A convergent route to novel aliphatic polyether dendrimers [21]

Full text of DOI:10.1021/ja983229b

12996
J. Am. Chem. Soc. 1998, 120, 12996-12997
Scheme 1. Synthesis of Dendrons [G-2] through [G-5]
A Convergent Route to Novel Aliphatic Polyether
Dendrimers
Manikandan Jayaraman and Jean M. J. Fre´chet*
Department of Chemistry, UniVersity of California
Berkeley, California 94720-1460
ReceiVed September 10, 1998
Interest in dendrimers has increased almost exponentially in
the past few years as the unique features of these globular
molecules are better understood and their potential applications
are explored.1 Dendrimers that are currently available include
aliphatic amides, aliphatic amines, aliphatic esters, aromatic
hydrocarbons, aromatic ethers, and aromatic esters.2 The conver-
gent method of synthesis3 we first introduced in 1989 has proven
to be very versatile and the aromatic polyether dendrons3 with
their distinct functionalities at their focal point and chain ends
have been widely used4 in the preparation of a broad array of
functional dendritic structures.
This communication describes the convergent synthesis of a
new family of dendrimers with an aliphatic polyether backbone.
This new class of well-defined dendrimers has great potential as
a result of the combination of its inert, low absorbance building
blocks, multiple reactive chain ends, and uniquely functionalized
focal point. In addition, these dendrimers with their polar
2-hydroxymethyl-1,3-propanediol building blocks might show
improved biocompatibility and be rendered water-soluble or water-
dispersible by varying their surface functionality
Scheme 1 shows the synthesis of dendrons [G-2]-ene to [G-5]-
ol. Compound 1 was prepared by reaction of 2 equiv of benzyl
alcohol with epichlorohydrin.7 This secondary alcohol with its
single branch point serves as the activated [G-1]-ol dendron.
Benzyl ether was chosen as the chain-end moiety both for its
ability to serve as an NMR “tag” for the characterization of the
growing molecule and for its ease of removal by hydrogenolysis.
Etherification of methallyl dichloride by the [G-1]-ol was achieved
by using NaH in THF. The stoichiometry of the reagents
determines the product that is obtained. Using 1.1 equiv of the
alcohol results in quantitative conversion of the methallyl dichlo-
ride to the [G-2]-ene, whereas using 2 equiv of methallyl
dichloride leads to the formation of the monosubstituted product
in high yield. This mono-etherification reaction constitutes a useful
approach to unsymmetrical dendrons8 for the construction of
complex dendritic architectures with different end groups or
building blocks.
Methallyl dichloride,5 readily obtained from Pentaerythritol,
was chosen as the monomer because its allylic functionality
provides for the facile nucleophilic substitution of its two
electrophilic sites, while the double bond itself acts as a masked
functionality for the subsequent activation-growth steps. There-
fore, in this approach the nucleophilic displacement of the allylic
chlorides in a Williamson ether synthesis is the growth step, while
the derivatization of the olefinic double bond is the activation
step. This activation may be accomplished either via hydro-
boration-oxidation to afford a primary alcohol or by ozonolysis
followed by reduction to give a secondary alcohol. Dendrons up
to generation 5 have been prepared in high yields through a
sequential growth and activation protocol. A divergent route to
analogous polyethers proposed earlier6 suffered from incomplete
coupling reactions due to excessive crowding.
The [G-2]-ene was easily separated from the excess alcohol
starting material by flash chromatography as the two compounds
have vastly different polarities, thus providing the desired product
in high yield (90-95%). Table 1 lists the yields obtained in the
synthesis of dendrons [G-2]-ene through [G-5]-ol.
(1) Matthews, O. A.; Shipway, A. N.; Stoddart, J. F. Prog. Polym. Sci.
1998, 23, 1. Xu, Z.; Moore, J. S. Acta Polym. 1994, 45(2), 83. Fre´chet, J. M.
J. Science 1994, 263, 1710. Evans, D. J.; Kanagasooriam, A.; Williams, A.;
Pryce, R. J. J. Mol. Catal. 1993, 85(1), 21. Roberts, J. C.; Adams, Y. E.;
Tomalia, D.; Mercer-Smith, J. A.; Lavallee, D. K. Bioconj. Chem. 1990, 1(5),
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(2) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendritic Molecules;
VCH: New York, 1996, and references therein.
(3) Fre´chet, J. M. J.; Jiang, Y.; Hawker, C. J.; Philippides, A. E. Proc.
IUPAC Int. Symp., Macromol., Seoul 1989, 19. Hawker, C. J.; Fre´chet, J. M.
J. J. Am. Chem. Soc. 1990, 112, 7638.
(4) See, for example: Zimmerman, S. C.; Zeng, F. W.; Reichert, D. C.;
Kolotuchin, S. V. Science 1996, 271, 1095. Jiang, D. L.; Aida, T. Nature
1997, 388, 454. Claussen, W.; Schulte, N.; Schluter, A. D. Macromol. Rapid
Commun. 1995, 16, 89. Karakaya, B.; Claussen, W.; Schafer, A.; Lehmann,
A.; Schluter, A. D. Acta Polym. 1996, 47, 79. Wenzel, A.; Neubert, I.; Schluter,
A. D. Macromol. Chem. Phys. 1998, 199, 745. Sadamoto, R.; Tomioka, N.;
Aida, T. J. Am. Chem. Soc. 1996, 118, 3978. Chen, Y. M.; Chen, C. F.; Liu,
W. H.; Li, Y. F.; Xi, F. Macromol. Rapid Commun. 1996, 17, 401. Peerlings,
H. I.; Trimbach, D. C.; Meijer, E. W. J. Chem. Soc., Chem. Commun. 1998,
497. Peerlings, H. I.; Meijer, E. W. Chemistry-A European Journal 1997, 3,
1563. Wang, Y.; Zeng, F. W.; Zimmerman, S. C. Tetrahedron Lett. 1997, 38,
5459. Leduc, M. R.; Hawker, C. J.; Dao, J.; Fre´chet, J. M. J. J. Am. Chem.
Soc. 1996, 118, 11111. Gitsov, I.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1996,
118, 3785. Fre´chet, J. M. J.; Gitsov, I. Macromol. Symp. 1995, 98, 441. Chen,
Y. M.; Chen, C. F.; Liu, W. H.; Xi, F. Polym. Bull. 1996, 37, 557.
(5) Lynch, K. M.; Dailey, W. P. J. Org. Chem. 1995, 60, 4666.
(6) Hall, H.; Padias, A.; McConnell, R.; Tomalia, D. A. J. Org. Chem.
1987, 52, 5305.
Activation of the focal point of the [G-2]-ene was achieved
by regioselective hydroboration-oxidation9 to afford the [G-2]-
ol. When the borane:THF complex was used as the hydroboration
reagent, some unwanted tertiary alcohol side-product was formed
along with the desired primary alcohol. Using the more sterically
hindered 9-BBN as the borane reagent essentially eliminates this
side product. The desired primary alcohol was then purified by
flash chromatography on silica gel with use of a mixture of
hexanes and ethyl acetate as the eluent affording isolated yields
of 80 to 90%. The two-step nucleophilic substitution-hydro-
boration-oxidation sequence was repeated to prepare dendrons
up to the 5th generation in multigram quantities. As the generation
increases, the increased steric crowding of the focal point only
marginally affects the yield of the desired product in the growth
step (Table 1). This small decrease may in part be attributable to
chromatographic losses as the resolution between [G-n]-ol and
(7) Nemoto, H.; Wilson, J. G.; Nakamura, H.; Yamamoto, Y. J. Org. Chem.
1992, 57, 435.
(8) Wooley, K. L.; Hawker, C. J.; Fre´chet, J. M. J. J. Chem. Soc., Perkin
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(9) Brown, H. C. Hydroboration; Benjamin: New York, 1962.
10.1021/ja983229b CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/01/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 49, 1998 12997
Table 1. Yields for the Preparation and Activation of Dendrons
[G-2] through [G-5]
generation
growth step
activation step
[G-2]
[G-3]
[G-4]
[G-5]
95
95
90
85
90
86
88
85
[G-n+1]-ene decreases with increasing “n”. The yields obtained
in the activation step did not vary appreciably with increasing
generation.
Figure 1. MALDI-TOF spectra of [G-4]-ene and [G-5]-ene.
The characteristic signals in the 1H NMR spectra of the
functional group at the focal point of the dendrons facilitate
identification of both the alkene and the alcohol. The spectrum
of the alkene shows a singlet at δ 5.1 ppm corresponding to the
terminal olefin and another singlet at δ 4.1 ppm corresponding
to the two allylic ether methylene groups. Integration of these
two singlets versus the singlet corresponding to the benzylic chain
end protons at δ 4.45 ppm serves as a reliable handle to assist in
characterizing all of the alkene dendrons.
Table 2. MALDI-TOF MS and SEC Data for Dendrons [G-3]-ene
to [G-5]-ol
compd
expected MW
MALDI MW
SEC MWa
[G-3]-ene
[G-3]-ol
[G-4]-ene
[G-4]-ol
[G-5]-ene
[G-5]-ol
1281
1299
2651
2669
5391
5409
1279
1299
2650
2669
5396
5414
1229
1200
2252
1820
3695
3500
The monosubstituted product also has characteristic peaks
corresponding to the alkene and allylic protons. The olefinic
protons appear as two sharp singlets at δ 5.2 and δ 5.15 ppm
and the allylic protons appear as singlets at δ 4.05 and δ 4.15
ppm.
a Relative molecular weights by size exclusion chromatography with
polystyrene standards.
To confirm the ready accessibility of the focal point of the
higher generation dendrons toward other low molecular weight
reagents, a hydrosilylation with trimethoxysilane was carried out.
This reaction proceeds quantitatively under typical hydrosilylation
conditions.
In conclusion, we have presented the convergent synthesis of
a new class of aliphatic polyether dendrons using Williamson
etherification chemistry. Work is currently in progress to attach
these dendrons to an aliphatic multifunctional core molecule to
make wholly aliphatic polyether dendrimers. The ability to make
the focal point of the core active toward both electrophilic and
nucleophilic substitutions as well as hydrosilylation and Heck type
coupling reactions adds versatility to the choice of the core
molecule and the chemistry that may be employed to incorporate
these dendrons into larger structures.
Formation of the alcohols was accompanied by the disappear-
ance of the olefinic and allylic protons and the appearance of a
triplet at 2.8 ppm corresponding to the alcoholic proton and a
multiplet at 2.1 ppm corresponding to the methine proton. Once
again, integration of the methine protons versus the benzylic
protons was used to characterize the primary alcohols.
Molecular weight determinations were carried out with FAB
MS, MALDI-TOF MS, and SEC. Dendrons up to the 3rd
generation were analyzed by both FAB MS and MALDI-TOF
MS while 4th and 5th generation dendrons could only be analyzed
by MALDI-TOF MS. The MALDI-TOF MS were recorded in
R-cyano-4-hydroxycinnamic acid matrix along with silver tri-
fluoroacetate without further purification of the material. Both
techniques confirmed the molecular weights of the dendrons
(Figure 1).
As expected, the molecular weights measured by size exclusion
chromatography (SEC vs polystyrene standards) were lower than
the calculated values and the differences between measured and
calculated values increased with generation number. This has been
well documented in the dendrimer literature and is attributed to
the compact nature of the dendrimers.3,10 Given the greater size
accuracy of the dendrons when compared to the polymer standards
used for SEC, it is not surprising that the polydispersities measured
were all below 1.01. Table 2 compares the calculated and
experimental molecular weights of [G-3]-ene to [G-5]-ol.
Acknowledgment. Financial support of this research by the U.S.
Army Research Office (MURI program, DAAG55-97-0126) and the
National Science Foundation (DMR-9796106) is acknowledged with
thanks.
Supporting Information Available: Experimental procedures for the
synthesis of [G-2]-ene and [G-2]-ol and analytical data (1H NMR and
FAB MS) (6 pages, print/PDF). See any current masthead page for
ordering information and Web access instructions.
(10) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A. Angew. Chem., Int.
Ed. Engl. 1990, 20, 138.
JA983229B