Synthesis of N,N'-Bis(thioacetoxyalkoxy)piperazine and its self-assembled monolayer (SAM) formation on gold electrode

Article abstract of DOI:10.1246/cl.2010.415

A novel terminal thioacetate-substitued alkoxy piperazine was successfully synthesized from 4-(benzyloxy)phenol after six-step reaction and employed as the surface-active material in fabrication of self-assembled monolayers (SAMs). Cyclic voltammetric (CV) results showed that the SAM-modified gold electrode had special capacity in recognition for Fe³⁺.

Full text of DOI:10.1246/cl.2010.415

doi:10.1246/cl.2010.415
Published on the web April 5, 2010
415
Synthesis of N,N¤-Bis(thioacetoxyalkoxy)piperazine
and Its Self-assembled Monolayer (SAM) Formation on Gold Electrode
Haitao Xi, Shenglan Ju, Zhidong Chen, and Xiaoqiang Sun*
Key Laboratory of Fine Petrochemical Engineering, Jiangsu Polytechnic University,
Changzhou, Jiangsu 213164, P. R. China
(Received January 18, 2010; CL-100051; E-mail: xqsun@jpu.edu.cn)
A novel terminal thioacetate-substitued alkoxy piperazine
Cl
OH
Pd/C
CH2O
OH
OH
CH2O
O
OH
was successfully synthesized from 4-(benzyloxy)phenol after
six-step reaction and employed as the surface-active material
in fabrication of self-assembled monolayers (SAMs). Cyclic
voltammetric (CV) results showed that the SAM-modified gold
MeOH
NaOH/EtOH
1
HN
NH
Br
Br
HO
O
O
Br
HO
HO
O
K2CO3 /MeCN
K2CO3 /MeCN
3
2
electrode had special capacity in recognition for Fe3+
.
MsCl
O
O
O
N
N
O
O
OH
DMF/Et3N
4
In recent years, self-assembled monolayer (SAM)-modified
electrodes have been in focus of research in the field of
electrochemistry.1 Much more effort has been taken to under-
stand the fundamental and applied research of SAMs of thiols on
Au(III) surfaces.2 Highly stable and ordered SAMs can be
formed because sulfur atoms have srong bond interactions with
gold electrodes. However, functional end groups of thiol
compounds commonly used are just limited to carboxyl, amino,
and hydroxy,3 which greatly limit the scope of the application of
such electrodes. This disadvantage can be circumvented with the
invention of new thiol compounds having specific function. On
the one hand, the introduction of groups of N-SH could greatly
increase orders of the self-assembled monolayers, reduce the
defects of the SAMs, and enhance intermolecular (³£³)
interactions between the benzene rings in order to further
stabilize the SAMs. On the other hand, owing to the conjunction
between lone pair electrons of piperazine and empty d orbitals of
metal atoms, N-functionalized piperazine has strong ability to
complex metal ions, such as transition-metal ions, heavy metal
ions, lanthanide ions, actinide ions, and even for organic or
inorganic anions.4
Usually, thioacetate-terminated conjuncted molecules have
been used for SAM fabrication because aromatic thiols can
easily undergo oxidation to form disulfide or other oxidized
products in the presence of a small amount of oxygen.
Furthermore, the oxides formed above could easily deposit on
surfaces of the gold electrodes, and they are so difficult to be
removed that self-assembly fails. Tour et al. have noted that
thioacetate groups could be used directly to assemble on the gold
surface without deprotecting the acetyl group although higher
concentration and longer adsorption time were required to
achieve similar surface coverage relative to those of thiol group.5
However, so far attention has mainly been paid to aliphatic
thiols. Terminal thioacetate-functionalized alkoxy piperazines
have not yet been explored.
CH3COSK
MsO
O
N
N
O
O
OMs
DMF
5
H3COCS
O
O
N
N
O
O
SCOCH3
6
Scheme 1. Synthesis procedure of 1,4-bis{2-[4-(2-thioacetoxy-
ethoxy)phenoxy]ethyl}piperazine.
N,N¤-bis(thioacetoxyalkoxy)piperazine (BTP) was prepared
according to the synthetic procedure as illustrated in Scheme 1.
First, 2-[4-(benzyloxy)phenoxy]ethanol (1) was prepared from
4-(benzyloxy)phenol and chlorohydrin heated to reflux in mixed
solution of ethanol and sodium hydroxide. Then it was
converted to 4-(2-hydroxyethoxy)phenol (2) by catalytic hydro-
genation with Pd/C in methanol solution at room temperature.
A key intermediate, an asymmetric hydroquinone alkoxy
compound of 2-[4-(2-bromoethoxy)phenoxy]ethanol (3), was
obtained by the reaction between compound 2 and 1,2-dibromo-
ethane. The nucleophilic substitution reaction of compound 3
and piperazine led to another crucial intermediate of 1,4-bis{2-
[4-(2-hydroxyethoxy)phenoxy]ethyl}piperazine (4).
The most important step was the introduction of the
thioacetate group. After exploratory research, we decided to
protect the two hydroxy groups of compound 4 as mesyl groups
by use of methanesulfonyl chloride. Finally, target product 6
(BTP) was successfully obtained through the transesterification
of compound 5 treated with potassium thioacetate.6 The
structure of key intermediates and target compound BTP were
identified by 1H NMR, 13C NMR, MS, IR sprectra and elemental
analysis.7
Then a SAM modified gold electrode (BTP/Au) was
obtained by modifing with BTP, based on the strong interaction
of -S- with gold surface. Cyclic voltammetry (CV) was
employed to assess the quality of monolayer films and
investigate the ionic selection of the SAM-modified gold
electrode. Electrochemical measurements were performed in a
conventional three-electrode electrochemical cell using a CHI-
411A electrochemical analyzer (CHI, Shanghai Chenghua Co.).
A Pt sheet auxiliary electrode and a saturated calomel reference
electrode (SCE) were used. The bare Au electrode and the BTP/
Au electrodes were used as the working electrodes. All the
Herein, we wish to report a novel terminal thioacetate-
substitued alkoxy piperazine which has been synthesized
recently in this laboratory. In this study, we mainly report the
synthesis of new functional surface-active material, 1,4-bis{2-
[4-(2-thioacetoxyethoxy)phenoxy]ethyl}piperazine. In addition,
application, preliminarily studied by cyclic voltammetric (CV)
technique, are briefly introduced.
Chem. Lett. 2010, 39, 415-417
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

416
Figure 2. (A) Energy minimized steric structure of BTP and
(B) idealized representation of a SAM of BTP on Au surface.
(Figure 1D-b) were not detected for BTP/Au electrode implying
that they cannot be adsorbed. It suggested that the SAM-
modified gold electrode formed above had selective recognition
for Fe3+ ions.
The most stable structure of BTP (Figure 2A) obtained
through Materials Studio software showed us that the two
thioacetate-terminated conjugated molecules were toward the
same direction, which meant that both of the sulfur atoms could
be bonded to the surface of the gold electrode. The idealized
representative structure of a BTP/Au SAM formed above is
shown in Figure 2B.
Figure 1. Cyclic voltammograms of (A) bare gold electrode in
0.5 M H2SO4 and (B) SAM of BTP on Au surface (a) and Cu2+
at the SAM of BTP on Au surface (b). (C) SAM of BTP on Au
surface (a) and Fe3+ at the SAM of BTP on Au surface (b). (D)
SAM of BTP on Au surface (a) and Ag+ at the SAM of BTP on
Au surface (b) in 0.1 M potassium chloride at a potential scan
¹1
rate of 50 mV s
.
electrochemical measurements were made at ambient temper-
ature (25 « 1 °C).
Morever, according to HSAB (Hard and Soft Acids and
Bases) theory, the piperazine is a kind of hard base, while the
Fe3+ is beyond hard acid, and then it can be adsorbed onto the
surface of BTP/Au electrode. It is greatly in accordance with the
above experimental result that BTP/Au electrode had special
selection of Fe3+ in the presence of Cu2+ and Ag+.
In summary, a novel functional end group of thioacetate was
prepared, and the SAM-modified gold electrode formed had
special selection of Fe3+. This ability has been exploited in the
design of redox responsive ligands, thus allowing the voltam-
metric detection of metallic cations in solutions, which will offer
the experimental and theoretical bases for their applications in
molecular device and biological sensors.
Immediately before use, the gold disk electrode (CHI, 2 mm
in diameter) was pretreated by polishing with alumina powder
(0.3 ¯m) on a microcloth. Then the electrode was ultrasonicated
in Millipore water to remove alumina particles. Meanwhile, it
was cleaned in “piranha” solution, which is a mixture of 30%
H2O2 and concentrated H2SO4 in 1:3 ratio (Caution! Piranha
solution is very corrosive and direct contact with skin and eye
should be avoided.). Finally, the polished gold disc electrode
was thoroughly cleaned, rinsed in Millipore water, and subjected
to electrochemical pretreatment by consecutive potential cycling
in a 0.5 M H2SO4 solution within a potential window between
¹1
¹0.50 and +1.60 V(vs. SCE) at 50 mV s before the SAM
formation. The cycling was continued until a reproducible
voltammogram (Figure 1A) showing the presence of gold oxide
formation and reduction was obtained.8
The pretreated Au electrode was immersed in a 10 mM BTP
chloroform solution in the dark for 24 h at room temperature of
25 °C. After the electrode was rinsed carefully with ethanol for
1 min and Millipore water for another 1 min consecutively, the
BTP-modified gold electrode (BTP/Au) was obtained.
References and Notes
1
A. Ulman, Chem. Rev. 1996, 96, 1533; R. A. Gu, R. Sun,
P. G. Cao, Spectrosc. Spectral Anal. (Beijing, China) 1999,
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2001, 20, 18; D. Wu, J. Wu, Chin. Chem. Soc. 2004, 2, 132.
T. H. Wink, S. J. van Zuilen, A. Bult, W. P. van Bennekom,
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Shang, Acta Phys. Chim. Sin. 2004, 20, 207; J. C. Love,
L. A. Estroff, J. K. Kriebel, R. G. Nuzzo, G. M. Whitesides,
Chem. Rev. 2005, 105, 1103.
2
Fe3+, Cu2+, and Ag+, carrying different charges, were used
to investigate the electrochemical properties of the BTP/Au
electrode. Immediately prior to use, the BTP/Au electrodes were
modified by immersion in a freshly prepared 5 mM aqueous
solution of iron trichloride, copper sulfate, and silver nitrate for
2 h followed by rinsing with Millipore water. CVs were recorded
3
4
D. Du, S. F. Wang, Chem. Res. Appl. 2001, 13, 617.
N. Krings, H.-H. Strehblow, J. Kohnert, H.-D. Martin,
Electrochim. Acta 2003, 49, 167; V. Ganesh, R. R. Pandey,
B. D. Malhotra, V. Lakshminarayanan, J. Electroanal.
Chem. 2008, 619-620, 87; B.-C. Yu, Y. Shirai, J. M. Tour,
Tetrahedron 2006, 62, 10303; M. Argese, M. Brocchetta,
M. D. Miranda, P. Paoli, F. Perego, P. Rossi, Tetrahedron
2006, 62, 6855.
¹1
in 0.1 M KCl at a scan rate of 50 mV s and presented in
Figure 1B, Figure 1C, and Figure 1D. It could be observed from
these figures that after modification by different metallic ions,
only the Fe3+ at the BTP/Au electrode (Figure 1C-b) showed
a reversible voltammogram especially at 0.17 and 0.084 V
implying a electron-transfer reaction, which illustrated that
Fe3+ had been adsorbed in the BTP/Au SAM. However,
the voltammetric peaks for Cu2+ (Figure 1B-b) and Ag+
5
6
L. Cai, Y. Yao, J. Yang, D. W. Price, Jr., J. M. Tour, Chem.
Mater. 2002, 14, 2905.
The general procedure for synthesis of BTP is presented as
Chem. Lett. 2010, 39, 415-417
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

417
bellow: 2-[4-(benzyloxy)phenoxy]ethanol (1): 4-(benzyl-
oxy)phenol (20.0 g, 0.1 mol) was dissolved in ethanol
(100 mL). When this whole solution was heated to reflux,
the mixed solvent which contained NaOH (11.2 g, 0.2 mol)
and ethanol (100 mL) was added dropwise over 20-30 min to
the above solution. The reaction mixture was then refluxed
for 0.5 h, and then a solution of chlorohydrin (16.1 g, 0.2 mol)
was added. Subsquently the whole solution was continually
refluxed at this temperature for 15 h. After cooling to room
temperature, the resulting solution was filtered. The collected
filtrate was concentrated under reduced pressure, and the
residue was washed with NaOH (20%). The crude product
was recrystallized by ethanol to afford the white solid
product 1 with good yields (97.5%); 4-(2-hydroxyethoxy)-
phenol (2): To a solution of compound 1 (24.6 g, 0.1 mol) in
MeOH (300 mL) was added Pd/C (0.5 g), running under
hydrogen with stirring at room temperature. After 4 h,
MeOH was evaporated in vacuo, and the yellow product 2
was directly obtained in 99.6% yield; 2-[4-(2-bromoethoxy)-
phenoxy]ethanol (3): A mixture of compound 2 (10.0 g,
0.06 mol), K2CO3 (17.9 g, 0.13 mol), and 1,2-dibromoethane
(3.5 g, 0.13 mol) in MeCN (150 mL) was heated under reflux
for 10 h. After cooling to ambient temperature, the mixture
was filtered. The solvent was removed under reduced
pressure, and then the residue was purified by column
chromatography (acetone/petroleum ether, 1:3) to yield the
white compound 3 in 38.6% yield; 1,4-bis{2-[4-(2-hydroxy-
ethoxy)phenoxy]ethyl}piperazine (4): To a stirred solution
of piperazine (0.78 g, 0.01 mol) in hot MeCN (50 mL) was
added compound 3 (5.0 g, 0.012 mol). The reaction mixture
was refluxed for 10 h. After completion of reaction, K2CO3
and the organic phase were obtained by filtered. The crude
product was purifed by water and recrystalled by methanol
to yield white compound 4 with the yield of 91.0%; 1,4-
bis(2-{4-[2-(methanesulfonyloxy)ethoxy]phenoxy}ethyl)-
piperazine (5): To an ice-cold solution of compound 4
(0.5 g, 1.12 mmol) in DMF (20 mL) was added a solution of
triethylamine (2 mL). Mesyl chloride was added dropwise
after the reaction mixture was cooled to ¹5 °C, and the
solution was stirred for 2 h at ¹5 °C, overninght at room
temperature. The reaction mixture was quenced with water.
Precipitation was filtered and purified by column chroma-
tography (dichloromethane/methanol, 30:1) to give yiellow
solide 5 in 87.4% yield; 1,4-bis{2-[4-(2-thioacetoxyethoxy)-
phenoxy]ethyl}piperazine (6): A mixture of compound 5
(1.0 g, 1.66 mmol) treating with potassium thioacetate
(1.52 g, 13.68 mmol) in DMF (20 mL), were stirred at room
temperature for 2 h. Water was added in the resulting
solution and a white product precipitated. Crude product was
obtained by filtered and was purified through column
chromatography (dichloromethane/methanol, 20:1) to give
white compound 6 in 84.9% yield.
7
Spectra of six compounds are summarized as follows:
Compound 1: mp: 100-102 °C; 1H NMR (500 MHz, CDCl3):
¤ 3.79-3.85 (2H, t, -CH2OH), 4.04-4.18 (2H, t, -OCH2-
CH2OH), 5.02 (2H, s, -OCH2C6H5), 6.85-6.93 (4H, m,
-C6H4-), 7.18-7.44 (5H, m, -C6H5); compound 2: mp: 84-
85 °C; 1H NMR (500 MHz, CDCl3); ¤ 2.01-2.03 (1H, t,
-CH2OH), 3.93-3.96 (2H, m, -CH2OH), 4.02-4.04 (2H, t,
-OCH2CH2OH), 4.49 (1H, s, -C6H4OH), 6.76-6.83 (4H, m,
1
-C6H4-); compound 3: mp: 79-80 °C; H NMR (500 MHz,
CDC13): ¤ 1.99-2.02 (1H, t, -CH2OH), 3.61-3.63 (2H, t,
-CH2Br), 3.93-3.96 (2H, m, -CH2OH), 4.03-4.05 (2H, t,
-OCH2CH2OH), 4.24-4.26 (2H, -OCH2CH2Br), 6.85-6.86
1
(4H, d, -C6H4-); compound 4: mp: 134-135 °C; H NMR
(500 MHz, CDCl3): ¤ 2.08 (2H, s, -OH), 2.64 (8H, s,
-NCH2CH2N-), 2.79 (4H, t, -CH2CH2OC6H4-), 3.93-3.94
(4H, s, -CH2OH), 4.02-4.04 (4H, m, -CH2OC6H4-), 4.05-
4.07 (4H, m, -C6H4OCH2CH2OH), 6.84 (8H, s, -C6H4-);
MS, m/z: 447 (M + H)+; CHN analysis: %C (calcd 64.55,
found 64.36), %H (calcd 7.67, found 7.41), %N (calcd 6.27,
found 6.03); compound 5: mp: 132-133 °C; 1H NMR
(500 MHz, CDCl3): ¤ 2.65 (8H, s, -NCH2CH2N-), 2.81
(4H, t, -CH2CH2OC6H4-), 3.06-3.11 (6H, s, -CH3), 4.05-
4.07 (4H, m, -C6H4OCH2CH2O-), 4.18-4.20 (4H, m,
-CH2OC6H4-), 4.54-4.56 (4H, m, -C6H4OCH2CH2O-),
6.84 (8H, s, -C6H4-); CHNS analysis: %C (calcd 51.81,
found 51.55), %H (calcd 6.35, found 6.14), %N (calcd 4.65,
found 4.46), %S (calcd 10.64, found 10.42); compound 6:
mp: 142-143 °C; 1H NMR (500 MHz, CDCl3): ¤ 2.36 (6H, s,
-CH3), 2.63 (8H, s, -NCH2CH2N-), 2.79 (4H, t,
-CH2CH2OC6H4-), 3.25 (4H, t, -CH2CH2S-), 4.03-4.04
(4H,
m,
-CH2OC6H4-),
4.05-4.06
(4H,
m,
-C6H4OCH2CH2S-), 6.83 (8H, s, -C6H4-); 13C NMR
(500 MHz, CDCl3): ¤ 195.37, 153.40, 152.67, 115.77,
115.68, 67.32, 66.64, 57.34, 53.61, 30.56, 28.64; MS, m/z:
563 (M + H)+; IR (KBr, ¯, cm¹1): 1689.6; CHNS analysis:
%C (calcd 59.76, found 59.53), %H (calcd 6.81, found
6.56), %N (calcd 4.98, found 4.75), %S (calcd 11.40, found
11.17).
8
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Chem. Lett. 2010, 39, 415-417
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/