Geometric Disassembly of Dendrimers: Dendritic Amplification

Full text of DOI:10.1021/ja0386694

Published on Web 11/26/2003
Geometric Disassembly of Dendrimers: Dendritic Amplification
Michael L. Szalai, Robert M. Kevwitch, and Dominic V. McGrath*
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721
Received September 22, 2003; E-mail: mcgrath@u.arizona.edu
Scheme 2. Divergent Synthesis of
2,4-Bis(hydroxymethyl)phenol-based Disassembling Dendrons with
Allyl Triggers
Since their development over two decades ago, dendrimers have
been used in an overwhelming variety of chemical and biological
systems.1 However, advantage has not yet been taken of the nature
of dendrimers as covalent assemblages of potentially active
monomeric species, nor has the impact that these species could
have on the properties of a system been considered. In a recent
report, we demonstrated linear dendrimer disassembly2 whereby
fragmentation of a dendrimer occurs through a cascade of cleavage
reactions initiated by a single triggering event. In this contribution
we demonstrate the degradation of dendrimers whereby each
cleavage event leads to two subsequent fragmentations per subunit,
or geometric dendrimer disassembly.3 In addition, we introduce the
concept of “dendritic amplification,” where an initial stimulus
triggers the efficient disassembly of a dendrimer that results in the
amplification of a certain property or quality of a system due to
the large increase in molecular species (dendrimer fragments)
contained therein.
Dendrimers with 2,4-bis(hydroxymethyl)phenol repeat units
should be capable of geometric disassembly since the corresponding
anionic phenoxide species are labile vinylogous hemiacetals as
shown in Scheme 1. Removal of the trigger group R from 2,4-bis-
(hydroxymethyl)phenol-based dendrimer subunit A results in the
formation of an o,p-bis(benzyl ether)phenoxide (B). This phenoxide,
a bis(vinylogous hemiacetal) anion, should cleave to liberate
alkoxide (-OR′ in Scheme 1) and p-quinone methide C, which will
be trapped by an appropriate nucleophile under the reaction
conditions, consistent with the electrophilic nature of quinone
methides.4 The resulting phenoxide D should cleave to liberate a
second equivalent of alkoxide -OR′ and o-quinone methide E, in
turn trapped by nucleophile to yield the fully cleaved phenoxide
F. We reasoned that if alkoxide -OR′ was analogous in structure
to phenoxide B, then subsequent cleavages could occur, resulting
in a geometric fragmentation through a dendrimer.
that complete cleavage would be indicated by the UV absorbance
of liberated p-nitrophenoxide ion. As a control, we prepared
4-allyloxynitrobenzene (5) with the allyl trigger group directly
attached to the nitrophenoxy reporter group.
Scheme 1. Proposed Disassembly Pathway of
2,4-Bis(hydroxymethyl)phenol-based Dendrons
To investigate the geometric disassembly process, compounds
3-5 were subjected to typical allyl deprotection conditions.5 The
absorption spectrum of the reaction mixture was monitored at
intervals. Rapid disassembly was indicated, after an initial incuba-
tion period,2 by a simultaneous rapid decrease in the initial
absorption at 310 nm with a sharp increase in the absorption of
p-nitrophenoxide ion (∼431 nm). Once begun, p-nitrophenoxide
generation from 3 and 5 was complete after approximately 1 min,
while the time course for molecule 4 indicated a slightly slower
process after the initial rapid increase. The entire spectral evolution
takes place within 15 min under these conditions (Figure 1). The
final absorbance values observed at 431 nm indicated disassembly
of dendrons 3 and 4 in yields of ca. 95% based on the measured
absorptivity of p-nitrophenoxide under the reaction conditions.
Under these conditions, the rate-limiting step in the disassembly
process appears to be the removal of the allyl trigger group, as
disappearance of the starting material band coincides with the
To test this geometric dendrimer disassembly strategy, we
prepared first- and second-generation dendrons 3 and 4 (Scheme
2). Compounds 3 and 4 consist of a single allyloxy residue at the
focal point and 2,4-branched benzyl ether dendrimer subunits. When
deprotection of the allyl group occurs as the initial triggering event,
subsequent cleavages should result in a disassembly according to
Scheme 1 toward the dendron periphery. p-Nitrophenoxy moieties
were intentionally installed at the periphery of each dendron so
9
15688
J. AM. CHEM. SOC. 2003, 125, 15688-15689
10.1021/ja0386694 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
of dendrimer fragmentationsgeometric disassembly and the release
of a high local concentration of subunitssconstitutes a concept we
term “dendritic amplification,” whereby dendrimer disassembly is
used to amplify a certain property or quality of a system by
increasing the number of molecular species contained therein. The
level of amplification depends on dendrimer generation as well as
the number of released subunits that participate in the amplification
(i.e., are “active” species). The nature of the amplification depends
on the nature of the released subunits. In the system described
herein, we released p-nitrophenoxide periphery units as “active”
species, amplifying the absorbance at 431 nm, although other
possibilities for dendritic amplification are dependent on the nature
of the properties of the released dendrimer fragments (e.g., drugs,
fluorescent dyes, catalysts, etc.).
In summary, we have demonstrated a method for the geometric
disassembly of dendritic structures into their individual subunit
components after a single initial triggering event.10 Disassembly
occurs rapidly and completely under the reported conditions.
Synthesis of higher-generation dendrons and the development of
further dendritic amplification systems is currently underway.
Figure 1. (Left) UV spectra recorded during the disassembly of 4 (37 s
intervals). (Inset) UV absorbance of the main absorption bands as a function
of time. (Right) UV absorbance at 431 nm (s) and 310 nm (- - -) as a
function of time during the disassembly of 3-5. Concentrations of 3-5
were normalized such that quantitative disassembly would result in the same
final concentrations of released p-nitrophenoxide.5
Acknowledgment. This work was generously supported by
grants from the National Science Foundation (CHE-0213537) and
the Petroleum research Fund (38421 AC-7). D.V.M. is a Cottrell
Scholar of Research Corporation and a Camille Dreyfus Teacher-
Scholar. We thank Seth R. Marder for helpful discussions.
appearance of the p-nitrophenoxide absorption. While optimum for
rapid disassembly, these conditions are inappropriate for kinetic
analysis of the disassembly process as a function of generation.
The fragments liberated during the disassembly of 3 and 4 were
1
characterized by a combination of NMR and GC-MS. In the H
Supporting Information Available: Details of the syntheses,
characterization data, and complete UV spectra of the disassembly of
compounds 3-4 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
NMR spectra6 the allyl resonances broaden and decrease with an
immediate growth of two singlets at ∼2.1 ppm, indicative of the
formation of 2,4-dimethylphenoxide. In addition, the resonances
of the p-nitrophenoxy moieties decrease, and new resonances
(AA′BB′ pattern, 7.7 and 6.0 ppm), consistent with p-nitrophenoxide
ion, arise. Molecular weights from GC-MS were consistent with
the formation of 2,4-dimethylphenol and p-nitrophenol as the major
products of disassembly. Trace amounts of triphenylphosphine and
triphenylphosphine oxide were also detected from catalyst decom-
position. These results support our proposed disassembly pathway
(Scheme 1), with the trapping of quinone methide species C and E
by excess hydride in solution to yield 2,4-dimethylphenol.
References
(1) (a) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendrimers and
Dendrons: Concepts, Syntheses, Applications; VCH: New York, 2001.
(b) Fre´chet, J. M. J.; Tomalia, D. A. Dendrimers and Other Dendritic
Polymers; John Wiley: New York, 2002.
(2) Li, S.; Szalai, M. L.; Kevwitch, R. M.; McGrath, D. V. J. Am. Chem.
Soc. 2003, 125, 10516-10517.
(3) Szalai, M. L.; McGrath, D. V. Polym. Mater. Sci. Eng. 2003, 89, 406-
407.
(4) (a) Wan, P.; Barker, B.; Diao, L.; Fischer, M.; Shi, Y.; Yang, C. Can. J.
Chem. 1996, 74, 465-475. (b) Veldhuyzen, W. F.; Shallop, A. J.; Jones,
R. A.; Rokita, S. E. J. Am. Chem. Soc. 2001, 123, 11126-11132 and
references therein.
The successful implementation of geometric dendrimer disas-
sembly has herein demonstrated an enhanced capability for
controlled dendrimer degradation technology. For a single cleavage
event at the focal point of a dendron the total number of periphery
and branching subunits released in a geometric disassembly is,
(5) General procedure for the disassembly of compounds 3-5: A quartz
cuvette was charged with 2.00 mL of a solution of NaBH4 in DMF (1.0
mg/1.0 mL). To this is added 20 µL of a solution of substrate in DMF (3:
1.5 mM.; 4: 0.75 mM.; 5: 3.0 mM) followed by 20 µL of a solution of
Pd(PPh3)4 in DMSO (4.0 mg/1.0 mL). Monitoring of the reaction on an
Ocean Optics CCD Array spectrometer began exactly 75 s following the
final addition.
(6) !H NMR conditions: 15 mM 3 or 7.5 mM 4; 6 mM Pd(PPh3)4; 190 mM
NaBH4 in DMSO-d6.
(7) For the geometric cleavage of a dendrimer, rather than a dendron, the
total number of subunits released is multipled by Nc, the multiplicity of
the core subunit.
(8) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A. Angew. Chem., Int. Ed.
Engl. 1990, 29, 138-175.
(9) Hawker, C. J.; Malmstro¨m, E. E.; Frank, C. W.; Kampf, J. P. J. Am. Chem.
Soc. 1997, 119, 9903-9904.
(10) During the editorial review of this manuscript, two independent literature
reports appeared introducing the concept of geometric dendrimer disas-
sembly, although both used different chemical structures and trigger groups
than reported herein: (a) de Groot, F. H. M.; Albrecht, C.; Koekkoek,
R.; Beusker, P. H.; Scheeren, H. W. Angew. Chem., Int. Ed. 2003, 42,
4490-4494. (b) Amir, R. J.; Pessah, N.; Shamis, M.; Shabat, D. Angew.
Chem., Int. Ed. 2003, 42, 4494-4499.
where Nb is the branching multiplicity and G is the generation.7
Hence, an exponential number of fragments are generated by a
single triggering event, and since dendrimers possess an overall
globular form in solution and in the condensed state,8,9 these
fragments are released into a relatively small volume, resulting in
a high local concentration. The combination of these two aspects
JA0386694
9
J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15689