10.1002/anie.201904203
Angewandte Chemie International Edition
COMMUNICATION
It is obvious that GlyTs is not polymerizable by the conventional
oxyanionic ROP relying on alkoxide initiators. In order to shed
light on the polymerization mechanism in case of monomer
activation, tetra-butyl-ammonium chloride was also employed as
an initiator instead of tetra-octyl-ammonium bromide, reducing
steric demand of the counter ion. In this case, no polymerization
was observed, although this system is well known to be capable
of polymerizing PO[13]. Additionally, we investigated the recently
published methods of G. Zhang[14] and Zhang[15] et al., using
P2-t-Bu, B(Et)3 as a Lewis acid and 2-(benzyloxy)ethanol as an
initiator, which has also shown to be a mild method for the
polymerization of epoxides and glycidyl ethers. As in the already
discussed experiment, no polymerization occurred. These
observations hint at a crucial role of the steric demand of the tetra-
octyl-ammonium counterion. We tentatively conclude that it
shields the alkoxide terminus, mitigating its nucleophilic
character, thereby preventing an attack at the tosylate. Based on
this effect, propagation via ring-opening of the epoxide becomes
strongly favored. Another approach could be the use of NHC
catalysts, as described in an interesting work by Naumann et
al.[16], which might be explored in the future.
deprotonated poly(ethylene glycol) monomomethyl ether (mPEG)
and sodium azide (Scheme 2).
For the nucleophilic substitution, P(PO-co-GlyTs) samples with
different amounts of GlyTs and added nucleophile were dissolved
in acetonitrile (or DMF, respectively), heated for 16 h and purified
via dialysis against methanol. As shown in Fig. 3 for the
1
substitution using dimethylamine, the H-NMR spectrum of the
substituted copolymer shows no signals belonging to the tosylate
moiety, and the methyl protons of the introduced dimethylamine
group can be observed. Similar observations could be made when
using mPEG-potassium alkoxide. In UV-vis spectra the
substituted copolymers do not show UV absorption, evidencing
complete substitution of the tosylate as an excellent leaving
group.
To sum up, copolymerization of glycidyl tosylate – at first glimpse
a structure that is non-polymerizable by nucleophilic techniques-
with common epoxides by the activated monomer method offers
access to a wide range of hitherto elusive polyether structures.
These materials are promising both for biomedical applications
and materials science.
Scheme 2. Selection of investigated post-polymerization modification reactions
via nucleophilic substitution of the tosylate.
The tosyl-substituted PEG and PPO copolymers can undergo a
vast variety of nucleophilic modification reactions to create
polyethers inaccessible by direct epoxide polymerization. The
approach may be viewed as a polyether analogue to the reactive
ester strategy for e.g., polypenta-fluorophenyl(meth)acrylates[17]
.
Figure 3. 1H-NMR spectra (400 MHz) of P(PO0,92-co-GlyTs0,08) before (top) and
after nucleophilic substitution with dimethylamine (bottom) in CDCl3. For the
substituted polymer, all peaks belonging to the tosylate-moiety disappear and a
singulet typical of the -N(Me)2-moiety appears.
For instance, dimethylamine-substituted PEG copolymers that
offer intriguing potential for gene-transfection are not directly
attainable, since the related N,N-dimethyl-aminoglycidyl ethers
are not stable. However, they can be prepared by nucleophilic
polymer modification (Scheme 2; details: Supp. Inf., Fig. S3).
Libraries of hitherto elusive substituted polyethers can
conveniently be prepared by replacement of the tosylate at the
polyether structures. Considering the broad usage of PEG e.g., in
medical and pharmaceutical applications, tosylate-containing
PEG copolymers also offer many options for bioconjugation, due
to the facile substitution of the tosylate by amines or lysine groups
of peptides and proteins. In contrast to the well-known post-
polymerization functionalization of glycerol-units[18], this method
allows the direct and quantitative introduction of tosylate-moieties
and therefore is much more reliable and efficient. An explorative
study of the nucleophilic substitution of the tosylate-moiety in the
copolymers has been conducted using dimethylamine,
Experimental Section
All solvents and reagents were purchased from Sigma-Aldrich, Acros
Organics or TCI and used as received, unless otherwise described.
Chloroform-d1 was purchased from Deutero GmbH.
To prepare P(PO-co-GlyTs), in a Schlenk-flask N(Oct)4Br (0,05 g, 1.1x10-
4 mol, 1 eq) and GlyTs (0.130 g, 5.7x10-4 mol, 5 eq) are dried with benzene
in vacuo overnight. Dry toluene (5 mL) and freshly over CaH2 distilled PO
(0.33 g, 5.7x10-3 mol, 50 eq) are added under argon atmosphere. The
mixture was cooled to -78 °C. Addition of the catalyst triisobutyl aluminum
(0.31 mL, 3.4x10-4 mol, 3 eq) in toluene (1.1 M) initiated the reaction. The
temperature was allowed to slowly rise to 25 °C. After 12 h, ethanol was
added to quench the reaction. The crude product was dialysed against
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