Synthesis of poly(amidoamine) dendrimer with a diphenyl diselenide core

Article abstract of DOI:10.1080/10426501003767102

We succeeded in the synthesis of a novel poly(amidoamine) dendrimer having diphenyl diselenide at the core. Modification of the dendrimer diselenide by the reaction with glucono-δ-lactone in methanol gave a water-soluble dendrimer diselenide having chiral

Full text of DOI:10.1080/10426501003767102

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of Poly(amidoamine)
Dendrimer with a Diphenyl Diselenide
Core
Tomoyuki Tajima a , Yukie Yamaguchi a , Yo-hei Shiomoto a & Yutaka
Takaguchi a
a Graduate School of Environmental Science, Okayama University,
Okayama, Japan
Published online: 13 Jan 2011.
To cite this article: Tomoyuki Tajima , Yukie Yamaguchi , Yo-hei Shiomoto & Yutaka Takaguchi (2010):
Synthesis of Poly(amidoamine) Dendrimer with a Diphenyl Diselenide Core, Phosphorus, Sulfur, and
Silicon and the Related Elements, 186:1, 2-11
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Phosphorus, Sulfur, and Silicon, 186:2–11, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426501003767102
SYNTHESIS OF POLY(AMIDOAMINE) DENDRIMER
WITH A DIPHENYL DISELENIDE CORE
Tomoyuki Tajima, Yukie Yamaguchi, Yo-hei Shiomoto,
and Yutaka Takaguchi
Graduate School of Environmental Science, Okayama University, Okayama, Japan
GRAPHICAL ABSTRACT
Abstract We succeeded in the synthesis of a novel poly(amidoamine) dendrimer having
diphenyl diselenide at the core. Modification of the dendrimer diselenide by the reaction
with glucono-δ-lactone in methanol gave a water-soluble dendrimer diselenide having chiral
terminal groups. The structures of dendrimers were satisfactorily confirmed by MAIDI-TOF
MS spectrometry, elemental analysis, and NMR spectroscopy. Interestingly, induced circular
dichroism (ICD) of the interaction between the diphenyl diselenide core and D-gluconamide
periphery of the dendrimer was observed at 300 nm.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Chiral; diselenide; gluncono-δ-lactone; PAMAM dendrimer
INTRODUCTION
Organoselenium compounds have been employed as very useful reagents in organic
synthesis.1 Selenium is an essential trace element that plays an important role in the pro-
and eukaryotic cells. It constitutes a functional element of selenium-containing enzymes,
Received 31 January 2010; accepted 10 March 2010.
This work was supported by Grants-in-Aid for Young Scientists (B) (No. 21750043) and Scientific Research
on Priority Areas (C) (No. 21510103) from the Ministry of Education, Culture, Sports, Science and Technology
(MEXT) of Japan.
Address correspondence to Yutaka Takaguchi, Graduate School of Environmental Science, Okayama Uni-
versity, 3-1-1 Tsushima-Naka, Kita-Ku, Okayama 700-8530, Japan. E-mail: yutaka@cc.okayama-u.ac.jp
2

SYNTHESIS OF POLY(AMIDOAMINE) DENDRIMER
3
such as glutathione peroxidase (GPx),2 iodethyronine deiodinase (ID),3 and thioredoxin re-
ductase (TrxR),4 which have been implicated in antioxidative defense, iodine homeostasis,
and regulation of gene expression. Based on the recognized GPx-like activity of ebselen,
several articles have appeared describing simple synthetic organoselenium compounds5
with this property (e.g., benzoselenazinones,6 benzoselenazolinones,7 camphor-devived se-
lenamide,8 and diaryl diselenides9). Mugesh et al. reported that diselenides derived from
enantiomerically pure R-(+)- and S-(−)-N,N-dimethyl(1-ferrocenylethyl)amine show ex-
cellent peroxidase activity.10 Therefore, the chemistry of chiral organo selenium compounds
has recently gained more and more attention.
Meanwhile, a variety of dendritic molecules have been synthesized so far, and their
unique properties have been extensively studied.11 In particular, their topology enforces a
globular shape that offers a unique opportunity to design artificial enzymes. Several studies
of dendrimers as enzyme-like catalysts have focused on the combination of catalytic groups
at the dendritic core with dendritic branches to modulate catalyst selectivity.12 Recently,
Zhang and coworkers reported the mimic of glutathione peroxidase using hyperbranched
polyselenide with multicatalytic sites at the branching units.13 Zhang et al. also reported the
generation-dependent glutathione peroxidase activity of the three generations of Fre´chet-
type poly(aryl ether)dendrimer with a dibenzyl diselenide core.14
However, we reported the first synthesis of poly(benzyl ether) dendron with a thiol
or selenocyanate group at the focal point together with their reversible redox behavior
between dendrons and dendrimer dichalcogenides.15 We also reported the photoinduced
isomerization of allyl alcohols to carbonyl compounds using dendrimer disulfide as a cat-
alyst.16 Because selenium compounds having an aryl group are more stable than dibenzyl
diselenides, to investigate some important active species containing selenium atom in cat-
alytic systems, i.e., SeOH, SeH, SeO2H, radical, and cation, diphenyl diselenide derivatives
are considered to be preferred model molecules. Although the synthesis of Fre´chet-type
poly(aryl ether) dendrimers dibenzyl diselenide has been already reported,14 there is no
report on the synthesis of a dendrimer containing a diphenyl diselenide at the core. In the
course of our studies on the investigation of dendrimer or dendron with chalcogen atom(s)
at the focal point, we became interested in the poly(amidoamine) dendrimer having a
diphenyl diselenide at the core. This article presents the synthesis and characterization of
a poly(amidoamine) dendrimer having diphenyl diselenide at the core together with the
synthesis of a water-soluble chiral dendrimer diselenide.
RESULTS AND DISCUSSION
Methyl 4-selenocyanatobenzoate (2) was selected as the starting material, which
was prepared by the reaction of KSeCN and methyl 4-aminobenzoate (1) (Scheme 1).17
Dendrimer diselenide 7, which has poly(amidoamine) dendritic wedges at the 4,4ꢁ position
of the diphenyl diselenide, was synthesized by the divergent method developed by Tomaria
1) NaNO2,
CH3COONa,
HCl
O
O
H2SO4, Zn
Et2O, 0 ºC
O
Se
Se
MeO
O
NH2
SeCN
2: 60%
OMe
MeO
2) KSeCN,
NaHCO3
MeO
1
3: 93%
Scheme 1 Synthesis of bis[4-(methoxycarbonyl)phenyl]diselenide (3).

4
T. TAJIMA ET AL.
O
H2N
H2NCH2CH2NH2
MeOH
Se
Se
NH
O
3
HN
NH2
4
O
O
H3CO
O
O
O
O
N
Se
OCH3
OCH3
OCH3
NH
4
HN
H3CO
H2N
Se
N
MeOH
O
5
O
O
NH2
HN
O
O
N
H2NCH2CH2NH2
MeOH
N
Se
Se
NH
5
NH
O
H
N
HN
H2N
NH
6
O
NH2
H3CO
N
O
H3CO
O
OCH3
O
OCH3
O
O
HN
O
N
OCH3
O
O
N
6
NH
NH
Se
NH
MeOH
HN
Se
HN
N
O
O
O
N
O
H3CO
O
N
7
H3CO
O
OCH3
O
OCH3
Scheme 2 Synthesis of dendrimer diselenide 7.
et al. (Scheme 2).18 Upon treatment of bis[4-(methoxycarbonyl)phenyl]diselenide (3) with
ethylenediamine in MeOH under a nitrogen atmosphere for 1 d, G0.0 dendrimer 4 was
obtained. The dendrimer 4 was immediately used in the next reaction due to its instability.
The treatment of G0.0 dendrimer diselenide 4, the core of dendrimer, with methyl acrylate
gave a G0.5 dendrimer 5 in 87% yield. This two-step process could be repeated to prepare
the dendrimer 7 in 82% yield. These methyl ester–terminated dendrimers 5 and 7 were found
to be stable towards air and light. The structures of G0.5 and G1.5 dendrimer diselenides
1
13
were satisfactorily confirmed by H, C and 77Se NMR, UV-vis and IR spectroscopy,
MALDI-TOF MS, and elemental analysis. The 77Se NMR spectra of 5 and 7 showed sharp
signals at 470 and 467 ppm, respectively. UV-vis spectra of 5 and 7 in CHCl3 showed
absorption maxima at 271 and 273 nm, respectively. Those absorptions were assignable
to the π–π∗ and/or n–σ∗ electron transitions for the PhSeSePh chromophore.19 Although
those absorptions show a blue shift compared to that of diphenyl diselenide (340 nm),19
those absorptions were similar to 3 (275 nm). Hence, the blue shift observed in the UV-vis
spectra might not arise from the steric effect of the dendritic wedges, but from the substituent

SYNTHESIS OF POLY(AMIDOAMINE) DENDRIMER
5
Figure 1 UV (top) and CD (bottom) spectra of 8 in H2O at 20 ◦C.
effect of ester groups at the 4,4ꢁ-positions of diphenyl diselenide moiety. The MALDI-TOF
MS spectra of dendrimers 5 and 7 clearly showed their parent peaks at m/z 832.07 and
1631.62, respectively. Those parent peaks and mass patterns were in good agreement with
the calculated one.
The water-soluble dendrimer was prepared from G1.0 dendrimer 6, which possesses
four primary amine groups at the terminals. The linking of the sugars was achieved by amide
formation.20 We selected gluconamide groups as sugar chain moieties of the dendrimer at
its terminals since gluconamide was known to form suprastructures, such as fibers20a and
helices.21 The thermal reaction of dendrimer 6 with glucono-δ-lactone in MeOH at 50◦C for
2 d gave a dendrimer diselenide 8 (Scheme 3). The structure of 8 was determined by NMR
spectra and MALDI-TOF MS. The IR spectra of 7 showed two absorptions assignable
to the stretching bands of carbonyl groups at 1655 cm−1 and 1646 cm−1. The IR spectra
for the OH stretching of the sugar group was observed at 3366 cm−1. The MALDI-TOF
MS spectra of dendrimer 8 showed a parent peak at m/z 1654.06. It is notable that the
dendrimer 8 is soluble in water. Saturated concentrations of 8 in 1 mL of H2O are 137
mg at 20◦C. Diselenide substituted with chiral alkyl groups exhibits Cotton effects within
the diselenide chromophore region. The PhSe-SePh unit of the dendrimer 8 is expected

6

SYNTHESIS OF POLY(AMIDOAMINE) DENDRIMER
7
to be small, and rotatory strength of the 300 nm Cotton effect will contain substantial
contributions from the chiral centers of gluconamide groups at the terminals. The circular
dichroism (CD) spectrum in aqueous solution showed a positive Cotton effect at around 300
nm, as shown in Figure 1. The specific rotations of the synthesized dendrimer diselenide 7
were as follows: [α]D +18.0◦ (c 1.002, H2O). Although many chiral selenium compounds
having chiral alkyl or amide groups have been reported, there is no report of glycoconjugate
of chiral diselenide having a sugar as a chiral source.
CONCLUSION
In conclusion, we have successfully synthesized a novel poly(amidoamine) dendrimer
having a diselenide unit at the core. The dendrimer bearing chiral units at the periphery was
also synthesized from achiral poly(amidoamine) dendrimer diselenide. In the viewpoint
of the wide utility and important role of selenium compounds in biochemical science and
organic synthesis, further investigation on the reactivity and catalytic activity of newly
obtained poly(amidoamine) dendrimer diselenides is currently in progress.
EXPERIMENTAL
All experiments were performed under a N2 atmosphere unless otherwise noted. 1H
NMR (300 MHz), 13C NMR (75 MHz), and 77Se NMR (57 MHz) spectra were measured
in CDCl3 or DMSO-d6 with JEOL JNM AL-300 spectrometer. 1H and 13C NMR chemical
shifts were recorded in ppm relative to tetramethylsilane (δ = 0 ppm) and the 13C resonance
of the solvent (CDCl3: δ = 77.2 ppm, DMSO-d6: δ = 39.5 ppm). 77Se NMR chemical shifts
were referenced with diphenyldiselenide (δ = 470 ppm) as an external standard. MALDI-
TOF MS spectral data were obtained on a Bruker Daltonics AutoFLEX spectrometer.
Electronic spectra were recorded on a Shimadzu UV-3150 spectrometer. Circular dichroism
(CD) experiments were performed at 20◦C on a Jasco J-720 spectropolarimeter (Jasco
Spectroscopic Co. Ltd., Japan). All melting points were determined on a MEL-TEMP
micro melting point apparatus and are uncorrected. Elemental analyses were carried out at
the Parkin Elmer 2400II. The reagents were obtained from Wako Pure Chemical Industries
Ltd., Tokyo Kasei Co. Ltd., or Aldrich Chemical Co. The reagents used as reaction solvents
were further purified by general methods.
Synthesis of Methyl 4-Selenocyanatobenzoate (2)
A mixture of water (14 mL), methyl 4-aminobenzoate (1) (0.73 g, 4.8 mmol), and
concentrated hydrochloric acid (12.0 N in H2O, 0.86 mL, 27.6 mmol) was cooled to
0◦C with NaCl/ice bath. An aqueous solution (2 mL) of NaNO2 (0.33 g, 4.8 mmol) was
added to the mixture at 0◦C. After the solution was stirred for a few min, sodium acetate
(1.33 g, 16.2 mmol) was added at 0◦C. KSeCN (0.58 g, 4.00 mmol), and NaHCO3 (0.10 g,
1.19 mmol) in water (2 mL) was added to the mixture at 0◦C, then stirred for 30 min
at this temperature. After the mixture was stirred at 55◦C for 30 min, the mixture was
extracted several times with CHCl3. The organic layers were combined, washed with
water, and dried over anhydrous magnesium sulfate. After removal of the solvent, the
residue was subjected to column chromatography (SiO2, eluent: CHCl3:hexane = 1:1)
followed by recrystallization from hexane to give methyl 4-selenocyanatobenzoate (2)
(571 mg, 2.38 mmol) as pale pink crystals in 60% yield.

8
T. TAJIMA ET AL.
Mp: 92–93◦C; 1H NMR (300 MHz, CDCl3) δ 3.94 (s, 3H), 7.66 (d, 4H, J = 6.5 Hz),
8.04 (d, 4H, J = 6.5 Hz); 13C NMR (75 MHz, CDCl3) δ 52.3 (q), 100.3 (s), 130.3 (d),
130.9 (d), 131.0 (s), 132.3 (s), 165.7 (s); Anal. Calcd for C9H7NO2Se: C, 45.02; H, 2.94;
N, 5.87 Found,; C, 45.32; H, 2.85; N, 5.65.
Synthesis of Bis[4-(methoxycarbonyl)phenyl]diselenide (3)17
A suspension of Et2O (14 mL), an aqueous solution of 20% H2SO4, Zn powder
(689 mg, 10.5 mmol), and methyl 4-selenocyanatobenzoate (2) (682 mg, 2.84 mmol) was
stirred at 40◦C for 50 min. The unconsumed Zn powder was removed by filtration, and
the residue was evaporated. After extraction with CHCl3 several times, and the organic
layers were combined, washed with water, and then dried with anhydrous magnesium
sulfate. After removal of the solvent, the residue was recrystallized from MeOH to afford
bis[4-(methoxycarbonyl)phenyl]diselenide (3) (565 mg, 1.32 mmol, 93% yield) as yellow
crystals.
1
Mp: 114–115◦C; H NMR (300 MHz, CDCl3) δ 3.90 (s, 6H), 7.64 (d, 4H, J =
8.0 Hz), 7.91 (d, 4H, J = 8.0 Hz); 13C NMR (75 MHz, CDCl3) δ 52.1 (q), 129.3 (d), 130.2
(d), 130.1 (s) 136.4 (s), 166.4 (s); UV/Vis (CHCl3) λmax 275 nm (ε = 5.0 × 104), Anal.
Calcd for C16H14O4Se2: C, 44.88; H, 3.30; N, 0.00 Found; C, 44.97; H, 3.18; N, 0.08.
Synthesis of G0.5 Dendrimer Diselenide 5
A solution of bis(4-methoxycarbonyl phenyl) diselenides (3) (302 mg, 0.706 mmol)
in methanol (16.9 mL) was added dropwise to ethylenediamine (16.9 mL, 281 mmol) at
0◦C. The mixture was stirred at room temperature for 3 d. After the removal of the solvent
and the reagent in vacuo, the residue was reprecipitated from a methanol/diethyl ether
(2 mL/120 mL) solution to afford the dendrimer 4 (0.377 mg, 0.779 mmol), which was
used for the following reaction without further purification. A mixture of 4 (0.377 mg,
0.779 mmol), methyl acrylate (2.82 mL, 31.2 mmol), and methanol (113 mL) was stirred
at 45◦C for 5 d. After removal of the solvent, the mixture was separated by column
chromatography (SiO2, eluent, ethyl acetate:methanol = 30:1) to afford the dendrimer 5
(560 mg, 0.676 mmol) as a yellow thick oil in 87% yield.
1H NMR (300 MHz, CDCl3) δ 2.43 (t, J = 6.3 Hz, 8H), 2.62 (t, J = 5.4 Hz, 4H),
2.74 (t, J = 6.3 Hz, 8H), 3.49–3.57 (m, 4H), 3.52 (s, 12 H), 7.29 (t, J = 4.8 Hz, 2H), 7.63
(d, J = 8.1 Hz, 4H), 7.79 (d, J = 8.1 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 32.5 (t), 37.3
(t), 48.8 (t), 51.5 (s), 52.8 (t), 128.0 (d), 130.6 (d), 134.1 (s), 134.2 (s), 166.4 (s), 173.1 (s);
77Se NMR (57 MHz, CDCl3) δ 470; IR (KBr) 1733 (C O), 1647 (NHCO), 1533 (C C,
phenyl), 1436 (CH2) cm−1; UV/Vis (CHCl3) λmax 271 nm (ε = 2.3 × 104), MALDI-TOF
MS (matrix, dithranol) m/z: calcd for C34H46N4O1080Se2 831.23 [MH+], found 832.070
[MH+]; Anal. Calcd for C34H46N4O10Se2: C, 49.28; H, 5.60; N, 6.76 Found; C, 49.07, H,
5.70; N, 6.67.
Synthesis of G1.5 Dendrimer Diselenide 7
A solution of 5 (220 mg, 0.265 mmol) in methanol (28.7 mL) was added dropwise to
ethylenediamine (14.4 mL, 212 mmol) at 0◦C. The mixture was stirred at room temperature
for 2 d. After removal of the solvent and the reagent in vacuo, the residue was reprecipitated
from a methanol/diethyl ether (2 mL/120 mL) solution to afford the dendrimer 6 (249 mg,

SYNTHESIS OF POLY(AMIDOAMINE) DENDRIMER
9
0.265 mmol), which was used for following reaction without further purification. A mixture
of 6 (249 mg, 0.265 mmol), methyl acrylate (2.0 mL, 21.7 mmol), and methanol (78.2 mL)
was stirred at 45◦C for 4 d. After the removal of the solvent, the residue was purified by
silica gel column chromatography (SiO2, eluent, chloroform:methanol = 18:1) and GPC
to give the dendrimer 7 (364 mg, 0.223 mmol) as a yellow thick oil in 82% yield.
1H NMR (300 MHz, CDCl3) δ 2.36–2.44 (m, 32H), 2.67 (t, J = 6.5 Hz, 20H), 2.81
(t, J = 5.0 Hz, 8H), 3.20 (q, J = 6.5 Hz, 8H), 3.54–3.60 (m, 4H), 3.64 (s, 24H), 6.87 (s,
4H), 7.63 (d, J = 8.5 Hz, 4H), 7.86 (brs, 2H), 7.88 (d, J = 8.5 Hz, 4H); 13C NMR (75
MHz, CDCl3) δ 32.6 (t), 33.8 (t), 37.0 (t), 37.7 (t), 49.1 (t × 2), 51.6 (s), 52.5 (t), 52.8
(t), 128.3 (d), 130.3 (d), 131.0 (s), 134.1 (s), 166.3 (s), 172.3 (s), 173.0 (s); 77Se NMR (57
MHz, CDCl3) δ 467; IR (neat) 3407 (N-H), 2947 (C H), 1735 (C O), 1647 (C O), 1637
(C O), 1560 (C C, phenyl), 1470 (CH2), 1200 (O C O), 840 (C H) cm−1; UV/Vis
(CHCl3) λmax 273 nm (ε = 3.8 × 104), MALDI-TOF MS (matrix, dithranol) m/z: calcd for
C70H110N12O2280Se2 1631.62 [MH+], found 1631.05 [MH+].
Synthesis of Water-Soluble Dendrimer Diselenide 8
A solution of G1.0 dendrimer diselenide 6 (591 mg, 0.629 mmol) and glucono-δ-
lactone (2.241 g, 12.6 mmol) in MeOH (134 mL) was heated at 50◦C for 2 d. The mixture
was recrystallized from the solution at 2◦C to give water-soluble dendrimer diselenide 8
(684 mg, 0.414 mmol) as a yellow powder in 66% yield.
1
Mp 110◦C (decomp); H NMR (300 MHz, DMSO) δ 2.13(t, 8H, J = 7.1 Hz),
2.42–2.49 (m, 8H), 2.61 (t, 8H, J = 7.2 Hz), 3.03 (brs, 8H+4H), 3.09 (brs, 4H), 3.40 (brs,
10H), 3.48–3.55 (m, 6H), 3.84 (brs, 4H), 3.91 (brs, 4H), 4.29- 4.49 (m, 20H), 5.31-5.33
(m, 4H), 7.62-7.74 (m, 8H), 7.82 (brs, 8H), 8.28 (brs, 4H), Signals of amide units are not
observed; 13C NMR (75.5 MHz, DMSO) δ 33.5 (t), 37.3 (t), 38.5(t), 49.7(t), 52.3(t), 63.7(t),
70.5(d), 71.8(d), 72.6(d), 73.2(d), 73.8(d), 128.5(d), 130.5 (d), 133.8 (s), 134.1 (s), 165.8
(s), 172.1 (s), 173.2 (s); 77Se NMR (57.3 MHz, DMSO) δ 460.7; IR (KBr) 3366 (NH and
OH), 2945 (C H), 1650 (C O), 1556 (C C, phenyl), 1434 (CH2), 1262 (O C O), 1084
(C O) cm−1; MALDI-TOF MS (matrix, dithranol) m/z: calcd for C62H102N12O3080Se2
1655.52 [MH+], found 1655.07 [MH+]. [α]D20 = + 17.9640 (c 1.002. H2O).
Circular Dichroism
An aqueous solution of the dendrimer diselenide 8 (46.4 µM) was recorded using a
Jasco J-720 spectropolarimeter at 20◦C. Spectrum was measured between 220 and 400 nm
with a data pitch of 1.0 nm. The bandwidth was set to 5.0 nm, with a data scanning speed
of 20 nm min−1 and a response time of 0.5 s. The path length was 10 mm in a demountable
Spectrosil quartz cuvette.
Supplementary Data
Copy of 1H, 13C, and 77Se NMR spectra for some compounds are available online in
the Supporting Information.

10
T. TAJIMA ET AL.
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