Orthogonal Click Postfunctionalization of Alternating Copolymers Prepared by Nitroxide-Mediated Polymerization

Article abstract of DOI:10.1002/chem.201605639

Nitroxide-mediated polymerization (NMP) was applied to prepare alternating copolymers using 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) 1 and ((6-trimethylsilyl)-hex-5-yn-1-yl)vinyl ether (THVE) 2 as monomers. The alternating sequence of the resulting poly(HFIPA-alt-THVE) 3 was proved by using tandem mass spectrometry (MS/MS) and further supported by ¹H NMR spectroscopy. Alternating alkyne and activated ester moieties of copolymer 3 were further functionalized with organic azides and amines using sequential Cu-catalyzed azide–alkyne click (CuAAC) and amidation reactions, providing dually functionalized poly(acrylamide-alt-triazole) polymers 5. Water-soluble alternating poly(acrylic acid-alt-triazole) copolymers 9 were obtained by saponification of HFIP esters. ¹H and ¹⁹F NMR spectroscopy, IR spectroscopy as well as gel permeation chromatography (GPC) were used to characterize the polymers before and after functionalization.

Full text of DOI:10.1002/chem.201605639

A Journal of
Accepted Article
Title: Orthogonal Click Postfunctionalization of Alternating Copolymers
Prepared by Nitroxide Mediated Polymerization
Authors: Matthias Tesch, Sergej Kudruk, Matthias Letzel, and Armido
Studer
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To be cited as: Chem. Eur. J. 10.1002/chem.201605639
Link to VoR: http://dx.doi.org/10.1002/chem.201605639
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Orthogonal Click Postfunctionalization of Alternating Copolymers
Prepared by Nitroxide Mediated Polymerization
Matthias Tesch, Sergej Kudruk, Matthias Letzel, and Armido Studer*[a]
Abstract: Nitroxide Mediated Polymerization (NMP) was applied to
prepare alternating copolymers using 1,1,1,3,3,3-hexafluoroisopropyl
acrylate (HFIPA) 1 and ((6-trimethylsilyl)-hex-5-yn-1-yl)vinyl ether
(THVE) 2 as monomers. The alternating sequence of the resulting
poly(HFIPA-alt-THVE) 3 was proved via tandem mass spectrometry
(MS/MS) and further supported by 1H NMR spectroscopy. Alternating
alkyne and activated ester moieties of copolymer 3 were further
functionalized with organic azides and amines using sequential Cu-
catalyzed azide-alkyne click (CuAAC) and amidation reactions,
providing dually functionalized poly(acrylamide-alt-triazole) polymers
5. Water-soluble alternating poly(acrylic acid-alt-triazole) copolymers
translation process of ribosomes to yield sequence-defined
polypeptides.[29]
Alternating radical polymerization has been achieved with nearly
perfect sequence control.[30–41] Along these lines, we have
recently introduced alternating NMP[42,43]
of 1,1,1,3,3,3-
hexafluoroisopropyl acrylate (HFIPA) 1 and (7-octenyl)vinyl ether
(OVE). The resulting poly(HFIPA-alt-OVE) was orthogonally
postfunctionalized via radical thiol-ene click reaction and
subsequent amidation.[38,44] It is well known that the properties of
polymers can be altered significantly by chemical
postfunctionalization and numerous recent reports deal with the
modification of polymers by thiol click chemistry,[16,45–49] Cu-
catalyzed alkyne-azide click reaction (CuAAC),[34,49–57] amidation
1
9 were obtained by saponification of HFIP esters. H and 19F NMR
spectroscopy, IR spectroscopy as well as gel permeation
chromatography (GPC) were used to characterize the polymers
before and after functionalization.
reactions,[46,47,58–60]
and
many
others,[53,61–64]
including
combinations thereof. Our conceptual approach introduced
allowed for preparation of a small library of alternating copolymers
using a single type of parent copolymer and diversifying
subsequent orthogonal postmodification.
The control over monomer sequence in polymer chemistry has
gained a lot of attention in recent years. It has even been identified
as “the next holy grail in polymer science”.[1,2] It is obvious that
synthetic polymers, as compared to biopolymers such as proteins
or nucleic acids, have much less complex primary structures due
to the lack of appropriate synthetic methods, which would allow
for accurate control over the sequence of a large number of
monomers. It is known that the primary structure of natural
polymers plays a key role for self-replication, self-assembly and
molecular recognition.[3] Therefore, it is reasonable to assume
that synthetic polymers with defined monomer sequence will set
the stage for the generation of highly organized materials and
man-made polymers with complex functions. Recently, valuable
advances have been made in the field of sequence-controlled
polymerization. Iterative multi-step approaches provide excellent
sequence-fidelity but are tedious to conduct and therefore limited
to oligomers and smaller polymeric chains.[4–17] Template-based
strategies,[18–21] polymerizations based on multicomponent
reactions,[22–25] and the polymerization of sequence-controlled
precursors[26,27] allow for higher molecular weights but are limited
to relatively simple repetitive patterns. Also pinpoint
functionalization of polymer chains has been achieved by time-
resolved addition of comonomers.[28] Although very rare, there are
examples of complex molecular machines which mimic the
We herein extend that valuable concept and present the
alternating copolymerization of HFIPA 1 and ((6-trimethylsilyl)-
hex-5-yn-1-yl)vinyl ether (THVE) 2 using alkoxyamine 6 as NMP
initiator as well as the highly efficient orthogonal
postfunctionalization of the resulting copolymers 3 (Scheme 1).
To our knowledge, this is the first example describing orthogonal
CuAAC/amidation postfunctionalization of alternating copolymers.
THVE 2 was readily prepared from commercially available hex-5-
yn-1-ol in a two-step procedure on a multi-gram scale in 56 %
overall yield (see supporting information, SI).
[a]
M.Sc. Matthias Tesch, B.Sc. Sergej Kudruk, Dr. Matthias Letzel,
Prof. Armido Studer
Organic Chemistry Institute
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster
E-mail: studer@uni-muenster.de
Scheme 1. Nitroxide mediated copolymerization of 1 and 2 and subsequent
dual click functionalization via CuAAC and amidation.
Supporting information for this article is given via a link at the end of
the document.
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Copolymerization of
2
with HFIPA
1
was systematically
Figure 1b shows the monomer conversion of HFIPA and
polydispersity index (PDI) plotted against reaction time (HFIPA (1
investigated. To this end, copolymerizations at different monomer
feed ratios f were performed using initiator 6 (2 mol%) in benzene
at 100 °C and reactions were stopped at low conversion (≤ 35%).
Ratio of incorporated monomers F was plotted against f in a
Mayo-Lewis plot (Figure 1a).[65] Using a monomer feed of 1:1
(f = 0.50) resulted in preferential HFIPA incorporation over THVE
with a ratio of F = 0.58. At f = 0.20 both monomers were
incorporated in equal amounts, suggesting an alternating
sequence of the copolymer, which was proved by tandem mass
equiv.), THVE (2 equiv.), and alkoxyamine
6 (2 mol%) in
benzene/HFIP (97/3) at 100 °C for 3-45 min). The plot of the
average molecular weight Mn,exp against HFIPA conversion is
depicted in figure 1c. Both plots show the typical linear behavior
for a controlled/living radical polymerization (PDI between 1.11
and 1.20).
After the in-depth investigation of the copolymerization of 1 and 2
we turned our attention to the post-polymerization
functionalization of poly(HFIPA-alt-THVE) 3 (Scheme 2).
spectrometry (see SI).
A further increase in vinyl ether
concentration (f = 0.11) did not lead to a higher incorporation of 2
over 1 (F = 0.50) due to the inability of vinyl ethers to form
homopolymeric sequences under conventional radical
polymerization conditions. In contrast, a large excess of 1
(f = 0.90) resulted in HFIPA-enriched copolymers (69:31).
Reactivity ratios r1 = 0.21 and r2 = 0.00 were then obtained by
fitting the data points to the Mayo-Lewis copolymerization
equation using the method of least squares (see SI). These
values reflect the tendency of the HFIPA/THVE monomer pair to
copolymerize in an alternating mode. It should be noted that
acrylate 1 tends to undergo homopolymerization to some extent
(r1 = 0.21) whereas vinyl ether
2 does not undergo any
homopolymerization (r2 = 0.00). From figure 1a one can extract
that good alternating sequence control can be achieved using a
fourfold excess of vinyl ether 2 which is unfortunately the more
expensive monomer in the mixture. We therefore tried to lower
the 2-loading keeping alternating sequence control and found that
upon addition of a small amount of HFIP (3 vol% compared to
benzene) good control is achieved with just a twofold excess of 2.
We attribute this effect to the efficient coordination of HFIP to the
acrylate monomer, decreasing its electron density and enhancing
cross-propagation. Under these conditions, Mn,exp was varied
from 5 300 to 11 100 g/mol using 6 (0.5-20 mol%). The
incorporation ratio (HFIPA/THVE) varied from 50/50 to 52/48
(details can be found in the SI). Notably, NMP-regulator 6 can be
Scheme 2. Chemical postmodification of poly(HFIPA-alt-THVE) 3. Results are
summarized in Table 1 and substituents for the postmodified copolymers 5a-g
and 9a,b are specified in Table 1.
replaced
by
commercially
available
4-cyano-4-
(phenylcarbonothioylthio)-pentanoic acid as a RAFT reagent
(2 mol%) and AIBN as radical initiator, providing poly(HFIPA-alt-
These studies were conducted using poly(HFIPA-alt-THVE) with
a DP of 16 monomer units each (Mn,exp = 7 900 g/mol; PDI 1.26).
The trimethylsilyl group in 3 could be quantitatively removed with
KF in DMF at room temperature to give 7. Copolymer 3 was
readily transferred into the corresponding alternating acrylic acid
THVE) with
a
50:50 incorporation of both monomers
(Mn,exp = 8 200 g/mol and PDI = 1.19) showing that this process is,
as expected, not restricted to NMP.
Figure 1. a) Mayo-Lewis plot of the copolymerization of 1 and 2. Reactivity ratios (r1 = 0.21, r2 = 0.00) were obtained by fitting the data points to the Mayo-
Lewis equation; b) monomer conversion and PDI plotted vs. time; c) Mn,exp plotted vs. HFIPA conversion.
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Na-salt 8 by saponification using NaOH in THF/H2O. Under these
conditions the TMS group was also removed.
confirmed by IR spectroscopy: the C=O stretching frequency of
HFIPA at 1778 cm-1 completely disappeared and a new prominent
amide C=O band at 1653 cm-1 emerged (see SI for spectra). In
addition, a broad peak at 3300 cm-1 corresponding to the N-H
stretching frequency of the amide is visible. In the 1H NMR
spectrum the HFIPA ester signal at 5.6 ppm disappeared and
alkene signals of the allylamide moiety appeared. GPC revealed
an Mn,exp of 4 900 g/mol and a PDI of 1.12. The underestimation
of Mn,exp is likely due to the different coiling behavior and the
resulting hydrodynamic volume of the poly(acrylamide-alt-
triazole) copolymer 5a as compared to the PMMA calibration
standard.
To further prove the high efficiency of both post-polymerization
processes, we followed a sequence by 19F NMR (Table 1, entry
2). To this end, 4-(trifluoromethyl)benzyl azide was reacted with 3
using CuBr and N,N,N′,N′′,N′′-pentamethyldiethylenetriamine
(PMDETA) as a catalyst. In addition to the HFIP fluorine signals
at around -74 ppm (see Figure 2a), a second fluorine signal from
the aromatic CF3 group appeared at -63 ppm (Figure 2b).
Next we attempted CuAAC of the alkyne functionality in the
copolymer and found that in most cases silyl deprotection prior to
the CuAAC is not necessary, since desilylation occurred under
the conditions of the click reaction.[66,67] Hence, reaction of 3 with
homobenzyl azide (1.0 equiv.) was achieved in THF/DMF (1:1) at
ambient temperature in the presence of CuSO4 as a catalyst
precursor and sodium ascorbate as a reducing reagent (Table 1,
entry 1). After extraction of the Cu catalyst using aqueous EDTA
solution and subsequent concentration in vacuo, the
monofunctionalized poly(HFIPA-alt-triazole) 4a obtained was
analyzed by 1H NMR spectroscopy (see SI for spectra). The
signal at 2.1 ppm, assigned to the propargylic CH2 group in 3
completely vanished, whereas a new signal for the corresponding
methylene group at the triazole ring appeared at 2.6 ppm,
indicating quantitative cycloaddition. Moreover, appearance of
new benzylic and homobenzylic as well as the expected aromatic
signals further confirmed successful CuAAC. Importantly, both 1H
NMR and IR spectroscopy showed that the HFIP ester was stable
under the applied CuAAC conditions.
Table 1. Dual functionalization of alternating copolymers 3, 7 and 8 using
various organic azides and amines. Functionalization degrees were ≥95 % in all
cases for both transformations.
Entry
(No.)
Mn,exp
yieldb
[%]
PDIa
[g/mol]a
1
(5a)
4 900 1.12 82
2
(5b)
6 100 1.31 53
5 800 1.23 89
2 400 1.37 69
3
(5c)
4
(5d)
Figure 2. 19F NMR spectra of a) poly(HFIPA-alt-THVE) 3, b) poly(HFIPA-alt-
triazole) 4b and c) poly(acrylamide-alt-triazole) 5b.
5
(5e)
c
c
-
-
36
Copolymer
4b
was
subsequently
treated
with
6
(5f)
2 800 1.41 38
3 800 1.18 86
4-fluorobenzylamine at 60 °C for 72 h. The excess amine was
removed by extraction with HCl and polymer 5b was isolated after
precipitation into pentane (53%). The 19F NMR spectrum
unambiguously showed high consumption of the HFIP esters as
only traces of the F-signals at around -74 ppm were visible (Figure
2c). Moreover, new signals at around -115 ppm proved
successful amidation with the fluorinated benzyl amine.
The sequential postmodification strategy was then successfully
applied to prepare copolymers 5c-g. Ester, alcohol and aliphatic
residues were introduced via the CuAAC (see Table 1, entries
4,5,7) and the subsequent amidation worked efficiently with
various primary amines (Table 1, entries 3-7). It is of note that
amidation with isopropylamine (Table 1, entries 4 and 6) delivers
7
(5g)
8
(9a)
c
c
-
-
-
-
82
16
9
(9b)
c
c
a Obtained by GPC in THF against PMMA standards; b Isolated yield over
2 functionalization steps; functionalization degree ≥95 % in all cases; c GPC
data could not be obtained due to poor solubility.
alternating
copolymers
of
poly(N-isopropylacrylamide)
Analysis of polymer 4a by GPC revealed an average molecular
weight of Mn,exp = 9 000 g/mol with a PDI of 1.26. For the second
postmodification, 4a was converted into the alternating
acrylamide 5a with allylamine (5.0 equiv.) at 70 °C in THF/DMF
(1:1) for 72 h in 82% overall yield. Completion of the reaction was
(PNIPAM).[68] We could also show that CuAAC can be conducted
with the polyelectrolyte 8 as a substrate. This was documented by
the successful preparation of alternating poly(acrylic acid-alt-
triazole) 9a (Table 1, entry 8). The biotin-conjugated congener 9b
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THF (0.2 mL), precipitated into pentane (5 mL) and the supernatant was
decanted. The dually functionalized target polymer 5 was isolated as a
viscous gel or solid. Functionalization degree was determined by using 1H
NMR spectroscopy, Mn,exp and PDI were determined by GPC.
(Table 1, entry 9) was prepared from biotinylated copolymer 4h
by saponification of the HFIP groups. In the latter case, the
isolated yield dropped to 16% over two functionalization steps due
to problems during workup. All other dually functionalized
copolymers were isolated in moderate to excellent overall yields
(36-89%). The functionalization degrees for both transformations
were ≥95% in all cases and alternating copolymers were
characterized using 1H NMR and IR spectroscopy as well as GPC
(see SI for details).
In summary, alternating copolymerization of HFIPA 1 and THVE
2 was achieved via NMP. The copolymerization could also be
conducted using a commercially available RAFT reagent under
otherwise identical conditions, demonstrating the robustness of
this approach. Dual postfunctionalization of 3 with azides and
amines was achieved via CuAAC and subsequent amidation. The
degree of functionalization for all of those transformations was
≥95%. The postmodification sequence was carefully analyzed by
1H and 19F NMR, IR, and GPC. To our knowledge, this is the first
example of orthogonal CuAAC/amidation postfunctionalization of
alternating copolymers, which should open up new pathways for
the preparation of functional polymeric materials. Notably,
sequence control in functionalized polymers is a challenging task
and the concept presented herein is highly valuable along those
lines.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (DFG) for
supporting us in the frame of the Sonderforschungsbereich 858
(SFB 858). The reviewer is acknowledged for helpful suggestions.
Keywords: Alternating Copolymerization • NMP •
Postfunctionalization • CuAAC • Amidation
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10.1002/chem.201605639
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COMMUNICATION
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COMMUNICATION
A protocol for alternating
copolymerization of an activated
ester (HFIPA) and an alkyne-
terminated vinyl ether (THVE) is
presented. Sequential
Matthias Tesch, Sergej Kudruk,
Matthias Letzel, Armido Studer*
Page No. – Page No.
Orthogonal Click
postfunctionalization with azides
and amines via CuAAC and
subsequent amidation provides
access to various alternating
copolymers in a modular
approach.
Postfunctionalization of
Alternating Copolymers
Prepared by Nitroxide Mediated
Polymerization
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