7612
J . Org. Chem. 2000, 65, 7612-7617
A Sim p le Meth od for Con tr ollin g Den d r itic Ar ch itectu r e a n d
Diver sity: A P a r a llel Mon om er Com bin a tion Ap p r oa ch
Adam W. Freeman, Lysander A. J . Chrisstoffels, and J ean M. J . Fre´chet*
Department of Chemistry, University of California, Berkeley, California 94720-1460
frechet@cchem.berkeley.edu
Received J uly 29, 2000
A novel parallel monomer combination approach to manipulating the architectural disposition of
dendritic macromolecules is described. It harnesses the synthetic speed and power of the double-
stage convergent growth approach and classical parallel synthesis to prepare diverse series of
dendrimers that possess a predetermined number and arrangement of “internal” functional moieties.
This methodology is applied for the preparation of a novel family of poly(benzyl ether) dendrimers
possessing 1-15 “internal” allyloxy groups, which are displayed in a highly controlled, layer-specific,
generational manner.
In tr od u ction
connect the core to the numerous chain ends and their
functionalization has received much less attention.6
Only a few examples of internally functionalized den-
drimers have been reported in the literature. Lochmann
et al. described the metalation and post-functionalization
of poly(benzyl ether) dendrimers using superbase.6a In
this way, up to ∼30 potassium ions were introduced into
the interiors of [G-4] dendrimers. Subsequent quenching
of those carbanionic sites with a variety of electrophiles
accessed several novel multifunctional dendrimers that
exhibited a range of new properties, such as unusual
solubility.
Another dendrimer post-functionalization was reported
by Newkome et al.,6b who described the generation-
specific introduction of boron superclusters into hydro-
carbon dendrimers via internal alkyne functionalities for
potential use in boron neuron capture therapy cancer
treatment and catalysis. The intercalated boron clusters
were rendered water-soluble by the surrounding den-
drimer.
The evolution of dendrimers over the past decade has
epitomized macromolecular engineering by permitting
unprecedented control of polymer architecture, especially
in terms of size and polydispersity, as well as the number
and spatial distribution of functional groups within
macromolecules.1 Many of the reports on the derivatiza-
tion of dendrimers have addressed chemical modification
of the core and/or peripheral moieties for a variety of
fundamental studies and applications.2 However, due to
the continued expansion of dendrimers into applications
that invoke their unique “internal” properties, such as
sequestering,3 drug delivery,4 and catalysis,5,6e there is
a growing interest in dendrimers possessing functional
moieties that are able to tune the nature of the “internal”
functionality and microenvironment. In almost all previ-
ous dendrimer families, the interior monomer units have
generally been employed as “inert” branched scaffolds to
Majoral and co-workers reported the most systematic
approach to the internal functionalization of dendrimers.
In several accounts, they have extensively investigated
the site-specific grafting of different functional and
charged groups,6c and even the growth of dendritic
wedges within the interior of large phosphorus-containing
dendrimers.6d
Recently, Piotti and co-workers described the prepara-
tion of reversed micellar, internally functionalized den-
drimers for the catalysis of simple nucleophilic displace-
ment and elimination reactions.6e They prepared poly(ben-
zyl ether) dendrimers of different generations having
methyl ester and benzylic alcohol interior moieties. A
pronounced microenvironmental effect on catalytic turn-
over was observed because larger dendrimers, containing
a greater number of more polar functional groups, proved
(1) (a) Fre´chet, J . M. J . Science 1994, 263, 1710. (b) Newkome, G.
R.; Moorefield, C. N.; Vo¨gtle, F. Dendritic Macromolecules, VCH: New
York, 1996. (c) Matthews, O. A.; Shipway, A. N.; Stoddart, J . F. Prog.
Polym. Sci. 1998, 23, 1. (d) Chow, H.-F.; Mong, K.-K.; Nongrum, M.
F.; Wan, C.-W. Tetrahedron 1998, 54, 8543. (e) Fischer, M.; Vo¨gtle, F.
Angew. Chem., Int. Ed. Engl. 1999, 38, 885.
(2) (a) Hawker, C. J .; Fre´chet, J . M. J . Macromolecules 1990, 23,
4726. (b) Bosman, A. W.; J anssen, H. M.; Meijer, E. W. Chem. Rev.
1999, 99, 1665. (c) Zeng, F.; Zimmerman, S. C. Chem. Rev. 1997, 97,
1681. (d) Leon, J . W.; Kawa, M.; Fre´chet, J . M. J . J . Am. Chem. Soc.
1996, 118, 8847.
(3) (a) Hawker, C. J .; Wooley, K. L.; Fre´chet, J . M. J . J . Chem. Soc.,
Perkin Trans. 1 1993. (b) J ansen, J . F. G. A.; Brabander-van den Berg,
E. M. M.; Meijer, E. W. Science 1994, 266, 1226. (b) Cooper, A. I.;
Londono, J . D.; Wignall, G.; McClain, J . B.; Samulski, E. T.; Lin, J . S.;
Dobrynin, A.; Rubinstein, M.; Burke, A. L. C.; Fre´chet, J . M. J .;
DeSimone, J . M. Nature 1997, 389, 368. (c) Baars, M. W. P. L.;
Froehling, P. E.; Meijer, E. W. Chem. Commun. 1997, 1959. (d) Balogh,
L.; Tomalia, D. A. J . Am. Chem. Soc. 1998, 120, 7355. (e) Zhao, M.;
Sun, L.; Crooks, R. M. J . Am. Chem. Soc. 1998, 120, 4877.
(4) (a) Liu, M.; Fre´chet, J . M. J . Pharmaceut. Sci. Technol. Today
1999, 2, 393. (b) Eichman, J . D.; Bielinska, A. U.; Kukovska-Latallo,
J . F. K.; Baker, J . R. Ibid. 2000, 7, 232. (c) Wiwattanapatapee, R.;
Carren˜o-Go´mez, B.; Malik, N.; Duncan, R. Pharmaceut. Res. 2000, 17,
989. (d) Liu, M.; Kono, K.; Fre´chet, J . M. J . J . Control. Release. 2000,
65, 121. (e) Malik, N.; Wiwattanapatapee, R.; Klopsch, R.; Lorenz, K.;
Frey, H.; Weener, J . W.; Meijer, E. W.; Paulus, W.; Duncan, R. Ibid.
2000, 65, 133.
(6) (a) Lochmann, L.; Wooley, K. L.; Ivanova, P. T.; Fre´chet, J . M.
J . J . Am. Chem. Soc. 1993, 115, 7043. (b) Newkome, G. R.; Moorefield,
C. N.; Keith, J . M.; Baker, G. R.; Escamilla, G. H. Angew. Chem., Intl.
Ed. Engl. 1994, 33, 666. (c) Larre´, C.; Bressolles, D.; Turrin, C.;
Donnadieu, B.; Caminade, A.-M.; Majoral, J .-P. J . Am. Chem. Soc.
1998, 120, 13070. (d) Galliot, C.; Larre´, C.; Caminade, A.-M.; Majoral,
J .-P. Science 1997, 277, 1981. (e) Piotti, M. E.; Rivera, F.; Bond, R.;
Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1999, 121, 9471.
(5) (a) Bhyrappa, P.; Young, J . K.; Moore, J . S.; Suslick, K. J . Am.
Chem. Soc. 1996, 118, 5708. (b) Zhao, M.; Crooks, R. M. Angew. Chem.,
Int. Ed. 1999, 38, 364.
10.1021/jo005592i CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/12/2000