Arylamide dendrimers with flexible linkers via haloacyl halide method

Article abstract of DOI:10.1021/ol050341n

(Chemical Equation Presented) Soluble arylamide dendrons with flexible linkers, peripheral ester or carboxyl groups (R), and focal amino or halogen functionalities (F) were synthesized from aryl glycineamide (AG) building blocks. The AG blocks were prepar

Full text of DOI:10.1021/ol050341n

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1761-1764
Arylamide Dendrimers with Flexible
Linkers via Haloacyl Halide Method
Sergei A. Vinogradov*
Department of Biochemistry and Biophysics, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
Vinograd@mail.med.upenn.edu
Received February 17, 2005
ABSTRACT
Soluble arylamide dendrons with flexible linkers, peripheral ester or carboxyl groups (R), and focal amino or halogen functionalities (F) were
synthesized from aryl glycineamide (AG) building blocks. The AG blocks were prepared in high yields from trivial starting materials by Fischer’s
haloacyl halide method, which also could be extended to the dendrimer synthesis itself. The G2 AG dendrons were coupled to a Pd porphyrin
core, demonstrating outstanding encapsulation efficiency in aqueous solutions.
Among all dendrimers1 with aromatic backbones, dendritic
arylamides2 are attractive because of their high chemical
stability, the low cost of their building blocks, and effective
protocols available for their assembly.3 Arylamide dendrimers
based on 5-aminoisophthalic acid (5-AIPA) were, in fact,
among the first reported dendritic macromolecules;4 however,
because of the difficulties in their handling and characteriza-
tion,4b the practical potential of these materials has barely
been uncovered even today. Such dendrimers, on the other
hand, could present interest for material science and also be
useful in applications where encapsulation in polyaromatic
scaffolds with multiple peripheral ester or carboxyl groups
is required, e.g., in the design of biomedical image tracers.5
The problems associated with the 5-AIPA building block
come mainly from (1) the low nucleophilicity of its amino
group and (2) impeded internal rotations of the 5-AIPA based
skeleton, which cause poor solubility and difficulties in
characterization of the resulting dendrimers. A way to make
the focal functionality more reactive and to simultaneously
increase the flexibility of the dendritic backbone is to extend
the amino end in the 5-AIPA molecule by a flexible
fragment, terminated with an appropriate group, e.g., aliphatic
amine. Voit et al.6 and others7-9 constructed a number of
(4) (a) Miller, T. M.; Neenan, T. X. Chem. Mater. 1990, 2, 346-349.
(b) Backson, S. C. E.; Bayliff, P. M.; Feast, W. J.; Kenwright, A. M.; Parker,
D.; Richards, R. W. Macromol. Symp. 1994, 77, 1-10.
(5) (a) Vinogradov, S. A.; Lo, L. W.; Wilson, D. F. Chem. Eur. J. 1999,
5, 1338-1347. (b) Rozhkov, V. V.; Wilson, D. F.; Vinogradov, S. A.
Macromolecules 2002, 35, 1991-1993. (c) Finikova, O. S.; Galkin, A. S.;
Rozhkov, V. V.; Cordero, M. C.; Ha¨gerha¨ll, C.; Vinogradov, S. A. J. Am.
Chem. Soc. 2003, 125, 4882-4893. (d) Rietveld, I. B.; Kim, E.; Vinogradov,
S. A. Tetrahedron 2003, 59, 3821-3831.
(6) (a) Voit, B. I.; Wolf, D. Tetrahedron 1997, 53, 15535-15551. (b)
Appelhans, D.; Komber, H.; Voigt, D.; Haussler, L.; Voit, B. I. Macro-
molecules 2000, 33, 9494-9503. (c) Clausnitzer, C.; Voit, B.; Komber,
H.; Voigt, D. Macromolecules 2003, 36, 7065-7074.
(7) (a) Mulders, S. J. E.; Brouwer, A. J.; Liskamp, R. M. J. Tetrahedron
Lett. 1997, 38, 3085-3088. (b) Mulders, S. J. E.; Brouwer, A. J.; van der
Meer, P. G. J.; Liskamp, R. M. J. Tetrahedron Lett. 1997, 38, 631-634.
(c) Brouwer, A. J.; Mulders, S. J. E.; Liskamp, R. M. J. Eur. J. Org. Chem.
2001, 1903-1915.
(1) For general reference on dendrimers see, for example: Dendrimers
and Other Dendritic Polymers; Fre´chet, J. M. J., Tomalia, D. A., Eds.;
Wiley: New York, 2001.
(2) Jikei, M.; Kakimoto, M. A. J. Polym. Sci. Part A: Polym. Chem.
2004, 42, 1293-1309.
(3) (a) Okazaki, M.; Washio, I.; Shibasaki, Y.; Ueda, M. J. Am. Chem.
Soc. 2003, 125, 8120-8121. (b) Washio, I.; Shibasaki, Y.; Ueda, M. Org.
Lett. 2003, 5, 4159-4161.
10.1021/ol050341n CCC: $30.25
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alkyl-aryl amide dendrimers applying similar strategies to
5-hydroxyisophthalic and other aromatic acids; however,
none of the reported chemistries became widely used in the
dendrimer practice. Here, we introduce an efficient synthesis
of alkyl-aryl amide dendrons with flexible linkers that
makes use of the classic Fischer haloacyl halide method.10
The developed approach is inexpensive, has a broad scope,
and allows for modification of the dendrimer periphery,
interior, focal functionality, and/or internal topology, without
changing its basic chemistry. The synthesis of aryl glycinea-
mide or simply aryl-glycine (AG) dendrimers is presented
to exemplify the developed methodology.
reaction is important because of the subsequent ammonolysis,
which occurs much faster in the case of the bromo derivative
4 than that of the chloro analogue. The ammonolysis of the
latter can be complicated by the side reactions, e.g., nucleo-
philic substitutions at the peripheral carbonyl groups, which
give rise to mono- and diamides. On the other hand, the
ammonolysis of 4 is fast and can be accomplished with no
loss of the ester functionalities, giving amine 5 in 78% yield.
Another important feature of the acylation (step v) in Scheme
1 is the use of Na2CO3 instead of more common organic
bases such as Et3N or pyridine. Apparently, the latter undergo
quantitative quarternization by bromide 4, leaving poorly
soluble and unreactive quaternary ammonium salts.
It is important to mention that neither of the intermediate
products 1 and 4 in the syntheses of 3 and 5 need to be
isolated and purified. They can be introduced into the
following transformations directly from the preceding syn-
theses, following the precipitation upon acidification (1) or
evaporation of the solvent (4). Building blocks 3 and 5, on
the other hand, and amino acid 2 are obtained in high yields
by precipitation/crystallization, which makes the overall
synthesis shown in Scheme 1 inexpensive and easily scalable
to multigram or larger quantities.
The building blocks 3 and 5 for assembly of AG
dendrimers were synthesized as shown in Scheme 1. The
Scheme 1. Synthesis of Aryl-glycine (AG) Building Blocksa
An example of the dendrimer assembly from blocks 3 and
5 is depicted in Scheme 2. The resulting dendrons are
abbreviated as F-AGn-T, where F is the focal group (e.g.,
CBzNH-benzyloxycarbonyl-protected amino group), AGn is
a Conditions: (i) 4 M NaOH aq, 0 °C, 94%; (ii) NH3 aq, 1-2 h,
98%; (iii) CBzCl/NaHCO3 aq, 2 h, 82%; (iv) NH4CO2H, Pd/C,
MeOH/THF, 93%; (v) Na2CO3, CH3CN, 98%; (vi) NH3/MeOH,
78%.
Scheme 2. Convergent Synthesis of G2 and G3 AG Dendrons
Using Coupling-Deprotection Procedurea
synthesis of diacid 3 starts with acylation of 5-AIPA with
chloroacetyl chloride under the classic Schotten-Baumann
conditions, giving chloride 1 in a nearly quantitative yield.
1 is further treated with aqueous ammonia, and amino acid
2 is isolated upon removal of the excess of ammonia and
addition of EtOH to the aqueous solution. The benzyloxy-
carbonyl (CBz) protection is installed on the amino end of
2 by reacting it with an excess of CBz-Cl in aqueous solution
over an excess of NaHCO3. The CBz-protected building
block 1 is isolated from the mixture upon filtration and
acidification by HCl.
The starting material in the synthesis of 5 is the dibutyl
ester of 5-nitroisophthalic acid (5-NIPA). Butyl esters were
employed in this work because they gave the desired
solubility to the AG dendrons and dendrimers. However,
other alcohols can be used for esterification of 5-NIPA as
well. For example, higher alcohols, e.g., hexyl, octyl, etc.,
would facilitate gelation of the AG dendrons in solvents such
as ethyl acetate, which can be useful for some applications.
Dibutyl 5-nitroisophthalate can be quantitatively reduced
by hydrogen or by ammonium formate in the presence of
Pd/C catalyst.11 The resulting dibutyl 5-aminoisophthalate
is acylated by bromoacetyl bromide in acetonitrile in the
presence of Na2CO3. Using bromoacetyl bromide in this
a Conditions: (i) CDMT/NMM, THF/DMF, 4 h, 0 °C, 81%; (ii)
H2, Pd/C, DMF, rt, 12 h, 97%; (iii) as in step i, 73%; (iv) as in
step ii, 82%.
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Org. Lett., Vol. 7, No. 9, 2005

the AG framework of generation n, and T is the terminal
group (e.g., OBu-butyl esters). In this nomenclature, diacid
3 and amine 5 would be termed CBzNH-AG1-OH and H2N-
AG1-OBu, respectively.
The coupling chemistry used in this particular implemen-
tation is CDMT/NMM.12 The advantage of the CDMT/NMM
system is the ease of the removal of unreacted coupling
reagents and side products, which are soluble in acidic
aqueous solutions. Thus, isolation of practically pure CBz-
protected dendrons consists of their precipitation from
reaction mixtures upon addition of water and washing of the
solids with aqueous 0.1 M HCl.
The hydrogenolysis, employed in steps ii and iv, is clean
and occurs quantitatively. However, it is difficult to remove
the catalyst (Pd/C) from the products, as AG dendrons tend
to support Pd/C particles in solution. It is, therefore, likely
that using Boc instead of CBz protection would benefit these
syntheses.
Both CBz-protected and unprotected G2 dendrons are
soluble in DMF, pyridine, and DMSO and slightly soluble
in hot EtOH, making it possible to purify CBzNH-AG2-OBu
from unreacted amine 5 by washing it with cold EtOH. On
the other hand, G3 dendrons show excellent solubility in most
common organic solvents and can be purified by precipitation
from CH2Cl2 solutions with ether or hexane.
phthalic dichloride with 5, followed by the reduction of nitro
derivative 6. The following reactions replicate Scheme 1 and
include the acylation of 7 with bromoacetyl bromide and
the ammonolysis of the intermediate bromo derivative
Br-AG2-OBu. Two molecules of the resulting G2 AG den-
dron can be further attached to 5-nitroisophthalic dichloride,
and the sequence of reduction, acylation, and ammonolysis
can be repeated to give the G3 dendron, etc. It is important
to note that, in this pathway, dendrons with Br atoms in the
focal points, e.g., Br-AG2-OBu, appear as intermediate
products. These are useful for couplings to phenols by
Williamson chemistry. On the other hand, given that the
entire synthesis requires only 5-amino- and/or nitroisophthalic
acid, bromoacetyl bromide, a chlorinating agent, e.g., SOCl2,
and ammonia, the AG dendrons appear to be among the least
expensive and most practical dendrons described.
It is worth pointing out that the haloacyl halide method,
employed in Schemes 1 and 3, can be naturally adopted to
introduce various groups R′ (see Abstract Graphic) in place
of the alkylamide hydrogens throughout the entire dendritic
skeleton. This can be done by simply changing the nucleo-
phile in the steps ii and vi (Scheme 1) or v (Scheme 3) from
ammonia to an appropriate amine. Moreover, different
functionalities can be included in the dendrimer interior using
different amines at different stages of the synthesis. In
addition, chiral centers can be placed throughout the den-
drimer by using various R-haloacyl halides, a variety of
which are readily available.
The dendrimer assembly, shown in Scheme 2, is effective
but relies on a two-step coupling/deprotection protocol.
Shortening the synthesis by removing the deprotection step
would benefit the entire scheme. This possibility is intrinsic
to Fischer’s haloacyl halide method, which could be extended
to the synthesis of AG dendrimers themselves (Scheme 3).
The key intermediate 7 in the synthesis of the G2 dendron
H2N-AG2-OBu can be obtained by coupling 5-nitroiso-
Finally, we would like to demonstrate how AG dendrons
can be used to modify functional centers and how the
peripheral groups on the AG dendrimers can be adjusted in
accordance with the demands of an application.
Pt and Pd porphyrins, due to their long-living emissive
triplet states, are commonly used as phosphorescent probes
for oxygen measurements in biological systems.13 When
dissolved directly in the blood, hydrophobic porphyrin
molecules tend to aggregate and bind to the cell surfaces,
blood vessel walls, and biomacromolecules such as albumin
and other proteins. To circumvent these problems, it has
been suggested to encapsulate phosphorescent chromophors
inside dendrimers.5 The periphery of the dendrimers can be
tuned to provide isolation of the phosphors from active
components of biological systems and to simultaneously
make them water soluble. On the other hand, the dendritic
matrix, if appropriately chosen, folds in aqueous solutions,
leading to more effective encapsulation of the core porphyrin
and enabling control over the oxygen diffusion inside
dendrimers.5a,b
Scheme 3. Synthesis of G2 AG Dendron Using Haloacyl
Halide Methoda
(8) Ashton, P. R.; Anderson, D. W.; Brown, C. L.; Shipway, A. N.;
Stoddart, J. F.; Tolley, M. S. Chem. Eur. J. 1998, 4, 781-795.
(9) (a) Romagnoli, B.; Ashton, P. R.; Harwood, L. M.; Philp, D.; Price,
D. W.; Smith, M. H.; Hayes, W. Tetrahedron 2003, 59, 3975-3988. (b)
Romagnoli, B.; van Baal, I.; Price, D. W.; Harwood: L. M.; Hayes, W.
Eur. J. Org. Chem. 2004, 4148-4157.
(10) Greenstein, J.; Winitz, M. Chemistry of Amino Acids; John Wiley
& Sons: New York, 1961; Vol. 2.
(11) Ram, S.; Spicer, L. D. Synth. Commun. 1987, 17, 415-418.
(12) Kaminski, Z. J. Synthesis 1987, 917-920.
a Conditions: (i) SOCl2, reflux, 1 h, (ii) CH2Cl2/DMF/pyridine,
61%; (iii) H2, Pd/C, DMF, 88%; (iv) Na2CO3, DMF, 87%; (v) NH3/
MeOH, 90%.
(13) Wilson, D. F.; Vinogradov, S. A. Tissue Oxygen Measurements
Using Phosphorescence Quenching. In Handbook of Biomedical Fluores-
cence; Mycek, M.-A., Pogue, B. W., Eds.; Marcel Dekker: New York, 2003;
Chapter 17.
Org. Lett., Vol. 7, No. 9, 2005
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product, PdP-AG2-OBu, could be isolated in about 70% yield
after purification by GPC. The dendrimer is well soluble in
organic solvents (e.g., CH2Cl2, THF) due to the 64 peripheral
butoxycarbonyl groups, and its UV-vis spectra indicate no
intermolecular aggregation. On the other hand, the 1H NMR
spectra in CDCl3 reveal quite significant restraints within
the dendrimer, which are expected due to the folding of the
dendritic matrix.
Scheme 4. Synthesis of G2 Pd Porphyrin-AG Dendrimera
The hydrolysis of the peripheral butoxycarbonyl groups
leads to the water-soluble polyacid PdP-AG2-OH. The rate
of oxygen diffusion in this dendrimer, reflected by the value
of the phosphorescence oxygen quenching constant (kq),5 i.e.,
kq ) 125 mmHg-1 s-1, was found to be about 30 times less
than that for the parent PdOCPP, which reveals a substantial
protection offered by the G2 AG dendrons to the core
porphyrin.
For biological applications, it is necessary that the sen-
sor molecules are uncharged while retaining good water
solubility. The periphery of PdP-AG2-OH could be esterified
by monomethoxypoly(ethylene glycol)s (av MW 350)
(PEG350) using DCC/BtOH coupling chemistry, yielding a
neutral, water-soluble dendrimer PdP-AG2-PEG350 with
excellent phosphorescent characteristics. Its oxygen quench-
ing constant was found to be decreased even further (kq )
93 mmHg-1 s-1) due to the bulk effect of 32 PEG peripheral
groups.
In conclusion, a versatile method of synthesis of arylamide
dendrimers with flexible linkers is developed. The method
has a broad scope and allows for convenient introduction of
functional groups at the dendrimer interior and periphery.
The aryl-glycine dendrons are very useful for encapsulation
of functional luminescent centers.
a Conditions: (i) CDI, DMF, 12 h; (ii) H2N-AG2-OBu, rt, 48 h;
68%; (iii) NaOH, THF/MeOH, rt, 1.5 h, 95%; (iv) PEG350, DCC/
BtOH/sym-collidine, rt, 72 h, 80%.
Acknowledgment. Support of Grant EB003663-01 from
the NIH USA is gratefully acknowledged.
Supporting Information Available: Synthetic details and
characterization of all new compounds, as well as details of
oxygen quenching experiments. This material is available
free of charge via the Internet at http://pubs.acs.org.
A modification of Pd octacarboxyporphyrin with eight AG
dendrons is shown in Scheme 4. Coupling of H2N-AG2-OBu
dendrons to PdOCPP was accomplished in a two-step, one-
pot synthesis using carbonyldiimidazol (CDI) chemistry. The
OL050341N
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