Facile synthesis of amine-terminated aromatic polyamide dendrimers via a divergent method

Article abstract of DOI:10.1021/ol0702425

A novel, rapid, inexpensive, and highly efficient divergent approach for the synthesis of a 32-amine-terminated G4 polyamide dendrimer has been developed. Each generation dendrimer was successfully obtained by the condensation of the preceding generation

Full text of DOI:10.1021/ol0702425

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1363-1366
Facile Synthesis of Amine-Terminated
Aromatic Polyamide Dendrimers via a
Divergent Method
Isao Washio, Yuji Shibasaki, and Mitsuru Ueda*
Department of Organic and Polymeric Materials, Graduate School of Science and
Engineering, Tokyo Institute of Technology, 2-12-1-H120 O-okayama, Meguro-ku,
Tokyo 152-8552, Japan
mueda@polymer.titech.ac.jp
Received January 30, 2007
ABSTRACT
A novel, rapid, inexpensive, and highly efficient divergent approach for the synthesis of a 32-amine-terminated G4 polyamide dendrimer has
been developed. Each generation dendrimer was successfully obtained by the condensation of the preceding generation dendrimer with the
building block and the deprotection with hydrazine in one pot. All the dendrimers were easily purified by precipitation in alkaline water, and
the purity was confirmed by NMR, MALDI-TOF mass spectra, and elemental analysis.
Dendrimers are hyperbranched three-dimensional macro-
molecules possessing a regular treelike array of branch units.
The possibility of effectively modifying the properties of
dendritic molecules by the introduction of reactive functional
groups at the core, peripheral surface, branching unit, or
multiple sites within the dendrimer leads to a variety of
applications in areas such as molecular light harvesting,1
catalysts,2 liquid crystals,3 molecular encapsulation,4 and drug
delivery systems.5
However, the synthetic procedures used for their prepara-
tion detract from their widespread use. Dendrimers are
generally formed by means of divergent6 or convergent7
methods that involve reiterative growth strategies. A stepwise
process is necessary for both these methods: attaching one
generation to the preceding one, purifying, followed by
changing the functional groups for the next-stage reaction.
(1) Jiang, D.-L.; Aida, T. Nature 1997, 388, 1681.
10.1021/ol0702425 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/06/2007

Scheme 1. Synthesis of AB2 Building Block 1
tion-deprotection procedures.14 This technique utilizes a
two-step method that consists of the activation of carboxylic
acids and condensation with an unprotected AB2 building
block having diamine moieties using the activating agent
diphenyl(2,3-dihydro-2-thioxo-3-benzoxazolyl)-phospho-
nate (DBOP)15 and later using a more versatile activating
reagent thionyl chloride.16 Recently, we have also reported
the facile synthesis of Fre´chet-type aryl ether dendrimers
using thionyl chloride by using the same concept.17 However,
these two-step methods are limited to only the convergent
approach because of the difficulties in the complete activation
of end groups at the dendrimer periphery and the quantitative
condensation of the resulting active intermediates with AB2
building blocks without side reactions such as the hydrolysis
of active intermediates, which would result in the formation
of defects, in a divergent approach.
1
Figure 1. Expanded H NMR spectra of reaction solutions.
Several methods such as double-stage growth,8 double-
exponential growth,9 hypermonomers,10 and orthogonal
coupling strategies11 have reported a decrease in the time
required for these lengthy syntheses by reducing the number
of steps.12 These approaches, however, still require multiple
steps to achieve the synthesis of high-generation dendrimers.
A one-pot multiple-addition convergent synthesis of poly-
carbonate dendrimers was recently reported in which the
second-generation dendrimer was prepared by the sequential
activation of an alcohol with 1,1-carbonyl diimidazole and
an AB2 triol.13 We demonstrated the rapid synthesis of a
perfectly branched third-generation (G3) polyamide den-
drimer using a convergent method without repetitive protec-
Scheme 2. Synthesis of G1 Dendrimer
(2) Knapen, J. W. J.; Van der Made, A. W.; de Wilde, J. C.; Van
Leeuwen, A. W.; Wijkens, P.; Grove, D. M.; Van Koten, G. Nature
(London) 1994, 372, 659.
(3) (a) Percec, V.; Cho, C. G.; Pugh, C.; Tomazos, D. Macromolecules
1992, 25, 1164. (b) Percec, V.; Kawasumi, M. Macromolecules 1992, 25,
3843. (c) Percec, V.; Johansson, G.; Heck, J.; Ungar, G.; Batty, S. J. Chem.
Soc., Perkin Trans. 1 1993, 1411. (d) Percec, V.; Chu, P.; Kawasumi, M.
Macromolecules 1994, 27, 4441. (e) Ponomarenko, S. A.; Eebrov, E. A.;
Bobrovsky, A. Yu.; Boiko, N. I.; Muzafarov, A. M.; Shibaev, V. P. Liq.
Cryst. 1996, 21, 1. (f) Busson, P.; Ihre, H.; Hult, A. J. Am. Chem. Soc.
1998, 120, 9070.
(4) (a) Jansen, J. F. G. A.; de Brabander-Van den Berg, E. M. M.; Meijer,
E. W. Science 1994, 266, 1226. (b) Hawker, C. J.; Fre´chet, J. M. J. J. Chem.
Soc., Perkin Trans. 1 1992, 2459.
(5) (a) Haensler, J.; Szoka, F. C. Bioconjugate Chem. 1993, 4, 372. (b)
Redemann, C. T.; Szoka, F. C. Bioconjugate Chem. 1996, 7, 703. (c) Meijer,
E. W.; Paulus, W.; Duncan, R. J. Controlled Release 2000, 65, 133.
(6) (a) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.;
Martin, S.; Roeck, J.; Ryder, J.; Smith, P. Polym. J. 1985, 17, 117. (b)
Tomalia, D. A.; Naylor, A. N.; Goddard, W. A. Angew. Chem., Int. Ed.
1990, 29, 138.
(7) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
(8) Wooley, K. L.; Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc.
1991, 113, 4252.
(9) Kawaguchi, T.; Walker, K. L.; Wilkins, C. L.; More, J. S. J. Am.
Chem. Soc. 1995, 117, 2159.
(10) Wooley, K. L.; Hawker, C. J.; Fre´chet, J. M. J. Angew. Chem., Int.
Ed. 1994, 33, 82.
Nevertheless, the divergent approach has several advan-
tages such as the simplicity of the purification process and
accessibility in large-scale industrial synthesis; this is
demonstrated by the fact that most commercially available
dendrimers are currently prepared using the divergent
method. Although several synthetic methods have been
(11) Spindler, R.; Fre´chet, J. M. J. J. Chem. Soc., Perkin Trans. 1 1993,
913.
(14) Okazaki, M.; Washio, I.; Shibasaki, Y.; Ueda, M. J. Am. Chem.
Soc. 2003, 125, 8120.
(15) Ueda, M.; Kameyama, A.; Hashimoto, K. Macromolecules 1988,
21, 19.
(16) (a) Washio, I.; Shibasaki, Y.; Ueda, M. Org. Lett. 2003, 5, 4159.
(b) Washio, I.; Shibasaki, Y.; Ueda, M. Macromolecules 2005, 38, 2237.
(17) Yamazaki, N.; Washio, I.; Shibasaki, Y.; Ueda, M. Org. Lett. 2006,
8, 2321.
(12) For reviews, see, for example: (a) Newcome, G. R.; Moorefield,
C. N.; Vo¨gtle, F. In Dendrimers and Dendrons, Concepts, Syntheses,
Applications; VCH: Weinheim, Germany, 2001. (b) Fre´chet, J. M. J.;
Tomalia, D. A. In Dendrimer and Other Dendritic Polymers; VCH:
Weinheim, Germany, 2002. (c) Grayson, M. S.; Fre´chet, J. M. J. Chem.
ReV. 2001, 101, 3819.
(13) Rannard, S. P.; Davis, N. J. J. Am. Chem. Soc. 2000, 122, 11729.
1364
Org. Lett., Vol. 9, No. 7, 2007

Scheme 3. Synthesis of Polyamide Dendrimers
developed to prepare entirely aromatic polyamide dendrim-
stability toward an acid, good affinity to common organic
solvents, and outstanding ability as a leaving group. It was
found that trifluoroacetanilide was completely converted into
aniline without producing any byproducts during the tran-
samidation reaction with 2 equiv of hydrazine in N-methyl-
2-pyrrolidone (NMP) at room temperature for 4 h, as shown
in Figure 1.19 On the contrary, benzanilidesa model com-
pound of the dendrimer backbonesfailed to react with
hydrazine even at 80 °C for 1 day.
ers,18 the divergent method is only applied to smaller
generation dendrimers.18d,e Moreover, to prepare each gen-
eration dendrimer, these methods require two-step reac-
tions: the condensation of benzoyl chloride derivatives with
amino groups at the periphery of the preceding generation
dendrimer and the reduction of all the nitro groups at the
periphery into amino groups with long reaction times.
Here, we have developed a two-step method for the facile
synthesis of amine-terminated aromatic polyamide dendri-
mers using 3,5-bis(trifluoroacetamido)benzoyl chloride as an
AB2 building block via a divergent approach in which the
condensation and deprotection reactions are carried out
rapidly in one pot. Furthermore, the purification of every
generation dendrimer only requires precipitation in alkaline
water.
Consequently, we synthesized 3,5-bis(trifluoroacetamido)-
benzoyl chloride 1 as a novel AB2 building block (Scheme
1). 3,5-Diaminobenzoic acid was first reacted with excess
amounts of trifluoroacetic anhydride in tetrahydrofuran,
followed by the addition of water to produce 3,5-bis-
(trifluoroacetamido)benzoic acid in 94% yield. Chlorination
was then conducted in thionyl chloride under reflux condi-
tions. The AB2 building block 1 was recrystallized twice from
tetrachloroethane followed by chloroform in 55% yield and
The protecting group of amines should fill at least three
requirements. First, it has to be stable under acidic conditions,
which result from the condensation reaction of acid chlorides
with amines. Second, the intermediates, protecting group
terminated dendrimers, have good solubility in a reaction
solvent. Third, it must be selectively deprotected while
maintaining the amide bonds of the dendrimer backbone.
Therefore, we selected a trifluoroacetyl group due to its high
1
was characterized by IR and H NMR spectroscopy and
elemental analysis.
The G1 dendrimer was prepared using p-phenylenediamine
(PDA) as a core molecule in one pot (Scheme 2). Further,
1.1 equiv of AB2 building block 1 was added to each amino
group in a solution of PDA in NMP at 0 °C and stirred for
1 h at room temperature to yield the trifluoroacetyl-
terminated G1 dendrimer (CF3-G1D) in situ. After achieving
(18) (a) Miller, T. M.; Neenan, T. X. Chem. Mater. 1990, 2, 346. (b)
Bayliff, P. M.; Feast, W. J.; Parker, D. Polym. Bull. 1992, 29, 265. (c)
Backson, S. C. E.; Bayliff, P. M.; Feast, W. J.; Kenwright, A. M.; Parker,
D.; Richards, R. W. Macromol. Symp. 1994, 77, 1. (d) Ishida, Y.; Jikei,
M.; Kakimoto, M. Macromolecules 2000, 33, 3202. (e) Hayakawa, T.;
Nakasugi, S.; Kakimoto, M.; Tokita, M.; Watanabe, J. High. Perform.
Polym. 2006, 18, 761.
(19) For deprotection using hydrazine, see: (a) Dzvinchuk, I. B.;
Lozinskii, M. O. Chem. Heterocycl. Compd. 2005, 41, 845. (b) Luo, J.;
Smith, M. D.; Lantrip, D. A.; Wang, S.; Fuchs, P. L. J. Am. Chem. Soc.
1997, 119, 10004.
Org. Lett., Vol. 9, No. 7, 2007
1365

complete condensation, the acid chloride of the unreacted
AB2 building block was hydrolyzed with a small amount of
water at 50 °C for 1 h to avoid undesired reactions of the
acid chloride with hydrazine. Then, 5.5 equiv of hydrazine
was added to 1 to form the amine-terminated G1 dendrimer
(NH2-G1D) by a transamidation reaction at 50 °C for 2 h.
Because the byproducts in the resulting final solution are
only trifluoroacetyl hydrazide, 3,5-diaminobenzoic acid, HCl,
and hydrazine, NH2-G1D can be purified simply by precipi-
tation in NaHCO3aq in quantitative yield. The formation and
isolation of NH2-G1D were confirmed by IR, 1H NMR, and
13C NMR spectroscopy and elemental analysis.
The synthetic route for the 32-amine-terminated G4
polyamide dendrimer is shown in Scheme 3. NH2-G2D, NH2-
G3D, and NH2-G4D were synthesized using a protocol
similar to that described above, that is, condensation of the
preceding generation dendrimer with the AB2 building block
1, followed by the deprotection of the trifluoroacetylamide
group in CF3-GnD in one pot. The deprotection reaction was
completely achieved at 50 °C within 3 h even in the case of
NH2-G4D synthesis. Interestingly, although the reaction time
of transamidation with hydrazine was prolonged by 1 day,
no changes were observed in every generation dendrimer,
suggesting that the excess hydrazine was inert to all the
dendrimers under those conditions. The yields of NH2-G2D,
NH2-G3D, and NH2-G4D after precipitation in alkaline water
were 94, 95, and 95%, respectively. The structures of all
Figure 2. MALDI-TOF MS spectrum of CF3-G4D.
was CF3-G4D. Further, the GPC traces of all the amine-
terminated dendrimers were unimodal and had narrow
distributions (see Supporting Information).
In summary, we have developed a facile synthetic method
for amine-terminated aromatic polyamide dendrimers via the
divergent approach. In this method, the trifluoroacetyl group
was employed as a protecting group for the AB2 building
block, which enabled a reduction in the deprotection reaction
time of amines using a transamidation reaction with hydra-
zine as well as the performance of the condensation and
deprotection reaction in one pot. Furthermore, the purification
of each generation dendrimer is performed by precipitation
in alkaline water. The simplicity and experimental ease of
this novel divergent method for the generation of polyamide
dendrimers makes it extremely attractive for the preparation
of dendrimers for use in both laboratories and industry.
the dendrimers were characterized by IR, 1H NMR, and 13
C
NMR spectroscopy and elemental analysis. Although the
MALDI-TOF MS measurement of NH2-G2D provided a
clear spectrum and indicated its formation and isolation, NH2-
G3D and NH2-G4D could not be analyzed by the MALDI-
TOF MS spectrum probably because of strong intermolecular
interactions of terminated amines and dendrimers. To reduce
the interactions, we isolated the intermediates, CF3-G3D and
CF3-G4D, without using any purification processes except
precipitation in alkaline water. Thus, we could obtain clear
charts of them on MALDI-TOF MS spectrometry. Because
the spectrum of CF3-G4D exhibits a desired single signal at
7228.3 as shown in Figure 2, we believe that the corre-
sponding NH2-G4D was isolated in high purity as well as
Supporting Information Available: Full synthetic de-
tails, spectral data of products, 1H NMR, 13C NMR, MALDI-
TOF MS spectra, and GPC charts. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0702425
1366
Org. Lett., Vol. 9, No. 7, 2007