Dual-pathway chain-end modification of RAFT polymers using visible light and metal-free conditions

Article abstract of DOI:10.1039/c6cc08370f

We report a metal-free strategy for the chain-end modification of RAFT polymers utilizing visible light. By turning the light source on or off, the reaction pathway in one pot can be switched between either complete desulfurization (hydrogen chain-end) or simple cleavage (thiol chain-end), respectively. The versatility of this process is exemplified by application to a wide range of polymer backbones under mild, quantitative conditions using commercial reagents.

Full text of DOI:10.1039/c6cc08370f

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Dual-pathway chain-end modification of RAFT
polymers using visible light and metal-free
conditions†
Emre H. Discekici,ab Shelby L. Shankel,a Athina Anastasaki,b Bernd Oschmann,b
In-Hwan Lee,b Jia Niu,b Alaina J. McGrath,b Paul G. Clark,c David S. Laitar,c
Javier Read de Alaniz,*ab Craig J. Hawker*abd and David J. Lunn*be
Cite this:DOI: 10.1039/c6cc08370f
Received 20th October 2016,
Accepted 19th December 2016
DOI: 10.1039/c6cc08370f
www.rsc.org/chemcomm
We report a metal-free strategy for the chain-end modification of RAFT chain-ends pose significant challenges due to their reactive nature.
polymers utilizing visible light. By turning the light source on or off, the For example, thiol end-capped polymers rapidly undergo coupling
reaction pathway in one pot can be switched between either complete through the formation of disulfide bonds, limiting their use in
desulfurization (hydrogen chain-end) or simple cleavage (thiol applications where molecular weight control is required. To address
chain-end), respectively. The versatility of this process is exemplified this reactivity, the conversion of RAFT chain-ends to a simple
by application to a wide range of polymer backbones under mild, hydrogen atom has been widely studied.6 Radical-induced reduction
quantitative conditions using commercial reagents.
using hypophosphite salts or tin reagents have been demonstrated.8
However, elevated temperatures and an excess of reagents are
Controlled radical polymerization (CRP) strategies, including atom required, potentially limiting their use with functional monomers.
transfer (ATRP),1 nitroxide-mediated,2 and reversible addition– Owing to the versatility of RAFT polymerizations and challenges
fragmentation chain transfer (RAFT) processes,3 are prevalent in associated with their reactive chain-ends, a mild and general proto-
both academia and industry for the preparation of well-defined col for the chain-end modification of RAFT polymers is therefore an
polymers. RAFT polymerization is one of the most versatile CRP important objective. Herein, we report a strategy for the conversion
methods and can be applied to a comprehensive range of functional of RAFT chain-ends into either thiol or hydrogen chain-ends
monomers under various polymerization conditions (e.g., solution, with the pathway being dictated by visible light irradiation
suspension and emulsion).3–5 The RAFT process requires the use of (Fig. 1). This simple approach is metal-free, mild and utilizes
a chain transfer agent (CTA), commonly a thiocarbonylthio-based commercial reagents.
compound, that acts to reversibly cap the reactive carbon-centered
In addressing this challenge our attention was drawn to the
radical responsible for chain propagation. While these polymeriza- radical-mediated desulfurization of thiols using tertiary phosphines.
tions are simple to perform and compatible with a range of mono- This radical-mediated desulfurization has almost exclusively been
mers, the presence of reactive and colored CTAs at the chain-end of employed in polypeptide synthesis as a convenient method to
the final product is often detrimental to material performance.6
convert cysteine residues to alanine, under biologically relevant
Several protocols have been developed to remove or modify the conditions.14,15 Interestingly, electron rich tertiary phosphines (e.g.,
reactive CTA chain-end. Generally these methods rely on either trialkylphosphines) have also been used in conjunction with amines
nucleophilic substitution7 or thermolysis.8 For example, the cleavage to prevent disulfide formation during the cleavage of RAFT chain-
of CTAs with primary or secondary amines affords a reactive thiol ends to thiols.16 Given recent interest in light-mediated polymeriza-
chain-end.9,10 This approach has been widely utilized for the pre- tions, particularly RAFT,17–20 the combination of photogenerated
paration of surface active polymers,11 or for further functionaliza-
tion.7,12,13 While of great utility for these applications, the thiol
a Department of Chemistry and Biochemistry, University of California, Santa Barbara,
California, 93106, USA
b Materials Research Laboratory, University of California, Santa Barbara, California,
93106, USA. E-mail: hawker@mrl.ucsb.edu
c The Dow Chemical Company, Midland, Michigan, 48674, USA
d Materials Department, University of California, Santa Barbara, California, 93106,
USA
e Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK
Fig. 1 Selective one-pot conversion of a trithiocarbonate CTA to either
the thiol or hydrogen chain-end.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6cc08370f
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Table 1 Photochemical desulfurization of small molecule thiols
Substrate Solvents Catalyst (eq.) Lights Time (h) Conversion (%)
radicals with phosphine-mediated desulfurization presents a unique
opportunity to develop a visible light-mediated, dual-pathway
reduction of RAFT polymers, where the reaction proceeds through
either a traditional nucleophilic pathway, or a sequential nucleophilic/
radical photochemical pathway.
DCM
DCM
0.10
0.10
On
Off
1
1
495
0
While a prior report of visible light-induced desulfurization of
polypeptides utilized a ruthenium-based photocatalyst,21 our aim
was to develop a metal-free and visible light-mediated CTA chain-end
reduction strategy. With this in mind, we initially investigated
the desulfurization of small molecule thiols using an organic
photocatalyst. Our groups have previously had success replacing
traditional Ir and Ru based photocatalysts, with metal-free
organocatalysts, including Eosin Y and phenothiazine.22–26
DCM
0.05
On
On
16
1
495
495
DMSO 0.05
H2O
0.05
On
2
495
Eosin Y is activated in the presence of visible light and is known the system.12 To illustrate the scope of this reaction, successful
to operate under either an oxidative or reductive quenching desulfurization was also demonstrated with a benzylic thiol
pathway.27 As such, we envisioned Eosin Y as an ideal candidate (4-methoxy-a-toluenethiol) and a tertiary thiol (adamantanethiol)
to generate the intermediate thiyl radical via a reductive quenching (Table 1 and Fig. S3 and S4, ESI†). Importantly, this reaction offers
pathway.28,29 Upon irradiation with 465 nm blue LEDs (Fig. S1, ESI†), a facile, metal-free and visible light-mediated desulfurization of
dodecanethiol was quantitatively converted to the corresponding thiols, and should be readily applicable to the biologically relevant
alkane in 1 h at room temperature in the presence of hexylamine, tri- polypeptide-based systems previously reported. For example,
n-butylphosphine and catalytic Eosin Y. Both 1H NMR (Fig. 2a) and N-acetyl-L-cysteine methyl ester was quantitatively converted to the
GC-MS (Fig. 2b) confirmed the quantitative conversion of the thiol corresponding alanine in water in 2 h under these desulfurization
with concomitant appearance of peaks corresponding to the tri-n- conditions (Fig. S5, ESI†). These promising small molecule results
butylphosphine sulfide byproduct. Significantly, when the same reac- encouraged us to transfer our method to a synthetic polymer system,
tion was attempted in the absence of visible light, no desulfurization utilizing common aminolysis conditions to offer two mechanistic
was detected. In both reactions, an excess of amine was used to pathways (for an in depth discussion of the mechanism see Fig. S6,
mimic the conditions commonly required for the reduction of a CTA ESI†) dependent on the absence or presence of light (Fig. 3).
chain-end to the corresponding thiol30 and as an additional benefit,
Due to reports in the literature outlining key diagnostic NMR
to facilitate the generation and transfer of thiyl radicals within signals for CTA and thiol end-capped polystyrene (PS),31 our inves-
tigation began with the synthesis of PS (Mn = 2200 g molÀ1, Ð = 1.16)
by traditional thermally-initiated RAFT polymerization using 2-(dode-
cylthiocarbonothioylthio)-2-methylpropionic acid (DDMAT) as the
CTA. Characterization by 1H NMR revealed a broad signal at
4.7 ppm, which corresponds to the literature value for the benzylic
methane proton alpha to the trithiocarbonate chain-end (Fig. 4).32
Upon subjection of the PS derivative to the conditions developed for
small molecule desulfurizations, quantitative removal of the RAFT
1
chain-ends was observed. As shown by H NMR, in the absence of
light, the signal for the benzylic proton shifted upfield to 3.5 ppm,
matching reported values for thiol end-capped PS.31 This suggests
that the presence of Eosin Y does not disrupt the expected amino-
lysis of the CTA, thus enabling the possibility for a dual-pathway
process. Further characterization by gel permeation chromatography
(GPC) of the thiol end-capped polymer after purification revealed the
appearance of a high molecular weight shoulder, indicative of
Fig. 2 1H NMR (a) and GC-MS (b) evidence for the quantitative metal-free
and visible light-mediated conversion of dodecanethiol to dodecane using
Eosin Y as a photocatalyst.
Fig. 3 Proposed mechanisms in absence and presence of light.
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Fig. 4 (a) Chemical scheme of dual-pathway reduction of PS-CTA (Mn = 2200 g molÀ1). (b) 1H NMR showing corresponding chain-end signals.
undesired disulfide coupling (Fig. S7, ESI†). In contrast, when the multiple sets of molecular ions, most likely due to the high reactivity
reaction mixture was irradiated with visible light, the complete of the thiol chain-end. Modulation of this reactivity by in situ capping
disappearance of signals in the region from 3.0 to 5.0 ppm was of the thiol chain-end by Michael addition to butyl acrylate, resulted
observed, suggestive of quantitative removal of the CTA and intro- in molecular ions corresponding to the expected thioether chain-end
duction of a hydrogen chain-end. Significantly, GPC analysis of the (Fig. S12 and S13, ESI†).33–35
irradiated product showed negligible change in peak shape and
Additionally, a water soluble and higher molecular weight
dispersity from the starting material, further supporting successful polymer, CTA-terminated poly(N,N-dimethyl acrylamide) (PDMA)
desulfurization (Fig. S7, ESI†). Notably, this desulfurization could was synthesized using 2-(n-butyltrithiocarbonate)-propionic acid
also be achieved using natural sunlight (Fig. S8, ESI†). Control (Mn = 25000 g molÀ1, Ð = 1.10). Under aqueous conditions,
experiments in the absence of Eosin Y and/or irradiation resulted PDMA was subjected to chain-end modification using tris(2-
1
in complete conversion to the thiol chain-end, confirming the carboxyethyl)phosphine (TCEP) and butylamine. H NMR analysis
requirement for both light and a photocatalyst to obtain the hydro- of the isolated polymers with and without irradiation showed
gen chain-end (Fig. S9, ESI†). Additionally, subjection of the purified quantitative removal of the CTA, with GPC-UV traces confirming
thiol end-capped PS to our desulfurization conditions resulted in its disappearance in both cases (Fig. S15, ESI†). The change in
quantitative conversion to the hydrogen chain-end (Fig. S10, ESI†). reactivity of the chain-end was clearly illustrated using a refractive
To provide further evidence for the installation of a hydrogen chain- index (RI) detector of the irradiated polymer (Fig. 6c), which shows a
end, d8-polystyrene was synthesized using thermally-initiated RAFT single peak with low dispersity, nearly identical to that of the starting
polymerization. The presence of deuterated repeat units facilitates CTA-terminated polymer (Fig. 6a). However, as previously observed
enhanced identification of the chain-end units. In this case, subject- in the case of PS, the GPC-RI trace for the non-irradiated sample
ing the deuterated polymer to Eosin Y and light revealed the showed a prominent high molecular weight shoulder, indicative
emergence of a broad signal at approximately 2.5 ppm in the of undesired disulfide coupling. To further confirm disulfide
1H NMR, which can be attributed to successful introduction of a
hydrogen chain-end (Fig. S11, ESI†).
To demonstrate the versatility of this approach, CTA-terminated
poly(methyl acrylate) (PMA) was synthesized using 2-cyano-2-propyl
dodecyl trithiocarbonate under thermal RAFT conditions (Mn
=
4800 g molÀ1, Ð = 1.09). Characterization by matrix assisted laser
desorption ionization time of flight mass spectrometry (MALDI-ToF-
MS) was diagnostic in identifying the chemical nature of the chain-
ends. As expected, analysis of the starting material yielded a single
set of molecular ions corresponding to the trithiocarbonate chain-
end. Upon irradiation with visible light, complete loss of the original
molecular ions was observed, with the appearance of a set of peaks
for the hydrogen terminated PMA (286 gmolÀ1 difference in m/z
between the trithiocarbonate and hydrogen chain-ends) (Fig. 5). In
direct contrast, analysis of the non-irradiated sample resulted in
Fig. 5 Scheme and enlarged MALDI-ToF-MS spectra of a sample of PMA,
before and after photo-induced desulfurization.
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