Chemical
Reagent Co.Ltd. and all the reagents used in the experiments
were of AR.
Hydroxylamine
Nitroxide radical
Oxoammonium cation
Therefore, in theory, the nitroxides with superior
reversible redox reaction could be improved antioxidant
activity, which are validated by the experimental results
of the cyclic voltammetry measurements. 4-OH-TEMPO
shows reversible redox behavior, while because of the
affect of amino group, the redox signal of 4-NH2-TEMPO
varied slightly. According to the CV measurements, half
of the sum of anodic and cathodic peak potentials
[(Epa+Epc)/2, E1/2] is 0.545V and 0.652V (Table 1),
respectively. Lower values of E1/2 should correspond to
higher antioxidant activity because the compounds could
be oxidized comparatively easier. The assays of the
antioxidant activity and the superoxide radical scavenging
activity indicate that the 4-OH-TEMPO is superior to the
4-NH2-TEMPO. For the novel compound 4a, the CV
measurements show there are two redox reaction
processes in their molecular structures, and its superoxide
radical scavenging activity precede other studied
compounds clearly. The results confirm that the process
of the compounds scavenging superoxide radicals is a
cycle redox reaction. While the mechanism of the
scavenging hydroxyl radicals is different, and the results
of the assays show there is no obvious difference among
the studied compounds. The nitroxyl radical play a major
role in the scavenging hydroxyl radicals.
Synthesis of N-[2-(p-vinylbenzylidene)benzothiazole] 4-
amino-2,2,6,6-tetramethyl-1-piperidinyloxy (3a) and N-[2-(p-
vinylbenzylidene)benzoxazole] 4-amino-2,2,6,6-tetramethyl-
1-piperidinyloxy (3b). An ethyl acetate solution (40 ml) of the
intermediate 2a (0.53 g, 0.002 mol) and 4-amino-TEMPO (0.34
g, 0.002 mol) with a small amount of acetic acid was heated to
reflux and the reaction was continued for 2 h. The reaction
mixture was concentrated in vacuo to give a crude solid that was
recrystallized from the solvent of ethyl acetate and n-hexane to
give the corresponding product as orange powdery solid (0.72 g,
86%): mp 182-184°C.
Using the alcohol solution, under similar conditions also
gave the 3b as orange powdery in 81% yield: mp 163-164°C
KBr
3a.EI-MS m/z: [M+]=418. IR: γmax (cm-1) 1640 (C=N), 1601
(C=C), 1375 (N-O). UV-Vis. λmax (nm) (in CH3OH): 231, 354.
Anal. Calcd. for C25H28N3O.S: C, 71.74; H, 6.74; N, 10.04.
Found: C, 71.70; H, 6.95; N, 9.83. EPR: α N in CH2Cl2:15.64G;
g value=2.0075
KBr
3b EI-MS m/z: [M+]=402.2. IR: γmax
(cm-1) 1640 (C=N),
1602 (C=C), 1375 (N-O). UV-Vis. λmax (nm) (in CH3OH): 233,
340. Anal. Calcd. for C25H28N3O2 : C, 74.60; H, 7.01; N, 10.44.
.
Conclusion. The scavenging effects of the compounds
on superoxide were measured and the result is consistent
with that of the ABTS assay. The results confirm that the
superoxide radical scavenging of the nitroxides is a redox
Found: C, 74.35; H, 7.12; N, 10.28. EPR: αN in CH2Cl2:15.64G;
g value=2.0071
Synthesis of N-[2-(p-vinylbenzyl)benzoxazole]4-amino-2,2,
6,6-tetramethyl-1-piperidinyloxy (4a) and N-[2-(p-vinyl-

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H. Zhao, J. Wu, X. Meng, S. Zuo, W. Wang, H. Yuan, M. Lan
Vol 45
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Under similar conditions also gave the 4b as orange crystals
in 34% yield: mp 119-120°C
4a EI-MS m/z: [M+]=420.2. IR: γmax KBr (cm-1) 3318 (N-H),
1621(C=N), 1605 (C=C), 1375 (N-O). UV-Vis. λmax (nm) (in
CH3OH): 232, 340. Anal. Calcd. for C25H30N3O.S: C,71.39; H,
7.19; N, 9.99. Found: C, 71.39; H, 7.37; N, 9.95. EPR: αN in
CH2Cl2: 15.64G; g value=2.0074
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H),1642(C=N), 1605 (C=C), 1375 (N-O). UV-Vis. λmax (nm) (in
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7.47; N, 10.39. Found: C, 74.21; H, 7.65; N, 10.13. EPR: αN in
CH2Cl2: 15.64G; g value=2.0072
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Acknowledgement. This work was supported by the EU
Framework Programme
6 Integrated Project Novel and
Improved Nanomaterials, Chemistries and Apparatus for Nano-
biotechnology (NACBO) (contract No.500804), National
Natural Science Foundation of China (contract No.20446001),
Shanghai Nano-Technology Promotion Center (SNPC)
0652nm020, the Ministry of Science and Technology of the
People's Republic of China (contract No.0424).
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