A facile route to end-functionalised polymers synthesised by SET-LRP via a one-pot reduction/thiol-ene Michael-type addition

Article abstract of DOI:10.1039/c0cc02395g

We report the facile synthesis of well defined, disulfide containing polymers via SET-LRP. A one-pot reduction/conjugation reaction enables post polymerisation modification with functional (meth)acrylates and acrylamides.

Full text of DOI:10.1039/c0cc02395g

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A facile route to end-functionalised polymers synthesised by SET-LRP
via a one-pot reduction/thiol-ene Michael-type additionw
Jay A. Syrett, Mathew W. Jones and David M. Haddleton*
Received 6th July 2010, Accepted 13th August 2010
DOI: 10.1039/c0cc02395g
3
0,31
We report the facile synthesis of well defined, disulfide containing
polymers via SET-LRP. A one-pot reduction/conjugation reac-
tion enables post polymerisation modification with functional
make biodegradable star polymers.
The precise mecha-
nism of Cu(0) catalysed SET-LRP is a subject of debate and
5
,32,33
current investigation.
However, reports have shown that
(
meth)acrylates and acrylamides.
near-monodisperse polymers can be synthesised at ambient
temperature at low reaction times when compared to conven-
5
,32
Advances in controlled radical polymerisation (CRP) allow
for the synthesis of functional polymers with excellent control
over molecular weight, molecular weight distribution, archi-
tecture and the incorporation of various functionalities. CRP
methods such as transition metal mediated living radical
polymerisation or atom transfer radical polymerisation
tional ATRP.
We have used Cu(0) as the catalyst, initiating
SET-LTP of methyl acrylate to poly(methyl acrylate), poly-
À1
[MA], (M
= 6400 g mol ), to a targeted molecular weight
n
and narrow polydispersity (M
w
/M
n
= 1.10) in 40 minutes at
vs. conver-
25 1C. The first order kinetic plots and M
n
sion graphs show characteristics typical for that of a living
polymerisation (see ESIw). This allows for a thiol-ene click
reaction, yielding macro-thiols in situ, as opposed to the con-
jugation of thiol-functional small molecules. The poly[MA]
was reduced and conjugated in one pot to a variety of
functional acrylates and methacrylates, allowing for further
modification if required (Fig. 1). This reaction is applicable to
most (meth)acrylates as well as most monomers that can be
polymerised by living radical polymerisation.
1
–4
(
ATRP), Single Electron Transfer Living Radical Polymeri-
11
and NMRP, all posses relative
5
sation (SET-LRP), RAFT
6–10
disadvantages, for example, functional monomers that can
1
2
promote side reactions or a loss of control, whilst others
can prove difficult to polymerise. Thus the majority of post
polymerisation modification procedures are focused on the poly-
merisation of inert monomers that are subsequently modified
1
2
into functional polymers. The development of click chemistry
has introduced a new class of reactions that enables the
chemist to synthesise macromolecules in high yield with short
The reaction conditions for the modification are mild,
and result in high conversion to products. A 1 : 1 ratio of
[phosphine] : [disulfide] is required for the reduction of the
disulfide bond as the reduction results in the formation of a
stable phosphine oxide. An excess of phosphine is used to
facilitate both the reduction and to subsequently catalyse the
Michael-type addition of the thiol to the (meth)acrylate. As it
1
3–15
reaction times, mild conditions and high selectivity.
particular, thiol-ene click has caught the attention of numerous
In
1
4,16–18
research groups.
meth)acrylates is an efficient, high yielding reaction that can
proceed in minutes under mild conditions with catalytic
The Michael-type addition of thiols to
(
1
9,20
amounts of amines or phosphines.
This chemistry has
is difficult to calculate the exact M of the polymer an excess of
n
been utilised by conjugating small thiols to vinyl terminated
the (meth)acrylate is used, and any remaining is removed
following precipitation.
macromolecules, and there are many examples of this in the
1
4
literature. Jones et al. have shown the versatility of the
approach, by cleaving the disulfide bridge in the peptide
Salmon Calcitonin and conjugating both sites to PEG-acrylate,
1
8
in a reaction that is 100% efficient. Polymers prepared by
RAFT can also undergo a one pot modification, due to the
unstable nature of the thiocarbonylthio end group. This can be
2
1–23
readily cleaved with primary or secondary amines
that can
also catalyse the Michael addition of an acrylate to the
2
4–28
thiol terminated polymer.
We report a one-pot post-
polymerisation modification of disulfide containing polymers,
prepared using SET-LRP.
Disulfide containing small-molecules capable of initiating
ATRP have been reported in the literature, and are commer-
2
9
cially available from Aldrich. This cleavable functionality is
also commonly employed in the synthesis of cross-linkers to
Department of Chemistry, University of Warwick, Coventry,
CV4 7AL, UK. E-mail: d.m.haddleton@warwick.ac.uk;
Fax: +44 (0)2476 528267; Tel: +44 (0)2476 523256
w Electronic supplementary information (ESI) available: Full experi-
mental details and spectra available. See DOI: 10.1039/c0cc02395g
Fig. 1 General scheme showing the one pot redox/conjugation
1
procedure. Also shown (i) H NMR (d = 2.5 ppm–4.5 ppm), (ii)
GPC (chloroform eluent, PMMA as calibrants) and (iii) MALDI-ToF
of the poly[MA] used in the conjugations reported.
This journal is c The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7181–7183 7181

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Progress of the reaction was monitored, and conjugation
1
confirmed, by H NMR. The shift of the CH alpha to the S
2
atom was monitored, which becomes a chiral multiplet at ca.
d = 2.7 ppm following conjugation, full analysis is presented
1
in the ESI.w One of the most striking features of the H NMR
is the disappearance of the (meth)acrylic vinyl peaks in the
conjugate, whilst the other protons remain. Analysis of
the rates of conjugation can be difficult when monitoring the
disappearance of vinylic protons as the initiation step of
the reaction involves nucleophilic attack of the phosphine at
the b-carbon of the vinyl group which can give a false
indication of conversion to final product. The phosphonium-
enolate intermediate is strongly basic which deprotonates the
thiol to the thiolate anion required for the Michael-type
2
0,34,35
addition.
Thus, MALDI-ToF MS was used to confirm
that all free thiols have been functionalised. Any unreacted
reduced polymer is readily detected, as shown for the initial
reaction with hydroxyethyl acrylate, see ESI.w
Fig. 3 MALDI-TOF of the poly[MA] (black) and the poly[MA]-
Two different functional acrylates were chosen to exemplify
the versatility of the reaction; hydroxyethyl acrylate and a
hostasol functional acrylate to give a hydroxyl-functional and
S-hostasol conjugate (blue).
range of other functional methacrylates, an acrylamide and
styrene, Fig. 4.
1
a UV/fluorescently tagged polymer respectively. The H NMR
The propargyl functionalised polymer, A, has the ability to
undergo further click reactions, with copper mediated azide–
indicates complete conjugation, Fig. 2. There is a disappearance
of the vinyl peaks post purification, whist the CH a and b to
2
1
3–15
alkyne click (CuAAC).
This reaction requires an azide
the ester in the HEA end group remain at d = 4.4 ppm.
The CH alpha to the sulfur in the original polymer shifts from
terminated molecule to be clicked onto the alkyne terminated
polymer. Thus a functional azide that cannot be incorporated
into polymers directly via SET-LRP could be introduced in a
similar fashion, Fig. 4 and ESI.w Methacrylates conjugate to
thiols at a slower rate than acrylates due to the electron
donating methyl group and associated steric hindrance reducing
2
d = 2.9 ppm to become a multiplet downfield at d = 2.7 ppm,
arising from the chiral coupling of the CH ’s either side of the
2
sulfur.
Fluorescently tagging polymers is of interest for a number
of applications, and there have been reports of using such
1
9,20
3
monomers (e.g. hostasol acrylate) in the literature. Hostasol
6
the rate of the nucleophilic thiol-ene reaction.
Fluorinated
acrylate was used in our study, to be conjugated to the reduced
1
polymer. All of the characteristic peaks in the H NMR
indicate that complete conjugation is observed (see ESIw).
MALDI-ToF of the original poly[MA] and the hostasol
acrylate conjugate using 2-(4-hydroxyphenylazo)benzoic acid
À1
À1
(
20 mg mL ) as the matrix and NaI salt (2 mg mL ) with the
À1
analyte (5 mg mL ) are shown in Fig. 3. Complete conjugation,
with no starting material remaining, is observed. The spacing
r
between peaks = 86.02 which corresponds to M for methyl
acrylate. The study was then expanded to propargyl acrylate, a
Fig. 4 Further conjugates made via the one pot red/con technique,
using the conditions outlined in Fig. 1; polymer : acrylate : DMPP =
0
3 2
.5 : 1.2 : 0.75, reaction carried out in CDCl , N atmosphere.
A = propargyl acrylate. B = trifluoroethyl methacrylate (TFEMA).
C = ethylene glycol methacrylate phosphate (EGMAP). D = methacryl-
1
Fig. 2 H NMR showing the reaction mixture in the absence of the
1
DMPP catalyst (black) and the conjugate post-modification (blue).
amide. See ESIw for full MALDI and H NMR analysis.
7
182 Chem. Commun., 2010, 46, 7181–7183
This journal is c The Royal Society of Chemistry 2010

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polymers are of interest and thus trifluoroethyl methacrylate
TFEMA) was successfully conjugated to the cleaved poly[MA]
to exemplify this. In addition to the conventional NMR analysis,
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F spectra were also obtained, showing that different species to
1
the starting materials were present in the conjugate, providing
further evidence for the conjugate species. Phosphate functional
polymers are of importance as dispersants and as surfac-
tants and thus EGMAP was conjugated to yield phosphate
3
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Styrene is much less prone to this type of Michael addition
due to lower electron withdrawing from the aryl group and
an attempt to conjugate styrene by the same method was
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This result is in line with previous mechanistic studies that
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1
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nucleophilic attack to occur. Thus, a sufficiently good electron
withdrawing group on the vinyl group is required for the
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the thiol polymers back to a disulfide containing polymer in
1
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both H NMR and GPC, see ESI.w
1
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functionality e.g. TFEMA and EGMAP. This can be applied
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modification with any (meth)acrylate or acrylamide allowing
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This journal is c The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7181–7183 7183