A chemoselective approach for the accelerated synthesis of well-defined dendritic architectures

Article abstract of DOI:10.1039/b703547k

A chemoselective and layered growth approach has been developed for the synthesis of dendrimers, combining Click chemistry with traditional esterification/etherification reactions, without the need for activation steps and with excellent overall yields. T

Full text of DOI:10.1039/b703547k

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COMMUNICATION
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A chemoselective approach for the accelerated synthesis of well-defined
dendritic architectures{
Per Antoni,a Daniel Nystro¨m,a Craig J. Hawker,b Anders Hulta and Michael Malkoch*a
Received (in Cambridge, UK) 8th March 2007, Accepted 30th April 2007
First published as an Advance Article on the web 14th May 2007
DOI: 10.1039/b703547k
Traditionally, two synthetic strategies are available for the
preparation of dendrimers, either the divergent6 or convergent7
growth approach. Both strategies yield high generation dendritic
structures from ABx-monomers through repetitive growth and
activation steps. To achieve ‘perfect’ structures, the chosen
chemistry needs to be essentially quantitative as inefficient reactions
lead to defects in the dendritic structures and may give rise to tedious
purification procedures. As a result, new synthetic strategies and
versatile coupling reactions that will enable the preparation of
dendritic macromolecules under accelerated conditions and with
unprecedented control are of significant interest. A reaction that has
gained tremendous attention since it was reported by Fokin and
Sharpless in 2002 and which fulfills all the criteria for the
construction of dendritic structure is the Cu catalyzed Click
reaction of azides with terminal alkynes.8 This reaction is highly
efficient and occurs under benign conditions in the presence of other
reactive groups with no byproducts. Due to its orthogonal, robust
nature, this example of Click chemistry has attracted significant
attention in the materials science community, especially for the
construction of complex polymeric materials.9 For example, the
construction of multifunctional AB-diblock dendrimers with both
targeting ligands and imaging agents for investigating the binding
with cell surfaces was successfully accomplished in high yields using
Click chemistry.10 Nonetheless, while the introduction of new
chemical reactions has greatly enabled the efficient construction of
dendrimers,11 the synthetic approaches employed still involve the
traditional multi-step, divergent or convergent approaches.
A chemoselective and layered growth approach has been
developed for the synthesis of dendrimers, combining Click
chemistry with traditional esterification/etherification reactions,
without the need for activation steps and with excellent overall
yields.
Dendrimers are highly branched polymers that have gained
increasing attention in a variety of nanotechnology applications
from microelectronics to biomedical devices.1 It is generally known
that dendrimers are time consuming and expensive to construct
using traditional multi-step techniques which limits their commer-
cial availability to PAMAM1, DAB1, Phosphorous PMMH
and 2,2-bis(methylol)propionic acid (bis-MPA) dendrimers.2,3
Nevertheless, their well-defined, modular structure with high
functional group density and 3-dimensional shape make these
synthetically challenging scaffolds extremely attractive molecular
targets. For example, PAMAM dendrimers have been modified
with sulfonic acid end groups to afford a novel dendritic HIV/
AIDS4 drug while the same PAMAM scaffolds with hydrophilic
oligo(ethylene glycol) end groups have been used as pore
generating agents for the development of dielectric layers for
advanced microelectronic devices.5
aFiber and Polymer Technology, Royal Institute of Technology,
Teknikringen 56-58, SE-10044 Stockholm, Sweden.
E-mail: Malkoch@polymer.kth.se; Fax: +4687908283;
Tel: +4687908768
bMaterials Research Laboratory (MRL), University of California
Santa Barbara, California 93106, USA. E-mail: Hawker@mrl.ucsb.edu;
Fax: +18058938797; Tel: +18058937161
To greatly increase the availability of functionalized dendrimers
and to accelerate their use in a variety of applications the
development of new methodologies for their synthesis is required.
The requirements for such an approach are that it should involve
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterization. See DOI: 10.1039/b703547k
Fig. 1 Graphical representation of the number of synthetic steps required for the preparation of a Gen = 4 dendrimer using an accelerated chemoselective
synthesis (top) versus a traditional divergent dendrimer synthesis (bottom).
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Chem. Commun., 2007, 2249–2251 | 2249

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fewer reaction steps, be quantitative in nature, compatible with a
variety of functional groups and occur under mild reaction
conditions. This can be accomplished through the synthesis of
AB2- and CD2-monomers that selectively react with each other
and employ reactions that proceed in very high yield (Fig. 1). If
this chemoselectivity can be achieved, AB2 + CD2 systems lead to
generation growth involving only a single reaction with little or no
purification required. The orthogonality required in the selection
of the A, B, C and D functional groups also dictates a high degree
of flexibility in the incorporation of reactive functional groups.
This communication describes the development of an acceler-
ated growth approach12 to dendrimers based on the combination
of Click chemistry with traditional esterification/etherification
reactions, for the synthesis of dendrimer derivatives of the classical
Fre´chet-type and bis-MPA dendritic macromolecules. These
structures were chosen due to their use in dendrimers as well as
to demonstrate the modular nature of this synthetic approach and
its applicability to different chemistries and monomer units. To
illustrate the efficiency of the accelerated approach methodology
the synthesis of analogs of Fre´chet-type dendrimers was initially
examined through the combination of Click and etherification
reactions. The required monomer units for one-step generation
growth are 1-(bromomethyl)-3,5-bis(prop-2-ynyloxy)benzene, 3, as
nominally the AB2-monomer, and 5-(azidomethyl)benzene-1,3-
diol 5, as the CD2-monomer unit.
24 terminal acetylene groups (Scheme 1). This synthetic strategy
allows the divergent preparation of a fourth generation dendrimer
9, containing 48 terminal phenolic groups, in only four steps and in
multi-gram quantities with an overall yield of 70% from the
starting triphenol, resulting in a layered dendritic block copolymer
with alternating layers of benzyl ether, triazole and benzyl ether
groups. The orthogonality and efficiency of this strategy were
demonstrated by monitoring each reaction with NMR and Maldi-
TOF techniques. As can be seen in Fig. 2, the growth progress of
1
the fourth generation dendrimer 9 was monitored by H NMR
and the Click reaction was found to reach completion within 12 h
at RT. This was confirmed since the peak corresponding to the
acetylene terminal groups at 3.55 ppm in DMSO was not
detectable. It should be noted that a traditional divergent growth
approach would require at least eight steps with multiple
purification procedures for the synthesis of a similar fourth
generation structure.
Moreover, the dendritic products obtained have alternating end
groups, either acetylene or phenolic, depending on the generation
number which allows for convenient and efficient post modifica-
tions without the need for elaborate activation of dormant species.
To further demonstrate the versatility of this concept, the
accelerated synthesis of analogs of bis-MPA type dendrimers
was addressed. Traditionally, bis-MPA dendrimers require
growth/activation steps involving esterification and deprotection
reactions. To develop bis-MPA type dendrimers via this acceler-
ated approach, esterification reactions were coupled with Click
chemistry. Initially, a bis-MPA based AB2-monomer containing
both an acyl chloride and azide functionalities was designed, 13,
and coupled with the corresponding CD2-monomer, 15, which is
the propargyl ester of bis-MPA (Fig. 3). Generation growth was
In this case, orthogonal reactivity is achieved by the Click
reaction of the terminal acetylenes with the azide group of 5 in the
presence of the phenolic moieties of 5 followed by the etherification
of the terminal phenolic groups of the growing dendrimer, 7, with
the bromomethyl group of 3 with the terminal acetylenes of 3
giving rise to the third generation dendrimer 8, containing
Scheme 1 Chemoselective synthesis of a Gen = 4 Fre´chet-type dendrimer using an accelerated AB2 + CD2 approach.
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1
Fig. 2 Crude H NMR spectra of a Gen = 4 Fre´chet-type dendrimer, 9, containing 48 terminal hydroxyl groups.
accomplished via an esterification reaction of 13 with the
trisphenolic hydroxyl core followed by a Click reaction of 15
to yield a second generation bis-MPA type dendrimer with
12 terminal hydroxyl groups. Repetition of this sequence of
reactions gives the fourth generation dendrimer, 19, which again is
obtained in excellent yield with high levels of purity after only four
reaction steps.
the repetitive utilization of two highly versatile reactions in
sequence which avoids numerous activation or deprotection steps.
As a result, growth is not only accelerated but a much richer family
of functionalized dendritic structures can be prepared. This
versatility is demonstrated by the accelerated synthesis of two
different types of dendrimers, analogs of bis-MPA-type and
Fre´chet-type dendrimers. The simple and orthogonal nature of
these strategies also allows the synthesis of a wide variety of other
macromolecular architectures and hybrid materials where mono-
mers from different families are combined to generate new
materials with unique features.
The distinct difference between this chemoselective accelerated
approach and the traditional strategies for dendrimer synthesis is
The authors would like to thank Willhelm Beckers
Jubileumsfond, the National Science Foundation through the
UCSB Materials Research Laboratory (NSF DMR-0520415),
Chemistry Division (CHE-0514031) and the Swedish Research
Council (VR) (Grant 2006-3617) for financial support.
Notes and references
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2 PAMAM, DAB and Phosphorous dendrimers are available from
Sigma-Aldrich. Web address: www.aldrich.com.
3 Bis-MPA dendrimers are available from Polymer Factory Sweden. Web
address: www.polymerfactory.com.
4 B. R. Matthews and G. Holan, US Patent 6,190,650, Feb 20, 2001.
5 C. J. Hawker, J. L. Hedrick, R. D. Miller and W. Volksen, MRS Bull.,
2000, 25, 54.
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Fig. 3 Accelerated synthesis of
a Gen = 4 bis-MPA dendrimer
synthesized in only four steps from 13 and 15.
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Chem. Commun., 2007, 2249–2251 | 2251