4084
J. Am. Chem. Soc. 1999, 121, 4084-4085
Scheme 1
An Alternative Synthetic Approach toward Dendritic
Macromolecules: Novel Benzene-Core Dendrimers
via Alkyne Cyclotrimerization
Stefan Hecht and Jean M. J. Fre´chet*
Department of Chemistry, UniVersity of California
Berkeley, California 94720-1460
ReceiVed December 7, 1998
We report an alternative method for the convergent1 synthesis
of dendrimers in which the dendrimer core is generated from a
dendritic precursor by an alkyne cyclotrimerization reaction.2 In
this method, convergent dendrons1,3 attached to an acetylenic
moiety are cyclized in a [2 + 2 + 2] cycloaddition process. The
cycloaddition can be mediated by various transition-metal com-
plexes and exhibits a high degree of chemoselectivity toward triple
bonds, rendering the reaction tolerant of many functional groups.2
If carried out with a difunctionalized dendritic alkyne, this reaction
affords a benzene moiety surrounded by six dendrons as depicted
in Scheme 1. A related approach was used by Ducheˆne and
Vo¨gtle4 for the synthesis of a dodecafunctionalized host-
molecule.
Scheme 2
An acetylenic system consisting of benzylic ethers of 2-butyne-
1,4-diol was chosen for commercial availability as well as its
synthetic compatibility. In particular, this linkage prevents the
occurrence of a Claisen rearrangement.5 The substituted alkynes
1a-d were obtained by the Williamson ether coupling of
2-butyne-1,4-diol with the appropriate polybenzyl ether-type1
dendritic bromide (Scheme 2). The trimerization reaction of 1a-d
was carried out in refluxing toluene using dicobalt octacarbonyl6
as the catalyst to afford the novel structures 2a-d. To our
knowledge, this represents the first time that such large and
precisely defined macromolecules (MW ≈ 10 000 for the third
generation) have been successfully prepared by a cyclotrimer-
ization reaction.
Table 1. Synthesis of Dendritic Alkynes 1a-d and Benzene-Cored
Dendrimers 2a-d
b
compound
R
yield of 1a
yield of 2a
time1f2
a
b
c
Bn
62%
62%
50%
41%
83%
80%
50%
36%
0.5 h
2 h
20 h
48 h
[G-1]
[G-2]
[G-3]
d
a Yields given are after chromatographic separation. Cyclotrimer-
ization conditions: substrate 1a-d (0.5 M in toluene) with 5 mol %
catalyst Co2(CO)8 at 111 °C.
As expected, the time required to complete the trimerization
reaction increased with generation (Table 1), while the yield
decreased as a result of steric crowding around the nascent core.
Because of the nature of the transformation, the reaction is
extremely clean, and no partially reacted products can be formed.
Therefore, aside from recovered starting materials, compounds
2a-d were the only products isolated after reaction. As a result,
their purification by column chromatography was greatly facili-
tated. The catalyst, dicobalt octacarbonyl, applied in amounts of
5 mol % or less, is fairly robust and easy to handle since it
operates in a variety of different solvents.7
Benzene-core dendrimers 2a-d have been fully characterized
by a variety of spectroscopic techniques. Both the MALDI-TOF
mass spectra and the size-exclusion chromatography traces (Figure
1) of the dendrimers confirm their monodispersity and high purity.
To probe their solution dynamics, NMR relaxation time (T1)
measurements were performed. Herein, a correlation of the
relaxation behavior of the spectroscopic probe, i.e., the proton,
with its local environment can be used to gain information about
the relative density distribution within the macromolecule.8
Because of the high spectral resolution allowing clear observation
of the different layers (Scheme 3) of the structure, this approach
was used to gain information about the entire dendrimer frame-
work.
As shown in Figure 2, the T1 values for the terminal benzylic
protons (e) are almost constant while a slight decrease in T1 is
observed for the exterior phenyl protons (f). This suggests that
there is no change in steric congestion at the periphery of the
dendrimer as the generation increases. The relaxation times for
the successive layers within the dendrimer decrease from the core
to the periphery, suggesting a radial increase in density of the
macromolecule. This finding fits the simplified model of de
(1) (a) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
(b) Fre´chet, J. M. J.; Jiang, Y.; Hawker, C. J.; Philippides, A. E. Proc. IUPAC
Int. Symp., Macromol. 1989, 19.
(2) For recent reviews on transition-metal-mediated [2 + 2 + 2]cyclo-
additions, see: (a) Fru¨hauf, H.-W. Chem. ReV. 1997, 97, 523. (b) Lautens,
M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (c) Grotjahn, D. B. In
ComprehensiVe Organometallic Chemistry II; Abel, E. A., Stone, F. G. A.,
Wilkinson, G., Eds.; Pergamon: Oxford, 1995; Vol. 12, pp 741-770. (d)
Melikyan, G. G.; Nicholas, K. M. In Modern Acetylene Chemistry; Stang, P.
J., Diederich, F., Eds.; VCH: Weinheim, 1995; pp 99-138. (e) Schore, N.
E. In ComprehensiVe Organic Synthesis; Trost, B. M., Flemming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 5, pp 1129-1162.
(3) (a) Hawker, C. J.; Fre´chet, J. M. J. J. Chem. Soc., Chem. Commun.
1990, 1010. (b) Miller, T. M.; Neenan, T. X. Chem. Mater. 1990, 2, 346. (c)
Wooley, K. L.; Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1991, 113,
4252. (d) Kwock, E. W.; Miller, T. M.; Neenan, T. X. Chem. Mater. 1991, 3,
775. (e) Leon, J. W.; Kawa, M.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1996,
118, 8847. (f) Jayaraman, M.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1998, 120,
12996-12997. (g) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendritic
Molecules: Concepts, Synthesis, PerspectiVes; VCH: Weinheim, 1996;
Chapter 5 and references therein.
(7) A cobalt-catalyzed cyclotrimerization has recently been performed in
aqueous solution: Sigman, M. S.; Fatland, A. W.; Eaton, B. E. J. Am. Chem.
Soc. 1998, 120, 5130.
(8) (a) Tomoyose, Y.; Jiang, D.-L.; Jin, R.-H.; Aida, T.; Yamashita, T.;
Horie, K. Macromolecules 1996, 29, 5236. (b) Jiang, D.-L.; Aida, T. Nature
1997, 388, 454. (c) Jiang, D.-L.; Aida, T. J. Am. Chem. Soc. 1998, 120, 10895.
(4) Ducheˆne, K. H.; Vo¨gtle, F. Synthesis 1986, 659.
(5) Olsman, H.; Graveland, A.; Arens, J. F. Recl. TraV. Chim. Pays-Bas
1964, 83, 301.
(6) (a) Kaufman, R. J.; Sidhu, R. S. J. Org. Chem. 1982, 47, 4941. (b)
Hu¨bel, W.; Hoogzand, C. Chem. Ber. 1960, 93, 103.
10.1021/ja9842215 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/13/1999