Dendrimers clicked together divergently

Article abstract of DOI:10.1021/ma050302r

Dendrimers containing 1,4-triazole linkages between each generation were grown divergently via the Click chemistry inspired Huisgen 1,3-dipolar cycloaddition reaction in the presence of a Cu(I) catalyst. The monomeric unit (1-propargylbenzene-3,5-dimethan

Full text of DOI:10.1021/ma050302r

5436
Macromolecules 2005, 38, 5436-5443
Dendrimers Clicked Together Divergently
Maisie J. Joralemon,† Rachel K. O’Reilly,†,‡ John B. Matson,† Anne K. Nugent,†
Craig J. Hawker,*,‡,§ and Karen L. Wooley*,†
Center for Materials Innovation and Department of Chemistry, Washington University in Saint Louis,
One Brookings Drive, Saint Louis, Missouri 63130-4899; IBM Almaden Research Center,
650 Harry Road, San Jose, California 95120; and Materials Research Laboratory,
University of California, Santa Barbara, California 93106
Received February 11, 2005; Revised Manuscript Received April 20, 2005
ABSTRACT: Dendrimers containing 1,4-triazole linkages between each generation were grown divergently
via the Click chemistry inspired Huisgen 1,3-dipolar cycloaddition reaction in the presence of a Cu(I)
catalyst. The monomeric unit (1-propargylbenzene-3,5-dimethanol) contained the alkyne functionality,
while the core (1,2-bis(2-azidoethoxy)ethane) and growing dendrimers presented the azide groups necessary
for this type of Click reaction. The first generation dendrimer was also functionalized with alkyne termini
to demonstrate an alternative pathway allowed by this chemistry. Synthesis and characterization, with
infrared (IR), 1H and 13C NMR spectroscopies, high-resolution mass spectrometry, gel permeation
chromatography (GPC), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA),
are reported for these divergently grown dendrimers.
Introduction
Both the convergent and divergent synthetic meth-
odologies provide routes for the production of dendritic
macromolecules; however, each has specific advan-
tages.73 The convergent growth approach has been
shown to provide for more exact macromolecular archi-
tectures having less defects, greater monodispersity, and
greater control over the placement of desired function-
alities, facilitated by fewer coupling reactions at each
generation growth step and convenient purifications.
The advantages of the divergent strategy are related
to the ability to achieve higher generation growth by
avoiding steric effects and to the employment of large
molar equivalents of readily accessible small molecules
to add mass to the structure at each generation growth.
Because of the high yields and lack of byproducts
provided by the Click strategy for stitching together
each generation, the ease of dendrimer purification is
enhanced and the disadvantages from the increasing
number of reactions for each generation are curbed, thus
improving the divergent methodology. The fundamental
study reported herein details the growth of dendrimers
divergently with triazole linkages between the core and
each generation, established via repetitive Click reac-
tions between alkyne and azide moieties. Ultimately,
the resulting alkynyl- and azido-terminated dendrimers
may be interesting as multifunctional, highly branched
globular macromolecules, and this study represents an
initial investigation into their preparation and proper-
ties.
The ability to tune the properties of dendrimers1-5
has allowed their development for use in diverse ap-
plications, including drug delivery,6-15 biomimicry,8,9,16-19
catalysis,15,20-26 organic light emitting diodes,15,21,27-29
molecular wires,30,31 sensors,32-35 imaging agents,7,9 and
various other utilities.15,36-42 Coincident with these
developments is the increasing need for facile, cost-
effective methods that provide covalent connections
between dendrimer generations, either convergently43
or divergently,44,45 and for variability in the composition
and properties of the dendritic scaffold. Although many
families of dendrimers have been produced, there
remain opportunities for further developments, espe-
cially given the iterative growth scheme, which require
efficient and versatile chemistries for the preparation
of well-defined dendrimers. One type of chemistry that
lends itself to such requirements is Click chemistry.
The Click chemistry concept encompasses a set of
reliable regiospecific chemical transformations that give
products that are easily isolated in high yields, benign
byproducts (or none), and utilize readily available
starting materials.46 The Huisgen 1,3-dipolar cyclo-
addition between azides and alkynes47 to yield triazoles
meets the requirements for definition as a Click reac-
tion48 and has recently been utilized to functionalize
surfaces,49-52 polymers,53,54 and sugars,55-57 probe bio-
logical systems,58-62 participate in multicomponent
cascade reactions,63,64 build libraries,65,66 and synthesize
analogues of vitamin D.67 Because of toleration of a wide
range of functionalities and high yielding reactions, the
Huisgen 1,3-dipolar cycloaddition Click reaction be-
tween azides and alkynes is an obvious tool for building
macromolecules,68-71 and dendritic macromolecules, as
demonstrated by the recent employment of this Click
reaction to construct dendrimers convergently.72
Experimental Section
Instrumentation. Infrared spectra were obtained on a
Perkin-Elmer Spectrum BX FT-IR system using diffuse re-
flectance sampling accessories or salt plates. 1H NMR (300
MHz) and 13C NMR (75 MHz) spectra were recorded as
solutions on a Varian Mercury 300 spectrometer with the
solvent signal as reference. Glass-transition temperatures (Tg),
crystalline temperatures (Tc), and melting temperatures (Tm)
were measured on a Mettler Toledo (Columbus, OH) DSC822
differential scanning calorimeter and analyzed with Thermal
Analysis PC software (version 7.01; Mettler Toledo). Heating
rates were 10 °C/min. The Tg was taken as the midpoint of
the inflection tangent, upon the third heating scan, the Tc was
† Washington University in Saint Louis.
‡ IBM Almaden Research Center.
§ University of California, Santa Barbara.
* Corresponding author. E-mail: hawker@mrl.ucsb.edu;
klwooley@artsci.wustl.edu.
10.1021/ma050302r CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/01/2005

Macromolecules, Vol. 38, No. 13, 2005
Dendrimers Clicked Together Divergently 5437
taken as the maximum upon the third heating scan, and the
Tm was taken as the minimum upon the third heating scan.
Thermogravometric analysis was performed on a Mettler
Toledo SDTA851 TGA module with Thermal Analysis PC
software (version 7.01; Mettler Toledo). Heating rates were
10 °C/min, and the onset temperature for weight loss was the
point at which two tangential lines in the TGA curves
intersected.
ArH). 13C (CDCl3): δ 52.7, 56.4, 76.5, 77.8, 120.5, 124.0, 132.1,
157.7, 166.1 ppm. HRMS (FAB): calcd for (C13H12O5 + H)+:
249.0763; found: 249.0766 ( 2.4 ppm (MH)+.
Synthesis of 1-Propargylbenzene-3,5-dimethanol (3).
Prior to use, all glassware and the magnetic stir bar were dried
in an oven (110 °C) for 1 h. To a slurry of LiAlH4 (5.80 g, 153
mmol) in THF (400 mL) within a flame-dried, two-neck 1 L
round-bottom flask and cooled in an ice bath was added 2
(10.10 g, 40.69 mmol) as a solution in THF (100 mL) dropwise
via an addition funnel. The reaction mixture was then allowed
to stir under N2, at reflux, for 18 h, while being monitored by
TLC (10% MeOH/CH2Cl2). A saturated aqueous solution of
NH4OH was added until no more H2 gas evolved, and then
dilute aqueous HCl was added until the pH reached 7. The
reaction mixture was filtered, the filter cake was washed with
THF, and the filtrate was concentrated by rotary evaporation.
The resulting solid was recrystallized in 1:1, EtOAc:hexane.
Isolated yield 5.82 g (75%). DSC: (Tg) ) -34 °C, (Tc) ) 22 C,
(Tm) ) 81 °C, TGA: 157-295 °C ) 39% mass loss, 351-414
°C ) 6% mass loss, 423-467 °C ) 6% mass loss, % mass
remaining at 600 °C ) 39. IR: 3650-3050, 2924, 2874, 1599,
Gel permeation chromatography injections were made on a
Waters Chromatography, Inc. (Milford, MA), 1515 isocratic
HPLC pump, equipped with a Waters Chromatography, Inc.,
inline degasser AF, Breeze (version 3.30, Waters Chromatog-
raphy, Inc.) software, a model 2414 differential refractometer
(Waters Inc.), a Precision Detectors, Inc. (Bellingham, MA),
model PD2020 dual-angle (15° and 90°) light scattering
detector, and four PLgel polystyrene-co-divinylbenzene gel
columns supplied by Polymer Laboratories, Inc. (Amherst,
MA), connected in the following series: 5 µm Guard (50 × 7.5
mm), 5 µm Mixed-C (300 × 7.5 mm), 5 µm 104 Å (300 × 7.5
mm), and 5 µm 500 Å (300 × 7.5 mm). Data collection was
performed with Precision Detectors, Inc., Precision Acquire 32
Acquisition Program. Data analysis was performed with
Precision Detectors, Inc., Discovery 32 (version 1.027.000)
software. Interdetector delay volume and the light scattering
detector calibration constant were determined from a nearly
monodisperse polystyrene calibrant (Pressure Chemical Co.,
Mn ) 90 000 g/mol, Mw/Mn < 1.04). The dn/dc values of the
analyzed polymers were then determined from the differential
refractometer response. Data from the differential refracto-
meter response was exported to Origin (Origin Lab Corpora-
tion, Northampton, MA, version 7.0300) and fit with either
Gaussian or Lorentzian curves to determine the relative
percent area of each peak.
1464, 1171, 849, 693 cm-1 1H NMR (300 MHz, CD3OD): δ
.
2.92 (t, J ) 2 Hz, 1H, CH2CtCH), 4.58 (s, 4H, CH2OH), 4.73
(d, J ) 2 Hz, 2H, CH2CtCH), 6.89 (d, J ) 2 Hz, 2H, ArH),
6.96 ppm (t, J ) 2 Hz, 1H, ArH). 13C (CD3OD): δ 56.7, 65.1,
76.8, 80.0, 113.3, 119.4, 144.6, 159.6 ppm. HRMS (FAB): calcd
for (C11H12O3 + H)+: 193.0865; found: 193.0857 ( 3.9 ppm
(MH)+.
Synthesis of (HO)4-[G-1] (4). A 250 mL round-bottom flask
fitted with an N2 inlet was charged with 3 (10.59 g, 55.09
mmol), t-BuOH:H2O (1:1, 65 mL total volume), and CuSO4‚
5H2O (1.56 g, 6.25 mmol). The mixture was allowed to stir at
RT for 15 min. A freshly prepared 5 wt % aqueous solution of
sodium ascorbic acid (49.5 mL, 12.5 mmol) was added to the
reaction flask, followed by 1 (5.0 g, 25 mmol). The reaction
was allowed to stir at RT for 46 h and was monitored by TLC
(30% H2O/isopropyl alcohol). The reaction mixture was con-
centrated by rotary evaporation. The residue was dissolved
in MeOH and eluted on a silica gel column with 20% diethyl
ether/ethyl acetate. Upon elution of the excess monomer, the
eluent was changed to 30% H2O/isopropyl alcohol. The product-
containing fractions were combined, concentrated via rotary
evaporation, and placed under vacuum overnight. Isolated
yield 13.73 g (94%). DSC: (Tg) ) 20 °C. TGA: 33-118 °C )
13% mass loss, 290-407 °C ) 43% mass loss, % mass
remaining at 600 °C ) 32. IR: 3600-3300, 3150-3000, 3000-
Materials. The procedures were performed on a double
manifold, vacuum (0.1 mmHg), 99.99% N2. Thionyl chloride
(99%) was received from Sigma-Aldrich Co. (St. Louis, MO)
and distilled from triphenyl phosphite (10 wt %) under N2 prior
to use. All other materials were used as received from Sigma-
Aldrich Co. Flash column chromatography was performed
using 32-63 D 60 Å silica gel from ICN SiliTech (ICN
Biomedicals GmbH, Eschwege, Germany).
Synthesis of 1,2-Bis(2-azidoethoxy)ethane (1). A 250
mL round-bottom flask fitted with a condenser was charged
with NaN3 (13.81 g, 212.4 mmol), water (100 mL), and 1,2-
bis(2-chloroethoxy)ethane (6.0 mL, 38 mmol). The reaction was
allowed to stir at reflux for 4 days, while being monitored by
1H NMR spectroscopy. Upon cooling to RT, the reaction was
extracted with CH2Cl2 (3 × 100 mL). The organic layers were
combined, dried over MgSO4, and filtered, and the filtrate was
concentrated by rotary evaporation. The resulting colorless
liquid was then dried under vacuum: Isolated yield 7.45 g
(97%). DSC: (Tg) ) -112 °C, (Tc) ) -76 °C, (Tm) ) -20 °C,
TGA: 84-220 °C ) 100% mass loss. IR: 3000-2800, 2103,
1
2800, 1597, 1452, 1290, 1060, 825 cm-1. H NMR (300 MHz,
DMSO-d6): δ 3.48 (s, 4H, CH2OCH2CH2), 3.77 (t, J ) 5 Hz,
4H, CH2OCH2CH2), 4.45 (s, 8H, CH2OH), 4.50 (t, J ) 5 Hz,
4H, CH2OCH2CH2), 5.10 (s, 4H, triazole-CH2O), 5.17 (br s, 4H,
OH), 6.84 (s, 4H, ArH), 6.88 (s, 2H, ArH), 8.16 (s, 2H, triazole)
ppm. 13C (DMSO-d6): δ 49.4, 61.0, 62.9, 68.7, 69.4, 110.9, 117.0,
124.8, 142.8, 144.0, 158.0 ppm. HRMS (FAB): calcd for
(C28H36N6O8 + H)+: 585.2673; found: 585.2684 ( 1.9 ppm
(MH)+.
1442, 1345, 1286, 1123, 932 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 3.38 (t, J ) 5 Hz, 4H, N3CH2CH2OCH2)2), 3.67 (s,
4H, (N3CH2CH2OCH2)2), 3.68 (t, J ) 5 Hz, 4H, (N3CH2CH2-
OCH2)2) ppm. 13C NMR (CDCl3): δ 50.8, 70.3, 70.9 ppm. HRMS
(FAB): calcd for (C6H12N6O2 + H)+: 201.1100; found: 201.1105
( 2.4 ppm (MH)+.
Synthesis of (N3)4-[G-1] (5). A 250 mL two-neck round-
bottom flask was charged with 4 (7.44 g, 12.7 mmol). One neck
was fitted with a septum, and the other neck was fitted with
a condenser that was attached to a dual inlet stopper. One
inlet was attached to the manifold and the other to a drying
tube, filled with NaOH and CaCl2, that was also attached to
an inverted funnel partially submerged in an aqueous NaOH
bath. The reaction vessel was charged with SOCl2 (80 mL, 1.1
mol) under N2 via cannula. The reaction was allowed to stir
in a 65 °C oil bath, under N2 overnight, and was monitored by
TLC (10% MeOH in CH2Cl2, Rf(product) ) 0.67). The dual inlet
stopper was replaced with a single inlet stopper that was
connected to the manifold, and the reaction flask was placed
under vacuum to remove thionyl chloride. The reaction vessel
was charged with DMSO (100 mL) and NaN3 (15.0 g, 231
mmol) and allowed to stir in a 90 °C oil bath, under N2, for 8
h, while being monitored by TLC (10% MeOH in CH2Cl2,
Rf(product) ) 0.56). The reaction mixture was allowed to cool to
RT and partitioned between H2O (100 mL) and CH2Cl2 (100
mL). The aqueous layer was extracted with CH2Cl2 (3×). The
Synthesis of the Propargyl Ether of Dimethyl 5-Hy-
droxyisophthalate (2). A two-neck 1 L round-bottom flask
was charged with dimethyl 5-hydroxyisophthalate (10.0 g, 47.6
mmol), acetone (200 mL), K2CO3 (7.9 g, 57 mmol), 18-crown-6
(0.13 g, 0.49 mmol), and propargyl bromide (80 wt %) in xylene
(6.3 mL, 57 mmol). The reaction was allowed to stir under N2
at reflux overnight. Upon cooling to RT, the reaction mixture
was filtered, the filter cake was washed (3×) with acetone, and
the filtrate was concentrated by rotary evaporation. The
residue was recrystallized in ethanol and dried under vacuum
overnight: Isolated yield 10.45 g (89%). TGA: 132-276 °C )
97% mass loss, % mass remaining at 600 °C ) 1. IR: 3274,
3081, 3011, 2960, 1722, 1597, 1433, 1248, 1052, 996, 753 cm-1
.
1H NMR (300 MHz, CDCl3): δ 2.56 (t, J ) 2 Hz, 1H, CH2Ct
CH), 3.95 (s, 6H, COOCH3), 4.79 (d, J ) 2 Hz, 2H, CH2Ct
CH), 7.84 (d, J ) 2 Hz, 2H, ArH), 8.34 ppm (t, J ) 2 Hz, 1H,

5438 Joralemon et al.
Macromolecules, Vol. 38, No. 13, 2005
combined organic layers were dried with MgSO4 and filtered,
and the filtrate was concentrated via rotary evaporation. The
residue was dried under vacuum overnight. Isolated yield 7.60
g (87%). Mn ) 600 Da, Mw/Mn ) 1.04 from GPC. DSC: (Tg) )
-30 °C. TGA: 45-177 °C ) 4% mass loss, 180-267 °C ) 18%
mass loss, 296-427 ) 21% mass loss, % mass remaining at
600 °C ) 47. IR: 3200-3000, 3000-2600, 2124, 1602, 1459,
120.1, 117.0, 114.2, 110.9, 69.4, 68.6, 62.9, 61.2, 61.0, 52.6, 49.5
ppm. HRMS (ESI): calcd for (C72H80N18O16+2H)2+: 727.3078;
found: 727.3055( 3.2 ppm (M2H)2+
.
Synthesis of (N3)8-[G-2] (8). A 250 mL three-neck round-
bottom flask was charged with 7 (3.04 g, 2.09 mmol). One neck
was fitted with a septum, one with a glass stopper, and the
third neck with a condenser that was attached to a dual inlet
stopper. One inlet was attached to the manifold and the other
to a drying tube, filled with NaOH and CaCl2, that was also
attached to an inverted funnel partially submerged in an
aqueous NaOH bath. The reaction vessel was charged with
SOCl2 (40 mL, 0.5 mol) under N2 via a cannula. The reaction
was allowed to stir in a 40 °C oil bath, under N2 overnight,
and was monitored by 1H NMR spectroscopy (DMSO-d6). The
dual inlet stopper was replaced with a single inlet stopper that
was connected to the manifold, and the reaction flask was
placed under vacuum to remove the thionyl chloride. The
reaction vessel was charged with DMSO (50 mL) and NaN3
(4.91 g, 75.5 mmol). The reaction was allowed to stir in a 95
°C oil bath, open to the air, for 24 h and was monitored by 1H
NMR spectroscopy (DMSO-d6). The reaction was allowed to
cool to RT, and then CH2Cl2 (100 mL) was added followed by
H2O (100 mL). The aqueous layer was extracted with CH2Cl2
(3×). The combined organic layers were dried over MgSO4 and
filtered, and the filtrate was concentrated via rotary evapora-
tion. The residue was dried under vacuum overnight. Isolated
yield 2.80 g (81%). Mn ) 1610, Mw/Mn ) 1.1 from GPC. DSC:
(Tg) ) -10 °C, TGA: 40-145 °C ) 5% mass loss, 145-266 °C
) 20% mass loss, 290-451 °C ) 19% mass loss, % mass
remaining at 600 °C ) 49. IR: 3422, 3139, 3000-2800, 2113,
1600, 1458, 1299, 1057, 845 cm-1. 1H NMR (300 MHz, DMSO-
d6): δ 3.46 (s, 4H, CH2OCH2CH2), 3.75 (t, J ) 5 Hz, 4H, CH2-
OCH2CH2), 4.42 (s, 8H, CH2N3), 4.49 (t, J ) 5 Hz, 4H,
CH2OCH2CH2), 5.10 (s, 4H, G1-triazole-CH2O), 5.15 (s, 8H,
G1-C6H3CH2), 5.55 (s, 8H, G2-triazole-CH2O), 6.91 (s, 2H, G1-
ArH), 6.96 (s, 4H, G1-ArH), 6.98 (d, J ) 0.9 Hz, 4H, G2-ArH),
7.02 (d, J ) 0.9 Hz, 8H, G2-ArH), 8.15 (s, 2H, G1-triazole),
8.30 ppm (s, 4H, G2-triazole). 13C (DMSO-d6): δ 158.5, 158.4,
142.8, 142.1, 138.0, 137.7, 125.0, 124.8, 120.7, 114.3, 114.2,
69.4, 68.6, 61.2, 53.3, 52.6, 49.4 ppm. HRMS (ESI): calcd for
(C72H72N42O8+2H)2+: 827.3337; found: 827.3309 ( 3.4 ppm
1
1303, 1056, 846 cm-1. H NMR (300 MHz, CDCl3): δ 3.53 (s,
4H, CH2OCH2CH2), 3.82 (t, J ) 5 Hz, 4H, CH2OCH2CH2), 4.31
(s, 8H, CH2N3), 4.50 (t, J ) 5 Hz, 4H, CH2OCH2CH2), 5.21 (s,
4H, triazole-CH2O), 6.89 (s, 2H, ArH), 6.90 (s, 4H, ArH), 7.75
(s, 2H, triazole) ppm. 13C (CDCl3): δ 159.1, 143.6, 137.9, 124.1,
120.6, 114.4, 70.5, 69.5, 62.3, 54.5, 50.4 ppm. HRMS (FAB):
calcd for (C28H32N18O4 + Li)+: 691.3014; found: 691.2983 (
4.5 ppm (MLi)+.
Synthesis of (Alkyne)4-[G-1] (6). A 250 mL two-neck
round-bottom flask was charged with 4 (0.5456 g, 0.9332
mmol). One neck was fitted with a septum, and the other neck
was fitted with a condenser that was attached to a dual inlet
stopper. One inlet was attached to the manifold and the other
to a drying tube, filled with NaOH and CaCl2, that was also
attached to an inverted funnel partially submerged in an
aqueous NaOH bath. The reaction vessel was charged with
SOCl2 (8.0 mL, 0.1 mol) under N2 via cannula. The reaction
was allowed to stir in a 65 °C oil bath, under N2 overnight,
and was monitored by TLC (10% MeOH in CH2Cl2, Rf(product)
)
0.67). The reaction flask was placed under vacuum to remove
the thionyl chloride. The dual inlet stopper was replaced with
a single inlet stopper that was connected to the manifold. The
reaction vessel was charged with propargyl alcohol (3.0 mL,
51 mmol) followed by a solution of potassium tert-butoxide
(0.8458 g, 7.548 mmol) dissolved in propargyl alcohol (10.0 mL,
169 mmol) under N2 via syringes. The reaction was allowed
to stir under N2 in an 80 °C oil bath overnight and was
monitored by 1H NMR spectroscopy (CD2Cl2). The reaction
mixture was concentrated via rotary evaporation, and the
resultant residue was dissolved in CH2Cl2 and then eluted on
a silica gel column with EtOAc:hexane 1:1, followed by 10%
MeOH in CH2Cl2 (Rf(product) ) 0.80). Isolated yield 0.459 g (68%).
DSC: (Tg) ) -19 °C. TGA: 242-317 °C ) 8% mass loss, 318-
398 °C ) 22% mass loss, 403-589 °C ) 19% mass loss, % mass
remaining at 600 °C ) 51. IR: 3283, 3143, 2900-2600, 2113,
(M2H)2+
.
1599, 1458, 1296, 1108, 848, 682 cm-1
.
1H NMR (300 MHz,
Synthesis of (HO)16-[G-3] (9). A 100 mL round-bottom
flask fitted with an N2 inlet stopper was charged with a
magnetic stir bar, 8 (0.8 g, 0.5 mmol), DMSO (9 mL), and 3
(0.76 g, 3.95 mmol). A freshly prepared solution of sodium
ascorbic acid (0.48 g, 2.42 mmol) in 10% H2O in DMSO (10
mL DMSO, 1 mL H2O) was added followed by CuSO4‚5H2O
(0.030 g, 0.120 mmol). The reaction was allowed to stir at RT
for 42 h and was monitored by 1H NMR (DMSO-d6). The
reaction was precipitated into cold H2O, and the solid was
isolated by vacuum filtration and redissolved in DMSO. The
solution was placed under vacuum overnight, the resulting
concentrated solution was precipitated in cold H2O, and the
product was isolated by centrifugation. Isolated yield 1.34 g
(87%). DSC: (Tg) ) 91 °C, TGA: 31-96 °C ) 8% mass loss,
101-146 °C ) 6% mass loss, 272-467 °C ) 25% mass loss, %
mass remaining at 600 °C ) 55. IR: 3600-3000, 3000-2800,
1600, 1458, 1297, 1059, 825 cm-1. 1H NMR (300 MHz, DMSO-
d6): δ 3.46 (s, 4H, CH2OCH2CH2), 3.75 (br s, 4H, CH2OCH2-
CH2), 4.48 (d, J ) 5 Hz, 36H, CH2OH, CH2OCH2CH2), 5.12 (s,
28H, G1-triazole-CH2O, G1-C6H3CH2, G2-C6H3CH2), 5.21 (br
t, J ) 5 Hz, 16H, OH), 5.57 (s, 24H, G2-triazole-CH2O, G3-
triazole-CH2O), 6.85 (s, 24H, G2-ArH, G3-ArH), 6.90 (s, 12H,
G2-ArH, G3-ArH), 6.93 (s, 2H, G1-ArH), 7.00 (s, 4H, G1-ArH),
8.16 (s, 2H, G1-triazole), 8.29 (s, 12H, G2-triazole, G3-triazole)
ppm. 13C (DMSO-d6): δ 158.5, 158.0, 144.0, 143.3, 138.1, 125.0,
124.7, 120.2, 117.1, 114.3, 110.9, 69.4, 68.6, 62.9, 61.2, 52.6,
CD2Cl2): δ 2.54 (t, J ) 2 Hz, 4H, CH2CtCH), 3.52 (s, 4H, CH2-
OCH2CH2-triazole), 3.80 (t, J ) 5 Hz, 4H, CH2OCH2CH2-
triazole), 4.15 (d, J ) 2 Hz, 8H, CH2CtCH), 4.49 (t, J ) 5 Hz,
4H, CH2OCH2CH2-triazole), 4.54 (s, 8H, CH2OCH2CtCH),
5.17 (s, 4H, triazole-CH2), 6.92 (s, 4H, ArH), 6.93 (s, 2H, ArH),
7.76 (s, 2H, triazole) ppm. 13C (CD2Cl2): δ 159.1, 144.0, 139.9,
124.5, 120.5, 114.0, 80.2, 75.0, 71.7, 70.9, 69.8, 62.4, 57.7, 50.8
ppm. HRMS (ESI): calcd for (C40H44N6O8 + Na)+: 759.3118;
found: 759.3107 ( 1.5 ppm (MNa)+.
Synthesis of (HO)8-[G-2] (7). A 500 mL round-bottom flask
fitted with an N2 inlet stopper was charged with a magnetic
stir bar, 3 (5.70 g, 29.6 mmol), EtOH (70 mL), CuSO4‚5H2O
(0.44 g, 1.76 mmol), and a freshly prepared 5 wt % aqueous
solution of sodium ascorbic acid (14.0 mL, 3.53 mmol). The
mixture was allowed to stir at RT for 15 min and was then
added to a 1 L round-bottom flask that was charged with 5
(4.84 g, 7.07 mmol) and a magnetic stir bar. DMSO (2 mL)
was added, and the reaction was allowed to stir at RT for 24
h. The precipitated product was collected via filtration, washed
(3×) with MeOH, and then placed under vacuum for 9 h.
Isolated yield 9.40 g (91%). DSC: (Tg) ) 33 °C. TGA: 33-110
°C ) 3% mass loss, 124-254 °C ) 5% mass loss, 270-446 °C
) 35% mass loss, % mass remaining at 600 °C ) 50. IR: 3620-
3000, 3254, 3133, 3000-2800, 1597, 1458, 1290, 1022, 838
cm-1. 1H NMR (300 MHz, DMSO-d6): δ 3.47 (s, 4H, CH2OCH2-
CH2), 3.75 (t, J ) 5 Hz, 4H, CH2OCH2CH2), 4.45 (d, J ) 5 Hz,
16H, CH2OH), 4.48 (t, J ) 5 Hz, 4H, CH2OCH2CH2), 5.10 (s,
12H, G1-triazole-CH2O, G1-C6H3CH2), 5.16 (t, J ) 5 Hz, 8H,
OH), 5.58 (s, 8H, G2-triazole-CH2O), 6.80 (s, 8H, G2-ArH), 6.85
(s, 4H, G2-ArH), 6.90 (s, 2H, G1-ArH), 6.95 (s, 4H, G1-ArH),
8.15 (s, 2H, G1-triazole), 8.25 ppm (s, 4H, G2-triazole). 13C
(DMSO-d6): δ 158.5, 158.0, 144.0, 143.3, 138.0, 125.1, 124.7,
49.5 ppm. HRMS (ESI): calcd for (C160H168N42O32+3H)3+
:
1064.4358; found: 1064.4342 ( 1.5 ppm (M3H)3+
.
Synthesis of (N3)16-[G-3] (10). A scintillation vial charged
with 9 (0.4050 g, 0.1269 mmol) and a magnetic stir bar was
fitted with a septum that had a needle connected to the
manifold and another needle connected to a drying tube, filled
with NaOH and CaCl2, that was also attached to an inverted

Macromolecules, Vol. 38, No. 13, 2005
Dendrimers Clicked Together Divergently 5439
Scheme 1. Synthesis of the Bis(azide) Dendrimer Core and Alkyne-Functionalized Monomer
Scheme 2. Synthesis of First Generation Dendrimers and Functionalization with Azido and Alkyne Termini
funnel partially submerged in an aqueous NaOH bath. The
reaction vessel was charged with SOCl2 (5.0 mL, 68 mmol)
under N2 via a cannula. The reaction was allowed to stir and
a 40 °C oil bath, under N2 overnight, and was monitored by
1H NMR spectroscopy (DMSO-d6). The needle connected to the
drying tube was removed and the reaction flask was placed
under vacuum to remove the thionyl chloride. The reaction
vessel was charged with DMSO (5 mL) and NaN3 (0.6 g, 9.2
mmol) and then allowed to stir in a 90 °C oil bath, open to the
air, overnight and was monitored by 1H NMR spectroscopy
(DMSO-d6). The reaction was allowed to cool to RT, CH2Cl2
(10 mL) was added followed by H2O (10 mL), and the aqueous
layer was extracted (3×) with CH2Cl2. The combined organic
layers were dried over MgSO4 and filtered, and the filtrate
was concentrated via rotary evaporation. The residue was
dried under vacuum overnight. Isolated yield 0.23 g (50%). Mn
) 3850, Mw/Mn ) 1.01 from GPC. DSC: (Tg) ) -9 °C. TGA:
32-87 °C ) 1% mass loss, 89-179 °C ) 11% mass loss, 183-
270 °C ) 14% mass loss, 276-434 °C ) 16% mass loss, % mass
remaining at 600 °C ) 49. IR: 3200-3000, 3000-2800, 2960,
1
2108, 1600, 1458, 1298, 1052, 844 cm-1. H NMR (300 MHz,
DMSO-d6): δ 3.44 (s, 4H, CH2OCH2CH2), 3.73 (s, 4H, CH2-
OCH2CH2), 4.42 (s, 36H, CH2N3, CH2OCH2CH2), 5.09 (s, 12H,
G1-triazole-CH2O, G1-C6H3CH2), 5.14 (s, 16H, G2-C6H3CH2),
5.53 (s, 24H, G2-triazole-CH2O, G3-triazole-CH2O), 6.84-7.10
(br m, 42H, G1-ArH, G2-ArH, G3 ArH), 8.14 (s, 2H, G1-
triazole), 8.30 ppm (s, 12H, G2-triazole, G3-triazole). 13C
(DMSO-d6): δ 158.6, 143.1, 142.9, 138.3, 137.9, 125.4, 125.2,
120.9, 120.4, 114.5, 114.2, 61.4, 61.2, 53.6, 52.9, 49.0 ppm.
HRMS (ESI): calcd for (C160H152N90O16+3H)3+
: 1197.4694;
found: 1197.4670 ( 2.0 ppm (M3H)3+
.
Results and Discussion
Core and Monomer Syntheses. The bis(azide) core,
designed to present two azide functionalities available
for dendrimer growth via Click reactions with the
monomer, was synthesized readily, as shown in Scheme

5440 Joralemon et al.
Macromolecules, Vol. 38, No. 13, 2005
Scheme 3. Synthesis of Generation 2 and 3
Dendrimers by a Divergent Click Strategy
1, from 1,2-bis(2-chloroethoxy)ethane and sodium azide.
Similarly, the monomer was crafted to present an
alkyne functionality available to participate in Click
reactions with the core or growing dendrimer during the
generation growth steps and began with the transfor-
mation of the alcohol group of dimethyl 5-hydroxyisoph-
thalate into a propargyl ether functionality. Reduction
of the methyl esters to alcohols afforded a monomer with
alcohol functionalities available for conversion to either
azide or alkyne groups during an activation step via a
chloro intermediate, thus providing a handle for genera-
tion growth.
Dendrimer Syntheses. Dendrimers were assembled
through an iterative process involving a Click reaction
followed by activation via in situ halogenation and azido
nucleophilic substitution, as illustrated in Schemes 2
and 3. The Click reactions were conducted in the
presence of Cu(I) generated in situ from CuSO4‚5H2O
and sodium ascorbic acid. Catalysis by Cu(I) ensured
regioselective formation of the 1,4-disubstituted 1,2,3-
triazole isomer, rather than a mixture with the corre-
sponding 1,5-disubstituted 1,2,3-triazole isomer.74 The
alcohol termini of the first generation dendrimer ((HO)4-
[G-1]) could be transformed into either alkyne groups
((alkyne)4-[G-1]) or azide groups ((N3)4-[G-1]), demon-
strating the versatility of the synthetic approach. The
alkyne-terminated dendrimer was synthesized from a
one-pot, two-step reaction sequence by initial reaction
of (HO)4-[G-1] with an excess of thionyl chloride to yield
as an intermediate, chloro terminal groups. Following
removal of the thionyl chloride in vacuo, a solution of
potassium tert-butoxide dissolved in propargyl alcohol
was added to transform the chloro termini into alkyne
termini. The azide-terminated dendrimer was prepared
by a similar process with the chloro-terminated inter-
mediate being dissolved in DMSO and then allowed to
undergo reaction with an excess of sodium azide. The
desired first generation azide-terminated dendrimer
((N3)4-[G-1]) was obtained in >97% purity by a simple
extraction into dichloromethane.
Dendrimer growth then proceeded via an iterative
sequence that involved Click reactions between azido
chain ends of the growing dendrimers with the alkynyl
group of the monomer, followed by reactivation via
transformation of the hydroxyl groups to azides, until
the third generation azide-terminated dendrimer was
afforded. The second generation hydroxyl-terminated
dendrimer ((HO)8-[G-2]) was obtained via a Click reac-
tion between the first generation azide-terminated
dendrimer ((N3)4-[G-1]) and the monomer. The desired
product formed as a precipitate during the reaction and
was isolated in >95% purity (as determined by GPC)
without further purification and represents ca. 99+ %
yield for each Click coupling reaction. The alcohol
termini of (HO)8-[G-2] were transformed into azide
groups, by the same procedure as was employed for the
first generation material, to yield (N3)8-[G-2]. Again, the
desired product was isolated by simple extraction into
dichloromethane to achieve >94% purity and was not
purified further. The third generation dendrimer
((HO)16-[G-3]) was synthesized using the same Click
reaction and obtained in >95% purity via precipitation
into water, without further purification. The alcohol
termini of the third generation dendrimer were trans-
formed into azide groups by the in situ two-step reaction
described previously for the earlier generations. The
desired third generation azide-terminated dendrimer
((N3)16-[G-3]) was isolated from the reaction mixture by
extraction into dichloromethane in >87% purity and
was not purified further.
Characterization. 1H NMR spectroscopy was an
especially useful tool for illustrating the growth of each
new dendrimer generation, as shown from the stacked
plots in Figure 1. As successive generations were added,
new resonances corresponding to the additional genera-
tions of monomer appeared as well as unique triazole
proton signals. Upon growth of the second generation,
the first generation triazole proton (d) remained visible
at 8.16 ppm in the (HO)8-[G-2] spectrum, while a second

Macromolecules, Vol. 38, No. 13, 2005
Dendrimers Clicked Together Divergently 5441
Figure 1. 1H NMR spectra of alcohol-terminated first, second, and third generation dendrimers. On going from generation 1 to
2 to 3, the resonances due to protons from the new generations are designated with asterisks.
higher molecular weight, corresponding to that of a
dimeric, [G-2]-like species, which constituted ca. 3% of
the total sample. Both higher molecular weight, [G-3]-
like species and lower molecular weight, [G-1]-like
species were observed in the GPC traces for (N3)8-[G-
2]; however, these impurities were present as only ca.
4% and 2%, respectively, of the total sample. Similarly,
the (N3)16-[G-3] dendrimer contained multiple low mo-
lecular weight impurities that totaled ca. 13% of the
entire sample and a high molecular weight contaminant
that was ca. 0.5% of the total product. The impurities
detected by GPC were also observed in the mass spectra,
for example, as shown for the MALDI-TOF spectrum
of (N3)16-[G-3] (Figure 2, inset). Although the structures
of the impurities could not be assigned definitively, the
observed levels of purity are expected given the absence
of any purification by chromatography, with the crude
reaction mixtures only having undergone precipitation
or extraction.
Each product was also characterized by IR spectros-
Figure 2. GPC traces for azide terminated dendrimers and
MALDI MS spectrum for (N3)16-[G-3].
copy, which clearly illustrated the terminal group
transformations, as shown in Figure 3. The alcohol
termini gave rise to a characteristic broad and strong
stretch from 3620 to 3000 cm-1, while the azide termini
triazole resonance (integration ratio of i:d was 2:1)
corresponding to the new generation (i) was observed
at 8.25 ppm. The triazole proton (d) for the first
generation layer was also apparent at 8.16 ppm in the
(HO)16-[G-3] spectrum; however, the signals due to the
second and third generation triazole protons (i and n,
respectively) were observed at overlapping chemical
shifts. The ratio of integrations for peaks i + n:d was
6:1 and corresponds with the expected structure based
on divergent growth of the third generation.
Because of a lack of solubility in THF for the alcohol-
terminated derivatives, analysis of the dendritic growth
strategy by gel permeation chromatography (GPC) was
performed for the azido-terminated species (Figure 2).
Small amounts of impurities were detected in each
generation. The contaminant in (N3)4-[G-1] was of
produced a characteristic strong stretch at 2110 cm-1
.
With each activation step, upon conversion of the OH
termini into azide groups, the OH stretch was elimi-
nated and the azide stretch became visible.
As expected, the behavior of the dendrimers was
controlled by the terminal functional groups and the
generation number. For example, the alkyne- and azide-
terminated dendrimers were soluble in a broad range
of organic solvents, such as THF, CH2Cl2, DMSO, etc.
In contrast, the alcohol-terminated dendrimers, beyond
the first generation, were only sparingly soluble in
DMSO and DMF. The first generation dendrimer,
(HO)4-[G-1], was soluble in methanol and aqueous
solvents, while higher generations, with increasing

5442 Joralemon et al.
Macromolecules, Vol. 38, No. 13, 2005
Fund, administered by the ACS (ACS PRF #38026-
AC7), for partial support of this work. M.J.J. was
supported by a Chemistry-Biology Interface Program
fellowship under an NIH Training Grant NIHNRSA T32
GM08785-05. R.O.R. was supported by a research
fellowship from the Royal Commission for the Exhibi-
tion of 1851. The authors thank Dr. Michael Malkoch
and Mr. Peng Wu for acquisition of mass spectrometry
data. Mass spectrometry analyses were also provided
by the Washington University Mass Spectrometry Re-
source with support from the NIH National Center for
Research Resources (Grant P41RR0954).
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