Synthesis and degradation of backbone photodegradable polyester dendrimers

Article abstract of DOI:10.1021/ol4004367

Dendrimers with fully photodegradable backbones were synthesized through the incorporation of photodegradable o-nitrobenzyl esters into a new dendrimer monomer based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA). Dendrons were synthesized using a divergent approach, and were subsequently coupled to a core molecule in the final step. Photodegradation was performed and it was demonstrated that the molecules degrade to release bis-MPA. The accessibility of these molecules opens new avenues for the preparation of well-defined, fully photodegradable materials.

Full text of DOI:10.1021/ol4004367

ORGANIC
LETTERS
2013
Vol. 15, No. 8
1830–1833
Synthesis and Degradation of Backbone
Photodegradable Polyester Dendrimers
Ali Nazemi,† Tyler B. Schon,† and Elizabeth R. Gillies*,†,‡
Department of Chemistry, and Department of Chemical and Biochemical Engineering,
The University of Western Ontario, 1151 Richmond Street, London, Canada
egillie@uwo.ca
Received February 15, 2013
ABSTRACT
Dendrimers with fully photodegradable backbones were synthesized through the incorporation of photodegradable o-nitrobenzyl esters into a
new dendrimer monomer based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA). Dendrons were synthesized using a divergent approach, and
were subsequently coupled to a core molecule in the final step. Photodegradation was performed and it was demonstrated that the molecules degrade to
release bis-MPA. The accessibility of these molecules opens new avenues for the preparation of well-defined, fully photodegradable materials.
Dendrimers are highly branched macromolecules with
exact molecular weights or very low polydispersity indices
resulting from their stepwise synthesis. Higher generation
dendrimers possess large numbers of functional groups on
their peripheries and often adopt globular conformations
with internal cavities. These properties have led to much
research in the application of dendrimers for light-
harvesting,1,2 organic light-emitting diodes,3,4 catalysis,5,6
and numerous biomedical areas.7ꢀ9 The development of
dendrimers that are responsive to specific stimuli is also of
significant interest as this can impart new properties and
further expand their scope of applications. For example,
the breakdown of a dendrimer in response to a stimulus
can provide a means of releasing encapsulated cargo or
fragmenting assemblies of dendritic materials.
The first reports on cleavable dendrimers emerged less than
two decades ago.10,11 Since then, a number of examples of
dendrimers that cleave in response to stimuli such as pH
change,12ꢀ14 light,15ꢀ24 transition metals,25,26 catalytic
antibodies,27,28 and reducing agents29,30 have been developed.
Among these stimuli, light is of particular interest for the
development of smart materials as it can be applied at a
specific time and location with control over its intensity and
wavelength. Thus far, several photodegradable dendrimer
systems have been developed through the incorporation of
photodegradable units either at the core of the dendrimer15,19
or at the junction between the hydrophobic and hydrophilic
portions of amphiphilic dendrons.16,20,22,23 The limitation of
these approaches is that following photodegradation, in most
cases large residual fragments of the dendrimer remain,
† Department of Chemistry.
(6) Helms, B.; Liang, C. O.; Hawker, C. J.; Frechet, J. M. J. Macro-
molecules 2005, 38, 5411.
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60, 1037.
(8) Astruc, D.; Boisselier, E.; Ornelas, C. Chem. Rev. 2010, 110, 1857.
(9) Mintzer, M. A.; Grinstaff, M. W. Chem. Soc. Rev. 2011, 40, 173.
(10) Seebach, D.; Herrmann, G. F.; Lengweiler, U. D.; Bachmann,
B. M.; Amrein, W. Angew. Chem., Int. Ed. 1996, 35, 2795.
(11) Tang, M. X.; Redemann, C. T.; Szoka, F. C. Bioconjugate Chem.
1996, 7, 703.
‡ Department of Chemical and Biochemical Engineering.
(1) Adronov, A.; Gilat, S. L.; Frechet, J. M. J.; Ohta, K.; Neuwahl,
F. V. R.; Fleming, G. R. J. Am. Chem. Soc. 2000, 122, 1175.
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(3) Huang, C.; Zhen, C.-G.; Su, S. P.; Loh, K. P.; Chen, Z.-K. Org.
Lett. 2005, 7, 391.
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M. M.; Janssen, R. A. J.; Bauerle, P. Angew. Chem., Int. Ed. 2007, 46,
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r
10.1021/ol4004367
Published on Web 04/01/2013
2013 American Chemical Society

limiting the application of these materials. For example,
residual hydrophobic fragments may undergo aggregation
in aqueous solutions. Self-immolative dendrons that frag-
ment in response to the cleavageofa photoresponsive focal
point moiety have also been developed.17,18,24 However,
due to the inherent design of these materials they have been
limited to dendrons rather than dendrimers and are thus
far limited to a very select set of backbone monomers that
are derivatives of dihydroxybenzylalcohols.
Scheme 1. Synthesis of Monomer 5 and G1 Dendron 8
Photodegradable linkages have not previously been incor-
porated throughout the backbones of dendrimers or den-
drons at each monomer unit. This approach would allow for a
rapid, simultaneous cleavage of multiple linkages through the
dendrimer backbone and is potentially applicable to various
dendrimer backbones. However, the incorporation of photo-
degradable moieties throughout the dendrimer backbone is a
significant synthetic challenge due to the requirement for
extremely clean and efficient chemistry in dendrimer synth-
esis. Despite the multitude of reports on dendrimer synthesis
over the last few decades, only a limited number of dendrimer
backbones have emerged as widely accessible synthetically,
and minor modifications to the monomer units can drama-
tically alter the synthetic process and results. We report here
the incorporation of photodegradable o-nitrobenzyl ester
moieties31,32 into the widely used 2,2-bis(hydroxymethyl)-
propionic acid (bis-MPA) dendrimer backbone and photo-
degradation studies of the resulting materials.
Our synthetic strategy, an adaptation of the polyester
dendrimer synthesis developed by Ihre et al.,33 involved the
divergent synthesis of first-, second-, and third-generation
(G1ꢀG3) dendrons with alkyne focal points followed by
an azide þ alkyne “click” conjugation of the dendrons
onto a trifunctional azide core to obtain the target G1ꢀG3
dendrimers. Due to the photosensitivity of the target
molecules and intermediates, all reaction flasks were pro-
tected from light using aluminum foil, but no special
measures were required during the isolation and purifica-
tion steps. 4-Bromomethyl-3-nitrobenzoic acid (1) was
used as the starting material in the synthesis (Scheme 1).
First, itwas necessarytomaskthe carboxylic acidgroup on
1 using a protecting group that would not require acidic or
basic conditions for deprotection as these conditions
would cause complications in subsequent steps of the
synthesis. Thus, an allyl ester was installed by reaction with
allyl alcohol using DCC to provide 2. Bis-MPA (3) was then
introduced in the presence of Cs2CO3 in DMF to provide 4
in quantitative yield. Finally, the principle monomer for
dendrimer growth (5) was synthesized by deprotection of
the allyl group in 4 using Pd(PPh3)4 and piperidine.
With the key monomer in hand, the next step was the
synthesis of the G1ꢀG3 dendrons. As an alkyne focal
point was desired for the eventual dendron coupling to the
core, the synthesis of the G1 dendron was carried out in a
manner similar tothatdescribedabovefor monomer5, but
using propargyl alcohol instead of allyl alcohol. This
provided first the propargyl ester derivative 6, followed
by the bis-MPA derivative 7 (Scheme 1). Another key
difference was that instead of cleaving the focal point
propargyl alcohol on 7, this was left intact and instead
the acetonide protecting group was removed using H2SO4
inMeOHtoprovidethe G1dendron 8 inhigh yield overall.
(13) Gillies, E. R.; Frechet, J. M. J. Bioconjugate Chem. 2005, 16, 361.
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(20) Kostiainen, M. A.; Smith, D. K.; Ikkala, O. Angew. Chem., Int.
Ed. 2007, 46, 7600.
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(22) Kostiainen, M. A.; Kasyutich, O.; Cornelissen, J.; Nolte,
R. J. M. Nature Chem. 2010, 2, 394.
(23) Kostiainen, M. A.; Kotimaa, J.; Laukkanen, M. L.; Pavan,
G. M. Chem.;Eur. J. 2010, 16, 6912.
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126, 1726.
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Shabat, D. Angew. Chem., Int. Ed. 2005, 44, 716.
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Org. Lett., Vol. 15, No. 8, 2013
1831

Scheme 2. Synthesis of G2 Dendron 10 and G3 Dendron 12
Scheme 3. Synthesis of G1ꢀG3 Dendrimers 14ꢀ16
under microwave conditions at 120 °C in 20 min.35 Follow-
up studies showed that the catalyst was still essential under
these conditions and that microwave irradiation played a
significant role in accelerating the reaction, even at this
temperature. The resulting dendrimers were characterized
by 1H and 13C NMR spectroscopy, MALDI mass spectro-
metry, IR spectroscopy, and size exclusion chromatogra-
phy (SEC). As shown in SEC traces (Figure 1a), the
resulting dendrimers exhibited monomodal molecular
weight distribution profiles with the expected increases in
hydrodynamicvolumewith eachgeneration, aswell asvery
narrow polydispersity indices (PDIs).
Having the three dendrimers in hand, their photodegra-
dation behaviors were then studied. First, ∼20 μg/mL
solutions of each dendrimer in THF were irradiated with
UV light for 1 h, and the UVꢀvis absorption spectra of the
solutions were recorded in 2 min intervals for the first 10
min followed by 5 min intervals for the remaining 50 min.
The results for the G3 dendrimer (16) are shown in
Figure 1b. A decrease in absorbance was observed for
the peak at 225 nm while increases in absorbance were
observed at 305 and 350 nm, along with corresponding red
shifts in their absorption maxima. The results for photo-
lysis of G1 (14) and G2 (15) dendrimers are shown in the
Supporting Information. These observations are in accor-
dance with the results obtained by other groups for this
photolabilegroup.15,16,20 The absorption band at350 nm is
attributed to o-nitrosobenzaldehyde, which is a product of
o-nitrobenzyl ester photolysis, and exhibits a weak absorp-
tion band at 350ꢀ360 nm that is solvent dependent.16
1H NMR spectroscopy was also used to study the
photodegradation of the dendrimers. A 10 mg/mL solution
Synthesis of the G2 dendron was accomplished by
coupling monomer 5 to the deprotected G1 dendron 8
using N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide
hydrochloride (EDC HCl) to provide 9 (Scheme 2). Re-
3
moval of the acetonide groups under acidic conditions
provided 10. Repetition of this coupling and deprotection
sequence provided G3 dendron 12 in high yield.
In order to construct the target photodegradable
G1ꢀG3 dendrimers, dendrons 8, 10, and 12 were attached
to a trifunctional azide core molecule 1334 via a copper(I)
catalyzedalkyneꢀazide cycloaddition reaction (Scheme 3).
It should be noted that 13 was handled with care as organic
polyazides can be potentially explosive (for more details,
see the Supporting Information). While heating the reac-
tion vessel in an oil bath at 70 °C overnight resulted in low
dendrimer yields, likely due to breakdown of ester linkages
under these conditions, the reaction proceeded smoothly
(34) Garrett, T. M.; McMurry, T. J.; Hosseini, M. W.; Reyes, Z. E.;
Hahn, F. E.; Raymond, K. N. J. Am. Chem. Soc. 1991, 113, 2965.
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130, 6662.
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Org. Lett., Vol. 15, No. 8, 2013

Figure 1. (a) SEC traces of G1 (14), G2 (15), and G3 (16)
dendrimers with their corresponding PDIs. (b) UVꢀvis spectra
for G3 dendrimer (16) upon irradiation with UV light for 60
min. Inset shows the expanded region between 285 and 450 nm.
of the dendrimer in deuterated DMSO was irradiated with
1
UV light in a quartz NMR tube for 1 h and H NMR
Figure 2. Evolution of 1H NMR spectra during the photolysis of
a 10 mg/mL sample of G3 dendrimer (16) in DMSO-d6. The
results for photolysis of G1 (14) and G2 (15) dendrimers as well
as extensive peak assignments for the degradation of all three
dendrimers are shown in the Supporting Information.
spectra were collected in 10 min intervals. As shown for the
G3 dendrimer (16) in Figure 2, the multiplets at 3.57 and
3.46 ppm, corresponding to the methylene groups of bis-
MPA in the dendrimer backbone decrease as irradiation
time increases. At the same time, a new sharp multiplet at
3.45 ppm appears, corresponding to the same methylene
groups in the released product bis-MPA, a starting material
for the dendrimer synthesis. The peak intensities of the
methyl groups in the dendrimer backbone at 1.46, 1.42, and
1.10 ppm also decrease and a single methyl peak at 1.00
ppm corresponding to the released bis-MPA compound
increases in intensity. The appearance of other smaller
multiplets in the region of 3.45 ppm and singlets in the
region of 1.00 ppm can result from the expected release of
other bis-MPA derivatives containing the photocleavable
aromatic groups. In addition, a general trend of peak
broadening in the aromatic region was observable, which
can be attributed to formation of different aromatic species
after photodegradation, as nitroso compounds are known
to be unstable and undergo side reactions to form other
aromatic species such as diazo compounds.31 However, if
the aromatic region is expanded and increased in intensity,
it is possible to see that the peaks at 7.27 and 8.31 ppm,
corresponding to the core molecule and triazole ring re-
spectively, are still present after 1 h as they do not partici-
pate in degradation process. Moreover, SEC traces of the
degraded 1H NMR samples showed that only small mole-
cules were present, demonstrating the successful full degra-
dation of the dendrimers (Supporting Information).
for the first time to undergo complete backbone photode-
gradation to small molecules. We expect that the incorpora-
tion of these dendrons and dendrimers into new materials
will impart new photoresponsive properties and functions.
In addition, tuning of their optical properties by changing
the photochemically responsive group or through the in-
corporation of other photophysical processes in such a way
that they can undergo photodegradation in the visible or
nearinfrared region can potentially open up new opportu-
nities to access materials with fully photodegradable hydro-
phobic blocks suitable for biological or other applications.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for funding. We
thank Dr. Workentin and Dr. Pagenkopf at the University
of Western Ontario for access to photochemistry instru-
mentation and a microwave reactor respectively.
Supporting Information Available. Synthetic proce-
dures and characterization data, additional UVꢀvis spec-
tra, NMR spectra, and SEC degradation data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have successfully designed and synthe-
sized a new series of dendrons and dendrimers that are able
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
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