Synthesis of functionalizable and degradable polymers by ring-opening metathesis polymerization

Article abstract of DOI:10.1002/anie.201300293

ROMP: A heterobicyclic olefin containing an oxazinone core is a new substrate for the ring-opening metathesis polymerization (ROMP). The polymers produced undergo degradation when exposed to either acidic or basic conditions. Furthermore, a monomer that c

Full text of DOI:10.1002/anie.201300293

Angewandte
Chemie
DOI: 10.1002/anie.201300293
Polymers
Synthesis of Functionalizable and Degradable Polymers by Ring-
Opening Metathesis Polymerization**
Joshua M. Fishman and Laura L. Kiessling*
A valuable approach for creating synthetic polymers is the
ring-opening metathesis polymerization (ROMP).[1,2] Well-
defined metal carbene catalysts have been devised that afford
control over the polymer chain length and architecture.[3–6] In
addition, ruthenium carbene initiators have been developed
with excellent air stability and functional group tolerance.[6,7]
These catalysts enable the synthesis of polymers with a range
of functionality,[8–15] thereby providing access to polymers for
diverse applications.[16–19]
Extant polymers from ROMP, like the majority of
synthetic polymers, are nondegradable. They therefore lead
to the accumulation of waste. A functional and degradable
polymer from ROMP would allow the synthetically useful
traits of ROMP reactions to be combined with the growing
need for new degradable polymer scaffolds. To date, efforts to
prepare degradable materials by using ROMP have afforded
polymers that are either functional or partially hydrolyzable,
but not both (Figure 1). For example, cargo can be attached
through a linker such that it can be released from the polymer
backbone by photolysis or hydrolysis in acid.[16,20–22] Still, the
polymeric backbone persists. Alternatively, partially degrad-
able polymers have been generated. A block copolymer can
be generated from a modifiable monomer and a sacrificial
dioxepine or dithiepine monomer.[8,23,24] In this scenario, one
block is composed of a nonhydrolyzable backbone and the
degradable block contains acid-labile acetals or thioacetals
that can be cleaved by hydrogenation. Polymers of this type
only undergo partial degradation, as one block persists. The
current state-of-the-art therefore demands a compromise
between generating polymers that can be customized and
polymers that can be easily degraded.
Figure 1. Strategies to synthesize functionalizable and degradable
ROMP polymers: A) ligand attachment through a cleavable linker,
B) copolymerization with a sacrificial monomer, and C) homopolymeri-
zation of a functionalizable, heterocyclic oxazinone.
it must contain core functionality that gives rise to a polymer
that can be degraded. Third, a means to append desired
functionality onto the monomer or polymer is needed to
enable polymer diversification. Monomers with all of these
attributes have been elusive. Many strained olefinic hetero-
cycles spontaneously aromatize.[26,27] In addition, attempts to
incorporate handles for diversification can further increase
monomer instability.[28] Thus, traditional monomers used in
ROMP cannot be simply modified to instill polymer degrad-
ability.
We sought a new class of monomers that would give rise to
degradable materials. The generation of substrates with an 8-
oxo-2-azabicylo[3.2.1]oct-6-en-3-one framework through
a novel aza-[4+3] cycloaddition was recently reported
(Scheme 1A).[29] We postulated that this bicyclic oxazinone
would be a substrate for ROMP. Calculations suggest that this
framework has a ring strain of 13.4 kcalmolÀ1, which is
comparable to that of trans-cyclooctene (a monomer that has
favorable kinetics of polymerization in ROMP).[25,30] Reports
of successful ring-opening cross metathesis on architecturally
analogous 8-oxo-bicyclo[3.2.1.]oct-6-en-3-ones provided
additional impetus.[31,32] Significantly, if the bicyclic oxazinone
serves as a monomer in ROMP, the resulting framework
should be both acid and base labile (Scheme 1B). Moreover,
we postulated that we could modify this core monomer at
a site distal to the polymerizable moieties and bridgehead
carbon atoms. Thus, without destabilizing the heterocycle, we
could tailor the properties of the resulting materials.
Applying ROMP to synthesize a modifiable homopoly-
mer with a degradable backbone requires a monomer with
three important attributes. First, it must be a strained cyclic or
bicyclic olefin, so that it undergoes polymerization.[25] Second,
[*] J. M. Fishman, Prof. L. L. Kiessling
Department of Chemistry, Departments of Biochemistry
University of Wisconsin—Madison
1101 University Ave., Madison, WI 53706 (USA)
E-mail: Kiessling@chem.wisc.edu
[**] This research was supported by the NIH (R01 GM049975). The UW-
Madison Chemistry NMR facility is supported by the NSF (CHE-
9208463 and CHE-9629688) and NIH (1s10 RRO 8389-01). The UW-
Madison Soft Materials Laboratory is supported by the NSF UW
Nanoscale Science and Engineering Center (NSEC, DMR-0425880)
and UW Materials Research Science and Engineering Center
(MRSEC, DMR-0520527).
Despite our optimism that bicyclic oxazinones would
serve as monomers, we had concerns that polymerization
would yield highly oxygenated polymer products that would
facilitate backbiting.[34,35] Our initial results confirmed our
suspicions. The reaction of 3a using Grubbsꢀ second gener-
ation catalyst (8)[33] in chloroform afforded polymer 4a
(Table 1, entry 1), but we observed a concomitant increase
Supporting information (including experimental details and 1H and
13C NMR data) for this article is available on the WWW under http://
dx.doi.org/10.1002/anie.201300293.
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extreme pH values and high temperatures). We assessed
milder conditions. By utilizing gel permeation chromatogra-
phy (GPC), we monitored the decomposition of polymer 4e
under a range of acidic and basic conditions at room
temperature (Figure 2). No appreciable breakdown occurred
at pH values between 4.6 and 9.1 over 48 h. This observation
indicates that the oxazinane backbone is able to withstand
exposure to a wide range of conditions, thereby facilitating
polymer handling or modification. Still, the polymers are
vulnerable under specific conditions. At pH values below 1.0,
degradation is fast with complete decomposition occurring in
under an hour. The acid-catalyzed backbone decomposition
also occurs readily at pH 2.5, with 66% of the polymer mass
Scheme 1. A) Synthetic route to bicyclic oxazinones. B) ROMP of these
monomers affords degradable polymers. HFIP=1,1,1,3,3,3,-hexafluoro-
isopropanol.
in the PDI and decrease in the number averaged molecular
weight (Mn) of the products as the polymerization progressed
(Supporting Information, Table S1). One strategy to mitigate
backbiting is to raise the reaction temperature to disrupt
dative bonds.[36,37] However, in our system, an increase in
temperature did not reduce backbiting (Table 1, entry 2). The
problem of backbiting, nevertheless, was solved. We per-
formed the polymerization reaction in tetrahydrofuran
(THF), a solvent system that can compete with the polymer
for catalyst coordination. We also employed catalyst 5, which
has superior polymerization kinetics to 8.[7,36] These changes
afforded dramatic improvements in the polymerization. We
obtained stable Mn or PDI values even at long reaction times
(Table 1, entries 5,6). In addition, the Mn value increased
proportionally to the monomer-to-catalyst ratio (Table 1,
entries 3–7), and the degree of polymerization was found to
be in good agreement with monomer conversion. Thus,
structures such as compound 3a undergo ROMP to afford
polymer scaffolds with a repeating oxazinane backbone.
We next investigated the degradability of the new poly-
oxazinone scaffold. Small molecule oxazinones have been
used to generate b-hydroxy carboxylic acids,[37,38] but the
conditions used for ring opening have been harsh (i.e.,
Figure 2. Degradation profile of polymer 4e under acidic and basic
conditions. Mno =18500 gmolÀ1
.
lost in 6 h. At pH values up to 4.5, slower degradation occurs.
We also observed polymer backbone cleavage under basic
conditions. Thus, either acid or base can promote degradation
of polymers with an N-alkoxy-oxazinone backbone. These
data indicate that these oxazinone polymers represent
a unique class of backbone-degradable ROMP polymer that
is stable at neutral pH values but labile in either acidic or
basic environments.
Further studies were conducted to characterize the
degradation products. Because it is difficult to obtain the
necessary quantities of specific polymer degradation frag-
ments for characterization, we employed a model. Specifi-
cally, compound 3e was subjected to a ring-opening cross
metathesis reaction with 1-hexene to yield heterocycle 6.
Table 1: Polymerization of monomer 3a using ROMP.
Solvent[a]
T
[8C]
t
[h]
Conversion
[%][b]
Yield
Mn
[gmolÀ1
Mn
[gmolÀ1
Mn
[gmolÀ1
PDI[f]
[Mn/Mw]
theo
NMR[e]
GPC[f]
Entry
[M]o/[I]
Catalyst
[%][c,d]
]
]
]
1
2
3
4
5
6
7
100/1
100/1
25/1
8
8
5
5
5
5
5
CHCl3
CHCl3
THF
THF
THF
20
45
20
20
20
20
20
4
18
1
1
1
84
81[g]
87
85
81
81
73
72
49
57
71
80
85
83
23600
22800
6100
12000
23100
23100
41000
103800
26000
6500
12500
22000
22100
45200
63200
24900
9300
16300
21600
22300
50300
2.8
2.6
1.4
1.4
1.4
1.4
1.5
50/1
100/1
100/1
200/1
THF
THF
18
1
[a] [M]o =1m. M=monomer, I=catalyst. [b] Based on 1H NMR integrations of monomer olefin signals to polymer olefin signals. [c] Yield of isolated
polymer. [d] Theoretical yield is based on monomer conversion. [e] Based on 1H NMR integrations of polymers olefin signals and polymers chain-end
phenyl signals. [f] Calibrated with polystyrene standards, eluted in THF. [g] Additional 10–15% cyclic dimer (see the Supporting Information for
structural characterization of byproduct).
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When the product was exposed to an acidic
methanol solution, ring cleavage occurred to
afford hydroxamic acid ester 7 (Scheme 2).[37]
This mode of reactivity would promote fragmen-
tation of the polyoxazinone backbone, thereby
causing polymer degradation. It is expected that
the acyclic compound 7 undergoes further hydrol-
ysis to a b-hydroxy carboxylic acid; however this
species was not isolated.
Scheme 3. Synthesis of glycopolymer 11.
Bicylic oxazinones can be used to access a new
class of degradable polymers. However, the afore-
polymers 4a, 4d, and 4e[46] with modified hydrocarbon
functionality were generated. Additionally, pyrene-conju-
gated hydroxylamine 1 f was leveraged to assemble polymer
4 f (Scheme 1B), which could serve as an optical sensor. This
substance exhibited a red-shifted fluorescence spectrum
indicative of pyrene exciplex emission (Supporting Informa-
tion, Figure S1).[47] When polymer 4 f undergoes hydrolytic
degradation, a monomeric pyrene derivative is released from
the backbone, thereby diminishing exciplex emission.
Changes in the ratio of fluorescence intensity of monomeric
Scheme 2. Ring-opening cross metathesis of monomer 3e and subse-
quent hydrolysis of a 3-alkoxy-1,3-oxazin-4-one under acid conditions.
pyrene (lmax = 377 nm) and polymeric exciplex (lmax
=
480 nm) over time report on the extent of backbone
hydrolysis. We followed this spectral change to reveal that
exposure to acidic conditions for 3 h resulted in the degrada-
tion of approximately 80% of the polymer (Figure 3).
mentioned monomers do not provide the means to imbue
polymers with desired functional properties. To expand the
utility of our strategy, we devised a monomer that can be
further elaborated. We envisioned a facile and modular
strategy to impart new functionality into the monomer is to
use a bifunctional hydroxylamine. This approach facilitates
the introduction of additional groups at a site distal from the
monomerꢀs core polymerizable group. Moreover, no changes
to the synthetic route are required (Scheme 1).
Starting with bromine-functionalized hydroxylamine 1b,
monomer 3b was accessed using the same synthetic strategy
as monomer 3a.[29] Monomer 3b was also a substrate for
ROMP, leading to polymer 4b. Additionally, monomer 3b can
be elaborated through nucleophilic displacement of its alkyl
bromide functionality. As a proof of concept, we exposed the
bromide 3b to sodium azide to yield compound 3c, which is
a substrate for the azide–alkyne [3+2] cycloaddition (AAC).
Because of the exquisite chemoselectivity of this click
chemistry reaction, it is widely used to introduce new
functionality into polymers.[39–43] Azides, however, have been
found to be incompatible with ruthenium catalysts.[22,44]
Therefore, compound 3c was conjugated to 1-propargyl-a-
d-mannose-2,3,4,6-tetraacetate by using a copper-catalyzed
AAC to afford monomer 9 (Scheme 3). The functionalized
monomer that resulted could undergo ROMP to afford
polymer 10. The acetate groups were hydrolyzed to produce
mannose-substituted polymer 11. The water solubility of this
polymer facilitated analysis of its degradation in aqueous
solution. At pH values similar to those that led to the
degradation of polymer 4e, we observed decomposition of
11.[45]
In conclusion, ROMP can be used to synthesize a new
class of degradable polymers. These polymers possess a back-
bone that is labile under either acidic or basic conditions. In
addition, the polymers can be decorated through a modular
monomer synthesis using bifunctional hydroxylamine build-
ing blocks. The process we describe affords functional and
degradable polymers that can be used in specific applications.
We envision that polymers of this type may yield new
degradable plastics or resins. ROMP can be used on an
industrial scale to generate new materials; therefore, the
strategy described here could generate consumables with
properties that complement those currently available from
ROMP.[2] In this way, ROMP can give rise to stable species or
Figure 3. Degradation of 4 f was monitored by comparing the ratio of
polymeric pyrene exiplex emission (lmax =480 nm) to monomeric
pyrene emission (lmax =377 nm). lex =250 nm, pH 0.25 (3:1 THF/
MeOH). Empty diamonds represent low emission ratios owing to
initial low polymer solubility; polymer completely dissolved in solution
within 40 min.
Substituents can be added to influence a polymerꢀs
bioactivity or its mechanical or optical properties. To illustrate
the generality of our strategy, we generated polymers from O-
octyl hydroxylamine (1a), O-ethyl hydroxylamine (1d), or O-
benzyl hydroxylamine (1e) as starting materials. In this way,
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Received: January 12, 2013
Published online: && &&, &&&&
Keywords: click chemistry · degradable polymers · metathesis ·
.
oxazinone · ring-opening polymerization
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Polymers
J. M. Fishman,
L. L. Kiessling*
&&&& — &&&&
Synthesis of Functionalizable and
Degradable Polymers by Ring-Opening
Metathesis Polymerization
ROMP: A heterobicyclic olefin containing
an oxazinone core is a new substrate for
the ring-opening metathesis polymeri-
zation (ROMP). The polymers produced
undergo degradation when exposed to
either acidic or basic conditions. Fur-
thermore, a monomer that can be readily
diversified to access degradable polymers
bearing tailored functionality was devel-
oped.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!