Highly orthogonal functionalization of ADMET polymers via photo-induced Diels-Alder reactions

Article abstract of DOI:10.1021/ma3007043

Within the current contribution, we introduce two strategies for the catalyst-free, modular, ambient temperature synthesis of ABC triblock copolymers via photoinduced Diels-Alder reactions. On the one hand, the 2-formyl-3-methylphenoxy (FMP) moiety (a second generation photoenol precursor) was employed for orthogonal polymer-polymer conjugations using terminal acrylates of diblock copolymers synthesized via acyclic-diene-metathesis (ADMET) polymerizations to directly prepare triblock copolymers. On the other hand, the disparate reactivity of 2,5-dimethylbenzophenone (first generation photoenol) and the FMP moiety was exploited to selectively synthesize complex triblock copolymers (6.5 kDa≥ M_n ≥11.5 kDa, 1.16≥ PDI ≥ 1.30) via a sequential one pot approach utilizing the extraordinary orthogonality of the photoinduced Diels-Alder reaction. Polymers functionalized with a photoenol (second generation) moiety were employed for conjugation reactions with polymers featuring an acrylate terminus, while polymers having a photoenol (first generation) end group were employed for selective conjugations of maleimide functional polymers. In this context, the selective head-to-tail ADMET polymerization was employed as a straightforward methodology for the preparation of bifunctional polymers having a terminal acrylate and a photoenol end-group.

Full text of DOI:10.1021/ma3007043

Article
pubs.acs.org/Macromolecules
Highly Orthogonal Functionalization of ADMET Polymers via Photo-
Induced Diels−Alder Reactions
Matthias Winkler,†,‡ Jan O. Mueller,† Kim K. Oehlenschlaeger,† Lucas Montero de Espinosa,‡
Michael A. R. Meier,*,‡ and Christopher Barner-Kowollik*,†
†Preparative Macromolecular Chemistry, Institut fur Technische Chemie und Polymerchemie, Karlsruhe Institute of Technology
̈
(KIT), Engesserstrasse 18, 76128 Karlsruhe, Germany
‡Laboratory of Applied Chemistry, Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6,
76131 Karlsruhe
S
* Supporting Information
ABSTRACT: Within the current contribution, we introduce two
strategies for the catalyst-free, modular, ambient temperature
synthesis of ABC triblock copolymers via photoinduced Diels−
Alder reactions. On the one hand, the 2-formyl-3-methylphenoxy
(FMP) moiety (a second generation photoenol precursor) was
employed for orthogonal polymer−polymer conjugations using
terminal acrylates of diblock copolymers synthesized via acyclic-
diene-metathesis (ADMET) polymerizations to directly prepare
triblock copolymers. On the other hand, the disparate reactivity of
2,5-dimethylbenzophenone (first generation photoenol) and the
FMP moiety was exploited to selectively synthesize complex
triblock copolymers (6.5 kDa≤ Mn ≤11.5 kDa, 1.16≤ PDI ≤ 1.30) via a sequential one pot approach utilizing the extraordinary
orthogonality of the photoinduced Diels−Alder reaction. Polymers functionalized with a photoenol (second generation) moiety
were employed for conjugation reactions with polymers featuring an acrylate terminus, while polymers having a photoenol (first
generation) end group were employed for selective conjugations of maleimide functional polymers. In this context, the selective
head-to-tail ADMET polymerization was employed as a straightforward methodology for the preparation of bifunctional
polymers having a terminal acrylate and a photoenol end-group.
often not accessible by the classic chain extension approach
due to the incompatibility of the desired functionalities with the
polymerization technique.7 In order to accelerate the
investigation and preparation of new polymeric materials, the
introduction of the click chemistry concept has possibly led to a
paradigm shift toward the modular construction of macro-
molecular materials.8 Additionally, modern conjugation proto-
cols enable the (reversible) linkage of biological molecules to
functional polymers.9 The most frequently employed con-
jugation method in polymer chemistry is the 1,3-dipolar
Huisgen cycloaddition, which often meets the extended criteria
for highly efficient modular macromolecular synthesis.10
However, also selected Diels−Alder reactions were classified
as click-type reactions as outlined by Sharpless and co-workers
when introducing the click chemistry concept.11 Diene/
dienophile functionalities employed in Diels−Alder polymer−
polymer conjugation reactions are furan/maleimide, anthra-
cene/maleimide, and butadiene or cyclopentadiene/electron-
deficient dithioesters.12 We recently introduced a highly
efficient photoinduced Diels−Alder conjugation approach,
INTRODUCTION
■
One of the main objectives of polymer chemistry is the
interdisciplinary bridging between synthesis and material
science to promote the preparation of functional materials for
potential high-value applications, such as biomedicine (e.g.,
drug delivery, bone tissue engineering or cell regeneration). To
meet the complex challenges that are imposed on such
functional materials, it is necessary to prepare well-defined
polymers with tailored properties.1 Specific properties can be
achieved by controlling, e.g., the polymer topology, composi-
tion, molecular weight and/or the polydispersity.2 An
important class of materials, which has achieved considerable
attention due to their unique and specific properties, are block
copolymers. Because of their characteristic micro- and nano-
phase morphologies, they can have unique properties that are
difficult to achieve by common homopolymers or polymer
blends.3−5 Classically, well-defined block copolymers are
prepared by controlled/living polymerization of one monomer
and subsequent chain extension. Of special interest is the
incorporation of functional groups during the block copolymer
synthesis, because they increase the application possibilities of
polymers and allow for a more advanced material design
depending on specific structure−property relationships.6
However, various designed macromolecular materials are
Received: April 5, 2012
Revised: May 26, 2012
Published: June 7, 2012
© 2012 American Chemical Society
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Characterization. FAB (fast atom bombardement) mass spectra
and high resolution mass spectra (HRMS) FAB were measured on a
Finnigan MAT 95.
which is based on the photoisomerization of o-methylphenyl
ketones or aldehydes and the resulting in situ formation of
hydroxy-o-quinodimethanes (photoenols) that are suitable for
modular polymer−polymer conjugations.13 Moreover, Meador
and co-workers demonstrated the usability and versatility of
such a photoinduced [4 + 2] cycloaddition as a polymerization
technique for bifunctional molecules to generate polyimides or
photocured polymer films.14,15 Most significantly, however, the
light triggered conjugation of photoenol functional polymers
has highly attractive features, including nondemanding reaction
conditions (e.g., no required catalyst, ambient temperature).
Moreover, in contrast to thermally induced Diels−Alder
reactions, the phototriggered [4 + 2] cycloaddition is
irreversible; this fact should result in thermally more stable
polymers that are not susceptible to retro-Diels−Alder
reactions. Additionally, we reported the 2-formyl-3-methyl-
phenoxy (FMP) moiety a (second generation photoenol) as a
significantly more reactive photoenol precursor compared to
the 2,5-dimethylbenzophenone (first generation photoenol)
due to the stabilization of the in situ formed photoenol
intermediate by hydrogen bond formation.16 However, so far
only very reactive dienophiles (e.g., maleimides or electron-
deficient dithioesters) have been used for polymer−polymer
conjugations via thermally or photoinduced Diels−Alder
reactions, whereas relatively unreactive dienophiles such as
acrylates have not yet been employed for polymer−polymer
conjugations via this method. In a recent publication, we
presented a strategy for the postpolymerization modification of
polymers having a terminal acrylate. The introduced ADMET−
Heck protocol was employed for the selective synthesis of di-
and triblock copolymers having an unsaturated backbone.17
Heck coupling reactions of acrylate terminated polymers with
aryl iodide functional polymers were performed at mild
temperatures under Jeffery’s conditions.18 As an orthogonal
and catalyst-free alternative to the above-noted Heck coupling
approach, we introduce herein a photoinduced Diels−Alder
modular ligation method, entailing the very efficient con-
jugation of acrylate terminated polymers with FMP-capped
polymers via photoinduced Diels−Alder reaction at ambient
temperature. Importantly, the disparate reactivity of the two
photoenol (first and second generation) moieties was exploited
for the synthesis of triblock copolymers by a sequential one-pot
approach, demonstrating the extraordinary orthogonality of
these phototriggered click reactions.
1H NMR measurements were performed on a Bruker Avance
1
spectrometer operating at 300 MHz for H and 75 MHz for 13C. All
samples were dissolved in CDCl3 or CD2Cl2 and the chemical shifts δ
are reported in ppm relative to TMS.
Determinations of molecular weights were performed on a Polymer
Laboratories PL-SEC 50 Plus system having an auto injector, a guard
column (PLgel Mixed C, 50 × 7.5 mm) followed by three linear
columns (PLgel Mixed C, 300 × 7.5 mm, 5 μm bead-size) and a
differential refractive index detector, operating in THF at 40 °C, with a
flow rate of 1 mL × min−1. The GPC system was calibrated with
poly(methyl methacrylate) standards (Polymer Standards Service
(PSS), Mainz, Germany) ranging from 700 to 2 × 106 Da. The
molecular weight distributions were determined relative to PMMA.20
SEC/ESI-MS spectra were recorded on a LXQ mass spectrometer
(Thermo Fisher Scientific, San Jose, CA) equipped with an
atmospheric pressure ionization source operating in the nebulizer-
assisted electrospray mode. The instrument was calibrated in the m/z
range 195−1822 using a standard containing caffeine, Met-Arg-Phe-
Ala acetate (MRFA), and a mixture of fluorinated phosphazenes
(Ultramark 1621) (all from Aldrich). A constant spray voltage of 4.5
kV, a dimensionless sweep gas flow rate of 2, and a dimensionless
sheath gas flow rate of 12 were applied. The capillary voltage, the tube
lens offset voltage, and the capillary temperature were set to 60 V, 110
V, and 275 °C, respectively. The LXQ was coupled to a Series 1200
HPLC-system (Agilent, Santa Clara, CA) consisting of a solvent
degasser (G1322A), a binary pump (G1312A), and a high-perform-
ance autosampler (G1367B), followed by a thermostated column
compartment (G1316A). Separation was performed on two mixed bed
size exclusion chromatography columns (Polymer Laboratories,
Mesopore 2504.6 mm, particle diameter 3 μm) with precolumn
(Mesopore 50−4.6 mm) operating at 30 °C. THF at a flow rate of
0.30 mL × min−1 was used as eluent. The mass spectrometer was
coupled to the column in parallel to an RI-detector (G1362A with
SS420x A/D) in the setup described previously, 0.27 mL × min−1 of
the eluent was directed through the RI detector, and 30 μL × min−1
was infused into the electrospray source after post column addition of
a 100 μM solution of sodium iodide in methanol at 20 μL × min−1 by
a micro flow HPLC syringe pump (Teledyne ISCO, Model 100DM).
A 20 μL aliquot of a polymer solution with a concentration of ∼3 mg
mL−1 was injected onto the HPLC system (the description was taken
from a recent publication).20
Synthesis of PEG−Acrylate (P5). Poly(ethylene glycol) methyl
ether acrylate (1.35 g, 0.675 mmol) was weighed into a round-bottom
flask and set under argon atmosphere. CHCl3 (20 mL) was added and
the reaction mixture was stirred for 5 min. Subsequently, acryloyl
chloride (0.122 g, 1.35 mmol) and, after further 5 min of stirring, Et3N
(0.171 g, 1.69 mmol) was added. The mixture was stirred for 16 h at
ambient temperature. The solvent was removed under reduced
pressure and the residue was rapidly filtered through a short column
(silica gel, ethyl acetate) to remove the ammonium salts. After
concentration of the solution the polymer was precipitated in cold
diethyl ether (Mn,SEC = 2.8 kDa, PDI = 1.03).
EXPERIMENTAL SECTION
■
Materials. Chloroform, dichloromethane and triethylamine were
distilled over CaH2. ε-Caprolactone (ε-CL) was distilled from CaH2
and stored over molecular sieves (4 Å) in a glovebox. Dioxane was
distilled over sodium pieces. Benzoic acid (99.5%, Sigma-Aldrich), 10-
undecen-1-ol (98%, Aldrich), hexyl acrylate (99%, Aldrich), butyl
acrylate (98%, Sigma-Aldrich) N,N′-dicyclohexylcarbodiimide (DCC,
99%, Acros), 4-(dimethylamino)pyridine (DMAP, 99% Acros),
succinic anhydride (≥99%, Sigma-Aldrich), 2-bromoethanol (95%,
Sigma-Aldrich), toluene (extra dry, water <30 ppm, Acros Organics),
poly(ethylene glycol) methyl ether (Mn = 2000 g·mol−1, Sigma-
Aldrich), poly(ethylene glycol) methyl ether methacrylate (PEG-
MMA, Mn = 950 Da, Sigma-Aldrich), 1,5,7-triazabicyclo[4.4.0]dec-5-
ene (TBD, 99%, Sigma-Aldrich), acryloyl chloride (97%, Sigma-
Aldrich), ethyl vinyl ether (99%, Sigma-Aldrich) were used as received.
Monomer 3,19 model compound 6,17 4-hydroxyethoxy-2,5-dimethyl-
benzophenone, FMP functional poly(ε-caprolactone) (P3) and
maleimide functional PEG (P14) were synthesized according to
published procedures.13,16
1H NMR (CDCl3, 300 MHz), δ/ppm: 6.42 (dd, J = 17.4, 1.5 Hz,
1H, −CHCH2), 6.14 (dd, J = 17.4, 10.3 Hz, 1H, −CH=CH2), 5.83
(dd, J = 10.3, 1.5 Hz, 1H, −CHCH2), 4.32−4.29 (m, 2H, −O−
CH2−CH2−OCO−), 3.75−3.71 (m, 2H, −O−CH2−CH2−OCO−),
3.67−3.59 (m, PEG backbone), 3.36 (s, 3H, −OCH3).
Synthesis of Photoenol Precursor (First Generation) (2-(4′-
Benzoyl-2′,5′-dimethylphenoxy)ethyl Acrylate) (5). 4-Hydrox-
yethoxy-2,5-dimethylbenzophenone (1.08 g, 4.00 mmol) was dissolved
in CHCl3 (40 mL). Subsequently, acryloyl chloride (0.72 g, 8.0 mmol)
and, after 5 min of additional stirring, Et3N (1.01 g, 10.0 mmol) was
added. The mixture was stirred for 16 h at ambient temperature. The
solvent was then removed under reduced pressure and the residue was
rapidly filtered through a short column (silica gel, ethyl acetate) to
remove the ammonium salts. After concentration of the solution the
crude product was purified by flash chromatography (silica gel,
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hexane:ethyl acetate, 2:1). The product was obtained as a highly
viscous yellowish oil (1.22 g, 94%).
lamp (Arimed B6, Cosmedico GmbH, Stuttgart, Germany) emitting at
320 nm ( 30 nm) at a distance of 40−50 mm in a custom-built
photoreactor. After evaporation of the solvent, the polymers were
dried under vacuum without any further purification.
1H NMR (CDCl3, 300 MHz), δ/ppm: 7.81 (d, J = 7.0 Hz, 2H,
ArH), 7.58 (t, J = 7.4 Hz, 1H, ArH), 7.45 (t, J = 7.5 Hz, 2H, ArH),
7.21 (s, 1H, ArH), 7.00 (s, 1H, ArH), 6.65 (dd, J = 17.3, 1.3 Hz, 1H,
−CHCH2), 6.37 (dd, J = 17.3, 10.4 Hz, 1H, −CH=CH2), 6.05 (dd,
J = 10.4. 1.3 Hz, 1H, −CHCH2), 2.32 (s, 3H, Ar−CH3), 2.20 (s,
3H, Ar−CH3).
RESULTS AND DISCUSSION
■
Initially, the suitability of the 2-formyl-3-methylphenoxy
(second generation photoenol) moiety as photoenol precursor
for the photoinduced conjugation of terminal acrylates via
Diels−Alder reactions was explored. Thus, two acrylates (P1,
2) and the FMP precursor (1) or FMP functional polymer P3
were employed in photoinduced Diels−Alder reactions
(Scheme 1).
13C NMR (CDCl3, 75 MHz), δ/ppm: 197.95 (Ar-C(O)-Ar′),
166.08 (-OC(O)−CHCH2), 158.33 (−CAr−O−), 138.85 (CAr),
137.69 (CAr), 132.58 (CAr), 131.39 (−OC(O)−CHCH2), 130.77
(CAr), 130.07 (CAr), 128.37 (2 × CAr), 128.17 (−OC(O)−CHCH2),
123.70 (CAr), 113.76 (CAr), 66.18 (−CH2−CH2−OC(O)−), 62.81
(−CH2−CH2−OC(O)−), 20.61 (−CAr-CH3), 15.69 (−CAr-CH3).
HRMS (FAB) of C20H20O4, [M + H]+: calcd, 325.1439; found,
325.1440.
Initially, the FMP precursor (1) was reacted with poly-
(ethylene glycol) methyl ether methacrylate (PEG-MMA, Mn =
950 Da, P1), and butyl acrylate (2) with FMP functional PCL
(P3). The photoinduced Diels−Alder reactions were per-
formed using a 1:1 molar ratio between the reactants and either
acetonitrile or dichloromethane as solvent. Congruent with the
click criteria defined for macromolecular chemistry,10 the SEC-
ESI/MS analysis of the crude reaction mixtures showed
quantitative conversion of the polymer end-groups after 3 h
of irradiation with UV-light (320 nm) (Figure 1, mass
assignments (Tables S1 and S2) and additional SEC-ESI/MS
spectrum (Figure S1); see also Supporting Information).
These promising model reactions demonstrated the utility of
the FMP moiety as a suitable photoenol precursor for
polymer−polymer conjugations with (meth)acrylate functional
polymers. Moreover, PEG with a methacrylate end-group as a
sterically more demanding dienophile (compared to an
acrylate) was successfully employed in the photoinduced
conjugation with the FMP moiety. However, we wanted to
focus on acrylate terminated polymers in order to facilitate
polymer−polymer conjugations. Such polymers are prepared in
a straightforward fashion by, e.g., acrylation of hydroxyl
terminated polymers or directly via acyclic diene metathesis
(ADMET) polymerization of unsymmetrical α,ω-dienes.21 We
recently introduced the concept of a selective head-to-tail
ADMET polymerization using a monomer containing both a
terminal double bond and an acrylate. Such monomers
polymerize with high cross-metathesis selectivity, opening
access to different polymer architectures, such as diblock or
star-shaped polymers, if a selective and irreversible chain-
transfer agent (mono- or multifunctional acrylate) is added.19
Such a chain-transfer agent allows controlling the molecular
General Procedure for ADMET Polymerizations. Monomer 3
and the selected chain-stopper (4, 5, P5) were weighed into a Supelco
conical vial. DCM (0.3 mL) was subsequently added and the vial was
closed with a screw cap comprising a rubber septum. After 5 min of
stirring at a temperature of 40 °C, the required amount of ruthenium-
catalyst (Hoveyda−Grubbs second generation) (1.0 mol % to 3) in
DCM (150 μL) was added and a needle was inserted into the rubber
septum. After 24 h the reaction was quenched by adding ethyl-vinyl
ether (9 eq. to catalyst) to the cooled reaction mixture and THF (ca. 2
mL) was added. The ADMET polymers were isolated by precipitation
in cold pentane. Yields ranged from 85 to 95%. The molecular weights
were determined by SEC analysis (see Table 1).
Table 1. Analytical Data (SEC) of Homopolymers and
Diblock Copolymers Prepared via Head-to-Tail ADMET
Polymerization with Selective Chain-Stoppers
chain-
stopper
ratio [3]:
[CS]
Mn,SEC /
[kDa]
monomer
copolymer
PDI
3
3
3
3
3
3
4
10:1
20:1
15:1
10:1
20:1
10:1
P6
3.9
7.2
5.1
3.5
7.1
5.6
1.34
1.76
1.63
1.42
1.77
1.30
5
P8
5
P9
5
P10
P11
P7
5
P5
General Procedure for Photoinduced Diels−Alder Reac-
tions. The dienophile (1 equiv) and the photoactive o-methylphenyl
ketone or aldehyde (1 equiv) were weighted in a vial (Pyrex, diameter
20 mm). A mixture of DCM/MeCN (1:2, 2 mL) was added and the
vial was sealed with a rubber septum. Argon was then percolated
through the solution for 15 min. The solution was irradiated for
selected times (3 or 24 h) with a 36 W compact low-pressure UV-A
Scheme 1. Model Reactions of the FMP Photoenol Precursor (1) or FMP Functional Poly(ε-caprolactone) (FMP−PCL, P3,
Mn,SEC = 2.2 kDa, PDI = 1.06)
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α,β-unsaturated ester function). These model studies should be
representative for possible conjugation reactions of the
ADMET polymers (see Supporting Information for details of
1
these experiments, in Scheme S1 and Figures S2 and S3). H
NMR analysis demonstrated that it is possible to achieve
orthogonal conjugation of the terminal acrylic double bond
without reaction of the internal α,β-unsaturated ester after 2 h
of irradiation with UV-light (320 nm) using the FMP functional
polymer (P3) in these photoinduced Diels−Alder reactions at
ambient temperature. Therefore, in subsequent reactions, the
terminal acrylate of the ADMET polymers was employed for
selective polymer−polymer conjugations via photoinduced
Diels−Alder reactions. Initially, polymer−polymer conjugations
were centered on the light triggered reaction of ADMET
homopolymers or diblock copolymers synthesized with hexyl
acrylate (4) or acrylated PEG (P5) chain stopper and the FMP
functional PCL (P3) (Scheme 3). It should be noted that, in
principle, two regio-isomers can be formed during the
photoinduced Diels−Alder reaction, which is predominantly
determined by secondary orbital interactions.22 However, for a
successful polymer−polymer conjugation it is not important
which regio-isomer will be formed. Therefore, all schemes
within this manuscript only depict one of the possible regio-
isomers.
Figure 1. Expanded ESI-MS spectrum (m/z = 1230−1380) of the
photoinduced [4 + 2] cycloaddition of P3 (top) and 2 to afford P4
(bottom).
weight and direct functionalization of the ADMET polymer by
reacting selectively with one of the end groups (terminal double
bond). On the basis of this principle, diverse homopolymers
and (amphiphilic) diblock copolymers were synthesized
(Scheme 2) for the current work using undec-10-enyl acrylate
Generally, the same conditions were used as for the model
studies except for the reaction time, which was extended to 24
h in order to ensure a full end-group conversion. In addition,
the photoinduced conjugation was performed with a 1:1 molar
ratio of the polymers. The successful polymer−polymer
conjugation of the ADMET polymer (P7) and the photo-
Scheme 2. Head-to-Tail ADMET Polymerization of
Monomer (3) in Presence of a Selective Chain-Stopper (4, 5,
or P5) at 40 °C Using the Hoveyda−Grubbs Second
Generation Catalyst (1-2 mol % to 3)
1
enol-capped PCL (PCL-FMP, P3) was shown via H NMR
analysis. The NMR spectrum of the crude reaction mixture
(after 24 h of irradiation with UV-light) showed complete
conversion of the photoenol (h, i) and acrylate (e, f, g) end
group signals, and the presence of the characteristic signals (j′,
k′) of the expected block copolymer in the expected integrals’
ratio (2:1) (Figure 2). Furthermore, the internal α,β-
unsaturated ester functions remained unaltered. The SEC
analysis of the crude product displayed a clear shift to higher
molecular weights, if compared to the starting polymers (Figure
3 and Table 2), which is further proof for the successful
polymer−polymer conjugation.
So far, it was shown that polymers with an FMP moiety can
be successfully employed in efficient polymer−polymer
conjugations with acrylate terminated polymers, while at the
same time the 2,5 dimethylbenzophenone moiety (first
generation photoenol precursor) has emerged as a very
efficient photoenol precursor for polymer−polymer conjuga-
tions with maleimide functional polymers.13 Therefore, we
intended to prepare functionalized ADMET polymers having
an additional terminal photoenol moiety. Such polymers are
readily accessible via an acrylated photoenol precursor as a
chain-transfer agent in ADMET polymerizations of monomer
(3), which leads directly to end-group functionalized ADMET
polymers (refer to Scheme 2). In this context, the acrylated
photoenol precursor (first generation) appears to be partic-
ularly well suited as selective chain-transfer agent, becausein
contrast to the aldehyde functional photoenol (second
generation)no compatibility problems with the metathesis
catalyst were observed. With regard to the end-groups, the
ADMET polymers are telechelic, having one photoenol and
one acrylate moiety. To assess their selectivity in photoinduced
Diels−Alder reactions, a blank test of the ADMET polymer
(3) as monomer, and either hexyl acrylate, acrylated PEG, or an
acrylated photoenol moiety (first generation) as chain-stoppers
(for analytical SEC data, see Table 1).
The generated ADMET polymers contain internal α,β-
unsaturated ester functions and acrylate end-moieties, allowing
for their postpolymerization functionalization. In order to
determine the selectivity of the photoinduced Diels−Alder
reaction between the acrylate end group and the internal α,β-
unsaturated esters, several test reactions were carried out using
a model compound (6 having both an acrylate and an internal
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Scheme 3. Synthesis of Diblock and Triblock Copolymers by Photo-Induced Diels−Alder Reaction of the ADMET Polymers
(P6, P7) and the FMP Functional PCL (P3)
1
Figure 2. Full scale and expansion of the H NMR (CDCl3, 300 MHz) spectra of the photoenol (second generation) functionalized poly(ε-
caprolactone) (Mn,SEC = 2.2 kDa, PDI = 1.06, P3, bottom), the ADMET diblock copolymer P7 (top), and the Diels−Alder product P13 (middle).
(P8) equipped with a terminal acrylate (ω-chain end) and a
photoenol moiety (first generation, α-chain end) was carried
out. In the absence of any further dienophile, inter- or
intramolecular reactions of this bifunctional ADMET polymer
were not observed, since 1H NMR and SEC analysis showed no
difference before and after this blank test. Thus, the photoenol
moiety (first generation) shows different reactivity compared to
the photoenol moiety (second generation), because it does not
react with the terminal acrylate (for details see Supporting
Information, Figures S1 and S7). After this successful study, the
generated bifunctional ADMET polymers were employed for
the synthesis of diblock copolymers using a maleimide
functional PEG (P14) as dienophilic substrate, which should
further demonstrate the applicability of the photoenol capped
ADMET polymer for selective photoinduced polymer−
polymer conjugations (see Supporting Information, Figures
S8 and S9). In order to prove the high orthogonality that
photoinduced Diels−Alder click reactions can display, we
employed both photoenol precursors (first and second
generation) in polymer−polymer conjugations with different
dienophiles using a sequential one pot procedure. Thus, the
photoenol moiety (first generation) was employed for selective
polymer−polymer conjugation with maleimide functional PEG,
and on the other hand, the photoenol moiety (second
generation) functioned in polymer−polymer conjugations of
macromolecules having a terminal acrylate, as already
demonstrated in synthesis of triblock copolymers described
above. We developed a strategy for the synthesis of triblock
copolymers from the already prepared bifunctional ADMET
polymers P9−P11 including the primary photoinduced
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Scheme 4. Sequential One Pot Approach for the Synthesis of
Triblock Copolymers Employing the Bifunctional ADMET
Polymer (P9, P10) as Middle Block
Figure 3. SEC analysis of the polymer conjugation of the FMP
functional poly(ε-caprolactone) (Mn,SEC = 2.2 kDa, PDI = 1.06, P3)
and the ADMET diblock copolymer (Mn,SEC = 5.6 kDa, PDI = 1.30,
P7) and thereof derived triblock copolymer (Mn,SEC = 7.5 kDa, PDI =
1.28, P13). The photoinduced Diels−Alder reaction was performed at
ambient temperature c(P7) = 5 g × L−1, for 24 h under irradiation
with UV light (λmax = 320 nm).
reaction of the photoenol end-group moiety (first generation)
with a maleimide functional PEG (P14) and the subsequent
phototriggered reaction of the terminal acrylate with a
photoenol (second generation) capped PCL (P3) (Scheme 4).
The ABC-triblock copolymer synthesis was carried out as a
CONCLUSIONS
■
Photoinduced Diels−Alder reactions are introduced as a highly
orthogonal polymer−polymer conjugation methodology for
polymers having a terminal acrylate and a photoenol precursor
moiety. Herein, the photoenol moiety (second generation)
proved to be a powerful diene for the remarkably selective
conjugation of acrylate terminated polymers (as dienophilic
substrates) having unsaturated entities in their backbone.
Notably, such a modular ligation of acrylate functional
polymers via Diels−Alder chemistry was thus demonstrated
for the first time, offering new opportunities in bioconjugation,
macromolecular synthesis and preparation of novel advanced
materials. In order to achieve additional orthogonality of the
photoinduced Diels−Alder reaction, we evidenced that both
click functionalities (photoenol first and second generation) can
be employed for highly orthogonal polymer−polymer con-
jugation reactions with selected dienophiles. Thus, the
selectivity of the photoenol functional groups toward different
dienophiles was employed for the synthesis of complex triblock
copolymers by performing two orthogonal Diels−Alder
reactions on the same telechelic polymers in a stepwise, one-
pot fashion. Here, the ADMET polymerization technique
confirmed its efficiency in preparing sophisticated end-group
1
sequential one-pot procedure, taking a control sample for H
NMR/SEC analysis after the first conjugation of P9 or P10
with P14 to test for full conversion of the end-groups and
formation of the corresponding AB-diblock copolymer P16 or
P17. After the subsequent photoinduced Diels−Alder reaction
of the diblock copolymers (P16 and P17) with P3, the final
ABC-triblock copolymers (P18 and P19) were analyzed via 1H
NMR and SEC analysis (see also Supporting Information,
Figures S10−S13).
Comparison of the NMR spectra of the diblock copolymer
P17, photoenol (second generation) capped PCL P3 and the
product P18 showed complete conversion of the end-group
signals (h-l) and display the expected signals of the conjugated
polymer (a−e, o′−q′) (Figure 4).
The SEC analysis of the crude product P18 displayed a clear
shift to higher molecular weights relatively to the starting
polymers P10, P14, and P3 (Figure 5, Table 3) and the
temporary diblock copolymer P17, which is a further proof for
the successful polymer−polymer conjugation to afford the
triblock copolymer.
Table 2. SEC Data of Diblock and Triblock Copolymers Prepared via Photo-Induced Diels−Alder Reaction of ADMET
Polymers and FMP-Terminated Polymer P3 (Scheme 3)
a
a
a
acrylate polymer
Mn,SEC (PDI) [kDa]
photoenol polymer
Mn,SEC(PDI) [kDa]
copolymer
Mn,SEC (PDI) [kDa]
P6
P7
3.9 (1.34)
5.6 (1.30)
P3
P3
2.2 (1.06)
2.2 (1.06)
P12
P13
6.9 (1.16)
7.5 (1.28)
a
Relative to linear PMMA Standards.
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Article
Figure 4. Full scale and expansion of the 1H NMR (CD2Cl2, 300 MHz) spectra of the photoinduced Diels−Alder reaction of diblock copolymer P17
(top) and FMP functional PCL P3 (bottom) to afford the triblock copolymer P18 (middle).
functionalized polymers in a straightforward fashion. Finally,
the additional selectivity of the photoinduced Diels−Alder click
reaction through the choice of the photoenol and dienophile
end group functionality is a unique attribute, which cannot
readily be achieved by any other click methodology, allowing
advanced macromolecular material design. Moreover, the one
pot procedure for the straightforward preparation of such
sophisticated triblock copolymers illustrates the versatility,
simplicity, and efficiency of the highly orthogonal photo-
triggered Diels−Alder click reaction for modular polymer−
polymer conjugations.
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional NMR spectra, SEC analyses, and ESI−MS spectra/
analyses related to the present investigation. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Figure 5. SEC analysis of the polymer−polymer conjugation of the
Corresponding Author
*E-mail: (C.B.-K.) christopher.barner-kowollik@kit.edu;
(M.A.R.M.): m.a.r.meier@kit.edu.
bifunctional ADMET polymer P10 (Mn,SEC = 3.5 kDa, PDI = 1.42),
maleimide functional PEG P14 (Mn,SEC = 2.6 kDa, PDI = 1.03), FMP
functional PCL P3 (Mn,SEC = 2.2 kDa, PDI = 1.06), temporary diblock
copolymer PEG-b-P10 P17 (Mn,SEC = 6.5 kDa, PDI = 1.33) and the
final triblock copolymer PEG-b-P10-b-PCL P18 (Mn,SEC = 9.4 kDa,
PDI = 1.20).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Table 3. Analytical Data (SEC) of the Triblock Copolymer
P18 and Its Components via a Sequential One-Pot
Procedure (Scheme 4)
■
C.B.-K. acknowledges continued funding from the Karlsruhe
Institute of Technology (KIT) in the context of the Excellence
Initiative for leading German universities and the German
Research Council (DFG) as well as the Ministry for Arts and
Science of the State of Baden-Wurttemberg. The authors are
thankful to Mathias Glassner (KIT) for supplying the
maleimide-capped poly(ethylene glycol).
Mn,SEC/ [kDa]
PDI
PCL−FMP (P3)
ADMET (P10)
2.2
3.5
2.6
7.9
9.4
1.06
1.42
1.03
1.21
1.20
̈
PEG−Mal (P14)
PEG-b-P10 (P17)
PEG-b-P10-b-PCL (P18)
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