A Facile Synthetic Route to a Third-Generation Dendrimer with Generation-Specific Functional Aryl Bromides

Article abstract of DOI:10.1021/ol005972q

(Formula Presented) The synthesis of three third-generation dendrimers that selectively carry one aryl bromide functional group in the first, second, or third generation, respectively, is described. These functions, regardless of their location, can be ch

Full text of DOI:10.1021/ol005972q

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1645-1648
A Facile Synthetic Route to a
Third-Generation Dendrimer with
Generation-Specific Functional Aryl
Bromides
Zhishan Bo,* Andreas Scha1fer, Peter Franke, and A. Dieter Schlu1ter
Institut fu¨r Chemie/Organische Chemie, Freie UniVersita¨t Berlin, Takustrasse 3,
D-14195 Berlin, Germany
adschlue@chemie.fu-berlin.de
Received April 20, 2000
ABSTRACT
The synthesis of three third-generation dendrimers that selectively carry one aryl bromide functional group in the first, second, or third
generation, respectively, is described. These functions, regardless of their location, can be chemically modified by Suzuki cross-coupling
chemistry with p-tert-butylbenzene boronic ester.
Dendrimers are highly branched, globular, monodispersed
macromolecules. They comprise a core, branching units, a
large number of (functional) end groups, and free interior
volume normally filled by solvent.1 The expansion of these
macromolecules to a range of several nanometers, the
existence of usable “surface”, and transport possibilities in
and with them have made dendrimers interesting candidates
for various applications.2 Many synthetic strategies have been
developed for this class of compounds, with structure control
and synthesis efficiency being the most important aspects.
Functional groups were introduced at the periphery, typically
one per terminus3 (but also less),4 in the interior at every
generation (repeat unit),5 at a certain generation,6 or at the
core.7 Here we describe a synthetic strategy that allows for
specific incorporation of a functional group at any given
generation. These groups can then serve as anchors both for
probes such as chromo-, fluoro-, and electrophores or
catalytically active moieties and for modifying the interior
of the dendrimer at predetermined positions. Facile access
to a collection of third-generation polyether (Fre´chet) type
dendrimers with functional aryl bromides in the first (G1),
second (G2), or third (G3) generation is provided. To prove
that these functional groups can actually serve as anchors,
p-tert-butylphenyl groups have been attached using Suzuki
cross-coupling in all cases. To the best of our knowledge
this is the first case where such a concept has been realized
(5) For a dendrimer with hydroxy groups at every repeat unit and its
use as a reverse micelle, see: Piotti, M. E.; Rivera, Jr., F.; Bond, R.; Hawker,
C. J.; Fre´chet, J. M. J.; J. Am. Chem. Soc. 1999, 121, 9471-9472. For a
less specific incorporation of functionalities in a dendrimer, see: Lochmann,
L.; Wooley, K. L.; Ivanova, P. T.; Fre´chet, J. M. J. J. Am. Chem. Soc.
1993, 115, 7043-7044.
(6) Newkome, G. R.; Moorefield, C. N.; Baker, G. R.; Johnson, A. L.;
Behera, R. K. Angew. Chem., Int. Ed. Engl. 1991, 30, 1176-1179.
Newkome, G. R.; Moorefield, C. N. Polym. Prepr. 1993, 34, 75-76. Marx,
H.-W.; Moulines, F.; Wagner, T.; Astruc, D. Angew. Chem., Int. Ed. Engl.
1996, 35, 1701-1704.
(1) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendritic Molecules.
Concepts, Syntheses, PerspectiVes; VCH: Weinheim, 1996.
(2) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. ReV. 1999,
99, 1665-1688. Schlu¨ter, A. D.; Rabe, J. P. Angew. Chem., Int. Ed. 2000,
39, 864-883.
(3) For the numerous examples, see: Zeng, F.; Zimmerman, S. C. Chem.
ReV. 1997, 97, 1681-1712. Newkome, G. R.; He, E.; Moorefield, C. N.
Chem. ReV. 1999, 99, 1689-1746.
(4) Hawker, C. J.; Fre´chet, J. M. J. Macromolecules 1990, 23, 4726-
4279.
(7) For example, see: Jin, R.-H.; Aida, T.; Inoue, S. J. Chem. Soc., Chem.
Commun. 1993, 1260-1261. Dandliker, P. J.; Diederich, F.; Gross, M.;
Knobler, K. B.; Lonati, A.; Sanford, E. Angew. Chem., Int. Ed. Engl. 1994,
33, 1079-1083.
10.1021/ol005972q CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/06/2000

to the point where one can start to systematically explore
and/or exploit the interior of a dendrimer in a generation-
specific manner.8
The target G3 dendrons A have one bromo function at
the branching point of the first (4c), second (8b), and third
generation (9b), respectively (Scheme 1). Aryl bromides were
1, which already carries the required bromo function at C-4.10
Reaction of 1 with benzyl bromide and Fre´chet-type G1 and
G2 bromides11 under standard Williamson etherification
conditions (K2CO3/acetone) gives the corresponding den-
drons G1 (2a), G2 (3a), and G3 (4a) with esters at the focal
point in high yields. LiBH4 reduction furnishes the corre-
sponding dendritic alcohols 2b, 3b, and 4b, which are then
converted to the corresponding bromides 2c, 3c, and 4c by
Appel bromination using CBr4/PPh3. The G2 and G3
dendrons 7a and 8a are obtained by reacting 2c with phenol
5, a “semi-dendron” 4 known in the literature, and 3c with
the corresponding “semi-dendron” 6, respectively (Scheme
2). Appel bromination of 7a and 8a converts these alcohols
Scheme 1
Scheme 2
into the corresponding bromides 7b and 8b. Finally, com-
bination of the G2 bromide 7b with 6 followed by Appel
bromination yields the dendron 9b.
For the synthesis of the target dendrimers 11a-c (Scheme
3) the dendrons 4c, 8b, and 9b are reacted with the last
remaining phenoxy group of the trifunctional core, 1,1,1-
tris(4′-hydroxyphenyl)ethane, which already carries two
chosen as anchor groups, because they easily undergo a
Suzuki cross-coupling (SCC) reaction9 in high yield, even
in situations where considerable steric congestion can be
expected in the interior of dendrimers. The synthetic
sequence starts from the aromatic AB2-type building block
(10) Compound 1 was obtained from the commercially available cor-
responding acid.
(11) Fre´chet, J. M. J.; Wooley, K. L.; Hawker, C. J. J. Am. Chem. Soc.
1991, 113, 4252-4261.
(8) Modrakowski, C.; Beinhoff, M.; Schlu¨ter, A. D., manuscript in
preparation.
(9) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
1646
Org. Lett., Vol. 2, No. 11, 2000

Scheme 3
regular (nonbrominated) Fre´chet-type G3 dendrons (10,4
any indication of side products. Specifically there is no signal
for unreacted 10.
structure not shown) under standard Williamson etherification
conditions using Cs2CO3 as base and acetone as solvent.
These dendrimers carry an aryl bromide function at one of
the three branching units of the first (11a), at one of the six
branching units of the second (11b), or at one of the 12
branching units of the third (11c) generation. The structure
of the dendrimers was proven by high-field NMR spectros-
copy, matrix-assisted laser desorption ionization time-of-
flight (Maldi-tof), mass spectrometry, and elemental analysis.
The purity was checked by gel permeation chromatography
(GPC), NMR spectroscopy, and Maldi-tof. The GPC elution
curves are monomodal with a polydispersity index of 1.01
in all three cases. The 500 MHz 1H NMR spectra indicate a
purity higher than 98%, and the mass spectra do not give
In the next step we checked how far the bromo functions
can be used as anchor groups. As a test reaction, dendrimers
11a-c were reacted with 4-tert-butylbenzene boronic acid
under SCC conditions. This boronic acid was chosen because
its tert-butyl group can be easily and quantitatively identified
by NMR spectroscopy. The SCC conditions were carried out
for 5 d with a 5-fold excess of p-tert-butyl benzene boronic
acid under standard reaction condition using 1-2 mol % of
freshly prepared Pd(PPh3)4 and THF/1 M NaHCO3 as the
solvent system.
The crude products were purified by column chromatog-
raphy and gave the modified dendrimers 11d-f in isolated
yields of 88%, 95%, and 97%, respectively (Scheme 3). The
Org. Lett., Vol. 2, No. 11, 2000
1647

GPC elution curves of these products are unchanged
compared to those of their precursors, which is reasonable,
because the spatial changes induced by the replacement of
a bromo function result in a negligible change of the
hydrodynamic volume.
The conversions of these reactions were determined by
NMR integration to be 96% (11d), 97% (11e), and 99%
(11f), respectively, and by comparing the intensities of the
protons of the tert-butyl group (δ ) 1.15 ppm) with that of
the 12 protons of the core AA′BB′ and CC′DD′ spin system
centered at δ ) 6.88 ppm. Further support for the bromo
group’s complete replacement by tert-butylphenyl is the
disappearance of the signal for the methylene protons near
the bromo which absorbs in all cases baseline separated from
all other methylenes at δ ) 5.02 (11a), 5.04 (11b), and 5.07
(11c).
and 5205 Da are observed, which are due to adducts of the
respective dendrimer with sodium and potassium ions. Peaks
of sodium or potassium adducts of the starting dendrimers
at 5136 and 5152 Da of starting material cannot be observed.
Thus, these replacements proceed quantitatively, which nicely
underlines the potential as anchor groups for even the
innermost bromine function.
Acknowledgment. This work was financially supported
by the Deutsche Forschungsgemeinschaft (Sfb 448, TP A1)
and the Fonds der Chemischen Industrie, which are gratefully
acknowledged.
Supporting Information Available: Experimental details
and spectroscopical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Maldi-tof mass spectra of 11d-f also reveal that the
conversion is virtually quantitative. Only two peaks at 5190
OL005972Q
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