Pushing the limits for Thiol-Ene and CuAAC reactions: Synthesis of a 6th generation dendrimer in a single day

Article abstract of DOI:10.1021/ma101242u

Dendrimer synthesis should not be tedious and time-consuming. By utilizing an AB₂-CD₂ approach and having orthogonal, "clickable" groups on each monomer, the time for dendrimer assembly can be drastically reduced. This was shown by preparation of a sixth generation dendrimer from starting monomer units in a single day.

Full text of DOI:10.1021/ma101242u

Macromolecules 2010, 43, 6625–6631 6625
DOI: 10.1021/ma101242u
Pushing the Limits for Thiol-Ene and CuAAC Reactions: Synthesis of a
6th Generation Dendrimer in a Single Day
Per Antoni,†,‡ Maxwell J. Robb,‡ Luis Campos,‡ Maria Montanez,† Anders Hult,†
†
Eva Malmstrom, Michael Malkoch,* and Craig J. Hawker*
,†
,‡
€
†Royal Institute of Technology, School of Chemistry and Chemical Science, Division of Coating Technology,
Teknikringen 56-58, 10044 Stockholm, Sweden, and ‡Department of Chemistry and Biochemistry,
Materials Department, and Materials Research Laboratory (MRL), University of California,
Santa Barbara, California 93106
Received June 3, 2010; Revised Manuscript Received July 7, 2010
ABSTRACT: Dendrimer synthesis should not be tedious and time-consuming. By utilizing an AB2-CD2
approach and having orthogonal, “clickable” groups on each monomer, the time for dendrimer assembly can
be drastically reduced. This was shown by preparation of a sixth generation dendrimer from starting
monomer units in a single day.
Introduction
facilitate the academic and commercial availability of dendritic
materials.12,13
The field of branched, globular polymers such as dendrimers
has undergone a remarkable development since they were first
postulated by Flory in 1952.1 Flory’s early ideas were syntheti-
cally realized almost 30 years later when the divergent growth
approach was introduced, followed in 1990 by the convergent
strategy for the synthesis of dendrimers.2-5 In recent years, the
dendrimer field has expanded with numerous scientific publica-
tions discussing the useoftheseunique macromolecules in various
applications such as multivalent affinity probes,6 micro-
electronics,7,8 and in light harvesting systems.9
The introduction of click chemistry in 2001 brought with it a
wide range of opportunities for dendrimer synthesis14-16 with
these highly efficient, robust, and orthogonal reactions being
ideal for the rapid and facile preparation of dendrimers.17 Within
this family of reactions are copper catalyzed azide alkyne cyc-
loaddition (CuAAC) and photochemical radical thiol-ene
coupling.18-22 The effectiveness of these reactions for dendrimer
synthesis has already been proven. In 2008, Hawker successfully
synthesized fourth generation dendrimers using thiol-ene cou-
pling reactions23 and in 2007, Malkoch demonstrated the accel-
erated assembly of a fourth generation dendrimer in 4 steps using
CuAAC coupling reactions in combination with esterification
chemistry.24 In an elegant expansion of this approach, Shen ex-
ploited the kinetically asymmetric reactivity of 2-[(methacryloyl)-
oxy]ethyl acrylate (AB monomer) via Michael additions with
cysteamine as a CD2 monomer. The key to this approach is the
orthogonality of the methacrylate unit which undergoes quanti-
tative reaction with the thiol and no reaction with the amino
group.25 A consistent feature in all of these accelerated ap-
proaches is the cessation of dendrimer growth at the fourth
generation and prolonged reaction/purification times.
An ongoing challenge in developing applications for dendritic
macromolecules is the elaboration of new methodologies for their
synthesis. Ideally, dendrimer synthesis should be fast, efficient,
and rely on simple purification methods with these attributes
being absent from many of the original divergent or convergent
growth approaches. A number of accelerated strategies have been
developed ranging from a branched AB4 monomer approach to
the rapid synthesis of dendrimers by an orthogonal coupling
strategy.10,11 In the latter strategy, Zimmerman combined differ-
ent AB2 and CD2 monomers with orthogonal Mitsunobu ester-
ification and Sonogashira chemistry to construct dendritic
macromolecules at a rate of one generation per step. While
accelerated, many of these strategies still suffer fromissues related
to efficiency and complicated purification steps which leads to a
considerable time investment. To overcome the long held view
that dendrimer synthesis is tedious, expensive, and time-consum-
ing, a robust and highly efficient strategy for the synthesis of
dendritic macromolecules based on the combination of two
orthogonal click reactions is presented. This approach takes
advantage of the quantitative nature of the coupling reactions,
an AB2/CD2 strategy, and facile purification requirements to
allow a sixth generation dendrimer to be prepared in a single
day from starting monomer units. While other approaches
have accelerated dendrimer synthesis by reducing the number
of steps, it is proposed that this focus on acceleration in terms
of steps, efficiency and most importantly, time, will further
In this report, we present the synthesis of a sixth generation
dendrimer using the accelerated AB2/CD2 approach employing
both CuAAC and thiol-ene coupling reactions. We present a
new methodology for dendritic growth including time efficient
and benign reaction conditions coupled with simplified purifica-
tion. The end result is the preparation of a sixth generation
dendrimer in a single day.
Experimental Section
General Methods. 1H and 13C nuclear magnetic resonance
(NMR) spectra were recorded using either a Bruker 200, 300, or
500 MHz or Varian 400 or 500 MHz spectrometer with the
solvent signal as internal reference. Deuterated solvents were
obtained from Cambridge Isotope Laboratories, Inc. CDCl3
was used unless otherwise noted. Column chromatography was
performed on a Biotage SP1 Flash Purification System using
FLASH 40þM cartridges. Gel permeation chromatography
*Corresponding authors. E-mail: (M.M.) Malkoch@kth.se; (C.J.H.)
Hawker@mrl.ucsb.edu.
r 2010 American Chemical Society
Published on Web 07/26/2010
pubs.acs.org/Macromolecules

6626 Macromolecules, Vol. 43, No. 16, 2010
Antoni et al.
(GPC) was performed in N,N-dimethylformamide (DMF) on a
Waters 2690 separation module equipped with a Waters 2414
refractive index detector. Molecular weights were calculated
relative to linear PS standards. Differential scanning calorime-
try (DSC) was performed on a TA Instruments DSC Q2000
fitted with a RCS90 refrigerated cooling system at a sampling
rate of 10 °C/min in the temperature range of -90 to 70 °C.
Thermogravimetric analysis (TGA) was performed on a TA
Instruments Q50 thermogravimetric analyzer under a nitrogen
atmosphere at a heating rate of 10 °C/min. Infrared spectra were
recorded on a Perkin-Elmer Spectrum 100 with a Universal
ATR sampling accessory. The MALDI-TOF mass spectra
were collected on a Bruker UltraFlex MALDI-TOF MS with
SCOUT-MTP Ion Source (Bruker Daltonics, Bremen)
equipped with a N2-laser (337 nm), a gridless ion source and re-
flector design. Spectra of the first and second generation den-
drimers were acquired using a reflector-positive method with an
acceleration voltage of 25 kV and a reflector voltage of 26.3 kV.
Higher generation (third generation and higher) dendrimers
were monitored using a linear mode. The detector mass range
was set to 500-20000 Da in order to exclude high intensity peaks
from the lower mass range. The laser intensity was set to the
lowest value possible to acquire high resolution spectra. Spectra
were analyzed with FlexAnalysis Bruker Daltonics, Bremen,
version 2.2. A Hamamatsu L5662-01 equipped with a 200W
Hg-Xe lamp (230-436 nm), λmax=365, was used as a UV-light
source. ESI mass spectrometry was performed on a Micromass
QTOF2 quadrupole/time-of-flight tandem mass spectrometer
with the cone voltage set to 45 V and the source temperature
at 80 °C. Chemicals were purchased from Sigma-Aldrich
(St. Louis, MO) and used without further purification unless
otherwise noted.
dissolved in 50 mL of DCM and added dropwise to the 0 °C
solution. The reaction was left overnight and the white precipi-
tate was filtered off the following morning. The crude solution
was washed with3 ꢀ 50 mL10wt% NaHSO4 (aq) and3 ꢀ 50 mL
10 wt % NaHCO3 (aq). The organic phase was washed once
more with brine, dried using MgSO4, concentrated, and purified
by flash chromatography eluting the product in 30:70 EtOAc:
hexanes as a colorless oil. Yield: 20.6 g (91%). 1H NMR: δ 1.24
(s, 6H, -CH3), 1.56-1.71 (m, 16H, -CH2CH2-), 2.34 (t, 8H,
-CdOCH2-), 2.90 (t, 4H, -SCH2CH2O-), 3.28 (t, 8H,
-CH2N3), 4.19 (d, 4H, J = 12 Hz, -CH2O-), 4.23 (d, 4H,
J = 12 Hz, -CH2O-), and 4.37 (t, 4H, -SCH2CH2O-) ppm.
13C NMR: δ 17.8, 22.0, 28.3, 33.4, 36.9, 46.3, 51.0, 62.6,
65.2, 172.4, and 172.5 ppm. MS (ESI): m/z [M þ Na]þ calcd
for [C34H54N12O12S2 þ Na]þ, 909.31; found, [M þ Na]þ
909.36.
2-((2-Mercaptoethoxy)carbonyl)-2-methylpropane-1,3-diyl Bis-
(5-azidopentanoate), HED-bis-MPA-N3, 4. 3 (14.0 g, 15.8 mmol,
1 equiv), dithiothreitol (DTT) (4.87 g, 31.6 mmol, 2 equiv), and
TEA (6.38 g, 63.2 mmol, 4 equiv) were dissolved in 100 mL of
DCM and flushed with argon for 15 min. The reaction was left
to stir overnight and then concentrated. The crude product was
purified by flash chromatography eluting the product in 30:70
EtOAc:Hexanes as a colorless viscous oil. Yield: 11.2 g (80%).
1H NMR: δ 1.24 (s, 3H, -CH3), 1.46 (t, 1H, -SH), 1.56-1.72
(m, 8H, -CH2CH2-), 2.33 (t, 4H, -OCHdOCH2-), 2.73 (q,
2H, -SCH2CH2O-), 3.27 (t, 4H, -CH2N3), 4.20 (d, 2H,
-CH2O-), 4.22 (t, 2H, -SCH2CH2O-), and 4.23 (d, 2H,
-CH2O-) ppm. 13C NMR: δ 17.8, 21.9, 23.1, 28.2, 33.4, 46.3,
50.9, 65.2, 65.3, 172.3, and 172.5 ppm. MS (ESI): m/z [M þ Na]þ
calcd for [C17H28N6O6S þ Na]þ, 467.15; found, [M þ Na]þ
467.17.
2,20-Disulfanediylbis(ethane-2,1-diyl) Bis(2,2,5-trimethyl-1,3-
dioxane-5-carboxylate), HED-bis-MPA-Ac, 1. Acetonide-pro-
tected bis-MPA(methyloypropionic acid) (42.6 g, 0.245 mol, 2.4
equiv) was dissolved in 150 mL of DCM (dichloromethane)
together with HED (2,20-bis(hydroxyethyl)dimercaptan) (15.75
g, 0.102 mol, 1 equiv) and DMAP (4-dimethylaminopyridine)
(4.98 g, 0.041 mol, 0.4 equiv). The solution was kept at 0 °C upon
addition of DCC (dicyclohexylcarbodimide) (50.50 g, 0.245
mol, 2.4 equiv). The reaction was left overnight to reach room
temperature. The slurry was filtered and the crude solution was
concentrated and purified by flash chromatography eluting the
product in 20:80 EtOAc:hexanes as a viscous oil. Yield: 40.5 g
(85%). 1H NMR: δ 1.19 (s, 6H, -CH3), 1.38 (s, 6H, -CH3), 1.42
(s, 6H, -CH3), 2.93 (t, 4H, -SCH2CH2O-), 3.63 (d, 4H, J = 12
Hz, -CH2O-), 4.18 (d, 4H, J = 12 Hz, -CH2O-) and 4.40 (t,
4H, -SCH2CH2O-) ppm. 13C NMR: δ 18.6, 22.5, 24.7, 37.0,
41.9, 62.4, 65.9, 98.0, and 174.0 ppm, MS (ESI): m/z [M þ Na]þ
calcd for [C20H34O8S2 þ Na]þ, 489.16; found, [M þ Na]þ
489.16.
3-(Allyloxy)-2-(allyloxymethyl)-2-methylpropanoic Acid, BAPA,
5. Bis-MPA (20.0 g, 0.149 mol, 1 equiv), NaOH (59.6 g, 1.49 mol, 10
equiv), and allyl bromide (125.3 g, 1.04 mol, 7 equiv) were added to
300 mL of toluene and left to reflux overnight under vigorous
stirring. The reaction was removed from heat and 100 mL of H2O
was added to the crude solution followed by dropwise addition of
concentrated HCl until pH = 1 was established. The reaction was
washed with H2O (2 ꢀ 50 mL), dried over MgSO4, and concen-
trated. The pure product was isolated as a yellow viscous oil.
Yield: 25.6 g (80%). 1H NMR: δ 1.22 (s, 3H, -CH3), 3.54 (d, 2H,
-CH2O-), 3.57 (ABq, 2H, -CH2O-), 3.98 (dt, 4H, J=6 Hz,
-OCHH2CHCH2), 5.10-5.30 (m, 4H, -CHCH2), 5.75-5.96 (m,
2H, -CHCH2), and 9.68 (bs, 1H, -OH) ppm. 13C NMR: δ 17.9,
48.1, 71.8, 72.3, 116.9, 1345, and 180.4 ppm. MS (ESI) m/z [M þ
Na]þ calcd for [C11H18O4 þ Na]þ, 237.09; found [M þ Na]þ,
237.12.
3-(Allyloxy)-2-(allyloxymethyl)-2-methyl-N-(prop-2-ynyl)pro-
panamide, BAP-Acet, 6. 5 (14.0 g, 0.065 mol, 1 equiv), DMAP
(1.59 g, 0.0131 mol, 0.2 equiv), and propargylamine (3.59 g,
0.065 mol, 1 equiv) were dissolved in 100 mL of DCM and
cooled down to 0 °C. DCC (13.47 g, 0.065 mol, 1 equiv) was
dissolved in 20 mL of DCM and added to the cold solution
where after the reaction was left to stir overnight. The white
precipitate was filtered off and the crude solution was con-
centrated and purified by flash chromatography eluting the
colorless, slightly viscous oil in 30:70 EtOAc:hexanes. Yield:
2,20-Disulfanediylbis(ethane-2,1-diyl) Bis(3-hydroxy-2-(hydroxy-
methyl)-2-methylpropanoate), HED-bis-MPA-OH, 2. 1 (30.0 g)
was dissolved in 300 mL of MeOH and stirred overnight vigo-
rously with 30 g of prewashed acidic Dowex. The full deprotec-
tion of the end-groups was monitored by TLC. The polymer
resin was filtered off and the solution was concentrated and used
without any further purification. Yield: 24.6 g (99%). 1H NMR
(acetone-d6): δ 1.11 (s, 6H, -CH3), 2.98 (t, 4H, -SCH2CH2O-),
3.64 (d, 4H, J = 10 Hz, -CH2O-), 3.67 (d, 4H, J = 10 Hz,
-CH2O-), 3.80 (bs, 4H, -OH), and 4.31 (t, 4H, -SCH2CH2O-)
ppm. 13C NMR: δ 17.2, 37.2, 49.4, 62.4, 68.0, and 175.6 ppm.
MS (ESI): m/z [M þ Na]þ calcd for [C14H26O8S2þNa]þ, 409.08;
found [M þ Na]þ, 409.08.
1
12.6 g (77%). H NMR: δ 1.17 (s, 3H, -CH3), 2.18 (t, 1H,
-CCH), 3.50 (d, 2H, -CH2O), 3.52 (ABq, 2H, -CH2O), 3.98
(m, 6H, -OCHH2CH- and -NCH2CCH), 5.13-5.28 (m, 4H,
-CHCH2), 5.80-5.91 (m, 2H, -CHCH2), and 7.28 (bs, 1H,
-NHCdO-) ppm. 13C NMR: δ 18.3, 29.0, 47.2, 71.2, 72.4,
73.0, 79.8, 117.1, 134.2, and 174.6 ppm. MS (ESI): m/z [M þ
Na]þ calcd for [C14H21NO3þNa]þ, 274.12; found, [M þ Na]þ
274.15.
2,20-(2,20-Disulfanediylbis(ethane-2,1-diyl)bis(oxy))bis(oxome-
thylene)bis(2-methylpropane-3,2,1-triyl) Tetrakis(5-azidopentano-
ate), HED-bis-MPA-N3, 3. 2 (10.0 g, 0.026 mol, 1 equiv),
5-azidopentanoic acid (17.8 g, 0.124 mol, 4.8 equiv), and DMAP
(2.50 g, 0.022 mol, 0.8 equiv) were dissolved in 300 mL of DCM
and cooled in an ice bath. DCC (25.6 g, 0.124 mol, 4.8 equiv) was
Dendrimer Synthesis. General Procedure for Synthesizing
Azide-Functional Dendrimers. The alkene-functional dendrimer,
AB2-monomer (2 equiv/alkene for G1, 4 equiv/alkene for G3
and 7 equiv/alkene for G5,), and DMPA (0.2 equiv/alkene) were

Article
Macromolecules, Vol. 43, No. 16, 2010 6627
Scheme 1. Synthesis of AB2, 4, and CD2, 6, Monomers Used for Dendritic Growth
dissolved in inhibitor free THF. The vessel was sealed using a
rubber septum and the solution was sparged with argon for 15
min before exposure to 365 nm UV-light for 45 min with stirring.
The first and third generation dendrimers were purified by
filtration through a silica plug while the fifth generation den-
drimer was purified by precipitating two times into diethyl ether.
General Procedure for Synthesizing Alkene-Functional Den-
drimers. The azide-functional dendrimer, CD2-monomer (1.1
equiv/azide for G2 and G4, 1.6 equiv/azide for G6), and NaAsc
(0.3 equiv/azide) were dissolved in an inhibitor free THF/H2O
mixture. The vessel was sealed using a rubber septum and
purged with argon for 10 min. CuSO4 (0.1 equiv/azide) was
dissolved in H2O and added to the solution. The reaction was
kept under stirring for 1 h where after the two phases were left to
separate followed by removal of the water phase. The second
and fourth generation dendrimers were purified by filtration
through a silica plug. For the sixth generation dendrimer, the
organic phase was first diluted with DCM, extracted with H2O
(2 ꢀ 2 mL) and brine (1 ꢀ 2 mL), dried over MgSO4, and
partially concentrated. The dendrimer solution was precipitated
two times into diethyl ether.
prior to irradiation with 365 nm UV light for 45 min followed by
simple filtration through a plug of silica to remove excess 4. The
IR spectrum of the purified first generation dendrimer, 7, showed
a strong absorption peak at 2091 cm-1 corresponding to the
azide end-groups and the complete disappearance of the core
alkene absorption at 923 cm-1. Similar spectral changes, for
example appearance of a triplet at 3.29 ppm corresponding to the
methylene protons adjacent to the azide end-groups and loss of
resonances for the olefinic protons, were observed in the 1H
NMR spectra (Figure 1) demonstrating that full addition to the
peripheral alkenes was achieved. Significantly, the high effi-
ciency/facile purification of the thiol-ene reaction, coupled with
short reaction times, allows full generation growth and product
purification to be accomplished in 2-3 h.
The pure first generation dendrimer 7 was then reacted with 1.1
equiv of 6 per azide unit in THF/H2O with CuSO4 and sodium
ascorbate (NaAsc). The CuSO4/NaAsc system15 was chosen be-
cause of its proven robust nature and monitoring of the CuAAC
1
reaction using H NMR and FT-IR spectroscopy revealed full
conversion of the peripheral azides. Concomitant with the loss of
the CH2N3 resonance at 3.3 ppm, new peaks in the region of
5.1-5.9 ppm corresponding to the terminal alkenes of the fully
converted second generation dendrimer 8 were observed in the 1H
NMR spectrum (Figure 1). Additionally, FT-IR showed complete
disappearance of the azide stretch at 2091 cm-1 and reappearance
of the terminal alkene vibrational transition at 923 cm-1, confirm-
ing the quantitative nature of the second generation growth step.
In analogy with the thiol-ene reaction, the time required for
synthesis and purification of the alkene-terminated second gen-
eration dendrimer 8, was minimal and the pure dendrimer was
obtained in less than 3 h. With the exception of the reaction to form
G6, the ratio of 1.1 alkyne/N3 was kept constant throughout the
synthesis. A slightly higher ratio of 1.6 equiv of 6/N3 and a slightly
increased reaction time of 2 h was required to completely convert
the fifth generation dendrimer in the final growth step.
Results and Discussion
The syntheses of the starting AB2 and CD2 monomers were
accomplished according to Scheme 1. The inexpensive and
commercially available starting material 2,2-bis(hydroxymethyl)-
propionic acid, bis-MPA, was used in both cases with the AB2
monomer 4, containing a single thiol and 2 azide groups, being
prepared in four steps with an overall isolated yield of 61%.
Similarly, the CD2 monomer 6, containing one alkyne and two
alkene groups, was prepared in just two steps with an overall
isolated yield of 62%. The structure and purity of the AB2 and
CD2 monomers were confirmed by NMR spectroscopy and mass
spectrometry.
The first generation dendrimer 7, Scheme 2, was obtained via a
thiol-ene reaction between 2.0 equiv of 4 per core alkene
functionality and tris(allyloxy)triazine (TAT), in the presence
of the radical initiator, 2,2-dimethoxy-2-phenylacetophenone
(DMPA). The reaction solution was sparged with argon for 15 min
This facile and time efficient synthetic strategy greatly
facilitates the preparation of higher generation dendrimers
with this iterative sequence of AB2/CD2 monomer additions

6628 Macromolecules, Vol. 43, No. 16, 2010
Scheme 2. Synthesis of a Sixth Generation Dendrimera
Antoni et al.
a Key: (i) 2 equiv of 4/ene, UV light for 0.75 h; (ii) 1.1 equiv of 6/N3, 1 h; (iii) 4 equiv of 4/ene, UV light for 0.75 h; (iv) 1.1 equiv of 6/N3, 1 h; (v) 7 equiv
of 4/ene, UV light for 0.75 h; (vi) 1.6 equiv of 6/N3, 2 h.
Figure 1. Sequence of 1H NMR spectra for first through sixth generation dendrimers showing the appearance and disappearance of chain end
functional groups.

Article
Macromolecules, Vol. 43, No. 16, 2010 6629
Figure 2. 1H NMR spectrum of the fourth generation dendrimer, 10.
Table 1. Molecular Weight and Thermal Characterization Data
a
dendrimer Mw,theoretical Mw,MALDI Mn,GPC PDI Tg
a
a
7
8
9
G1-[N3]6
G2-[Ene]12
G3-[N3]24
1 582.80
3 090.72
8 424.78
14 456.46
35 792.94
59 919.66
1605.2
3112.9
8557.5
14 985
35 900
60 200
3350
6210
10 700
16 200
26 600
34 300
1.02 -72
1.02 -34
1.03 -54
1.03 -23
1.21 -51
1.29 -13
10 G4-[Ene]48
11 G5-[N3]96
12 G6-[Ene]192
a Molecular weights reported in g/mol.
by comparison of the integration values for the various genera-
tion layers within the dendritic structures with Figure 2 showing
1
the high degree of resolution that can be obtained for the H
NMR spectrum of the fourth generation alkene functional
dendrimer, 10.
Characterization of the dendrimers by mass spectrometry
(MALDI) and gel permeation chromatography (GPC) showed
essentially single molecular ions and narrow polydispersity peaks
for generations 1 through 4 (Figure 3). The end-group variation
between generations affected the selection of the MALDI-TOF
matrix. The alkene functional dendrimers were analyzed using
dihydroxybenzene (DHB) as matrix whereas the azide functional
dendrimers were analyzed using 9-nitroanthracene. The theore-
tical molecular weights expected for the dendrimers were con-
firmed by MALDI-TOF (Table 1); however, a linear mode was
used for the higher generations which resulted in poor isotopic
resolution for the fifth and sixth generation dendrimers 11 and 12.
Evaluation of these materials by GPC showed increasing amounts
of coupled products at generation 5 and generation 6 which cor-
relates with dendrimer-dendrimer cross coupling reactions (radi-
cal combination) in the fifth generation growth step. With 7.0
equiv of thiol per alkene for the synthesis of the fifth generation
dendrimer, thiol-ene reaction with the 48 chain end alkene units
resulted in a small (∼10%) high molecular weight fraction. These
coupled impurities are a direct result of the divergent growth
strategy (percent is consistent with the level of failure sequences
observed for other divergent dendrimers such as PAMAM) and
our deliberate attempt to eliminate any complicated purification
strategies. This level of coupled products could be significantly
reduced by column chromatography if required.
Figure 3. GPC chromatograms illustrating generational growth from
the first to sixth generation dendrimer.
being repeated to ultimately obtain a sixth generation dendrimer
(Scheme 2). To illustrate the robust nature, generations 1-4 were
synthesized on multigram scales and purified by filtration thro-
ugh a silica plug while generations 5 and 6 were purified by simple
precipitation or a combination of extraction and precipitation.
Isolated yields were high for each growth step where the complete
sequence of reaction, purification and isolation could be per-
formed in less than 3 h. A direct consequence of this is that a sixth
generation dendrimer was prepared in less than a single 24 h time
period from the starting monomers, 4 and 6.
Critical to the success of this accelerated approach to dendri-
mers was not simply a dramatic reduction in the time required for
preparation but also the needto maintain a highlevel of purityfor
the dendritic macromolecules from G1 to G6. Structural evolu-
tion and purity was monitored using a variety of techniques. For
example, the quantitative exchange of chain end functional
1
groups was monitored throughout the synthesis by H NMR
spectroscopy with Figure 1 showing the alternating appearance
and disappearance of alkene and azide end groups. The high
fidelity of the accelerated growth process based on the com-
bination of thiol-ene and CuAAC chemistry can also be gauged
The ability to accelerate the synthesis of dendrimers by
combining click reactions not only results in a dramatic increase

6630 Macromolecules, Vol. 43, No. 16, 2010
Antoni et al.
Scheme 3. Post Functionalization of a Third, Fourth, and Fifth
Generation Dendrimera
(alkene) generation dendrimers 9-11. This demonstrates the
versatility of this thiol-ene/CuAAC reaction sequence and the
ease with which these materials can be chemically modified at
each stage of the synthesis (Scheme 3). Transformation of the
native dendrimers yieldedanassortment of new materialsranging
from dendrimers with hydrophilic (13 and 16) and hydrophobic
(17) surfaces to those having bioactive groups at the chain ends
(14 and 15). All of the post functionalization reactions showed
good yields and required simple purification protocols (i.e.,
precipitation, dialysis, etc.).
Conclusions
A highly orthogonal and time efficient protocol for the
assembly of high generation, high molecular weight dendrimers
has been demonstrated based on the combination of orthogonal
click reactions. The full assembly and purification of each den-
drimer generation was realized within 3 h resulting in an overall
sixth generation dendrimer with a total assembly time of less than
a day from the corresponding branched monomer units. The
power of this accelerated AB2/CD2, dual click strategy is the
demonstration that dendrimer synthesis should not be tedious
and time-consuming, breaking a long held viewpoint concerning
dendritic macromolecules and allowing high generation dendri-
mers to be readily accessed.
a Key: (i) 1.1-2 equiv of post-functionalizing reagent/N3, 45 min;
(ii) 7 equiv of 1-thioglycerol/ene, UV light for 1 h; (iii) 1.6 equiv of
1-decyne/N3, 3 h.
in time efficiency but alsoallowshigher generation materials to be
prepared more readily. This is a critical feature as many reported
dendrimer syntheses proceed only to generation 3 or 4 where the
true benefit of the dendritic architecture may not be apparent.
This is especially true in the examples described above where
comparison of the absolute molecular weights with the polystyr-
ene equivalent molecular weights clearly demonstrates the power
of proceeding to higher generations. For generation 1 to 4, the
polystyrene equivalent molecular weight is larger than the actual
molecular weight (i.e., for G = 3; MWactual = 8560 amu; while
MWpst = 10 700 amu), a direct result of the larger, less compact
AB2 and CD2 repeat units. It is only when the dendrimers are
grown to generation 5 and 6 that the traditional and expected
dendritic effect of a significant reduction in polystyrene equiva-
lent molecular weight when compared to the actual molecular
weight is observed. For the sixth generation dendrimer, the poly-
styrene equivalent molecular weight of 34 300 amu is significantly
less that the theoretical molecular weight of 59 900. As a result,
the novel dendritic properties for these materials, resulting from
the globular and compact nature of the macromolecule would
only be expected to become fully apparent at G = 5 and above,
again demonstrating the power of this accelerated approach.
The thermal properties of the different dendrimer generations,
7-12, were analyzed using thermogravimetric analysis (TGA)
and differential scanning calorimetry (DSC). Interestingly, al-
kene functional dendrimers 8, 10, and 12 depicted a higher onset
for thermal degradation of 270, 250, and 260 °C respectively,
corresponding to the degradation of the polyester backbone. The
azide terminal dendrimers 7, 9 and 11 exhibited a significantly
decreased onset temperature for thermal degradation of 200 °C
for 7 and 9 and 140 °C for 12. These low temperature decom-
positions are assigned to azide fragmentation and release of N2 at
elevated temperatures. For example, the observed mass loss of
13 wt % was in good correlation with the theoretical mass loss of
11 wt % corresponding to six N2 molecules (6 ꢀ 28 = 168 g/mol)
evolved from 7 (1582.78 g/mol). The Tg’s for the dendrimers were
also found to be highly dependent on the end group functionality
rather than molecular weight with alkene functional dendrimers
displaying higher Tg’s than the azide terminal generations
(Table 1).
Acknowledgment. Financial support from the NSF (CHE-
0957492, the MRSEC Program DMR-0520415 (MRL-UCSB)),
UC Regents for a President’s Fellowship (L.M.C.) and Graduate
Fellowship (M.J.R.), the Swedish Research Council (M.M.) (Grant
2006-3617), Bengt Lundqvists Minnesfond (P.A.), and Instituto de
Salud Carlos III (M.I.M.) is greatly acknowledged.
Supporting Information Available: Text giving detailed
experimental procedures and figures showing chemical struc-
1
tures and H NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
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