"Click" synthesis of intrinsically hydrophilic dendrons and dendrimers containing metal binding moieties at each branching unit

Article abstract of DOI:10.1021/ma500126f

A new family of water-soluble triazole dendrimers composed of tri(ethylene glycol) (TrEG) and bis(methylol)propionic acid (bis-MPA) was created through Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) between specifically designed complementary building blocks. Dendrimers up to generation three were synthesized by CuAAC to a trifunctional core with yields ranging from 72% for generation one, through 67% for generation two, and 64% for third generation dendrimer. The two triazole rings at each bis-MPA branching site could serve as efficient chelating pockets for some VIIIA group elements. As proof-of-principle, the [PdCl₂(PhCN)₂] coordination chemistry of these hydrophilic dendritic ligands was studied by ¹H NMR, dynamic light scattering, transmission electron microscopy, and DFT calculations. The results showed that the complexation is completed within 5 min. The novel hydrophilic dendritic Pd complexes were able to catalyze Suzuki-Miyaura coupling reactions in water within 3 h at 100 °C, at 60 °C, and even at 50 °C with practically quantitative conversion.

Full text of DOI:10.1021/ma500126f

Article
pubs.acs.org/Macromolecules
“
Click” Synthesis of Intrinsically Hydrophilic Dendrons and
Dendrimers Containing Metal Binding Moieties at Each Branching Unit
Lili Wang, David J. Kiemle, Connor J. Boyle, Eoghan L. Connors, and Ivan Gitsov*
†
†
†
†
,†,‡
†
‡
Department of Chemistry and The Michael M. Szwarc Polymer Research Institute, State University of New York-ESF, Syracuse,
New York 13210, United States
*
S Supporting Information
ABSTRACT: A new family of water-soluble triazole den-
drimers composed of tri(ethylene glycol) (TrEG) and bis-
(
methylol)propionic acid (bis-MPA) was created through
Cu(I)-catalyzed alkyne−azide cycloaddition (CuAAC) be-
tween specifically designed complementary building blocks.
Dendrimers up to generation three were synthesized by
CuAAC to a trifunctional core with yields ranging from 72%
for generation one, through 67% for generation two, and 64%
for third generation dendrimer. The two triazole rings at each
bis-MPA branching site could serve as efficient chelating
pockets for some VIIIA group elements. As proof-of-principle,
the [PdCl (PhCN) ] coordination chemistry of these hydro-
2
2
1
philic dendritic ligands was studied by H NMR, dynamic light scattering, transmission electron microscopy, and DFT
calculations. The results showed that the complexation is completed within 5 min. The novel hydrophilic dendritic Pd complexes
were able to catalyze Suzuki−Miyaura coupling reactions in water within 3 h at 100 °C, at 60 °C, and even at 50 °C with
practically quantitative conversion.
8
INTRODUCTION
Despite some early attempts and prognoses, until recently little
■
attention was focused on exploiting the benefits of the triazole
Dendrimers are perfectly branched and monodisperse macro-
molecules with layered architecture. By regulating dendrimer
synthesis, it is possible to precisely manipulate both their
molecular weight and chemical composition, thereby inducing
9
moiety outside its simple linking functions. Most application
attempts associated with this group occurred outside the
dendrimer/polymer “domain” and were centered on the
investigation of the coordination properties of small triazole
heterocycles to transitional metal ions. It was shown that the
1,2,3-triazole ring could serve as a ligand, which can provide
1
predictable properties and diverse applications. The two major
synthetic approaches for constructing dendrimers are the
2
3
divergent and convergent methods. It should be mentioned
that both strategies require efficient and high yield reactions in
order to produce macromolecular structures with defect-free
architecture. Therefore, the development of effective synthetic
strategies toward dendrimers with sophisticated architecture and
broad application potential is a continuing theme in dendrimer
synthesis. Among those efficient approaches to dendrimers,
8
9,10
suitable coordination sites via nitrogens N3 and/or N2
or
11
10a,c
through C4 as carbene to transitional metals such as Pd,
12
13
11c,9b,14
11a,14
Cu, Pt, Re,
and Ag.
Among those complexes, the
palladium complex is of specific interest because of its catalytic
properties in various cross-coupling organic reactions. Pd-
mediated catalysis has provided a general and mild procedure
for carbon−carbon bond construction. Palladium-containing
dendrimers have long been used as promising catalysts for these
15
4
the Huisgen cycloaddition is increasingly used. The copper-
catalyzed azide−alkyne cycloaddition (CuAAC), introduced in
001, could be considered as a variation of this method. Since
then, it attracted considerable attention for the reason that it is
quantitative and robust process, which is functional-group
tolerant, and can proceed under mild conditions. These features
make the “click” reaction particularly suitable for the synthesis of
18
5
reactions, but studies on triazole-containing dendritic polymers
2
as Pd ligands and catalysts in C−C couplings are relatively
19,20
rare.
Interesting current investigations also suggest that the
modification of dendrimer periphery with short poly(ethylene
glycol) chains might favorably affect the activity and stability of
dendritic palladium catalysts in Suzuki−Miyaura reactions.
The motivation for this study originates from these
21
6
dendrimers as shown initially by Wu et al. and others. Currently
CuAAC is used in a broad array of dendrimer syntheses and
1
9,21
7
publications.
Herein, we report the convergent synthesis
modifications.
Notably, the major interest in the CuAAC is due to the fact
that it is an efficient synthetic approach to covalently link func-
tional building blocks through the formation of a 1,4-disubstitued
Received: January 16, 2014
Revised: March 5, 2014
Published: March 17, 2014
1
,2,3-triazole ring, which is rather stable under various conditions.
©
2014 American Chemical Society
2199
dx.doi.org/10.1021/ma500126f | Macromolecules 2014, 47, 2199−2213

Macromolecules
Article
and characterization of a new family of water-soluble triazole
dendrimers composed of triethylene glycol, TrEG, as the water-
soluble interior spacer and bis(methylol)propionic acid, bis-
MPA, as the branching unit. Dendrons and dendrimers up to
generation 3 are produced by iterative coupling/modification
involving alkyne−azide “click” reactions with novel AB2
monomers. The resulting TrEG/bis-MPA-based triazole den-
drimers are freely water-soluble and show promising metal ion
binding abilities. Model Suzuki−Miyaura cross-coupling reac-
tions confirm the high catalytic activity of their Pd complexes in
aqueous media.
The palladium concentration in solution was determined on a
PerkinElmer Elan DRC-e inductively coupled plasma mass spectrom-
eter (ICP-MS).
Syntheses. 2,2-Bis(propargyl)propargyl Propionate (1). Bis-MPA
(
1.63 g, 12.16 mmol) was dissolved with 15 mL of dry DMF in a flame-
dried two-neck flask. The system was cooled to 0 °C, and NaH (964 mg,
0.2 mmol) was added carefully at once. The reaction mixture was
stirred until hydrogen evolution was complete. Then, propargyl bromide
80 wt % in toluene, 8.75 g, 58.8 mmol) was added slowly. The mixture
4
(
was stirred at 0 °C for 30 min and then at room temperature (RT) for
12 h. The reaction was quenched with 10 mL of water and extracted with
EtOAc (3 × 50 mL). The organic layers were combined, washed with
brine, dried over MgSO , and concentrated to give a dark brown oily
4
1
product (1.01g, 34%). H NMR (300 MHz, CDCl ) δ, ppm: 1.25 (s,
3
EXPERIMENTAL SECTION
■
3H), 2.42 (t, J = 2.4 Hz, 2H), 2.46 (t, J = 2.5 Hz, 1H), 3.67 (s, 2H), 4.15
(d, J = 2.4 Hz, 4H), 4.70 (d, J = 2.5 Hz, 2H).
2,2-Bis(propargyl)propionic Acid (2). 1 (877.45 mg, 3.53 mmol) was
Materials. 2-[2-(2-Chloroethoxy)ethoxy]ethanol (96%); p-toluene-
sulfonic acid monohydrate (≥98.5%); sodium hydride, NaH (95%, dry
powder); N,N,N′,N″,N″-pentamethyldiethylenetriamine, PMDETA
dissolved in 30 mL of THF and 5 mL of H
Then 25 mL of LiOH·H O (0.67 N) was slowly added to the flask. The
O at 0 °C in a two-neck flask.
2
(
99%); copper(I) bromide, CuBr (98%); 1,1,1-tris(hydroxymethyl)-
2
propane (97%); propargyl bromide (80 wt % in toluene); N,N′-
completion of the reaction was monitored by TLC. After completion,
the reaction mixture was cooled to 0 °C, neutralized with 2 M HCl, and
extracted with EtOAc (3 × 30 mL). The organic layers were combined
and washed with brine. EtOAc was evaporated off, and the crude
dicyclohexylcarbodiimide, DCC (99%); and trifluoroacetic acid, TFA
(
2
99%), were all purchased from Sigma-Aldrich and used as received.
,2-Bis(hydroxymethyl)propionic acid, bis-MPA (99+%), and sodium
azide, NaN (98%, powder), were purchased from Acros and used as
product was purified by column chromatography with hexane/EtOAc
3
1
received. Dichlorobis(benzonitrile)palladium, Pd(PhCN) Cl (99%),
(53/47 v/v) to give pale yellow oil (571.26 mg, 77%). T
NMR (300 MHz, CDCl
g
= −42.2 °C. H
2
2
and ethyl acetate, EtOAc (reagent grade), were purchased from Strem
Chemicals, Inc., and Pharmco, respectively, and used without further
purification. 4-(Dimethylamino)pyridinium p-toluenesulfonate
3
) δ: 4.17 (d, J = 2.4 Hz, 4H), 3.67 (d, J = 0.8 Hz,
4H), 2.43 (t, J = 2.3 Hz, 2H), 1.25 (s, 3H). C NMR (75 MHz, CDCl
13
)
3
δ: 179.87, 79.34, 74.58, 71.46, 58.70, 47.77, 17.79.
(
DPTS) was synthesized using the procedure developed by Moore
2,2-Bis(propargyl)-2-[2-(2-chloroethoxy)ethoxy]ethyl Propionate
3). 2 (970.55 mg, 4.62 mmol), 2-[2-(2-chloroethoxy)ethoxy]ethanol
22
(
and Stupp.
(
932.05 mg, 5.54 mmol), and DPTS (272.24 mg, 0.93 mmol) were
Instrumentation. Size exclusion chromatography (SEC) analyses
were performed on a line consisting of a Waters M510 pump, a Waters
U6K universal injector, three 5 μm PL Gel columns (50 Å, 500 Å,
and Mixed C), and a Viscotek 250 dual refractive index/viscometry
detector. The separation was achieved at 40 °C with freshly distilled
tetrahydrofuran (THF) eluting at 1 mL/min. The apparent molecular
masses and molecular mass distributions were determined using
dissolved in 15 mL of dry CH Cl . After the reaction system was
2
2
degassed with argon, 1.34 g of DCC (6.49 mmol) was added. The
reaction mixture was stirred at RT overnight under argon. After the
reaction was completed, the dicyclohexyl urea (DCU) formed, was
filtered, and washed with CH
flash chromatography on silica gel with eluting solvent of EtOAc/hexane
(33/67, v/v) to give 3 as colorless oily product (1.38 g, 84%). T =
g
Cl . The crude product was purified by
2
2
2
0 monodisperse poly(styrene) standards (162 Da−200 kDa) and
1
Viscotek OmniSEC 3.1 software.
−61.9 °C. H NMR (600 MHz, CDCl
3
) δ: 4.30 (t, J = 4.8 Hz, 2H), 4.17
The mass spectrometric measurements were made on a Bruker
Autoflex III MALDI-TOF MS instrument with Smartbeam ion source
equipped with a Nd:YAG laser (266 and 355 nm). All spectra were
acquired using a reflect-positive mode. The laser attenuation was set to
the lowest value possible to get high resolution spectra. Matrix was
prepared by dissolving recrystallized 2,5-dihydroxybenzoic acid (DHB)
in methanol at a concentration of 40 mg/mL. Sample was prepared in
methanol at a concentration of 1 mg/mL. Samples were spotted using
the dried-droplet method, where sample and matrix were premixed with
a ratio of 1:7. 1 μL of mixed solution was spotted on an AnchorChip
target plate (MTP 384 polished steel, Bruker Daltonics).
(d, J = 2.3 Hz, 4H), 3.79 (t, J = 5.9 Hz, 2H), 3.73 (t, J = 4.8 Hz, 2H),
3.71−3.62 (m, 10H), 2.44 (t, J = 2.3 Hz, 2H), 1.26 (s, 3H). C NMR
(151 MHz, CDCl ) δ: 174.08, 79.71, 74.33, 71.77, 71.44, 70.73, 70.63,
1
3
3
69.19, 63.81, 58.67, 48.05, 42.72, 17.85.
Isopropylidene-2,2-bis(methoxy)propionic Acid (IBPA) (4). Bis-
MPA (21.15 g, 157.8 mmol), 2,2-dimethoxypropane (29 mL, 235.0
mmol), and p-toluenesulfonic acid monohydrate were dissolved in
100 mL of dry acetone. The reaction mixture was stirred overnight at RT
under argon. Then 1 mL of NH
to quench the catalyst. The solvent was evaporated, and the crude
product was then dissolved in 250 mL of CH Cl and extracted three
times with deionized H O (50 mL). The organic layer was dried over
MgSO and concentrated to give the target compound as white solid
/EtOH (1/1, v/v) solution was added
3
2
2
1
13
H NMR and C NMR spectra were recorded using CDCl3
2
or DMSO-d as solvents with Bruker AVANCE 300 or 600 MHz
4
6
1
1
1
instruments. H− H 2D gradient enhanced homonuclear correlation
spectroscopy (ge-COSY) NMR experiments were performed using a
delay time of 1.9 s, obtaining 128 increments and 1 scans per increment,
within a spectral width of 4807 Hz operating at 600 MHz. The DEPT
edited heteronuclear single quantum coherence spectroscopy (DEPT-
HSQC) experiments were executed using a delay time of 2 s, obtaining
(24.21 g, 88%). H NMR (600 MHz, DMSO) δ: 4.03 (d, J = 11.6 Hz,
2H), 3.56 (d, J = 11.6 Hz, 2H), 1.35 (s, 3H), 1.28 (s, 3H), 1.10 (s, 3H).
13
C NMR (151 MHz, DMSO) δ: 175.92, 97.74, 64.43, 41.22, 24.93,
23.40, 18.90.
Isopropylidene-2,2-bis(methoxy)-2-[2-(2-chloroethoxy)]ethyl Pro-
pionate (5). 4 (3.060 g, 17.6 mmol), 2-[2-(2-chloroethoxy)ethoxy]-
ethanol (2.864 g, 17.0 mmol), and DPTS (0.997 g, 3.39 mmol) were
2
7
56 increments and 4 scans per increment, within spectral widths of
212 Hz ( H) and 25 000 Hz ( C) and operating at 125 and 600 MHz.
1
13
dissolved in 20 mL of CH Cl . After the reaction flask was degassed with
2 2
The DLS measurements were performed on a Malvern Zetasizer
argon, DCC (4.037 g, 19.6 mmol) was added. The reaction mixture was
stirred at RT overnight under an argon atmosphere. After the reaction
was completed, DCU was filtered and washed with CH Cl . The crude
ZS instrument. The instrument was equipped with a 633 nm laser source
and a backscattering detector at 173°. Data were analyzed using a
CONTIN procedure.
2
2
product was purified by column chromatography eluting with EtOAc/
TEM measurements were performed on JEOL 2000EX instrument
operated at 100 kV with a tungsten filament. A drop of sample solution
at a concentration of 0.5−1 mg/mL was placed on a carbon-coated
hexane (33/67, v/v). The solvent was removed to obtain 5 as colorless
1
oil (4.59 g, 81%). T = −66.3 °C. H NMR (600 MHz, CDCl ) δ: 4.32
g
3
(m, J = 4.8 Hz, 2H), 4.22 (d, J = 11.7 Hz, 2H), 3.77 (t, J = 5.9 Hz, 2H),
3.74 (t, J = 4.8 Hz, 2H), 3.71−3.61 (m, 8H), 1.45 (s, 3H), 1.40 (s, 3H),
4
00 square mesh copper grid. Excess of solution was blotted with a lint-
free filter paper after 1 min, and the grid was allowed to dry under
1.25 (s, 3H). 13C NMR (151 MHz, CDCl ) δ: 174.16, 98.07, 71.42,
3
ambient temperature.
70.71, 70.62, 69.11, 65.97, 63.86, 42.68, 41.84, 24.24, 23.07, 18.70.
2
200
dx.doi.org/10.1021/ma500126f | Macromolecules 2014, 47, 2199−2213

Macromolecules
Article
Isopropylidene-2,2-bis(methoxy)-2-[2-(2-azideethoxy)]ethyl Pro-
42.80, 41.87, 24.59, 22.75, 18.68, 17.92. MS (MALDI-TOF MS, positive
+
pionate (6). 5 (3.116 g, 9.60 mmol) and NaN (3.203 g, 49.3 mmol)
mode): calculated for C107H175ClN O : [M] m/z = 2420.18 Found:
3
18 42
+
were dissolved in 15 mL of DMF. The reaction was allowed to react at
[M + Na] m/z = 2442.11.
6
0 °C for 18 h under argon. The slurry was cooled to RT followed by
adding 10 mL of water. The mixture was extracted with EtOAc (3 ×
0 mL), and the combined organic layers were washed twice with 50 mL
Synthesis of N -[G2]. Cl-[G2] (1.50 g, 0.62 mmol) and NaN
3
3
(204.23 mg, 3.14 mmol) were dissolved in 5 mL of DMF. The reaction
was allowed to react at 60 °C under argon. The completion of the
reaction was monitored via MALDI-TOF MS. Then, the reaction
mixture was cooled to RT followed by addition of 10 mL of water and
extraction with EtOAc (3 × 30 mL). All organic layers were combined,
5
of brine and dried over MgSO . EtOAc was removed under vacuum to
4
1
yield 6 (2.874 g, 91%) as colorless oil. T = −73.2 °C. H NMR (600
MHz, CDCl ) δ: 4.33 (t, J = 4.8 Hz, 2H), 4.22 (d, J = 11.8 Hz, 2H), 3.75
g
3
(
t, J = 4.8 Hz, 2H), 3.72−3.64 (m, 8H), 3.41 (t, J = 5.0 Hz, 2H), 1.45 (s,
washed twice with 30 mL of brine, and dried over MgSO . The solvent
4
1
3
1
2
H), 1.41 (s, 3H), 1.25 (s, 3H).). 13C NMR (151 MHz, CDCl ) δ:
was removed to give the product as colorless oil (1.385 g, 92%). H
3
74.16, 98.07, 70.75, 70.68, 70.10, 69.14, 65.97, 63.88, 50.71, 41.83,
4.18, 23.14, 18.70.
Synthesis of Cl-[G1] (7). In a typical “click” reaction, a flask sealed
with a rubber septum was charged with 3 (1.280 g, 3.55 mmol) and 6
2.414 g, 7.28 mmol) in 4 mL of DMF. The reaction system was
NMR (600 MHz, CDCl ) δ: 7.70 (s, 6H), 4.62 (s, 12H), 4.54 (t, J = 5.2
3
Hz, 12H), 4.34−4.29 (m, 8H), 4.24 (m, 6H), 4.21 (d, J = 11.8 Hz, 8H),
3.89 (m, 12H), 3.75−3.55 (m, 64H), 3.40 (t, J = 5.0 Hz, 2H), 1.45 (s,
13
12H), 1.39 (s, 12H), 1.25−1.14 (m, 21H). C NMR (151 MHz,
(
CDCl ) δ: 174.22, 174.14, 144.98, 123.56, 98.07, 72.19, 72.13, 70.58,
3
degassed by three freeze−pump−thaw cycles and backfilled with argon.
Then, CuBr (1.184 g, 8.16 mmol) was added under argon followed by
addition of PMDETA (1.372 g, 7.93 mmol) via an argon-purged syringe.
The mixture was further degassed by two freeze−pump−thaw cycles
and stirred under argon at RT for 24 h. After completion, the mixture
was passed through a short column of aluminum oxide twice, using
EtOAc as eluent to remove the copper catalyst. The product was further
purified by flash chromatography eluting with methanol/EtOAc
70.55, 70.49, 70.46, 69.52, 69.50, 69.06, 65.97, 65.00, 63.79, 63.62, 50.69,
50.16, 48.31, 41.87, 24.59, 22.66, 18.68, 17.91. MS (MALDI-TOF MS,
+
positive mode): calculated for C107H175N O : [M] m/z = 2426.22
Found: [M + Na] m/z = 2449.81.
21
42
+
Synthesis of Cl-[G3]. A flask sealed with a rubber septum was charged
with N -[G2] (756 mg, 0.31 mmol) in 1.5 mL of DMF and 54 mg of 3 in
3
533 μL of DMF from a stock solution (0.15 mmol). The reaction system
was degassed by three freeze−pump−thaw cycles and backfilled with
argon. Then, CuBr (91 mg, 0.63 mmol) was added under argon followed
by PMDETA addition (106 mg, 0.62 mmol) with an argon purged
syringe through the septum. Two freeze−pump−thaw cycles was
performed to degas the system, which was left stirring at RT under
argon. After completion, the mixture was passed twice through a short
column of aluminum oxide using methanol and EtOAc as eluent. The
crude product was purified using flash chromatography eluting with
(
5/95, v/v). Colorless oil (3.266 g, 87%) was obtained after removing
1
the solvent. T = −32.3 °C. H NMR (600 MHz, CDCl ) δ: 7.70 (s, 2H),
4
2
g
3
.63 (s, 4H), 4.55 (t, J = 5.2 Hz, 4H), 4.32 (t, J = 5.0, 4H), 4.25 (t, J = 5.0,
H), 4.21 (d, J = 11.8 Hz, 4H), 3.90 (t, J = 5.2 Hz, 4H), 3.76 (t, J = 5.8
Hz, 2H), 3.73−3.58 (m, 20H), 1.43 (s, 6H), 1.38 (s, 6H), 1.22 (s, 6H),
1
1
6
2
.21 (s, 3H). 13C NMR (151 MHz, CDCl ) δ: 174.24, 174.12, 145.02,
3
23.52, 98.05, 72.14, 71.36, 70.65, 70.58, 70.54, 70.47, 69.51, 69.10,
9.04, 65.95, 65.00, 63.77, 63.69, 50.15, 48.31, 42.76, 41.84, 24.58,
2.73, 18.66, 17.90. MS (MALDI-TOF MS, positive mode): calcu-
methanol/EtOAc (33/67, v/v) to give colorless oil (560 mg, 72%). T =
g
1
−24.8 °C. H NMR (600 MHz, CDCl ) δ: 7.70 (s, 14H), 4.62 (m, 28H),
3
+
+
lated for C H ClN O : [M] m/z=1023.48. Found: [M + Na] m/z =
4.54 (t, J = 4.7 Hz, 28H), 4.37−4.27 (m, 16H), 4.26−4.22 (m, 14H),
4.21 (d, J = 11.8 Hz, 16H), 3.89 (m, 28H), 3.76 (t, J = 5.9 Hz, 2H), 3.72−
45
75
6
18
1
045.55.
1
3
Synthesis of N -[G1]. 7 (2.307 g, 2.24 mmol) and NaN (916 mg,
3.55 (m, 136H), 1.45 (s, 24H), 1.39 (s, 24H), 1.24−1.15 (m, 45H).
C
3
3
1
6
4.1 mmol) were dissolved in 6 mL of DMF. The reaction was left at
0 °C for 24 h under argon. Then, the system was cooled down to
NMR (151 MHz, CDCl ) δ: 174.09, 144.92, 123.55, 98.07, 72.12, 70.58,
3
70.54, 70.49, 70.45, 69.51, 69.06, 65.97, 64.99, 63.79, 63.62, 50.16, 50.12,
41.87, 24.61, 22.74, 18.68, 17.93. MS (MALDI-TOF MS, positive
RT followed by adding 10 mL of water and extracted with ethyl acetate
+
(
3 × 30 mL). All organic layers were combined, washed with 30 mL of
mode): calculated for C231H375ClN O : [M] m/z = 5215.58 Found:
42
90
+
brine twice, and dried over MgSO . The solvent was evaporated to give
product as colorless oil (2.272 g, 98%). H NMR (600 MHz, CDCl ) δ:
[M + Na] m/z = 5241.26.
Synthesis of N -[G3]. Cl-[G3] (450 mg, 86 μmol) and NaN
3
4
1
3
3
7
4
.66 (s, 2H), 4.60 (s, 4H), 4.51 (t, J = 5.3 Hz, 4H), 4.28 (t, J = 4.9 Hz,
H), 4.22 (t, J = 5.0 Hz, 4H), 4.17 (d, J = 11.8 Hz, 4H), 3.87 (t, J = 5.3
(180 mg, 2.77 mmol) were dissolved in 3 mL of DMF. The reaction
was allowed to proceed at 60 °C under argon. After completion, the
reaction mixture was cooled to RT, followed by the addition of 10 mL of
water. The mixture was extracted with EtOAc (3 × 20 mL). All organic
layers were combined and washed with 20 mL of brine. The solvent was
Hz, 4H), 3.69−3.56 (m, 28H), 3.37 (t, J = 5.2 Hz, 4H), 1.42 (s, 6H), 1.37
(
s, 6H), 1.18 (s, 6H), 1.17 (s, 3H). 13C NMR (151 MHz, CDCl ) δ:
3
1
7
5
74.23, 174.11, 145.04, 123.50, 98.06, 72.13, 70.69, 70.61, 70.58, 70.48,
0.05, 69.52, 69.13, 69.05, 65.96, 65.02, 63.78, 63.70, 60.36, 50.68,
1
removed to give the desired product as colorless oil (396 mg, 88%). H
0.16, 48.31, 41.85, 24.56, 21.02, 18.67, 17.90. MS (MALDI-TOF MS,
NMR (600 MHz, CDCl ) δ: 7.70 (s, 14H), 4.62 (m, 28H), 4.54 (t, J =
3
+
positive mode): calculated for C H N O : [M] m/z = 1029.52.
5.1 Hz, 28H), 4.34−4.29 (m, 16H), 4.24 (m, 14H), 4.21 (d, J = 11.8 Hz,
45
75
9
18
+
Found: [M + Na] m/z = 1052.61.
16H), 3.89 (m, 28H), 3.72−3.56 (m, 136H), 3.39 (t, J = 5.0 Hz, 2H),
13
Synthesis of Cl-[G2]. A flask, sealed with a rubber septum, was
1.44 (s, 24H), 1.39 (s, 24H), 1.24−1.15 (m, 45H). C NMR (151 MHz,
charged with N -[G1] (1.78 g, 1.73 mmol) and 3 (302.41 mg, 0.84
CDCl ) δ: 174.31, 174.02, 144.95, 144.39, 123.50, 98.07, 72.12, 70.58,
3
3
mmol) dissolving in 2 mL of DMF. The reaction system was degassed by
70.53, 70.49, 70.45, 69.51, 69.49, 69.06, 65.97, 64.99, 63.79, 63.62, 50.69,
50.16, 50.12, 48.36, 48.31, 41.87, 30.89, 24.60, 22.75, 18.68, 17.93. MS
(MALDI-TOF MS, positive mode): calculated for C231H375N O :
three freeze−pump−thaw cycles and backfilled with argon. Then, CuBr
(
648 mg, 4.47 mmol) was added under argon followed by PMDETA
45
90
+
+
addition (766 mg, 4.52 mmol) with an argon-purged syringe through
the septum. The reaction system was further degassed by two freeze−
pump−thaw cycles. The reaction was left to stir under argon at RT. After
completion, the mixture was passed through a short column of
aluminum oxide twice eluting with methanol and EtOAc. The product
was further purified by flash chromatography on silica gel eluting with
[M] m/z = 5221.62. Found: [M + Na] m/z = 5246.32.
Synthesis of the Triacetylene Core. 1,1,1-Tris(hydroxymethyl)-
propane (90.29 mg, 0.67 mmol) in 4 mL of dry DMF was placed in a
flame-dried flask, and NaH (62.9 mg, 2.62 mmol) was added to the flask
at 0 °C. After no further bubble evolution was observed, 503 mg of
propargyl bromide (80 wt % toluene, 3.41 mmol) was added. The
reaction was kept at 0 °C for 1 h and at RT for 5 h. The process was
stopped at 0 °C using 7 mL of 1 M HCl and then extracted with EtOAc
(3 × 15 mL). The crude product was purified by flash chromatography
eluting with EtOAc/hexane (33/67, v/v) to give 132 mg (79%) of
2
0/80 methanol/EtOAc. Colorless oil (1.64 g, 81%) was obtained after
1
evaporating off the solvent. T = −26.8 °C. H NMR (600 MHz, CDCl )
g
3
δ: 7.70 (m, 6H), 4.62 (s, 12H), 4.54 (t, J = 5.2 Hz, 12H), 4.35−4.28 (m,
8
H), 4.27−4.22 (m, 6H), 4.21 (d, J = 11.8 Hz, 8H), 3.89 (m, 12H), 3.76
1
(
t, J = 5.8 Hz, 2H), 3.73−3.56 (m, 64H), 1.44 (s, 12H), 1.39 (s, 12H),
yellowish oily product. T = −74.3 °C. H NMR (600 MHz, CDCl ) δ:
g
3
13
1
1
7
.23−1.17 (m, 21H). C NMR (151 MHz, CDCl ) δ: 174.42, 174.13,
3.41 (s, 6H), 2.40 (t, J = 2.4 Hz, 3H), 1.42 (q, J = 7.6 Hz, 2H), 0.88 (t, J =
7.6 Hz, 3H). C NMR (151 MHz, CDCl ) δ: 80.16, 77.25, 77.04, 76.83,
3
13
44.98, 123.56, 98.07, 72.20, 72.14, 71.36, 70.66, 70.58, 70.55, 70.49,
0.46, 69.51, 69.11, 69.06, 65.97, 65.00, 63.79, 63.71, 63.62, 50.16, 48.31,
3
74.02, 70.30, 58.63, 42.76, 22.71, 7.52, 7.50.
2
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1
Synthesis of Dendrimer-[G1], D-[G1]. A flask, sealed with a rubber
deprotection was confirmed by H NMR, 13C NMR, and MALDI-
septum, was charged with N -[G1] (197.74 mg, 0.19 mmol) in 1.0 mL of
TOF MS.
3
1
DMF and 14.4 mg of triacetylene core in 733 μL of DMF from a stock
solution. The reaction system was degassed by three freeze−pump−
thaw cycles and backfilled with argon. Then, CuBr (105 mg, 0.72 mmol)
was added under argon followed by PMDETA addition (126 mg,
D-[G1](OH) . H NMR (600 MHz, DMSO) δ: 8.00 (s, 6H), 8.00 (s,
12
3H), 4.57−4.46 (m, 30H), 4.44 (s, 6H), 4.11−4.07 (m, 18H), 3.88−
3.77 (m, 18H), 3.61−3.54 (m, 18H), 3.53−3.47 (m, 82H), 3.45 (d,
J = 5.6 Hz, 8H), 1.25 (q, J = 7.4 Hz, 2H), 1.07 (s, 9H), 1.05 (s, 18H), 0.67
1
0.73 mmol) with an argon-purged syringe through the septum. Two
(t, J = 7.5 Hz, 3H). H NMR (600 MHz, D O) δ: 8.07 (s, 6H), 8.05 (s,
2
freeze−pump−thaw cycles were performed to degas the system. The
reaction mixture was stirred under argon atmosphere at RT. After
reaction completion was verified by TLC, the organic phase was washed
twice with brine to extract the copper catalyst. The solvent was evap-
orated, and the crude product was purified using flash chromatography
3H), 4.64 (m, 30H), 4.55 (s, 6H), 4.33−4.25 (m, 12H), 4.23−4.18 (m,
6H), 3.99 (t, J = 4.8 Hz, 12H), 3.95 (t, J = 4.8 Hz, 6H), 3.78 (d, J = 11.3
Hz, 12H), 3.76−3.72 (m, 12H), 3.71−3.55 (m, 84H), 1.26 (q, J = 7.1
1
3
Hz, 2H), 1.20 (s, 9H), 1.17 (s, 18H), 0.66 (t, J = 7.4 Hz, 3H). C NMR
(151 MHz, DMSO) δ: 174.54, 143.51, 124.11, 71.73, 69.67, 69.50,
68.68, 68.26, 64.03, 63.79, 63.04, 50.14, 49.30, 47.81, 39.94, 39.80, 39.66,
eluting with methanol/EtOAc (25/75, v/v). Colorless oil (151 mg,
1
7
2%) was obtained after the evaporation of the solvent. T = −7.5 °C. H
39.52, 39.38, 39.24, 39.10, 17.49, 16.79. MS (MALDI-TOF MS, positive
g
+
NMR (600 MHz, CDCl ) δ: 7.70 (s, 9H), 4.60 (s, 18H), 4.55−4.53 (m,
mode): calculated for C132
[M + Na] m/z = 3119.489.
H
221
N
27
O
57. [M] m/z = 3096.52. Found:
3
+
1
1
1
8H), 4.36−4.28 (m, 12H), 4.26−4.22 (m, 6H), 4.21 (d, J = 11.8 Hz,
D-[G2](OH)24. 1H NMR (600 MHz, DMSO) δ: 8.00 (s, 12H), 8.00 (s,
9H), 4.56−4.45 (m, 78H), 4.44 (s, 6H), 4.23−4.03 (m, 42H), 3.89−
3.77 (m, 42H), 3.66−3.35 (m, 240H), 1.25 (q, J = 14.5, 7.2 Hz, 2H),
1.11−0.98 (m, 63H), 0.66 (q, J = 7.5 Hz, 3H). H NMR (600 MHz,
D O) δ: 8.07 (d, J = 9.0 Hz, 12H), 8.05 (s, 9H), 4.67−4.56 (m, 78H),
2H), 3.91−3.88 (m, 18H), 3.73−3.57 (m, 80H), 1.43 (s, 18H), 1.37 (s,
13
8H), 1.24−1.15 (m, 29H), 0.75 (t, J = 7.5 Hz, 3H). C NMR (151
MHz, CDCl ) δ: 174.21, 174.12, 145.30, 144.93, 123.57, 123.48, 98.05,
3
1
7
6
2
7.27, 77.06, 76.85, 72.10, 70.63, 70.55, 70.50, 70.46, 70.44, 69.49, 69.04,
5.95, 64.96, 64.90, 63.78, 63.60, 50.14, 50.08, 48.28, 43.13, 41.85, 24.63,
2.68, 18.65, 17.91, 7.59. MS (MALDI-TOF MS, positive mode):
2
4.53 (s, 6H), 4.30−4.23 (m, 24H), 4.20−4.17 (m, 18H), 4.00−3.89 (m,
42H), 3.76 (t, J = 10.3 Hz, 24H), 3.74−3.69 (m, 24H), 3.69−3.55 (m,
192H), 1.24 (q, J = 7.1 Hz, 2H), 1.18 (s, 36H), 1.16 (s, 18H), 1.13 (s,
9H), 0.63 (t, J = 7.5 Hz, 3H). MS (MALDI-TOF MS, positive mode):
+
+
calculated for C148H241N O . [M] m/z = 3338.72. Found: [M + Na]
27
57
m/z = 3360.21.
Synthesis of Dendrimer-[G2], D-[G2]. A flask sealed with a rubber
+
+
septum was charged with N -[G2] (246.71 mg, 0.10 mmol) in 1.0 mL of
calculated for C300H N O129. [M] m/z = 7046.43. Found: [M + Na]
497 63
3
DMF and 7.07 mg of triacetylene core in 621 μL of DMF from a stock
solution. The reaction system was degassed by three freeze−pump−
thaw cycles and backfilled with argon. Then, CuBr (91 mg, 0.63 mmol)
was added under argon, and PMDETA was added (106 mg, 0.62 mmol)
with an argon-purged syringe through the septum. Two freeze−pump−
thaw cycles were performed, and the reaction mixture was stirred at RT
under argon. After completion, the organic phase was washed twice with
brine. The solvent was evaporated, and the crude product was purified
by flash chromatography with methanol/EtOAc (29/81, v/v) as eluent.
m/z = 7078.93.
D-[G3](OH)48. 1H NMR (600 MHz, DMSO) δ: 8.00 (s, 24H), 8.00 (s,
21H), 4.53−4.46 (m, 174H), 4.44 (s, 6H), 4.24−4.02 (m, 90H), 3.89−
3.76 (m, 90H), 3.63−3.40 (m, 510H), 1.14−0.97 (m, 135H), 0.66 (t, J =
1
7.4 Hz, 3H). H NMR (600 MHz, D
O) δ: 8.07 (s, 24H), 8.05 (s, 12H),
2
8.04 (s, 9H), 4.66−4.54 (m, 174H), 4.52 (s, 6H), 4.25−4.24 (m, 48H),
4.18−4.14 (m, 42H), 4.00−3.94 (m, 48H), 3.93−3.86 (m, 12H), 3.75
(d, J = 11.2 Hz, 48H), 3.73−3.68 (m, 48H), 3.68−3.51 (m, 438H), 1.16
(s, 72H), 1.14 (s, 36H), 1.12 (s, 18H), 1.11 (s, 9H), 0.61 (t, J = 7.5 Hz,
3H). 13C NMR (151 MHz, DMSO) δ: 174.58, 173.45, 143.62, 124.08,
71.72, 69.67, 69.50, 68.68, 68.26, 68.13, 67.40, 64.03, 63.81, 63.25, 63.05,
50.15, 49.30, 47.81, 46.18, 43.61, 39.94, 39.80, 39.66, 39.52, 39.38, 39.24,
39.10, 17.49, 17.06, 16.80. MS (MALDI-TOF MS, positive mode):
Colorless oil (147 mg, 67%) was obtained after the solvent removal. T =
g
1
−
6.2 °C. H NMR (600 MHz, CDCl ) δ: 7.70 (s, 21H), 4.64−4.56 (m,
3
4
4
1
2H), 4.55−4.53 (m, 42H), 4.36−4.28 (m, 24H), 4.26−4.22 (m, 18H),
.21 (d, J = 11.8 Hz, 23H), 3.91−3.88 (m, 42H), 3.73−3.57 (m, 198H),
13
+
+
.45 (s, 36H), 1.39 (s, 36H), 1.24−1.15 (m, 63H). C NMR (151 MHz,
calculated for C636H N O273. [M] m/z = 14 946.24. Found: [M]
1049 135
CDCl ) δ: 174.22, 174.14, 144.96, 123.58, 98.07, 72.12, 70.58, 70.53,
m/z = 14 952.66.
3
7
0.49, 70.45, 69.51, 69.06, 65.97, 64.99, 63.79, 63.62, 50.16, 50.12, 48.31,
The geometry optimizations of the model bis-MPA compound for
the dendrimer branching site and its complex with palladium(II) were
4
1.87, 24.61, 22.75, 18.68, 17.93. MS (MALDI-TOF MS, positive
2
3
+
mode): calculated for C336H545N O . [M] m/z = 7529.81. Found:
performed using density functional theory (DFT), employing the
63
129
24
+
[
M + Na] m/z = 7554.
Synthesis of Dendrimer-[G3], D-[G3]. A dried flask was charged with
Becke 3-parameter Lee−Yang−Parr (B3LYP) functional. LAN2DZ
25
pseudopotential was utilized to model the palladium(II) ions, while
2
6
N -[G3] (284 mg, 0.054 mmol) in 600 μL of DMF and 3.76 mg of
the 6-31G(d) basis set was chosen for all remaining elements. The
geometry minima were confirmed by frequency analysis, and zero point
vibrational energy (ZPVE) was included in the results for energies. All
3
triacetylene core in 581 μL of DMF from a stock solution. The reaction
system, equipped with rubber septum, was degassed by three freeze−
pump−thaw cycles and backfilled with argon. Then, CuBr (41 mg, 0.28
mmol) and PMDETA (47 mg, 0.27 mmol) were consecutively added
under argon. Two freeze−pump−thaw cycles were performed to degas
the system, and the reaction was stirred at RT under argon. After
reaction completion, the crude product was purified by flash
27
calculations were performed with the Gaussian 09 program.
General Procedure for Palladium Complexaton of Dendrimers.
Acetal- or hydroxyl-terminated dendrons or dendrimers were dissolved
in DMSO followed by adding 3 equiv of Pd(PhCN) Cl according to
2 2
the number of potential chelating sites. The complexation was con-
ducted at RT under argon and is complete within 5 min as monitored by
chromatography using methanol/EtOAc (50/50, v/v) as eluent and
1
1
oily product (154 mg, 64%) was obtained. T = −4.9 °C. H NMR (600
H NMR. The excess of Pd(PhCN)
. The products were obtained by removing
the solvent under vacuum. An example is shown below.
Cl-[G1]-PdCl . Cl-[G1] (24.73 mg, 0.024 mmol) and Pd(PhCN)
(25.68 mg, 0.067 mmol) were dissolved in 2 mL of CH CN (or DMSO)
under argon. The reaction solution was stirred at 30 °C for 1 h. The
excess of Pd(PhCN) Cl was removed by cold filtration and washed
with cold CHCl . A yellowish oil (24 mg, 84%) was obtained by
removing the solvent under vacuum. H NMR (600 MHz, CDCl
2 2
Cl was isolated by cold filtration
g
MHz, CDCl ) δ: 7.71 (s, 45H), 4.62−4.61 (m, 90H), 4.55−4.53 (m,
and washed with cold CHCl
3
3
9
4
(
0H), 4.35−4.28 (m, 48H), 4.25−4.22 (m, 42H), 4.21 (d, J = 11.8 Hz,
8H), 3.91−3.88 (m, 90H), 3.73−3.56 (m, 413H), 1.45 (s, 72H), 1.39
Cl
2 2
2
13
s, 72H), 1.23−1.18 (m, 135H). C NMR (151 MHz, CDCl ) δ:
3
3
1
6
74.22, 174.14, 144.96, 123.58, 98.07, 72.12, 70.58, 70.52, 70.49, 70.45, 69.51,
9.49, 69.06, 65.97, 64.99, 63.79, 63.62, 50.17, 50.12, 48.30, 41.87, 24.63,
2.74, 18.68, 17.94.MS (MALDI-TOF MS, positive mode): calculated for
2
2
2
3
+
+
1
C708H1145N135O273. [M] m/z = 15 912.00. Found: [M] m/z = 15 804.
General Procedure for the Deprotection of Dendrimer
Peripheral Acetal Groups. The peripheral acetal groups were easily
deprotected with TFA. Dendrimers were dissolved in a mixture of
DCM/MeOH/TFA (40/40/20, v/v/v) and stirred for 2 h at RT. The
solvent and excess of TFA were removed in a vacuum to afford hydroxyl-
terminated dendrimers in high yield. The purity of the compounds after
) δ:
3
7.74 (s, 2H), 5.01 (d, J = 11.4 Hz, 2H), 4.88 (d, J = 11.4 Hz, 2H), 4.57 (t,
J = 4.6 Hz, 4H), 4.38 (d, J = 8.4 Hz, 2H), 4.33−4.30 (m, 6H), 4.23−4.16
(m, 6H), 3.87 (t, J = 4.7 Hz, 4H), 3.77 (t, J = 5.8 Hz, 2H), 3.7 (t, J = 4.8
Hz, 2H), 3.72−3.55 (m, 20H), 1.44 (s, 6H), 1.39 (s, 6H), 1.32 (s, 3H),
1.20 (s, 6H). 13C NMR (151 MHz, CDCl ) δ: 174.67, 174.17, 145.94,
3
125.14, 98.08, 71.86, 71.41, 70.69, 70.65, 70.57, 70.33, 69.15, 69.09,
2
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2
1,29
6
1
8.70, 65.99, 63.79, 62.54, 51.83, 47.84, 42.86, 41.91, 24.91, 22.46,
9.29, 18.66. H NMR (600 MHz, DMSO) δ: 8.26 (s, 2H), 4.87 (d,
modify dendritic periphery for specific applications,
but
1
PEGs or PEOs have been much less frequently used as interior
building blocks of dendrimers. TrEG is expected to provide
water solubility and flexibility of the branches, while still
preserving certain size selectivity of the dendritic interior. The
readily available 2,2-bis(hydroxymethyl)propionic acid, bis-
MPA, was considered suitable compound to meet requirement
b and was used as the parent branching fragment because of its
J = 11.3 Hz, 2H), 4.80 (d, J = 11.3 Hz, 2H), 4.64−4.57 (t, J = 4.8 Hz,
30
4
4
1
H), 4.25−4.13 (m, 6H), 4.06−4.01 (m, 6H), 3.84 (t, J = 5.0 Hz,
H), 3.74−3.37 (m, 28H), 1.35 (s, 6H), 1.25 (s, 6H), 1.20 (s, 3H),
.07 (s, 6H).
Stock Solution of D-[G1](OH) (PdCl ) . A stock solution of palladium
1
2
2 3
complex was made by dissolving 5.7 mg of waxy D-[G1](OH) (PdCl ) in
1
12
2 3
mL of DI H O. After being filtered through a 0.2 μm PVDF membrane,
2
31
part of the solution was further diluted 30 times for the ICP-MS
measurement. The palladium concentration of the diluted solution was
measured to be 3.0 ppm.
Suzuki−Miyaura Coupling Reaction. 5 mL of conical reaction
vial was charged with 4-bromoacetophenone (48.42 mg, 0.24 mmol),
phenylboronic acid (45.49 mg, 0.37 mmol), triethylamine (49.22 mg,
versatility in dendrimer synthesis and potential biodegrad-
32
ability and biocompatibility.
The synthetic strategy for the AB monomer is depicted in
2
Scheme 1. A bis-alkyne-modified bis-MPA derivative (2) is syn-
thesized via Williamson ether synthesis. Unfortunately, the reac-
tion proceeds through intermediate 1, produced in low yield of
0
.49 mmol), and 800 μL of H O. The appropriate amount of
2
3
4%, and an extra hydrolysis is required to obtain 2. This
D-[G1](OH) (PdCl ) stock solution (0.02 mol %) was withdrawn
12
2 3
particular step could be considered as the yield-determining
reaction of the entire synthetic procedure. A chlorinated
derivative of TrEG, 2-[2-(2-chloroethoxy)ethoxy)]ethanol, is
then attached as a short spacer to 2 via DCC-mediated
and added to the mixture. The reaction mixture was kept at 60 °C for 3 h.
After completion, the product was extracted with ethyl acetate (3 × 7
mL). The combined organic layer was dried over MgSO , and the
solvent was removed under vacuum to give solid white crystals as
product (43.82 mg, 100%). The identification of the product was
conducted by 300 MHz NMR. H NMR (300 MHz, CDCl ) δ: 8.04 (d,
4
esterification reaction affording the AB ether−ester monomer 3.
2
1
3
A complementary azide derivative of bis-MPA TrEG 6 was
synthesized by DCC coupling of the same 2-[2-(2-
chloroethoxy)ethoxy)]ethanol with acetyl protected bis-MPA,
J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 6.9 Hz, 2H), 7.53−
1
3
7
.44 (m, 2H), 7.42 (dd, J = 5.0, 3.6 Hz, 1H), 2.64 (s, 3H). C NMR (75
MHz, CDCl ) δ: 197.79, 145.89, 140.00, 136.02, 129.07, 129.02, 128.34,
3
followed by converting the ∼CH Cl end group into the cor-
responding azide (6, Scheme 1). Azide 6 is a structural analogue
2
1
27.38, 127.33, 26.74.
of the AB monomer and serves as the starting reagent in the
2
RESULTS AND DISCUSSION
■
convergent synthetic scheme. It also provides the opportunity to
cover the dendrimer periphery with terminal hydroxyl groups,
which are created and available for further modification after a
simple deprotection process.
The convergent method, employed in the new dendrimer
synthesis, is shown in Scheme 2. The dendron growth proceeds
The strategic goal of this study was to develop and produce a
dendrimer which could be employed in a broad array of
functionsfrom “green” chemistry to biomedical. Two key
design elements were considered at the planning stage: (a)
intrinsic water solubility at the periphery and throughout the
interior of the macromolecule and (b) potential hydrolysability
of the entire dendritic framework. The building block, chosen to
meet the first (a) requirement was triethylene glycol, TrEG, a low
molecular weight member of the poly(oxyethylene) family. This
polymer, also known as poly(ethylene glycol), PEG, or poly-
by “click” reaction of the AB monomer 3 with slight stoi-
2
chiometric excess (1.1 equiv) of azide segments 6. The product
is easily purified by column chromatography (see Experimental
Section for separation conditions) due to the significant
molecular weight difference between the starting reagents
and the newly produced macromolecules. In this way dendrons
up to third generation are successfully synthesized with
(
ethylene oxide), PEO, has long been known for its versatility
28
and wide-ranging applications. PEGylation was often used to
Scheme 1. Synthesis of AB Monomer and Complementary Azide
2
2
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Macromolecules
Article
relatively high yields and high structural purity as evidenced by
SEC (Figure 1), MALDI-TOF (Figure 2), and NMR anal-
yses (Figure 3).
Table 1. Molecular Mass Characteristics of Dendrons
Cl-[G1]−Cl-[G3] Obtained by SEC Using Conventional
Calibration
The SEC traces of chloro-dendrons Cl-[G1]−Cl-[G3]
a
theor
mass
SEC (THF)
(
Figure 1) reveal traditionally monomodal and sharp peaks
b
dendron
Mn
Mw
Mp
M /M
w
n
with the polydispersity indices (PDIs) varying from 1.01 to 1.03.
As expected, the apparent molecular masses, calculated by
conventional calibration, increasingly deviate from the expected
theoretical values (Table 1). The SEC analyses of the azide
derivatives show a similar trend. Convincing evidence for the
high purity and structural integrity of the dendrons formed is
Cl-[G1]
Cl-[G2]
Cl-[G3]
1022
2419
5212
750
1710
3810
760
1760
3880
770
1810
3960
1.01
1.03
1.02
a
b
PSt standards were used. M
peak maximum.
is the apparent molecular mass at the
p
Scheme 2. Convergent Growth of Dendrons
Figure 1. SEC traces (THF, dRI detector) of (1) Cl-[G1], blue trace, (2) Cl-[G2], red trace, and (3) Cl-[G3], green trace. (T) Toluene: an internal
standard.
2
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+
+
Figure 2. MALDI-TOF spectra of Cl-[G1], blue trace, [M + Na] = 1045.551; Cl-[G2], red trace, [M + Na] = 2442.106, and Cl-[G3], green trace,
+
[
M + Na] = 5241.263.
1
Figure 3. 600 MHz H NMR spectra of 6 (A), 3 (B), and Cl-[G1] (C), recorded in CDCl at 298 K.
3
provided by the MALDI-TOF analyses (Figure 2), where single
molecular ion [M + Na] peaks are observed in the spectra and
molecular masses matching the theoretical ones.
and the ester methylene protons (f and p, Figure 3C) show as
+
triplets at 4.21 and 4.25 ppm, respectively. All signals have been
further identified by full COSY assignments. An example is
shown in Figure 4, where the several pairs of structural protons
are highlighted: k and l, p and o, q and q. Finally, the structural
and chemical purity of the dendrons is independently confirmed
by the integral intensity ratios of the TrEG end group protons
and the triazole protons. An example with dendrons [G1]-N3−
[G3]-N3 is shown in Figure 5.
In the final act of the synthetic sequence first-, second-, and
third-generation dendrimers are constructed by connecting
azide-terminated dendrons to a triacetylene core using the
same type of “click” chemistry. A 1.2 stoichiometric excess
of the corresponding dendron is employed, and the reaction is
The chemical composition of the dendrons formed is
confirmed by NMR analyses (Figure 3). The acetylene protons
in 3 (t, Figure 3B) disappear. The signals for the methylene
protons next to the azide group in 6 (k, Figure 3A) and
the methylene protons adjacent to the acetylene group in 3 (v,
Figure 3B) shift downfield (Figure 3C, k and i, respectively). The
formation of the triazole ring and the preservation of ester
linkages during the synthetic sequence are also proven by NMR
analyses: triazole protons (j, Figure 3C) appear as clean singlets
at 7.70 ppm; the methylene protons adjacent to the triazole rings
(
i and k, Figure 3C) are visible at 4.63 and 4.55 ppm, respectively,
2
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1
Figure 4. 600 MHz H NMR ge-COSY spectra of Cl-[G1], recorded in CDCl at 298 K.
3
1
Figure 5. 600 MHz H NMR overlay of N -[Gn] dendrons recorded in CDCl , 298 K.
3
3
performed at room temperature. It is worth mentioning that the
short TrEG segments are seemingly reducing the steric
congestion at the bond-forming event and facilitate the growth
of dendrimers free of structural defects in relatively high yields:
The chemical structure of all dendrimers is characterized by
NMR. An example for hydroxyl-coated dendrimers is shown in
1
13
Figure 7 (for an example of 2D H− C DEPT-HSQC NMR
analysis see Figure S5 in the Supporting Information). An
important feature of the layered structure, seen in dendrimers of
generations higher than 1, is the differentiating in the proton
chemical shifts at the branching sites. Indeed, the same trend is
clearly evident in the newly produced macromolecules: the bis-
MPA methyl protons show different chemical shifts in the range
between 1.04 and 1.12 ppm for the three different generations.
More importantly, the peak deconvolution of the signals for
the triazole protons (7.95−7.99 ppm) also demonstrates the
7
2% for D-[G1], 67% for D-[G2], and 64% for D-[G3]. The
azide dendron “click” coupling to the triacetylene core is
monitored by SEC (Figure 6). It is evident that the process could
proceed to completion even when relatively large dendrons
(
molecular mass >5000 Da) are involved. At this time we cannot
explain the appearance of the higher molecular mass shoulder in
peak 2 (Figure 6, 16.7 min).
2
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34
chemical composition. The small broad peak around 11 kDa is
probably caused by partial fragmentation of the dendrimer due to
the increased laser beam attenuation, required to volatize the
macromolecule. The structural homogeneity of the third-
generation dendrimer is independently confirmed by DLS,
another size-sensitive technique (Figure 9). The sizes deter-
mined by this method (3.8, 6.4, and 11.5 nm for D-[G1](OH) ,
1
2
D-[G2](OH) , and D-[G3](OH) , respectively) are higher
24
48
than the usually encountered values for dendrimer generations
1
−3 and reflect the presence of the hydrophilic TrEG spacers
throughout the dendritic skeleton.
The results obtained show that the synthetic strategy can
successfully lead to defect-free third-generation dendrimers,
which have 48 protected primary hydroxyl groups, 45 hydro-
lyzable ester linkages, and 21 potential metal-binding sites
Figure 6. SEC traces of N -[G3] (1) and dendrimer D-[G3] (2).
3
(
Figure 10). These dendrimers are freely soluble in water,
increasingly reduced local mobility in the layers from the
periphery to the core even for groups not in the immediate
vicinity of the branch (Figure 7). The molecular mass and
structural uniformity of the dendritic macromolecules are further
verified by SEC and MALDI-TOF (Figure 8a,b), respectively.
Interestingly, dendrimer D-[G1] appears to have well-
pronounced low molecular mass tail in the SEC chromatogram
methanol, CH Cl , CHCl , CH CN, ethyl acetate, DMF,
DMSO, THF, and other solvents, mostly due to the substantial
2
2
3
3
presence of TrEG blocksa total of 45 such fragments in D-
[
G3]. While these chemical functionalities and solution
properties make the newly formed macromolecules intriguing
candidates for biomedical applications, this study will explore
only the chelating potential of the triazole moieties distributed
across the dendrimer framework and the catalytic activity of
dendritic Pd complexes in Suzuki−Miyaura reactions.
(
Figure 8a, 1) but shows as a single peak, perfectly matching the
theoretical molecular mass in the MALDI-TOF spectrum
(
Figure 8b, 1).
We believe that this is due to the extended low-molecular-mass
resolution capacity of the SEC column set, used for the analysis.
A model compound consisting of bis-MPA branching unit
connected to two triazole rings via the primary hydroxyl groups is
used to predict the most suitable location of the binding sites.
Methyl groups attached to the N1 and N4 atoms in the triazole
rings and the bis-MPA COO unit represent the links to the rest
of the dendrimer (Figure 11a). The optimized geometry of the
model compound is presented in Figure 11b. The Millikan atomic
charges on the N1−N6 atoms in 1,2,3-triazole rings are calcu-
lated to be −0.235, −0.094, −0.350, −0.218, −0.083, and −0.327,
33
On the opposite, dendrimer D-[G3] is seen as single peak in the
chromatography analysis but appears as a broad poorly resolved
peak in the MALDI-TOF traces regardless of the matrix and
analysis conditions used (Figure 8b). The failure of the mass
spectrometric analysis to confirm the structural purity and
uniformity of D-[G3] is certainly regrettable, but similar
broadening is not uncommon for dendrimers of this size and
1
Figure 7. Overlay of 600 MHz H NMR spectra of dendrimers D-[Gn](OH) recorded in D O, 298 K.
m
2
2
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Figure 8. Chromatographic and mass spectrometric analyses of dendrimers D-[G1] (1), D-[G2] (2), and D-[G3] (3): (a) SEC traces; (b) MALDI-
TOF spectra.
DEPT-HSQC) show convincingly the formation of the chelate
ring, postulated by the theoretical modeling. The spectrum of
D-[G2] before and after the complexation is shown in Figure 13.
The signals of several protons are shifted downfield, compared
to those in the starting dendrimer, suggesting a deshielding pro-
cess in result of changes in their architectural arrangement and
appearance of electron-withdrawing groups (PdCl ). For
2
example, the triazole protons (Figure 13a, j) are probably facing
inward in the starting dendrimer but facing outward after the
heterocycles “flip” during the coordination process with PdCl2
(
Figure 13b). The reduced segmental mobility of the groups in
the 12-memebered ring leads to inequivalent surroundings and
is manifested by transformation of the peaks due to methylene
protons i and g from singlets at 4.55 and 3.5 ppm, respectively
Figure 9. DLS traces of dendrimers D-[Gn](OH) in water.
m
(
Figure 12a), into doublets of doublets (Figure 13b). Both NMR
and ICP-MS analyses show that the complexation efficiency
5 ± 5% for all dendrimers, suggesting the formation of dendritic
complexes with 3, 9, and 21 Pd moieties (for generations 1, 2, and
, respectively).
The incorporation of multiple PdCl groups and the formation
respectively, indicating that N1/N4 and N3/N6 pairs are the
most possible electron donors for the metal complexation.
The two coordination modes of N1−N4 and N3−N6 pairs in
the two heterocycles are also evaluated in the model study. The
results show that N3−N6 coordination is the most thermody-
namically favorable since the Gibbs free energy of the reaction
9
3
2
−1
−1
of multiple rings throughout the dendritic macromolecules
would most probably affect their size as well. Indeed, both DLS
and TEM analyses confirm this assumption. The increases in
the hydrodynamic diameter of the dendrimers D-[G1], D-[G2],
and D-[G3] after the complexation are evident in the DLS traces
shown in Figure 14. It should also be noted that the mixture
CH CN/H O is not as good solvent as pure water, and the
dendrimers sizes shrink from 3.8, 6.4, and 11.5 nm to 3.0, 4.9, and
7.2 nm for D-[G1](OH)12, D-[G2](OH)24, and D-[G3](OH)48
respectively (compare to Figure 9). All species, however, retain
their monomodal size distribution during this process. The
dendrimer size expansion after complexation amounts to 30%
(3.9 ± 0.9 nm), 49% (7.3 ± 0.5 nm), and 117% (15.6 ± 0.2 nm)
for generations 1, 2, and 3, respectively, measured in the same
CH CN/H O solution. We believe that the size increase is
(
ΔG°2
) is −46.1 kcal mol compared to 13.7 kcal mol
98.15 K
for N1−N4 coordination. As shown in Figure 12b, the geometry
optimization of Pd(II) complex via N3/N6 coordination leads to
a complex with square-planar geometry with the two triazoles
forming a bidentate ligand in preferable trans position. In this way
the theoretical models predict that a 12-membered ring would
form as the chelate pocket at the branching sites in the dendrimer
molecules.
3
2
The dendron Cl-[G1] was initially used as a model com-
pound to investigate the possible coordination chemistry of the
triazole “clefts” to palladium(II) by interaction with 3 mol equiv
,
(
Pd(PhCN) Cl ) in CH CN or DMSO. The binding in both
2 2 3
solvents is fast and is complete within 5 min as revealed by
1
H NMR analysis in situ. The study is further extended to
dendrimers of generations 1−3 with similar outcome. Remark-
3
2
1
ably, the data from the NMR analyses ( H-, ge-COSY, and
predominantly caused by the incorporation of the voluminous
2
208
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Figure 10. Chemical structure of dendrimer D-[G3]. The ester linkages are marked in magenta, and the potential binding sites are encircled.
Figure 11. Chemical structure (a) and ORTEP diagram (b) of the model compound, representing the branching sites in the TrEG dendrimer. C atoms
gray spheres), H atoms (white spheres), N atoms (orange spheres), and O atoms (red spheres).
(
Pd moieties, but partial contribution of the increased osmotic
pressure due to complex charges should also be taken into
account. The notable broadening in the DLS trace of D-[G3]-Pd
suggests a possible formation of aggregates, and complementary
TEM analyses hint at their presence (Figure 15). Compared with
the hydrodynamic diameters of the empty D-[G3](OH) (7.2 ±
4
8
0.2 nm) and Pd-loaded D-[G3](OH) (PdC ) (15.6 ±
4
8
l2 21
0.2 nm), the increased diameter size of the species observed by
2
209
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Figure 12. Chemical structure (a) and ORTEP diagram (b) of the palladium(II) complex for the model compound representing the metal-binding sites
in the TrEG dendrimer. C atoms (gray spheres), H atoms (white spheres), N atoms (orange spheres), O atoms (red spheres), Cl atoms (blue spheres),
and Pd atom (green sphere).
1
Figure 13. H NMR spectra of (a) dendrimer D-[G2] and (b) palladium(II) complex of D-[G2]. Analysis conditions: 600 MHz, DMSO-d , 298 K.
6
Scheme 3. Suzuki−Miyaura Reaction Catalyzed by D-[G1](OH) (PdCl )
1
2
2 3
TEM (13.9 ± 1.8 and 23.9 ± 0.9 nm, respectively; see Figure S9
experiments with conventional reagentsphenylboronic acid
and 4-bromoacetophenone (Scheme 3). The preliminary results
show that with D-[G1](OH) (PdCl ) and triethylamine (Et N)
and Table S1) could only be partially attributed to the natural
“flattening” of these soft nano-objects. On the other side, the careful
12
2 3
3
examination of the TEM images of the dendrimers (Figure 15)
shows several overlapping pairs of ovoid structuresan indication
for a possible dimer aggregation.
The catalytic activity of the new dendritic palladium complexes
for Suzuki−Miyaura reactions in water is evaluated by pilot
as the base the conversion is quantitative at 100 °C. Further
experiments show that lowering the reaction temperature to
60 °C does not affect the yield, which stays at 100%. When
K CO is used as base, quantitative yield could be achieved even
2
3
at 50 °C (Table 2). Comparison to previously published results
2
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Table 2. Suzuki−Miyaura Reaction between
4
-Bromoacetophenone and Phenylboronic Acid, Catalyzed
a
by Different Pd Complexes in Water
temp (°C)
Pd (mol %)
time (h)
yield (%)
ref
5
6
7
8
9
0
0
8
0
0
0.029
0.01
3
99
this work
35a
3
92
0.04
0.5
4−40
2
60
18g
35b
36a
0.00001−0.01
0.1
85−100
94−96
81−95
94−99
>99
Figure 15. TEM micrographs of dendrimer D-[G3](OH)48 before (a)
1
1
1
1
1
1
1
1
00
00
00
00
00
00
10
20
0.1
2
36b, c
37a
and after (b) complexation with Pd(PhCN) Cl . Dendrimers deposited
2
2
0.001−0.01
0.25
1−3
16
from CH CN/H O (30/70, v/v) solution.
3
2
37b
38a
0.003
0.1
5
94−95
95
CONCLUSIONS
8
38b
39
■
In summary, we have synthesized a new class of poly(ether−
ester) dendrimers with expandable and flexible hydrophilic
triethylene glycol spacers and triazole rings at the ester branching
sites. The materials range in size between 3 and 12 nm and are
soluble in a broad variety of solvents. The excellent accessibility
and binding ability of the triazole/bis-MPA branching sites were
demonstrated by fast and quantitative formation of PdCl2
complexes under mild reaction conditions, which in turn can
quantitatively catalyze classic Suzuki−Miyaura cross-couplings in
water. These results provide encouraging indication that the
triazole poly(ether−ester) dendrimers might behave similarly
toward other VIIIa group elements, which makes them suitable
carriers of diverse functions from environmentally friendly
catalysis to specific drug delivery. Our group is currently per-
forming further experiments to validate this assumption.
0.3
4−7.5
2−4
1
92−94
59→99
100
0.001−1.0
0.1
40
41
a
Reaction conditions: [bromoacetophenone]:[phenylboronic acid]:
K CO ] = 1:1.5:2 mol equiv.
[
2
3
ASSOCIATED CONTENT
Supporting Information
■
*
S
Additional experimental procedures, SEC and DSC traces, NMR
spectra, DLS and TEM size, and size distribution data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail igivanov@syr.edu (I.G.).
■
*
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the kind assistance of Mr. Robert P.
Smith (SUNY ESF) and Prof. Stephan Wilkens (SUNY Upstate
Medical University) with the TEM analysis of the dendrimers.
Thanks are due to Dr. Hongyi Hu (SUNY ESF) for her help with
the theoretical calculations and Prof. Mathew M. Maye (Syracuse
University) for the provided access to DLS instrumentation.
Partial financial support for this study was granted by NSF
Figure 14. Hydrodynamic diameter of dendrimers before (a) and after
(
b) interaction with Pd(PhCN) Cl . DLS analysis in CH CN/H O
2 2 3 2
(
30/70, v/v).
(
CBET 0853454 and EEC-1156942).
for the reaction of the same reagents, in the same solvent (H O)
2
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