Synthesis of aliphatic polyamide dendrimers based on facile convergent method

Article abstract of DOI:10.1021/ma300735w

A novel and rapid approach for the synthesis of aliphatic polyamide dendrimers, consisting of the 3,4-dialkoxyhydrocinnamamide structure as a repeating unit, has been developed. Aliphatic polyamide dendrons and dendrimers were easily prepared by a converg

Full text of DOI:10.1021/ma300735w

Article
pubs.acs.org/Macromolecules
Synthesis of Aliphatic Polyamide Dendrimers Based on Facile
Convergent Method
Yumiko Ito, Tomoya Higashihara, and Mitsuru Ueda*
Department of Organic and Polymeric Materials, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1
O-okayama, Meguro-ku, Tokyo 152-8552, Japan
S
* Supporting Information
ABSTRACT: A novel and rapid approach for the synthesis of aliphatic
polyamide dendrimers, consisting of the 3,4-dialkoxyhydrocinnama-
mide structure as a repeating unit, has been developed. Aliphatic
polyamide dendrons and dendrimers were easily prepared by a
convergent approach involving activation of a carboxylic acid at the
focal point using (2,3-dihydro-2-thioxo-3-benzoxazolyl)phosphonate
(DBOP) as the activating agent, followed by condensation with an
unprotected AB2 building block. Dumbbell-shaped and star-shaped
third generation dendrimers were prepared from the third generation
dendron and core molecules containing two or three functional groups.
All the above products could be purified only by precipitation, and their
1
structures were confirmed by H NMR, IR, and matrix-assisted laser
desorption ionization time-of-flight mass (MALDI−TOF−MS) spec-
troscopies and elemental analysis.
synthetic method of aliphatic polyamide dendrimers. Haridas et
al. reported the time-efficient synthesis of peptide dendrimers
using the 1,3-dipolar cycloaddition (Click) reaction.23 Al-
Hamra et al. reported peptide dendrimers with a
petaaminecobalt(III) complex at the core as a facile synthetic
method.24 However, these methods still have the following
problems: (i) the dendrimers synthesized by the former
method contain a triazole unit and that could change the
property of the dendrimers, and (ii) though the latter synthetic
method succeeds to facilitate the purification steps, the number
of reaction steps was still high and the protection−deprotection
steps are still required. From this standpoint, it is important to
develop a facile synthetic method of aliphatic polyamide
dendrimers. In this article, we report the facile synthesis of a
aliphatic polyamide dendrimer having the 3,4-dialkoxyhydro-
cinnamamide structure as a repeating unit based on the
convergent method by extending the facile synthetic method of
aromatic polyamide dendrimers.
INTRODUCTION
■
Dendrimers are hyperbranched and three-dimensional macro-
molecules with a well-defined core, backbone and multivalent
periphery. Their characteristic structures give dendrimers
specific characteristics such as a low viscosity in solution,
numerous functionalization possibilities and accommodation of
guest compounds. These specifities have encouraged the
pursuit of new polymeric materials for applications in areas,
such as catalysts,1 liquid crystals,2 photonic devices,3 and drug
delivery systems.4−6 Although dendrimers have received much
attention as new materials, their widespread uses were
interfered because the synthesis of dendrimers requires a
tedious multistep procedure with repetitive protection−
deprotection and purification processes. To solve this problem,
we have focused on the development of facile synthetic
approaches of dendrimers, and reported the rapid syntheses of
aromatic polyamide dendrimers via both divergent and
convergent methods,7−11 in which the total number of
reactions decreased to half that required in the conventional
approaches. Whereas a few aromatic polyamide dendrimers
have been reported as functional materials, there are many
reports on the development of aliphatic polyamide den-
drimers12,13 as the functional materials, such as polyamide
amine (PAMAM) dendrimers, lysine dendrimers and airbol.
These aliphatic polyamide dendrimers have been receiving
attention especially as medical,14−17 biological,18,19 catalytic,20
and encapsulation materials.21,22 These aliphatic polyamide
dendrimers were prepared by the repetitive conversion of the
terminal groups or protection−deprotection, and purification
processes, and a few papers were reported about the facile
EXPERIMENTAL SECTION
■
Materials. N-Methyl-2-pyrrolidinone (NMP) was distilled under
reduced pressure over calcium hydride, and then stored under
nitrogen. Triethylamine (TEA) was distilled over calcium hydride
under nitrogen, and then stored under nitrogen. DBOP was supplied
from KYOCERA Chemical Corporation and recrystallized from
hexane, then stored under nitrogen in a refrigerator. Other reagents
Received: April 10, 2012
Revised: May 4, 2012
Published: May 14, 2012
© 2012 American Chemical Society
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and solvents were obtained commercially and used as received unless
otherwise noted.
6.65−6.85 (m, 9H). Anal. Calcd for C65H100N6O18: C, 62.28; H, 8.04;
N, 6.70. Found: C, 62.52; H, 8.12; N, 6.62. MALDI−TOF MS: Calcd:
[M]+ = 1274.7, Found: [M + Na]+ = 1272.0.
Synthesis of Protected First Generation Dendrons (pro-
tected-G1-dendron). To a mixture of 3-bromopropyl-1-NHBoc (1,
9.00 g, 37.8 mmol), K2CO3 (7.84 g, 56.7 mmol) and molecular sieves
(12 g) in DMF (25 mL) was added methyl 3,4-dihydroxyhydrocinna-
mate (2.47 g, 12.6 mmol) at room temperature under nitrogen. The
reaction mixture was stirred at 60 °C overnight, cooled to room
temperature and filtered. The filtrate was diluted with ethyl acetate
(EtOAc)/ether = 1/1, and the organic phase was washed with water
and brine. The organic phase was dried over MgSO4, concentrated in
vacuo, and purified by column chromatography (methanol/EtOAc/
hexane = 1/3/15). Recrystallization from methanol/water gave white
solid (4.36 g, 68%). Mp: 83−84 °C. IR (KBr, cm−1): 1172 (Ar−O−
alkyl), 1689, 1728 (CO, amide and carbamate), 2938, 2977 (Ar−
Synthesis of Third Generation Dendrons (G3-dendron). To a
solution of G2-dendron (1.51 g, 1.20 mmol) in NMP (4.0 mL) were
added DBOP (0.460 g, 1.20 mmol) and TEA (0.17 mL, 1.20 mmol)
under nitrogen. The reaction solution was stirred at room temperature
for 1.5 h. Then, the reaction solution was added dropwise to a NMP
(4.5 mL) solution of TEA (1.50 mL, 10.8 mmol) and AB2 which was
synthesized from 0.274 g (0.552 mmol) of G1-dendron. The reaction
solution was stirred at room temeperature for 3 h. The reaction
solution was poured in water and acidified with 1 M HCl (aq). The
precipitate was collected and dried. The crude product was dissolved
in methanol (30 mL), diluted with acetone (60 mL), and then hexane
(240 mL) was added to the solution. The precipitate was collected and
dried in vacuo at 40 °C to give white powder (1.33 g, 87%). Tg: 45 °C.
IR (KBr, cm−1): 1172 (Ar−O−alkyl), 1650, 1697 (CO, carbamate,
carboxylic acid and amide), 2931, 2969 (Ar−H), 3347, 3402 (N−H,
1
H), 3379 (N−H, carbamate). H NMR (MeOH-d4, δ, ppm): 1.43 (s,
3
18H), 1.87−1.99 (m, 4H), 2.60 (t, 2H, 3J = 7.7 Hz), 2.84 (t, 2H, J =
7.7 Hz), 3.21−3.29 (m, 4H) 3.64 (s, 3H) 4.02 (m, 4H) 6.73 (dd, 1H,
4
4
3
3J = 8.0, J = 2.0), 6.82 (d, 1H, J = 2.0) 6.86 (d, 1H, J = 8.0). Anal.
Calcd for C26H42N2O8: C, 61.16; H, 8.29; N, 5.49. Found: C, 60.96;
H, 8.15; N, 5.45.
1
carbamate and amide). H NMR (THF-d8, δ, ppm): 1.39 (s, 72H),
1.78−1.95 (m, 28H), 2.31−2.41 (m, 12H), 2.49 (t, 2H, J = 7.8 Hz)
2.79 (t, 14H, J = 7.8 Hz), 3.17−3.40 (m, 28H) 3.79−4.01 (m, 28H),
6.13−6.25 (m, 8H), 6.59−6.82 (m, 21H) 7.16−7.29 (m, 6H) 6.65−
6.85 (m, 9H). Anal. Calcd for C145H220N14O38: C, 62.93; H, 8.01; N,
7.09. Found: C, 63.26; H, 8.13; N, 6.98. MALDI−TOF MS: calcd
[M]+ = 2787.5; found [M + Na]+ = 2787.6.
Synthesis of First Generation Dendrons (G1-dendron). A
mixture of the compound protected-G1-dendron (4.05 g, 7.93 mmol)
and KOH (0.620 g, 9.80 mmol) in methanol/water (45 mL/15 mL)
was refluxed for 2 h. The reaction solution was cooled to room
temperature and acidified with acetic acid. Then, the organic layer was
diluted with dichloromethane (DCM) and washed with water three
times, and dried over MgSO4. After filtration, the solvent was removed
under reduced pressure. The G1-dendron was obtained as white solid
after the recrystallization from toluene/hexane (3.32 g, 84%). Mp:
102−103 °C. IR (KBr, cm−1): 1172 (Ar−O−alkyl), 1704, 1735 (C
O, carbamate and carboxylic acid), 2938, 2977 (Ar−H), 3332 (N−H,
Synthesis of Dumbbell-Shaped Third Generation Den-
drimers (DS-G3-dendrimer). To a solution of G3-dendron (0.274
g, 0.100 mmol) in NMP (0.6 mL) were added DBOP (38.3 g, 0.100
mmol) and TEA (14.0 μL, 0.100 mmol) under nitrogen. The reaction
solution was stirred at room temperature for 1.5 h. Then, the reaction
solution was added dropwise to a solution of p-xylylenediamine (6.26
mg, 0.0460 mmol) in NMP (0.6 mL), and the reaction solution was
stirred at room temperature for 6 h. The reaction solution was poured
in 1 wt % NaHCO3 (aq). The precipitate was collected and dried. The
crude product was dissolved in DMF (1.2 mL) and diluted with
MeOH (6.0 mL), and then acetone (24 mL) and hexane (12 mL)
were added to the solution. The precipitate was collected and dried in
vacuo at 40 °C to give white powder (0.174 g, 75%). Tg: 52 °C. IR
(KBr, cm−1): 1172 (Ar−O−alkyl), 1643, 1697 (CO, carbamate and
amide), 2931, 2969 (Ar−H), 3309, 3347 (N−H, carbamate and
amide). 1H NMR (DMSO-d6, δ, ppm): 1.37 (s, 144H), 1.71−1.92 (m,
56H), 2.25−2.46 (m, 28H), 2.66−2.82 (m, 28H), 3.02−3.16 (m,
32H) 3.16−3.26 (m, 24H, overlapped with H2O), 3.81−4.00 (m,
1
carbamate). H NMR (MeOH-d4, δ, ppm): 1.43 (s, 18H), 1.87−2.01
(m, 4H), 2.60 (t, 2H, 3J = 7.7 Hz), 2.84 (t, 2H, 3J = 7.7 Hz), 3.21−3.29
(m, 4H) 4.02 (m, 4H) 6.75 (dd, 1H, 3J = 8.0, 4J = 2.0), 6.83−6.88 (m,
2H). Anal. Calcd for C25H40N2O8: C, 60.47; H, 8.12; N, 5.64. Found:
C, 60.38; H, 8.09; N, 5.63.
Synthesis of AB2 Building Blocks (AB2). The G1-dendron (50.0
mg, 0.1 mmol) was dissolved in trifluoroacetic acid (TFA) (0.5 mL),
and the reaction solution was stirred at room temperature for 1.5 h.
The solvent was evaporated to dryness to give white sticky oil. The oil
was washed with ether three times and dried under reduced pressure
to give white stickly oil (51.1 mg, 97%). IR (NaCl, cm−1): 1133 (Ar−
O−Alkyl), 1203 (C−F), 1681 (CO, carboxylate), 2700−3300 (N−
3
56H), 4.22 (d, 4H, J = 5.8 Hz), 6.50−6.89 (m, 58H), 7.11 (s, 4H),
1
7.69−7.91 (m, 12H), 8.17 (t, 2H, 3J = 5.8 Hz). Anal. Calcd for
C294H448N30O74: C, 63.52; H, 8.01; N, 7.46. Found: C, 63.39; H, 8.02;
N, 7.36. MALDI−TOF MS: calcd [M]+ = 5653.2; found [M + Na]+ =
5653.3.
H, ammonium), H NMR (MeOH-d4, δ, ppm): 2.08−2.24 (m, 4H),
2.58 (t, 2H, 3J = 7.6 Hz) 2.86 (t, 2H, 3J = 7.6 Hz), 3.13−3.23 (m, 4H)
4.09−4.21 (m, 4H), 6.81 (dd, 4H, 3J = 8.2 Hz, 4J = 2.0 Hz), 6.59−6.82
(m, 9H) 7.16−7.29 (m, 2H) 6.65−6.85 (m, 9H). Anal. Calcd for
C19H26F6N2O8: C, 43.52; H, 5.00; N, 5.34. Found: C, 43.70; H, 4.91;
N, 5.04.
Synthesis of Protected Three Functional Core (Protected-3-
core). To a mixture of 1 (1.43 g, 6.00 mmol), K2CO3 (1.24 g, 9.00
mmol), and molecular sieves (2 g) in DMF (2 mL) was added
phloroglucinol (0.126 g, 1.00 mmol) at room temperature under
nitrogen. The reaction mixture was stirred at 60 °C overnight, cooled
to room temperature and filtered. The filtrate was diluted with EtOAc/
ether = 1/1, and the organic phase was washed with water and brine.
The organic phase was dried over MgSO4, concentrated in vacuo, and
purified by column chromatography (methanol/EtOAc/hexane =1/3/
15). Recrystallization from methanol/water two times gave white solid
(0.155 g, 26%). Mp: 109−110 °C. IR (KBr, cm−1): 1164 (Ar−O−
alkyl), 1689 (CO, carbamate), 2977 (Ar−H), 3370 (N−H,
carbamate). 1H NMR (DMSO-d6, δ, ppm): 1.38 (s, 27H), 1.75−
Synthesis of Second Generation Dendrons (G2-dendron).
To a solution of G1-dendron (1.49 g, 3.00 mmol) in NMP (4.8 mL)
were added DBOP (1.00 g, 2.85 mmol) and TEA (0.4 mL, 2.85
mmol) under nitrogen. The reaction solution was stirred at room
temperature for 1.5 h. Then, the reaction solution was added dropwise
to a NMP (4.8 mL) solution of TEA (1.20 mL, 8.10 mmol) and AB2
which was synthesized from 0.670 g (1.35 mmol) of G1-dendron, and
the reaction solution was stirred at room temperature for 3 h. The
reaction solution was diluted with EtOAc/ether = 1/1. The organic
layer was washed with 1 M HCl (aq) and brine, and then dried with
MgSO4. After filtration, the solvent was removed under reduced
pressure to give pale yellow oil. The oil was diluted with acetone (18
mL), and hexane (54 mL) was added to the solution. The precipitate
was collected and dried in vacuo at 40 °C to give white powder. (1.26
g, 75%) Mp: 74 −75 °C. IR (KBr, cm−1): 1172 (Ar−O−alkyl), 1643,
1689 (CO, carbamate, carboxylic acid and amide), 2931, 2969 (Ar−
H), 3363 (N−H, carbamate and amide). 1H NMR (THF-d8, δ, ppm):
1.39 (s, 36H), 1.80−1.95 (m, 12H), 2.30−2.39 (m, 4H), 2.57 (t, 2H, J
= 7.8 Hz) 2.79 (t, 6H, J = 7.8 Hz), 3.17−3.40 (m, 12H) 3.86−3.99 (m,
12H), 6.07−6.24 (m, 4H), 6.59−6.82 (m, 9H) 7.16−7.29 (m, 2H)
3
1.85 (m, 6H), 3.02−3.10 (m, 6H) 3.92 (t, 6H, J = 6.6) 6.05 (s, 3H),
6.60−6.80 (brs, 3H). Anal. Calcd for C26H42N2O8: C, 60.28; H, 8.60;
N, 7.03. Found: C, 60.09; H, 8.34; N, 7.07.
Synthesis of the Three Functional Core (3-core). The
protected-3-core (60.0 mg, 0.1 mmol) was dissolved in TFA (1
mL), and the reaction solution was stirred at room temperature for 1.5
h. The solvent was evaporated to dryness to give a white sticky oil. The
oil was washed with ether three times and dried under reduced
pressure to give white stickly oil (62.1 mg, 97%). IR (NaCl, cm−1):
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Scheme 1. Synthesis of G1-dendron and AB2
1172 (Ar−O−Alkyl), 1203 (C−F), 1681 (CO, carboxylate), 2500−
RESULTS AND DISCUSSION
Synthesis of G1-dendron and AB2. Scheme 1 shows the
■
1
3300 (N−H, ammonium), H NMR (DMSO-d6, δ, ppm): 1.94−2.07
3
(m, 6H), 2.89−3.03 (m, 6H) 4.02 (t, 6H, J = 6.3 Hz), 6.14 (s, 3H).
synthetic route for G1-dendron and AB2. 3-Bromo-propyl-1-
NHBoc (1) was prepared according to a previous paper.25
Methyl 3,4-dihydroxyhydrocinnamate (2) was prepared by the
Fischer esterification of 3,4-dihydroxyhydrocinnamic acid with
methanol.26 2 was reacted with 1 in the presence of K2CO3 and
molecular sieves to yield a protected G1-dendron (Protected-
G1-dendron), which was converted into the G1-dendron by
the hydrolysis of the methyl ester group of Protected-G1-
dendron. Protected-G1-dendron and G1-dendron were
Anal. Calcd for C21H30F9N3O9: C, 39.44; H, 4.73; N, 6.57. Found: C,
39.18; H, 4.64; N, 6.75.
Synthesis of Star-Shaped Third Generation Dendrimers (SS-
G3-dendrimer). To a solution of G3-dendron (0.554 g, 0.200 mmol)
in NMP (0.7 mL) were added DBOP (76.6 g, 0.200 mmol) and TEA
(27.9 μL, 0.200 mmol) under nitrogen. The reaction solution was
stirred at room temperature for 3 h. Then, the reaction solution was
added dropwise to a NMP (0.3 mL) solution of TEA (72 μL, 0.513
mmol) and 3-core which was synthesized from 0.034 g (0.057 mmol)
of protected-3-core, and the reaction solution was stirred at room
temperature for 1 day. The reaction solution was poured in 1 wt %
NaHCO3 (aq). The precipitate was collected and dried. The crude
product was dissolved in DMF (2.4 mL) and diluted with methanol
(73 mL), and then water (12 mL) was added to the solution. The
precipitate was dissolved again in DMF (1.2 mL) and diluted with
methanol (37 mL), and then water (6 mL) was added to the solution.
The precipitate was collected and dried in vacuo at 40 °C to give white
powder (0.200 g, 41%). Tg: 48 °C. IR (KBr, cm−1): 1168 (Ar−O−
alkyl), 1643, 1689 (CO, carbamate and amide), 2931, 2973 (Ar−
1
characterized by H NMR and IR spectorcopy and elemental
1
analysis. The H NMR spectrum of G1-dendron is shown in
Figure 1. All signals are well assigned to the corresponding
1
H), 3100−3600 (N−H, carbamate and amide). H NMR (DMSO-d6,
δ, ppm): 1.36 (s, 216H), 1.72−1.89 (m, 90H), 2.28−2.39 (m, 42H),
2.65−2.80 (m, 42H), 3.03−3.15 (m, 48H) 3.16−3.26 (m, 44H,
overlapped with H2O), 3.84−4.01 (m, 90H), 6.06 (s, 3H), 6.55−6.84
(m, 87H), 7.72−7.84 (m, 21H). Anal. Calcd for C450H681N45O114 4.75
H2O: C, 62.64; H, 8.06; N, 7.31. Found: C, 62.82; H, 7.92; N, 7.13.
MALDI−TOF MS: calcd [M]+ = 8539.9; found [M + Na]+ = 8562.07
Measurements. 1H NMR spectra were recorded in deuterated
methanol (MeOH-d4), tetrahydrofuran (THF-d8) or dimethyl
sulfoxide (DMSO-d6) on a BRUKER DPX-300 spectrometer at 300
MHz. Infrared spectra were recorded on a Horiba FT-720
spectrophotometer. Matrix-assisted laser desorption ionization with
time-of-flight (MALDI−TOF) MS spectra were recorded on a Kratos
Kompact MALDI instrument operated in linear detection mode to
generate positive ion spectra using dithranol as a matrix, THF as a
solvent, and sodium trifluoroacetate as an additive.
1
Figure 1. H NMR spectrum of G1-dendron.
structure. The N-tert-Boc group of G1-dendron was depro-
tected using TFA to afford the AB2. AB2 was also characterized
by H NMR and IR spectroscopies and elemental analysis.
Synthesis of G2-dendron and G3-dendron. As
described in the Introduction, we previously developed a facile
synthetic method of aromatic polyamide dendrimers using
DBOP as the condensing agent.7 In this method, coupling
reactions for synthesis of the dendrons were conducted by a
two-step method consisting of (1) activation of a carboxylic
1
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Scheme 2. Synthesis of G2-dendron
acid by DBOP, i.e., generation of an active amide, and (2)
condensation of this active amide with an amino group by
addition of the AB2 building block.
the other hand, only HyC−Amide was obtained as the
expected product when benzoic acid was used instead of
MeO−HyC−OH (Scheme 3b). This result is probably due to
the higher nucleophilicity of the aliphatic carboxylate anion
than the aromatic carboxylate anion. In the former reaction
(Scheme 3a), the MeO−HyC−OH anion reacted with HyC−
Act to form the acid anhydride together with the formation of
HyC−Amide from HyC−Act and 2-EHA. The mixed acid
anhydride reacted with 2-EHA to yield HyC−Amide and
MeO−HyC−Amide (Scheme 4). The formation of the acid
anhydride was investigated by the reaction of HCy-Act with
MeO−HyC−OH in the presence of TEA. After removal of
We then prepared G2-dendron following the procedure
described above (Scheme 2). G1-dendron was activated with a
0.98 equiv of DBOP in the presence of TEA in NMP at room
temperature for 30 min, and then reacted with AB2 in the
presence of TEA in NMP at room temperature for 3 h.
However, the MALDI−TOF MS spectrum of the isolated
products showed strong signals corresponding to not only G2-
dendron, but also higher molecular weight byproducts which
were not observed in the synthesis of the aromatic polyamide
dendrimers (Figure 2).
1
MeO−HyC−OH, the product was characterized by H NMR
1
and IR spectroscopies. The H NMR spectrum in CDCl3
showed a decrease in the signal at 8.1 ppm which corresponded
to the active amide and appearance of the signal at 3.8 ppm,
which was due to the methyl ether group of MeO−HyC−OH.
The IR spectrum of the product showed peaks at 1727 and
1812 cm−1 which corresponded to the CO stretching of the
active amide and acid anhydride, respectively. These results
clearly indicated the formation of the acid anhydride.
To avoid the formation of the acid anhydride, the HyC−Act
solution was added dropwise to a solution of MeO−HyC−OH
and 2-EHA and TEA in NMP. This procedure successfully
reduced the formation of MeO−HyC−Amide to 2% (Scheme
5).
On the basis of these model reactions, the second and third
generation dendrons (G2-dendron, G3-dendron) were pre-
pared as shown in Scheme 6. The solution of the activated G1-
dendron or G2-dendron was added dropwise to the solution of
AB2 and TEA in NMP. G2-dendron and G3-dendron were
simply purified by reprecipitation in 75 and 87% yields,
respectively.
Figure 2. MALDI−TOF MS spectrum of G2 dendron.
The possible reasons for the presence of higher molecular
weight products are (1) the presence of remaining DBOP in
the condensation step, and (2) an undesired side reaction of
the active amide with the aliphatic carboxyl group of AB2. Thus,
the molar ratio of DBOP to the substrate was decreased from
0.98 equiv to 0.93 equiv and the activation time was extended
from 30 min to 1.5 h However, the signals of the higher
molecular weight products still remained. The following model
reactions were then carried out to confirm the reactivity of
aliphatic carboxyl group to the active amide (Scheme 3). The
reaction conditions are noted in the Supporting Information,
The formations of G2-dendron and G3-dendron were
confirmed by 1H NMR and IR spectroscopies, elemental
analysis, and MALDI−TOF MS spectroscopy. The1H NMR
spectrum of G2-dendron is shown in Figure S2, Supporting
Information. The IR spectrum of G3-dendron showed strong
absorptions at 3401, 3347, 1697, and 1650 cm−1 due to the
characteristic N−H and CO stretchings of the carbamate and
amide groups, respectively. Furthermore, the characteristic
1
and the H NMR spectra of the model compounds are shown
1
ether stretching was observed at 1172 cm−1. The H NMR
in Figure S1, Supporting Information.
spectrum of G3-dendron showed signals corresponding to the
carbamate protons (A) at 6.13−6.25 ppm, amide protons (B
and C) at 7.28−7.41 ppm, aromatic protons (e, f, g, m, n, o, u,
v, w) at 6.61−6.79 ppm, and tert-butyl protons of the end unit
(a) at 1.39 ppm, respectively (Figure 3).
Furthermore, the MALDI−TOF MS spectra of the G2-
dendron and G3-dendron showed peaks observed at M/Z ([M
+ Na]+) = 1272.0 and 2787.6 and well agreed with the
The active amide of hydrocinnamic acid (HyC−Act) was
synthesized by the reaction of hydrocinnamic acid (HyC−OH)
with DBOP. When a solution of 4-methoxyhydrocinnamic acid
(MeO−HyC−OH), 2-ethylhexylamine (2-EHA), and TEA
were added to a solution of HyC−Act, N-(2-ethylhexyl)-3-
phenylpropanamide (HyC−Amide) (79%) and N-(2-ethyl-
hexyl)-3-(4-metoxyphenyl)propanamide (MeO−HyC−
Amide) (21%) were obtained as products (Scheme 3a). On
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Scheme 3. Model Reaction 1
Scheme 4. Reaction of HCy-Act with 2-EHA under the Presence of MeO−HCy−OH
Scheme 5. Model Reaction 2
calculated masses (1274.7 and 2787.5), together with minor
peaks which could be assigned to the partially deprotected
dendrons (Figure 4 and Figure 5). The deprotection probably
occurred during the measurement. Moreover, no signals
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Scheme 6. Synthesis of G2-dendron and G3-dendron
Figure 4. MALDI−TOF MS spectrum of G2-dendron.
1
Figure 3. H NMR spectrum of G3-dendron.
at 3347, 3309, 1697, and 1643 cm−1 due to the characteristic
N−H and CO stretchings of the carbamate and amide
groups, respectively. Furthermore, the characteristic ether
stretching was observed at 1172 cm−1.
derived from dendrons having lower or higher molecular
weights were observed in Figure 4 and Figure 5.
Synthesis of Dumbbell-Shaped Dendrimers. Dumb-
bell-shaped dendrimers (DS-G3-dendrimer) were synthesized
by a procedure similar to the dendron synthesis (Scheme 7).
The activated G3-dendron was added dropwise to a solution of
p-xylylenediamine in NMP. DS-G3-dendrimer was purified by
reprecipitation in 75% yield. DS-G3-dendrimer was charac-
terized by 1H NMR (Figure 6) and IR spectroscopies,
elemental analysis, and MALDI−TOF MS spectroscopy. The
IR spectrum of DS-G3-dendrimer showed strong absorptions
The 1H NMR spectrum of DS-G3-dendrimer showed
signals corresponding to the amide protons (B, C and D) at
7.69−7.91 and 8.17 ppm, aromatic protons of the core (∗) at
7.11 ppm, carbamate and aromatic protons (A, e, f, g, m, n, o, u,
v and w) at 6.50−6.89 ppm, benzyl protons of the core (z) at
4.22 ppm, and tert-butyl protons of the end unit (a) at 1.37
ppm. Furthermore, the MALDI−TOF MS spectrum of DS-G3-
dendrimer showed a peak observed at M/Z ([M + Na]+) =
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Figure 5. MALDI−TOF MS spectrum of G3-dendron.
1
5653.3, which well agreed with the calculated mass (5653.2),
together with minor peaks which could be assignable to
partially deprotected dendrimers, probably obtained during the
measurement (Figure 7). Moreover, no extra signals derived
from dendrons having defect structures were observed in Figure
7.
Figure 6. H NMR spectrum of DS-G3-dendrimer.
Synthesis of Star-Shaped Dendrimers. A coupling
reaction of G3-dendrons with a trifunctional core molecule
(3-core) was performed to obtain star-shaped dendrimers (SS-
G3-dendrimer) (Scheme 8).
Activation and condensation reactions were conducted using
similar conditions for the synthesis of the SS-G3-dendrimer.
The activated G3-dendron was added dropwise to a solution of
TEA and 3-core in NMP. SS-G3-dendrimer was purified by
reprecipitation in 41% yield. SS-G3-dendrimer was charac-
terized by 1H NMR (Figure 8) and IR spectroscopies,
elemental analysis, and MALDI−TOF MS spectroscopy. The
IR spectrum of SS-G3-dendrimer showed strong absorptions
at 3600−3100, 1689, and 1643 cm−1 due to the characteristic
N−H and CO stretchings of the carbamate and amide
groups, respectively. Furthermore, the characteristic ether
stretching was observed at 1168 cm−1 (see Figure S3 in
Figure 7. MALDI−TOF mass spectrum of DS-G3-dendrimer.
protons (A, e, f, g, m, n, o, u, v and w) at 6.55−6.89 ppm,
aroatic protons of the core (∗) at 6.06 ppm, and tert-butyl
protons of the end unit (a) at 1.36 ppm.
Furthermore, the MALDI−TOF MS spectrum of SS-G3-
dendrimer showed a peak observed at M/Z ([M + Na]+) =
8562.1, which well agreed with the calculated mass (8561.9),
together with minor peaks which could be assignable to
1
Supporting Information). The H NMR spectrum of SS-G3-
dendron showed signals corresponding to the amide protons
(B, C and D) at 7.72−7.84 and ppm, carbamate and aromatic
Scheme 7. Synthesis of DS-G3-dendrimer
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Scheme 8. Synthesis of SS-G3-dendrimer
Figure 9. MALDI−TOF spectrum of SS-G3-dendrimer.
1
Figure 8. H NMR spectrum of SS-G3-dendrimer.
CONCLUSIONS
■
We have developed a facile synthetic method of aliphatic
polyamide dendrons and dendrimers based on a convergent
approach, which consists of the direct condensation of a
carboxylic acid and unprotected AB2 building block using
DBOP as the condensing agent. By this method, each of the
dendrons and dendrimers was purified only by extraction and/
or reprecipitation. The MALDI−TOF MS spectra supported
the expected formation of each dendron and dendrimer. This
novel convergent route for the aliphatic polyamide dendrimers
is attractive both for use in the laboratory and industry, since it
could be extended to the synthesis of other aliphatic
dendrimers, such as polyamide amine dendrimers and lysine
dendrimers, which have already been used as functional
materials in many fields.
partially deprotected dendrimers (Figure 9). Moreover, no
extra signals derived from dendrons having defect structures
were observed in Figure 9.
In summary, we successfully developed a facile synthetic
method of aliphatic polyamide dendrimers. To synthesize
dendrons and dendrimers without byproducts, it was necessary
that the solution of the activated dendrons was added dropwise
to that of AB2 or core molecules. Thus, the addition order of
reagents is very important. On the basis of these findings, we
succeeded in synthesizing DS-G3-dendrimer and SS-G3-
dendrimer.
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(24) Al-Hamra, M.; Ghaddar, T. H. Tetrahedron Lett. 2005, 46,
5711−5714.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures of model reactions. H NMR spectra
of model compounds and G2-dendron, and the IR spectrum of
SS-G3-dendrimer. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
(25) van Scherpenzeel, M.; van den Berg, R. J.; Donker-Koopman,
W. E.; Liskamp, R. M.; Aerts, J. M.; Overkleeft, H. S.; Pieters, R. J.
Bioorg. Med. Chem. 2010, 18, 267−73.
1
(26) Dorrestein, P. C.; Poole, K.; Begley, T. P. Org. Lett. 2003, 5,
2215−2217.
AUTHOR INFORMATION
Corresponding Author
■
*Telephone and Fax: + 81-3-5734-2127. E-mail: ueda.m.ad@
polymer.titech.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Y.I. thanks the Japan Society of the Promotion of Science
(JSPS, No. 2208196) for financial supports.
■
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