Facile access to internally functionalized dendrimers through efficient and orthogonal click reactions

Article abstract of DOI:10.1039/b921598k

A simple synthetic strategy has been developed for accessing internally functionalized dendrimers. The key feature of this approach is the use of two orthogonal and efficient reactions - 'epoxy-amine' and 'thiol-ene' coupling - for rapid growth of the dendritic scaffold. This sequence of reactions allows for the introduction of reactive hydroxyl groups at each dendritic layer. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b921598k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Facile access to internally functionalized dendrimers through efficient
and orthogonal click reactionsw
Taegon Kang,ab Roey J. Amir,a Anzar Khan,a Kaoru Ohshimizu,cd Jasmine N. Hunt,ac
Kulandaivelu Sivanandan,a Maria I. Montanez,e Michael Malkoch,e Mitsuru Uedad and
Craig J. Hawker*abc
Received (in Cambridge, UK) 15th October 2009, Accepted 14th January 2010
First published as an Advance Article on the web 28th January 2010
DOI: 10.1039/b921598k
A simple synthetic strategy has been developed for accessing
internally functionalized dendrimers. The key feature of this
approach is the use of two orthogonal and efficient reactions—
‘epoxy–amine’ and ‘thiol–ene’ coupling—for rapid growth of the
dendritic scaffold. This sequence of reactions allows for the
introduction of reactive hydroxyl groups at each dendritic layer.
dendrimers containing unprotected internal functional
groups. The orthogonal nature and modularity of this
approach is exemplified by carrying reactive hydroxyl
functionalities through all synthetic steps in an unprotected
form (Scheme 1).
The choice of epoxy–amine and thiol–ene chemistries was
governed by two factors: the efficiency of both reactions and
their potential for orthogonality. As has been previously
demonstrated, ‘epoxy–amine’ coupling possesses many of the
attributes of a click reaction. The reaction is highly efficient,
can proceed at room temperature in the absence of a catalyst
and tolerates a number of functional groups. Importantly for
the synthesis of internally functionalized dendrimers, ring
opening of the epoxy group leads to the formation of a
secondary alcohol. This secondary alcohol can serve as a point
of attachment for various kinds of functionalities, while at the
same time being orthogonal to subsequent epoxy–amine
reactions. As a partner reaction to ‘epoxy–amine’ chemistry,
‘thiol–ene’ coupling has been exploited in the construction of
dendrimers, modification of polymer backbones/chain ends,
fabrication of thin-film and hydrogel materials.13 The high
efficiency, simplicity, and functional group tolerance of
‘thiol–ene’ chemistry makes it an ideal reaction to be used
in combination with an ‘epoxy–amine’ strategy for the
accelerated growth of internally functionalized dendrimers
from readily available starting materials in a limited number
of steps.
Traditionally, the chemical identity of dendritic macromolecules1,2
originates from the presence of functionalities at the
periphery3 and/or core4 with few studies investigating the
influence of functional groups placed at internal repeat units.5
The synthetic difficulty and increased level of sophistication
required to prepare these internally functionalized dendrimer6
have hindered research in this field even though the number
of internal functional groups can exceed the number of
chain ends.
The potential influence of internal functional groups can be
gauged from the related field of hyperbranched macro-
molecules where the added versatility of readily available
and internal functional groups has been exploited by a wide
range of researchers.7 For hyperbranched macromolecules, a
direct consequence of their one-step synthetic strategy is the
presence of linear sequences throughout the structure which
provides for reactive handles, typically of the same nature as
the chain ends.8,9 The increased availability of internally
functionalized dendrimers would permit the optimized
placement of catalytically active moieties,10 creation of energy
gradients—allowing for cascade processes to occur,11 while
also increasing the drug loading capacity of dendrimers via
internal anchor groups.12
Herein, we demonstrate that by employing two robust and
highly efficient orthogonal reactions—‘epoxy–amine’ and
‘thiol–ene’ coupling—it is possible to efficiently synthesize
a Materials Research Laboratory, University of California,
Santa Barbara, CA 93106-5121, USA
b Materials Department, University of California, Santa Barbara,
CA 93106-5121, USA
c Department of Chemistry and Biochemistry, University of California,
Santa Barbara, CA 93106-5121, USA.
E-mail: hawker@mrl.ucsb.edu
d Department of Organic and Polymeric Materials, Tokyo Institute of
Technology, 2-12-1, O-okayama, Meguro-Ku, 152-8552, Tokyo,
Japan
e Division of Coating Technology, Fiber and Polymer Technology,
KTH, Teknikringen 56-58, SE-10044, Stockholm, Sweden
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral information. See DOI: 10.1039/b921598k
Scheme 1 General scheme for generation growth using epoxy–amine
and thiol–ene chemistry.
ꢀc
This journal is The Royal Society of Chemistry 2010
1556 | Chem. Commun., 2010, 46, 1556–1558

View Article Online
generation dendrimer, G3(OH28)-Ene16 7, which features
twenty-eight internal hydroxyl groups and sixteen terminal
alkene moieties. For all steps, the orthogonality and high
efficiency of the ‘epoxy–amine’ and ‘thiol–ene’ reactions
results in a lack of byproducts which allows the dendrimers
to be purified by simple precipitation methods with yields
greater than 90%. The high degree of functionalization
and efficient construction of these dendritic macromolecules
necessitated careful characterization of these materials using a
variety of techniques such as 13C{1H}-NMR spectroscopy,
mass spectrometry, IR spectroscopy, and SEC. As described
previously, the 13C{1H}-NMR spectra proved to be diagnostic
due to the appearance and disappearance of unique
resonances during construction of the dendritic framework.
In addition, systematic increases in dendrimer size and mono-
dispersity were observed in the SEC.14 To confirm the presence
of multiple, internal hydroxyl groups, IR and NMR spectra
revealed characteristic signals due to the secondary alcohols
with MALDI mass spectrometry allowing rigorous identifica-
tion of the amino and alkene-terminated dendrimers at each
generation level. Only at the third generation dendrimer did
MALDI reveal any impurities. As can be seen in Fig. 2, the
MALDI mass spectrum for the third generation dendrimer,
G3(OH28)-Ene16 7, reveals a prominent set of molecular
ions correlating to the expected molecular formula of
Fig. 1 1H NMR spectra of the core molecule, 1,4-bis(aminomethyl)-
benzene 1 (top), and its product, G1(OH4)-Ene4, 3, after amine–epoxy
coupling reaction (middle), and the next generation dendrimer,
G1(OH4)-Amine4, 5, after subsequent thiol–ene reaction.
The synthetic strategy for generation growth is illustrated in
Scheme 1. Starting from 1,4-bis(aminomethyl)benzene, 1, as
the core, reaction with commercially available allyl glycidyl
ether, 2, results in branching and the introduction of 4
secondary alcohol and 4 terminal alkene units. Significantly,
the reaction between 1 and 2 was carried out at room
temperature in methanol with complete disappearance of the
starting material being observed after 12 hours. The resulting
molecule, G1(OH4)-Ene4, 3, could be easily isolated by
precipitation into hexanes and obtained in >95% yield. The
1H NMR spectrum of G1(OH4)-Ene4 is shown in Fig. 1
and shows unique signals for repeat units derived from 1
(7.22 ppm—aromatic protons) and 2 (4.6–6.0 alkene protons)
with integration values verifying the attachment of four
dendritic arms to the core molecule. An enabling feature of
the epoxy–amine reaction between 1 and 2 is that the first
generation dendrimer, 3, is obtained in excellent yield
without the need for chromatographic purification and, more
importantly, with a high degree of purity.
C
200H376N14O56S12 and a molecular weight of 4258 a.m.u. A
minor set of peaks can be observed at ca. 4050 a.m.u.
(no peaks were observed below 3900 a.m.u.) which likely
corresponds to a failure sequence resulting from incomplete
alkylation of a terminal amino group in 6 during the reaction
with 2. When compared to other dendrimers prepared by
the divergent growth approach, this level of purity is high
(ca. 90+%; cf. 50% for DAB dendrimers) and approaches
that observed for convergent strategies involving chromato-
graphic purifications at each step of the synthesis.14 The final
outcome of this synthetic sequence is the preparation of high
purity, internally functionalized dendrimers, such as 7, in just
five steps from commercial starting materials.
The presence of internal hydroxyl groups and chain end
alkene units opens up the intriguing possibility of performing
regiospecific chemical reactions within the same dendritic
framework. To demonstrate this potential, the internal
hydroxy groups of the G-1, G-2 and third generation
dendrimers, G3(OH28)-Ene16 7, were initially esterified with
The terminal alkene functionalities were then exploited for
further dendrimer growth by the reaction of G1(OH4)-Ene4, 3,
with the commercially available cysteamine hydrochloride, 4,
under thiol–ene conditions. Exposure to 365 nm light in the
presence of trace amounts of photoinitiator (2,2-dimethoxy-2-
phenylacetophenone) was shown to result in complete
consumption of the starting material and formation of the
corresponding G1(OH4)-Amine4, 5, after neutralization. As
with the epoxy–amine reaction, the yield for this step was high
with no detectable impurities. Fig. 1 shows the 1H NMR
spectrum of the G1(OH4)-Amine4, 5, and complete loss of
resonances for the terminal alkene units with concomitant
appearance of signals diagnostic for thioether units derived
from 4.
Repetition of this stepwise process then produces the second
generation dendrimer, 6, by the reaction of 5 with allyl glycidyl
ether, 2. Significantly, no reaction was observed to occur at the
4 internal secondary alcohol groups which allows for the
clean introduction of 8 terminal alkene units. Thiol–ene
reaction followed by epoxide ring opening results in the third
Fig. 2 MALDI-TOF mass spectra of G3(OH28)-Ene16, 7.
Chem. Commun., 2010, 46, 1556–1558 | 1557
ꢀc
This journal is The Royal Society of Chemistry 2010

View Article Online
the internal and chain end functional groups (ca. 90+%)
demonstrated (Scheme 2).
In conclusion, the successful synthesis and functionalization
of internally functionalized dendritic macromolecules
demonstrate the power of combining click reactions for the
rapid and facile construction of traditionally challenging
macromolecular structures. Starting from readily available
precursors, the combination of epoxy–amine and thiol–ene
chemistry allows for the introduction of reactive hydroxyl
groups at each dendritic layer while also allowing the chain
end alkene groups to be regiochemically functionalized.
We gratefully acknowledge support from the National
Science Foundation, CHE-0514031 and DMR05-20415.
Michael Malkoch acknowledges the Swedish Research
Council (VR) Grant 2006-3617 and Maria I. Montanez
support from Instituto de Salud Carlos III (ISCIII).
Notes and references
1 B. M. Rosen, G. Lligadas, C. Hahn and V. Percec, J. Polym. Sci.,
Part A: Polym. Chem., 2009, 47, 3940–3948; M. W. Grinstaff,
J. Polym. Sci., Part A: Polym. Chem., 2008, 46, 383–400.
2 B. Helms and E. W. Meijer, Science, 2006, 313, 929–930; C. C. Lee,
´
J. A. MacKay, J. M. J. Frechet and F. C. Szoka, Nat. Biotechnol.,
2005, 23, 1517–1526; A. Khan, A. E. Daugaard, A. Bayles,
S. Koga, Y. Miki, K. Sato, J. Enda, S. Hvilsted, G. D. Stucky
and C. J. Hawker, Chem. Commun., 2009, 425–427; R. Vestberg,
A. M. Piekarski, E. D. Pressly, K. Y. Van Berkel, M. Malkoch,
J. Gerbac, N. Ueno and C. J. Hawker, J. Polym. Sci., Part A:
Polym. Chem., 2009, 47, 1237–1258; C. J. Hawker and J. M. J.
Frechet, Polymer, 1992, 33, 1507–1511.
´
3 For various examples see: F. Zeng and S. C. Zimmerman, Chem.
Rev., 1997, 97, 1681–1712.
Scheme 2 Internal and chain end functionalization of G3(OH28)-
Ene16, 7, to give G3(Naphtha28)-TEG16, 9.
4 For various examples see: S. Hecht and J. M. J. Fre
Chem., Int. Ed., 2001, 40, 74–91.
´
chet, Angew.
naphthalene-1-acetyl chloride, resulting in the introduction
of 4, 12, and 28 internal naphthalene groups respectively.
In a second step, the terminal alkene functionalities were
5 P. Antoni, Y. Hed, A. Nordberg, D. Nystrom, H. von Holst,
¨
A. Hult and M. Malkoch, Angew. Chem., Int. Ed., 2009, 48,
2126–2130 and references therein.
6 K. Sivanandan, S. V. Aathimanikandan, C. G. Arges,
C. J. Bardeen and S. Thayumanavan, J. Am. Chem. Soc., 2005,
127, 2020–2021; L. Lochmann, K. L. Wooley, P. T. Ivanova and
coupled with monomethyl(triethyleneglycol)mercaptan,
(TEG), resulting in the formation of amphiphilic dendrimers,
such as G3(Naphtha28)-TEG16, 9.
8
J. M. J. Frechet, J. Am. Chem. Soc., 1993, 115, 7043–7044.
´
A variety of spectroscopic and chromatographic techniques
were used to evaluate the extent of internal and chain end
functionalization reactions for these dendrimers. At lower
generation numbers (G-1 and G-2), MALDI provided strong
evidence for full functionalization of both the interior and
chain end functional groups with essentially quantitative
functionalization being observed. These data were further
supported by NMR and UV spectroscopy. For the third
generation derivative, 7, MALDI mass spectral data could
7 B. I. Voit and A. Lederer, Chem. Rev., 2009, 109, 5924–5973.
8 E. Burakowska, J. R. Quinn, S. C. Zimmerman and R. Haag,
J. Am. Chem. Soc., 2009, 131, 10574–10580.
9 F. J. Klos, H. J. Roder and H. Frey, J. Am. Chem. Soc., 2009, 131,
7954–7955.
10 C. O. Liang and J. M. J. Fre
6276–6284.
11 W. R. Dichtel, S. Hecht and J. M. J. Fre
4451–4454.
´
chet, Macromolecules, 2005, 38,
´
chet, Org. Lett., 2005, 7,
12 J. B. Wolinsky and M. W. Grinstaff, Adv. Drug Delivery Rev.,
2008, 60, 1037–1055.
1
13 L. M. Campos, K. L. Killops, R. Sakai, J. M. J. Paulusse,
D. Damiron, E. Drockenmuller, B. W. Messmore and
C. J. Hawker, Macromolecules, 2008, 41, 7063–7070; A. Gress,
A. Volkel and H. Schlaad, Macromolecules, 2007, 40, 7928–7933;
R. L. A. David and J. A. Kornfield, Macromolecules, 2008, 41,
1151–1161; B. Yu, J. W. Chan, C. E. Hoyle and A. B. Lowe,
J. Polym. Sci., Part A: Polym. Chem., 2009, 47, 3544–3557.
14 A. W. Bosman, H. M. Janssen and E. W. Meijer, Chem. Rev., 1999,
not be obtained reproducibly and so H NMR spectroscopy
was employed for structural characterization. While not
providing quantitative conformation of full functionalization,
the presence of unique resonances for 9 (i.e. four protons
for the dendritic core at 7.05 ppm, naphthalene aromatic
resonances at 7.25–8.00 ppm and resonances for the
tri(ethylene glycol) units at ca. 4.05 ppm) allowed these regions
to be integrated and high levels of functionalization at both
99, 1665–1688; K. L. Wooley, C. J. Hawker and J. M. J. Fre
Angew. Chem., Int. Ed. Engl., 1994, 33, 82–85.
´
chet,
ꢀc
This journal is The Royal Society of Chemistry 2010
1558 | Chem. Commun., 2010, 46, 1556–1558