Preparation and electrochemical behavior of N-substituted phenothiazine oxide

Article abstract of DOI:10.3987/COM-16-13437

The chemical properties of promazine oxide (Prom-O) and promazine (Prom) were compared. Cyclic voltammetry (CV) experiments showed a higher oxidation potential of Prom-O compared to that of Prom. The results of CV measurements also suggested the potential applicability of Prom-O as an n-type semiconductor.

Full text of DOI:10.3987/COM-16-13437

HETEROCYCLES, Vol. 92, No. 8, 2016
1441
HETEROCYCLES, Vol. 92, No. 8, 2016, pp. 1441 - 1449. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 17th May, 2016, Accepted, 31st May, 2016, Published online, 13th June, 2016
DOI: 10.3987/COM-16-13437
PREPARATION
AND
ELECTROCHEMICAL
BEHAVIOR
OF
N-SUBSTITUTED PHENOTHIAZINE OXIDE
Hideki Hayashi1,* and Take-aki Koizumi2,#
1Nagoya Municipal Industrial Research Institute, 3-4-41, Rokuban, Atsuta-ku,
Nagoya 456-0058, 2Chemical Resources Laboratory, Tokyo Institute of
Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503
#Present address: Laboratory for Chemistry and Life Science, Institute of
Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku,
Yokohama 226-8503 (owing to organization reorganization of Tokyo Institute of
Technology)
Abstract – The chemical properties of promazine oxide (Prom-O) and promazine
(Prom) were compared. Cyclic voltammetry (CV) experiments showed a higher
oxidation potential of Prom-O compared to that of Prom. The results of CV
measurements also suggested the potential applicability of Prom-O as an n-type
semiconductor.
Polymers containing diphenylamine with a bridging structure, such as O,1,2 S,3-5 SO,4,5, SO2,5 -CH=CH-,2
-SiR2-,6-15 and -SiR2SiR2-,16 often show interesting optical and electrochemical properties, and thus have
been widely researched. We previously reported the preparation, properties, and applications of Si17,18
and ethylene19,20 unit-bridged diphenylamine-containing polymers (Scheme 1).
X
X
R'
X
N
R
N
R
N
R
n
n
copolymer
homopolymer
X : bridging unit
Scheme 1. Previously reported polymers having a bridged diphenylamine derivative as a monomer unit

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HETEROCYCLES, Vol. 92, No. 8, 2016
We also reported the preparation of poly(dibenzazepine)s ((PAzep)s) by oxidative polymerization of the
corresponding dibenzazepines ((Azep)s) and their use as a fluorescent additive for resins (Scheme 2).
However, our efforts to synthesize poly(phenothiazine)s using the same method failed to give the desired
polymer. In the case of phenothiazine, we hypothesized that the oxidation of phenothiazine occurred
prior to the oxidative polymerization. Therefore, we attempted to analyze the oxidation products derived
from phenothiazine.21 Mass and IR spectral data strongly indicated that phenothiazine oxide is produced
under the oxidative polymerization conditions, as shown in Scheme 2. Since (PAzep)s are useful as
functional additives for resins, the potential applications of the oxidation products of phenothiazine
derivatives should also be investigated.
X = -CH2CH2-
N
X
N
n
R
PAzep
(NH4)2S2O8
O
R
S
X = -S-
X = -CH2CH2-, -S-
N
R
Scheme 2
Promazine (N,N-dimethyl-3-(10H-phenothiazin-10-yl)-propan-1-amine, Prom) and its hydrochloride salt
(Prom-HCl) are derivatives of phenothiazine that are easily available owing to studying for medical
use.22,23 However, the oxidation of Prom and the chemical properties of the resulting products have not
been investigated. In the present study, we have compared the optical and electrochemical properties of
Prom-O and Prom.
In order to compare the physical and chemical properties of phenothiazine and phenothiazine oxide, it is
preferable to introduce the same substituent on the N atom of the diphenylamine unit in the phenothiazine
skeleton.
From this point of view, we synthesized N-(3-trimethylammoniopropyl)-substituted
phenothiazine (Prom-MeI) and its S-oxide derivative (Prom-O-MeI) from the common precursor
Prom-HCl (Scheme 3). The oxidation of promazine hydrochloride using m-chloroperbenzoic acid
(mCPBA)22 afforded 10-(3-(N,N-dimethylamino)-1-propyl)-10H-phenothiazine-5-oxide (promazine
S-oxide, Prom-O). The 3-dimethylaminopropyl group of both Prom and Prom-O was converted
ammonium salt to Prom-MeI and Prom-O-MeI, by the reported method.24 Prom-MeI shows low
solubility in CHCl3, whereas Prom-O and Prom-O-MeI show good solubility.

HETEROCYCLES, Vol. 92, No. 8, 2016
1443
O
O
S
1) NaOH
2) MeI
1) mCPBA
2) NaOH
S
N
S
N
S
N
MeI
91 %
83 %
96 %
N
Prom-O
Prom-HCl
Prom-O-MeI
Prom-MeI
N+Me3I-
N+Me2HCl-
NMe2
N+Me3I-
Scheme 3
The 1H NMR spectra of oxidized and unoxidized products obtained from Prom-HCl are shown in Figure
1. Prom was prepared by treatment of Prom-HCl with NaOH in water. In the case of Prom,
quaternization of the alkylamine unit shifts the adjacent protons to a lower magnetic field (Hc, ꢀG 2.4 to G
3.9, Figures 1(a) and 1(b)). However, the other two signals associated with the alkyl chain do not change
so much upon quaternization (Ha: G 3.9; Hb: G 1.9, Figure 1(a)). However, the signal assigned to
Ar2NCH2CH2CH2NMe2 (G 2.4, Hc in Figure 1(a)) is shifted to G 3.8 (Figure 1(b)). Additionally, the
quaternization of dimethylalkylamine unit of Prom changes the chemical shift of N–CH3 from G 2.2 to G
3.0.
In the case of phenothiazine and phenothiazine oxide, several peaks assigned to the aromatic protons of
phenothiazine shifted to a lower magnetic field upon S-oxidation. In Prom-O, the signal assigned to Ha
shifted to a lower magnetic field (G 4.5, Figure 1(c)) as compared to that of Prom (G 3.9, Figure 1(a)) by
the formation of the S-oxide, whereas the chemical shifts of Hb, Hc, and -NMe were unaffected. The
lower shift of Ha was promoted by the introduction of the electron-withdrawing S-oxide.
O
S
(a) Prom
(c) Prom-O
S
N
NMe
NMe
N
Ha
Hb
Ha
Hb
Hc
Hc
NMe 2
TMS
NMe 2
*
aromatics
*
Hc
Hb
Ha
Hc
aromatics
Hb
*
Ha
S
N
O
S
(b) Prom-MeI
(d) Prom-O-MeI
TMS
*
NMe
Ha
Hc
Hb
N+Me 3I-
N
NMe
*
Ha Hb
Hc
*
TMS
0
N+Me 3I-
Ha Hc
*
aromatics
Ha
aromatics
Hb
Hc
Hb
10
8
6
4
2
0
10
8
6
4
2
G / ppm
G / ppm
Figure 1. 1H NMR spectra of (a) Prom, (b) Prom-MeI, (c) Prom-O, and (d) Prom-O-MeI in CDCl3. The *
mark in the figure indicates the peak due to solvent impurities.

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HETEROCYCLES, Vol. 92, No. 8, 2016
The electrochemical behavior of Prom-MeI and Prom-O-MeI was studied using cyclic voltammetry (CV).
The redox responses of the compounds are shown in Figure 2. In the oxidative region, the CV of
Prom-MeI and Prom-OMeI showed complicated redox wave. Because these compounds contain I- as a
counter anion, the redox process of I-/I2 also appears at this region (cf. E1/2(I-/I2) = ca. +0.4 V vs AgCl/Ag
in teraalkylammonium iodide).25 On the other hand, in contrast to Prom-MeI, Prom-O-MeI shows an
irreversible reduction peak in the negative region at Epc = -2.77 V (vs. Fc+/Fc, Figure 2 (c)).
Electrochemical properties of phenothiazine and phenothiazine oxide have been reported previously,
however only the oxidation properties of the compounds have been described in the articles.5,26 We tried
to investigate the reduction behavior of Prom-MeI and Prom-O-MeI. The results are shown in Figures
2(b) and 2(d). As shown in Figure 2(d), not only whole scan (Figure 2 (c)) but also negative scan show
an irreversible reduction peak at Epc = -2.77 V (vs. Fc+/Fc) although Prom-MeI shows no reduction peak
in the reduced region (Figure 2(b)). These results suggest that phenothiazine oxides have potential
applications as n-type semiconducting materials.
(a)
(c)
(d)
20 μA
20 μA
1.0
(b)
-2.77
-3.0
-2.0
-1.0
0
1.0
-3.0
-2.0
-1.0
0
E / V (vs Fc+ / Fc)
E / V (vs Fc+ / Fc)
Figure 2. Cyclic voltammograms of Prom-MeI ((a): whole scan, (b): negative scan) and Prom-O-MeI ((c):
whole scan, (d): negative scan).
The absorption spectra of Prom-O-MeI and Prom-MeI are shown in Figure 3, and the data are
summarized in Table 1. Usually, N-substituted diphenylamines show absorption Omax corresponding to
the S-S* transition at ca. 300 nm, for example, diphenylamine (Omax = 297 - 305 nm)27 and phenazasiline
(Omax = 295 nm).28 In agreement with the literature, the S-S* transition of Prom-MeI is observed at Omax
=
307 nm. However, the S-S* transition in Prom-O-MeI is red-shifted by ca. 35 nm (Omax = 341 nm) due to
the narrow SꢁS* gap resulting from the S-oxide. Comparison of CV between Prom-MeI and Prom-O-MeI
also agreed with the result.

HETEROCYCLES, Vol. 92, No. 8, 2016
1445
Prom-O-MeI shows fluorescence at 369 nm in CHCl3 (Figure 3c), although Prom-MeI shows no
fluorescence under the same conditions. Generally, an iodine ion works as a fluorescence quencher,29,30
therefore, fluorescent spectra of Prom and Prom-O were also measured. As shown in Table 1, Prom
shows no fluorescence whereas Prom-O shows fluorescence at same wavelength with Prom-O-MeI.
These results suggest that the difference of fluorescence properties between Prom and Prom-O comes
from not existence of I- but formation of S-oxide mainly.
(a)
3
(c)
2
(b)
1
0
300
400
500
Wavelength / nm
Figure 3. Absorption spectra of CHCl3 solution of (a) Prom-MeI and (b) Prom-O-MeI; (c) fluorescence
spectrum of Prom-O-MeI.
Table 1. Optical properties of prepared phenothiazine derivatives
Absorption ꢀOmax/nma
Fluorescence ꢀOEM/ nma
Compound
Prom-MeI
Prom-O-MeI
Prom
307, 254
b
341, 295, 275
310, 257
369
b
Prom-O
344, 300, 278
369
a CHCl3 solution. b not detected.
In summary, we have reported that diphenylamine with a bridged structure can be functionalized by the
introduction of appropriate substituent(s) on the N atom.18 Furthermore, we found that the S atom of the
phenothiazine unit can be functionalized to give the S-oxide using the mCPBA oxidation protocol. Since
the S-containing S-conjugated system, thiophene, has been functionalized by oxidation to form thiophene
S-oxide,31 functionalization of phenothiazine derivatives using the S-oxidation method and applications of
the derivatives in are also expected.

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HETEROCYCLES, Vol. 92, No. 8, 2016
EXPERIMENTAL
Prom-HCl was purchased from SIGMA. Other reagents were commercially available from either Tokyo
Chemical Industry or Kanto Chemical Industry and used as received.
MEASUREMENT
NMR and IR spectra were recorded on Varian INOVA400 and JASCO FT/IR-410 spectrometers,
respectively. Absorption and fluorescence spectra were recorded on JASCO UV-570 and Hitachi F
4010 spectrometers, respectively. Cyclic voltammetry (CV) was performed using a Hokuto Denko
HSV-100 automatic polarization system.
Preparation of 10-(3-(trimethylammonio)-1-propyl)-10H-phenothiazine iodide (Prom-MeI)
Iodomethane (3 mL) was added to a benzene solution (10 mL) of Prom, which was prepared by the
neutralization of Prom-HCl (1.08 g, 3.4 mmol) using sodium hydroxide, and stirred for 24 h to yield a
yellow precipitate. The precipitate was separated by filtration, washed with hexane, and dried in vacuo
to afford Prom-MeI as a yellow powder in 91% yield (1.31 g, 3.1 mmol, from Prom-HCl). Mp
241-244 °C (decomp.)
1H NMR (DMSO-d6) G 7.15-7.40 (m, 4H, Ar), 7.05-7.15 (m, 2H, Ar), 6.90-7.05 (m, 2H, Ar), 3.94 (t, 2H,
J = 7.0 Hz, ArN-CH2-), 3.40-3.60 (m, 2H, -CH2-NMe3), 3.02 (s, 9H, -NMe3), 2.00-2.20 (m, 2H,
-CH2-CH2-CH2-).
13C NMR (DMSO-d6) G 144.39, 127.76, 127.32, 123.87, 122.88, 115.90, 63.15, 52.32, 43.48, 20.21. IR
(ATR) 3001, 2957, 2870, 1591, 1566, 1487, 1455, 1420, 1353, 1340, 1311, 1283, 1253, 1235, 1197, 1155,
1139, 1123, 1104, 1051, 1032, 962, 940, 917, 858, 759, 752, 728, 694, 672, 618 cm-1
Preparation of 10-(3-(N,N-dimethylamino)-1-propyl)-10H-phenothiazine-5-oxide (Prom-O)
Under N2 atmosphere, 0.69 g (2.15 mmol) of Prom-HCl was dissolved in 10 mL of CHCl3; then, 0.53 g
(3.07 mmol) of m-chloroperbenzoic acid was added to the solution at 0ꢀ°C and stirred overnight. The
reaction was stopped by the addition of aqueous NaOH, and the solution was extracted by CHCl3. The
organic phase was dried over MgSO4, then the solvent was removed by evaporation. The residue was
purified by alumina column chromatography (eluent: CHCl3) and dried in vacuo to afford Prom-O as a
pale yellow powder in 83% yield (0.53 g, 1.8 mmol). Mp 114.5-116.0 °C.
1H NMR (CDCl3) G:7.90-8.00 (m, 2H, Ar), 7.55-7.70 (m, 2H, Ar), 7.40-7.55 (m, 2H, Ar), 7.20-7.30 (m,
2H, Ar), 4.33 (t, 2H, J = 7.8 Hz,, ArN-CH2-), 2.47 (t, 2H, J = 6.8 Hz, -CH2-NMe2), 2.29 (s, 6H, -NMe2),
2.00-2.20 (m, 2H, -CH2-CH2-CH2-).
13C NMR (CDCl3) G:138.35, 132.84, 131.69, 124.12, 121.72, 115.76, 56.65, 45.96, 45.69, 24.59.

HETEROCYCLES, Vol. 92, No. 8, 2016
1447
IR (ATR) 2924, 2856, 2809, 2789, 2755, 1584, 1572, 1482, 1456, 1375, 1364, 1250, 1225, 1165, 1152,
1095, 1043, 1019, 967, 955, 897, 858, 826, 779, 764, 742, 706, 668, 634, 604 cm-1.
Preparation
of
10-(3-(trimethylammonio)-1-propyl)-10H-phenothiazine-5-oxide
iodide
(Prom-O-MeI)
Iodomethane (0.2 ml) was added to a benzene solution (2.5 mL) of Prom-O (87.5 mg, 0.29 mmol) and
stirred for 24 h to yield a colorless precipitate. The precipitate was separated by filtration, washed with
hexane, and dried in vacuo to afford Prom-O-MeI as a colorless powder in 96% yield (123.4 mg, 0.28
mmol). Mp 245-247 °C (decomp.).
1H NMR (CDCl3) G:7.80-7.90 (m, 2H, Ar), 7.60-7.80 (m, 4H, Ar), 7.20-7.35 (m, 2H, Ar), 4.66 (t, 2H, J =
5.7 Hz, ArN-CH2-), 3.60-3.75 (m, 2H, -CH2-NMe2), 3.02 (s, 9H, -NMe3), 2.30-2.50 (m, 2H,
-CH2-CH2-CH2-).
13C NMR (CDCl3) G:138.86, 133.40, 130.26, 127.23, 122.77, 117.95, 62.62, 53.65, 43.40, 22.04.
IR (ATR) 3006, 2957, 1586, 1575, 1489, 1462, 1380, 1254, 1200, 1178, 1148, 1102, 1053, 1023, 999,
971, 922, 907, 853, 786, 748, 708, 669, 627, 606 cm-1.
Electrochemical measurements
A conventional three-electrode configuration was used, with a glassy carbon electrode (BAS PFCE 3
carbon electrode), a platinum wire auxiliary electrode (Tokuriki, special order), and 0.1 M AgNO3/Ag
reference (BAS RE-5). Cyclic voltammograms were recorded at a scan rate of 50 mV s-1. The sample
concentration was 1 mM in DMF containing 0.1 M n-Bu4NBF4 as the supporting electrolyte.
ACKNOWLEDGEMENTS
A part of this research was performed under the Cooperative Research Program of "Network Joint
Research Center for Materials and Devices."
REFERENCES
1.
2.
3.
4.
Y. Ito, T. Shimada, J. Ha, M. Vacha, and H. Sato, J. Polym. Sci. A Polym. Chem., 2006, 44, 4338.
T. Kanbara, Y. Yokokawa, and K. Hasegawa, J. Polym. Sci. A Polym. Chem., 2000, 38, 28.
X. Kong, A. P. Kulkarni, and S. A. Jenekhe, Macromolecules, 2003, 36, 8992.
L. Y. Yang, L. Q. Li, C. Wang, F. J. Zhu, Y. Lu, S. Janietz, A. Wedel, Y. L. Hua, and S. G. Yin, J.ꢀ
Lumin., 2007, 122-123, 714.
5.
L. Y. Yang, C. Wang, L. Q. Li, S. Janietz, A. Wedel, Y. L. Hua, and S. G. Yin, J. Polym. Sci. A
Polym. Chem., 2007, 45, 4291.

1448
HETEROCYCLES, Vol. 92, No. 8, 2016
6.
7.
H. Kondo, M. Sato, and M. Yokoyama, J. Polym. Sci., Polym. Chem. Ed., 1983, 21, 165.
G. Casalbore-Miceli, G. Beggiato, S. S. Emmi, A. Geri, S. Daolio, L. Favaretto, and D.
Pietropaolo, J. Appl. Electrochem., 1990, 20, 989.
8.
9.
G. Casalbore-Miceli, A. Geri, G. Giro, S. Daolio, and G. Zotti, Synth. Met., 1991, 40, 317.
G. Casalbore-Miceli, G. Beggiato, N. Camainoi, L. Favaretto, D. Pietropaolo, and G. Poggi, Ann.
Chim. (Rome), 1992, 82, 161.
10.
11.
M. Mastragostino, A. Zanelli, G. Casalbore-Miceli, and A. Geri, Synth. Met., 1995, 68, 157.
K. Ono, T. Kobayashi, Y. Sato, K. Eguchi, S. Kato, N. Kishi, and T. Soga, Heterocycles, 2011, 83,
1977.
12.
13.
Y. Fujinami, J. Kuwabara, W. Lu, H. Hayashi, and T. Kanbara, ACS Macro Lett., 2012, 1,67.
W. Lu, J. Kuwabara, T. Iijima, H. Higashimura, H. Hayashi, and T. Kanbara, Macromolecules,
2012, 45, 4128.
14.
15.
H. Nakao, H. Hayashi, T. Yoshino, S. Sugiyama, K. Otobe, and T. Ohtani, Nano Lett., 2000, 2,
475.
H. Nakao, H. Hayashi, F. Iwata, H. Karasawa, K. Hirano, S. Sugiyama, and T. Ohtani, Langmuir,
2005, 21, 7945.
16.
17.
18.
19.
K. Otobe, H. Nakao, H. Hayashi, F. Nihei, M. Yudasaka, and S. Iijima, Nano Lett., 2002, 2, 1157.
H. Hayashi, H. Nakao, and K. Iida, Bunseki Kagaku, 2011, 60, 215.
H. Hayashi, Koubunshi Ronbunsyu, 2006, 63. 529.
H. Hayashi, K. Murakami, H. Inoue, H. Hirota, M. Harada, K. Iida, Y. Onouchi, and K. Hirano,
Curr. Trends Polym. Sci., 2010, 14, 11.
20.
21.
22.
H. Hayashi, Y. Ishigaki, J. Kuno, T. Naruo, H. Hirota, T. Ogawa, H. Hattori, H. Seno, Y. Onouchi,
and M. Oda, J. Adhes. Soc. Jpn., 2015, 51, 298.
H. Hayashi, H. Inoue, H. Nakao, H. Hattori, And Y. Onouchi, Int. J. Polym. Anal. Charact., 2012,
17, 189.
T. Kanamori, K. Kuwayama, K. Tsujikawa, H. Miyaguchi, Y. Iwata, H. Inoue, and T. Kishi, Jpn.
J. Forensic Sci. Tech., 2007, 12, 237.
23.
24.
25.
26.
27.
28.
R. Aoki, T. Arinobu, T. Kumazawa, H. Hattori, and H. Noguchi, Forensic Toxicol., 2007, 25, 8.
K. Hirano, H. Fukuda, and S. L. Regan, Langmuir, 1991, 7, 1045.
I. S. El-Hallag, J. Chil. Chem. Soc., 2010, 55, 67.
K. D. Theriault and T. C. Sutherland, Phys. Chem. Chem. Phys., 2014, 16, 12266.
T. Yamamoto, S.-B. Kim, and T.-a. Koizumi, Polym. J., 2009, 41, 810.
H. Hayashi, M. Murase, T.-a. Koizumi, K. Ohara, T. Miyabayashi, and M. Kojima, Bull. Chem.
Soc. Jpn., 2010, 83, 1282.

HETEROCYCLES, Vol. 92, No. 8, 2016
1449
29.
30.
31.
T. Asakawa, K. Iriyama, A. Ohta, and S. Miyagishi, J. Oreo. Sci., 2004, 53, 445.
A. Chmyrov, T. Sandén, and J. Widengren, J. Phys. Chem. B, 2010, 114, 11282.
T. Yamamoto, I. Nurulla, H. Hayashi, and H. Koinuma, Synth. Met., 1999, 107, 137.