Fast and efficient [2 + 2] UV cycloaddition for polymer modification via flow synthesis

Article abstract of DOI:10.1021/ma500751j

The alkene-enone [2 + 2] photocycloaddition reaction between polymer-bound maleimide and functional alkenes has been tested in a UV-flow reactor, demonstrating a very high efficiency of the reaction. As a test reaction, polymer end group modifications were carried out on maleimide-functional poly(butyl acrylate). The polymer was prepared by atom transfer radical polymerization (ATRP) using a N-hydroxysuccinimide-functionalized initiator, followed by exchange reaction of the activated ester with a maleimide amine linker. Good control over the polymerization and successful exchange of the end group under mild reaction conditions was confirmed by electrospray ionization mass spectrometry (ESI-MS). The terminal maleimide group was then reacted quantitatively with alkenes in a custom-made tubular UV-flow reactor within a minute reaction time. Compared to reaction times in batch of several hours to days, the reaction proceeds to full conversion within 1 min under flow conditions. This significant acceleration of the reaction was achieved by employing a photosensitizer in combination with the flow reactor technique. Via the cycloaddition a variety of functional groups can be introduced to the polymer chain ranging from multifunctional allyl compounds to hydroxyl-functional alkenes, demonstrating the general versatility and high potential of the approach for polymer modification reactions.

Full text of DOI:10.1021/ma500751j

Article
pubs.acs.org/Macromolecules
Fast and Efficient [2 + 2] UV Cycloaddition for Polymer Modification
via Flow Synthesis
Matthias Conradi and Thomas Junkers*
Polymer Reaction Design Group, Institute for Materials Research (IMO-IMOMEC), Universiteit Hasselt, Campus Diepenbeek,
Agoralaan Building D, B-3590 Diepenbeek, Belgium
*
S Supporting Information
ABSTRACT: The alkene−enone [2 + 2] photocycloaddition
reaction between polymer-bound maleimide and functional
alkenes has been tested in a UV-flow reactor, demonstrating a
very high efficiency of the reaction. As a test reaction, polymer
end group modifications were carried out on maleimide-
functional poly(butyl acrylate). The polymer was prepared by
atom transfer radical polymerization (ATRP) using a N-
hydroxysuccinimide-functionalized initiator, followed by ex-
change reaction of the activated ester with a maleimide amine
linker. Good control over the polymerization and successful
exchange of the end group under mild reaction conditions was
confirmed by electrospray ionization mass spectrometry (ESI-MS). The terminal maleimide group was then reacted
quantitatively with alkenes in a custom-made tubular UV-flow reactor within a minute reaction time. Compared to reaction times
in batch of several hours to days, the reaction proceeds to full conversion within 1 min under flow conditions. This significant
acceleration of the reaction was achieved by employing a photosensitizer in combination with the flow reactor technique. Via the
cycloaddition a variety of functional groups can be introduced to the polymer chain ranging from multifunctional allyl
compounds to hydroxyl-functional alkenes, demonstrating the general versatility and high potential of the approach for polymer
modification reactions.
1
. INTRODUCTION
conjugations; thus, two of the most prominent click-type
9
−15
approaches used in macromolecular chemistry.
Another
Photoinduced [2 + 2] cycloadditions are a well-known
1
,2
advantage of photocycloadditions is its orthogonality toward
synthetic tool in organic chemistry. Via this class of reactions,
simple access is given to four-membered (heteroatom) ring
structures. Different varieties of [2 + 2] reactions have been
extensively applied for the preparation of natural products or
16,17
“
classical” heat-induced reactions.
The [2 + 2] additions
can hence be independently triggered, and different ligation
reactions toward maleimide-containing substrates can be
achieved in a controlled manner by switching from thermal
activation to photo irradiation, allowing for a “dual use” of the
functionalities.
3
drug design where four-membered ring structure are a
4
−6
common leitmotif.
2 + 2] reactions is extended by using them also as conjugation
tools to couple two building blocks to each other. In previous
Buchi reaction (between
Next to total synthesis, the scope of
[
In many cases photoreactions suffer from long reaction
times; several hours to days are not uncommon to form a
desired product in high yield, which poses a significant
disadvantage when comparing the method with other photo-
studies we had shown that the Patero−
̀
̈
a terminal aldehyde and a vinyl compound) can be a useful tool
7
for polymer end group modification as well as for dense
surface grafting of nanoparticles. Conjugation proceeds in
18−21
8
ligation procedures.
The long reaction times stem mainly
from low light efficiencies, which is often due to too strong light
absorption (leading to light intensity gradients) or inefficient
batch mode under high efficiency; however−as a general
limitation−quite large excesses of the vinyl compound (>10
equiv) have to be used alongside extended UV illumination
times (>15 h), which somewhat limits the applicability of the
reaction for material design purposes. In order to optimize
22−24
energy redistribution.
Generally, for [2 + 2] cycloadditions
to proceed, the first step is the excitation of the ground state of
a UV-absorbing ene to create a reactive intermediate which can
be quenched by a second alkene, yielding the [2 + 2]
cycloadduct. It is assumed that the mechanism proceeds
[2 + 2] reactions as conjugation tools, different substrates were
tested with good results for maleimide (drivatives) in alkene−
enone photocycloadditions. Maleimides are easily excited to a
triplet state via UV irradiation and can thus serve as excellent
conjugation moieties (see Scheme 1).
Maleimdies are also known as key functionalities in polymer
conjugation reactions, namely, in thiol−ene and Diels−Alder
25−27
through an exciplex.
It should be noted that different
Received: April 11, 2014
Revised: June 26, 2014
Published: August 12, 2014
©
2014 American Chemical Society
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Scheme 1. Alkene−Enone Maleimide [2 + 2] Cycloaddition as a Conjugation Tool in Polymer Synthesis
stereo- and regioisomers can be obtained in the reaction, which
poses a certain limitation for its use in natural product
synthesis. For pure conjugation reactionsthus the formation
of stable C−C linkages as often required in polymer
reactionsplay regio- and stereoselectivity a minor role. In
such case, only the yield per time is a limitation, which can,
however, be greatly improved when changing the reaction
yields when reaction conditions are chosen carefully. The
[2 + 2] cycloadditions can hence generally serve as a highly
useful tool in polymer reactions for a variety of modification
reactions.
2. EXPERIMENTAL PART
Materials. Ethanolamine (>99%, Sigma-Aldrich), Boc-anhydride
(97%, Acros), THF (tech., Prolabo), maleimide (99% Aldrich),
diisopropyl azodicarboxylate (DIAD 98%, Aldrich), triphenylphosphin
28−33
mode from batch to a flow chemistry approach.
By applying the alkene−enone [2 + 2] cycloaddition
between a variety of alkenes and maleimide in a continuous
UV-flow reactor, we demonstrated that the reaction rate was
increased from days to minutes at equimolar reagent ratios
while still allowing for complete conversion to the [2 + 2]
cycloadduct. Hence, reaction conditions were met that come in
terms of efficiency at least close to classical click conjugation
(99%, Acros), TFA (99%, Acros), N-hydroxysuccinimide (NHS 98%,
Aldrich), 2-bromopropionyl bromide (97%, Aldrich), 2-bromo-2-
methylpropionyl bromide (98%, Aldrich), (99%, DCM (tech.
Prolabo), pyridine (99+%, Acros), butyl acrylate (BA 99+%, Acros),
CuBr (98%, Sigma-Aldrich), PMDETA, ethyl acetate (EtOAC tech.,
Prolabo), triethylamine, thioxanthen-9-one (TXS 97%, Aldrich). 2-
Methylpentene (99%, Acros), 1-octene (98%, Aldrich), cyclooctene
(95% COE, Fluka), allylamine (98%, Aldrich), buten-3-ol (96%,
Aldrich), allyl ethyl ether (95%, Aldrich), styrene (99.5%, Acros), and
triallyl cycanurate (97%, Aldrich). The BA was deinhibited over a
column of basic alumina, prior to use. Copper(I) bromide was first
washed with acetic acid, later ethanol, and then diethyl ether (tech.)
and dried in vacuo. All other compounds were used as received.
3
4
reactions. For the flow process, a relatively simple custom-
made UV-flow reactor consisting of thin translucent PFA
tubing wrapped around a quartz cooling mantle containing a
high-power UV-light source was employed. Efficiencies are in
such reactors generally increased due to the small optical path
lengths that need to be passed, which is followed by a
homogeneous excitation in the whole reaction medium. UV-
initiated/triggered reactions can in this manner be speed up
significantly, be it in the realm of polymer synthesis or in the
1
Characterization. H NMR spectra (300 and 400 MHz, Oxford
Instruments Ltd.) were recorded in deuterated chloroform at a pulse
delay of 12 s using a Varian probe (9 mm 4-nucleus AutoSWPFG).
Analytical SEC (size exclusion chromatography) was performed on
a Tosoh EcoSEC HLC-8320GPC, comprising an autosampler, a PSS
guard column SDV (50 × 7.5 mm) followed by three PSS SDV
analytical linear XL (5 μm, 300 × 7.5 mm) columns thermostated at
35,36
realm of organic chemistry.
Also, flow reactions have the
advantage that the optimized reaction can be upscaled without
3
7
too much effort.
2
6
−1
4
0 °C (column molecular weight range: 1 × 10 −1 × 10 g mol ),
In here we demonstrate how the [2 + 2] alkene−enone
cycloaddition between alkenes and maleimides is translated
from a small molecule reactionas we had previously
describedto a polymeric system, i.e., poly(butyl acrylate),
pBA, substrates. Before the photocycloaddition is discussed, we
will introduce a mild synthesis route toward maleimide
functional polymers from a combination of controlled polymer-
and a differential refractive index detector (Tosoh EcoSEC RI) using
−
1
THF as the eluent at with a flow rate of 1 mL min . Toluene was used
as a flow marker. Calibration was performed using linear narrow
polystyrene (PS) standards from PSS Laboratories in the range of
6
−1
4
70−7.5 × 10 g mol .
Electrospray ionization mass spectrometry (ESI-MS) was per-
formed on an LTQ Orbitrap Velos Pro mass spectrometer
ThermoFischer Scientific) equipped with an atmospheric pressure
(
38−41
ization and activated ester transformation.
This synthesis
ionization source operating in the nebulizer-assisted electrospray
mode. The instrument was calibrated in the m/z range 220−2000
using a standard solution containing caffeine, MRFA, and Ultramark
1621. A constant spray voltage of 5 kV was used, and nitrogen at a
dimensionless auxiliary gas flow rate of 3 and a dimensionless sheath
gas flow rate of 3 were applied. The capillary voltage, the tube lens
offset voltage, and the capillary temperature were set to 25 V, 120 V,
and 275 °C, respectively. A 250 μL aliquot of polymer solution with a
approach features the advantage over classical maleimide-
functional polymer synthesis that the introduction of the
maleimide does not require high temperatures and can be
carried out under as mild reaction conditions as the later
photoligation. The so-obtained polymers are then tested
toward their performance in photocycloadditions in a
32
custom-made continuous UV-flow reactor. As we will show,
2 + 2] photoconjugations between polymer and a variety of
−1
concentration of 10 μg mL was injected. A mixture of THF and
[
methanol (THF:MeOH = 3:2), all HPLC grade, was used as solvent.
Continuous Tubular Reactor Setup. The tube flow UV reactor
consists of a HPLC pump (Knauer BlueShadow 20P), a quartz cooling
mantle (Photochemical Reactors Ltd., UK) which was wrapped tightly
by a 25 m fluorinated gastight transparent PFA tubing (VICI, 1/16 in.
alkenes proceed fast (in the order of few minutes) under these
conditions, whereby the photostability of compounds and
reaction rates were largely improved by applying an aromatic
2
3,42,43
photosensitizer.
Efficiencies close to that of UV-induced
×
0.75 mm, 25 m, Vtubing = 11 mL), and a 400 W medium pressure
UV-lamp (λmax = 365 nm). The whole tubing is irradiated
thiol−ene conjugations are achieved. The flow reactor can
thereby be operated under stable conditions without clogging
of the reactor lines, giving direct access to a scalable process.
More than a synthesis method for end-functional polymer
materials, the demonstrated photoreaction can be seen as a
proof that this type of reaction proceeds quickly and in high
homogeneously by the UV-lamp. The reaction temperature (T = 4
°
C) was controlled by a cryostat (Grant LTD6/20) filled with water.
Furthermore, the irradiation source and reactor are mounted in a
3
4
closed box for safety reasons. More details on the employed setup
can be found in a previous publication.
3
4
5
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Scheme 2. (1) Synthesis of the NHS Bearing ATRP Initiator; (2) Controlled Polymerization Employing the Initiator
Synthesis of NHS-Modified ATRP Initiators: (a) 2,5-Dioxo-
pyrrolidin-1-yl 2-Bromo-2-methylpropanoate and (b) 2,5-
Dioxopyrrolidin-1-yl 2-Bromopropanoate. Both initiators were
synthesized following modified literature procedures. NHS (6 g, 1.2
equiv, 52.1 mmol), 100 mL of dry DCM, and pyridine (3.86 g, 1.1
equiv, 47.8 mmol) were placed into a 250 mL three-necked round-
bottom flask fitted with a condenser, a magnetic stirrer, a nitrogen
inlet−outlet, and an addition funnel containing a mixture of the
corresponding acid bromide [(a) 2-bromopropionyl bromide (9.38 g,
(D O, 400 MHz): δ = 6.86 (s, 2H, H ), 3.80 (m, 2H, CH ), 3.19 (m,
2 ring 2
+
2H, CH NH ).
2
3
Exchange of NHS Group by Maleimide Ammonia Trifluor-
44
oacetate. NHS-functional poly(butyl acrylate) (1 equiv, 1.31 g, 1.08
−1
mmol, 1200 g mol ) was mixed with ammonia trifluoroacetate salt
(2.2 equiv, 605 mg, 2.38 mmol) and triethylamine (TEA) (2.2 equiv,
−3
790 μL, 0.7255 g cm , 2.38 mmol) in solution of 10 mL of dry THF.
The mixture was stirred for 2 days at 30 °C in the dark. The excess of
TFA-salt and amine were removed via passing the solution through a
1
equiv, 43.4 mmol) and (b) 2-bromo-2-methylpropionyl bromide
3−4 cm thick layer of silica, three times (1.28 g, 98%). ESI-MS (3
+
(
10.00 g, 1 equiv, 43.4 mmol)] and 50 mL of DCM. The flask was
THF:2 MeOH, positive mode): C79
H
131
N
2
O
23BrNa ; theory:
−1
−1
placed into an ice−water bath. The solution of the acid bromide was
added dropwise over a period of 0.5 h under nitrogen. Then the
mixture was stirred at room temperature overnight, after which 100
mL of DCM was added. The solution was washed three times with 1
M HCl, once with 150 mL of H O, and brine (150 mL). Finally, the
organic phase was dried with MgSO , and the solvent was removed,
1577.822 g mol ; found: 1577.8 g mol .
General Procedure for ATRP Polymerization. The purified
Cu(I)Br (1 equiv, 1.38 mmol, 198 mg), BA (75 equiv, 104.13 mmol
15 mL), and PMDETA (2 equiv, 2.75 mmol, 575 μL) were added into
a sealed Schlenk tube. A second Schlenk tube with 2,5-dioxopyrrolidin-
1-yl 2-bromopropanoate (1 equiv, 1.38 mmol, 348 mg) and 1 mL of
EtOAc was prepared. Both tubes were deoxygenized via three freeze−
pump−thaw cycles. The initiator solution was then added via a
degassed needle to the monomer solution, and the reaction mixture
was placed in a preheated oil bath (65 °C). After 30 min,
polymerization was stopped by cooling in liquid nitrogen, and a
NMR sample was taken for conversion determination. The polymer/
monomer mixture was dissolved in THF, and the copper catalyst was
removed by passing the diluted reaction mixture over silica. After
evaporating of the excess solvent and monomer, the polymer was
2
4
yielding fine white crystals. Yield: (a) 7.82 g (72%) and (b) 8.72
(
76%). Further purification was performed via column chromatog-
raphy (silica) using hexane:EtOAc = 3:1, v/v. (a) Secondary NHS-
ester initiator: H NMR (300 MHz, CDCl ) = 4.45−4.36 (q, 1H,
CHBr, J = 7 Hz), 2.76 (s, 4H, CH ), 1.84 (d, 3H, CH , J = 7 Hz). (b)
Tertiary NHS-ester initiator: H NMR (300 MHz, CDCl ) = 2.85 (s,
4
1
3
2
3
1
3
H, CH ), 2.06 (s, 6H, CH ).
Preparation of Boc-Protected Ethanolamine. Ethanolamine
2
3
4
5
(
1 equiv, 1.4 g, 22.91 mmol) was dissolved in 50 mL of dry THF and
characterized; yielding 1.3 g (9.8% conversion) of polymer with M =
cooled down to 0 °C. Boc-anhydride (1 equiv, 5.0 g, 22.91 mmol) was
added, and a white precipitate formed immediately, which disappeared
again. The reaction mixture was allowed to reach room temperature
and stirred for 4−6 h. Then the solvent was removed, and the
remaining clear oil was dissolved in DCM. The organic layer was
n
−1
1
300 g mol and Đ = 1.18 (by THF-SEC).
3
. RESULTS AND DISCUSSION
The flow reaction of maleimide with vinyl components had
been demonstrated in our previous study; we hence focused in
this work directly on polymers bearing maleimide end groups
to extend the scope of the reaction. As a model polymer pBA
was chosen. To allow the use of ESI-MS as characterization
tool, end-functional pBA has been modified in the following.
Reactions should, however, proceed with similar results also on
materials bearing multiple maleimide functions and with
different polymer types.
consecutively washed with 25 mL of NaHCO solution, 25 mL of
3
water, and 25 mL of brine and dried over MgSO . The solvent was
4
1
removed in vacuo, yielding a clear oil as product (3.05 g, 83%). H
NMR (CDCl , 300 MHz): 5.02 ppm (br s, 1H, NH), 3.69 (t, 2H,
3
CH ), 3.06 (t, 2H, CH ), 2.97 (br s, 1H, OH), 1.43 (s, 9H, CH ).
2
2
3
Preparation and Deprotection of 1-(2-Aminoethyl)-1H-
4
6
pyrrole-2,5-dione Trifluoroacetate. Ph P (1 equiv, 11.74 g,
4
3
−
3
4.79 mmol) and DIAD (1 equiv, 8.79 mL, 1.03 g cm , 44.79 mmol)
was dissolved in 250 mL of dry THF at 0 °C and stirred for 20 min,
yielding a yellow cloudy mixture. Then the Boc-protected amino-
ethanol (1 equiv, 7.22 g, 44.79 mmol), dissolved in 100 mL of dry
THF was added at 0 °C and stirred for 20 min. When the maleimide
3
.1. Preparation of a Maleimide-Functional pBA.
Preparation of maleimide-functional polymerseven though
being highly valuable materials as noted aboveis not very
straightforward. Maleimide-functional initiators are classically
protected in Diels−Alder reactions with furane prior to
polymerization to avoid copolymerization. After reaction, the
furane is then removed via thermal treatment of the polymer in
a retro-Diels−Alder reaction. Since one of the advantages of
photoligation is the use of mild reaction conditions, we thus
opted to use an alternative pathway by employing an activated
ester strategy to realize also the maleimide building block
(
1.2 equiv, 5.22 g, 53.75 mmol) was added at 0 °C, the solution
changed color quickly to orange. The reaction was the stirred at room
temperature for 2 days. The solvent was removed, and the orange oil
was washed twice with hexane:Et O (1:1, v/v) to remove Ph PO
2
3
residues. The product was purified via column chromatography with
petrol ether:EtOAc (5:2 → 2:1, v/v). The product was obtained as
1
white powder (7.04 g, 65.4%). H NMR (CDCl , 300 MHz): δ = 6.71
3
(
s, 2H, Hring), 4.72 (br s, 1H, NH), 3.66 (m, 2H, CH ), 3.33 (m, 2H,
2
CH NH), 1.40 (s, 9H, CH ).
2
3
Deprotection was carried out with 40% TFA solution in DCM at 0
38
4
7
synthesis under mild conditions. Isolatable activated esters,
°
C and stirring for 2−3 h. The solvent and excessive TFA were
48
such as pentafluorophenyl groups, can be used in versatile
fashion to introduce a variety of functional groups in polymer
substrates by simple exchange reactions. Being mostly used in
removed under reduced pressure. The residue was dissolved in 5 mL
of MeOH and precipitated into 50 mL of Et O, yielding the ammonia
2
1
trifluoroacetate salt as a fine fluffy powder (4.38 g, 86.6%). H NMR
5
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Scheme 3. Introduction of a Maleimide End Group to the NHS-Activated Polymer End Group
biochemistry, also N-hydroxysuccimide (NHS) esters are well-
functional product B . The only mentionable side products
Br
known functions to serve this purpose.
observed is a species that is isobaric formally with a maleimide
dimerization reaction product between the maleimide amine
49
A NHS-functional ATRP initiator was obtained by reacting
NHS with 2-bromopropanoyl bromide, yielding 2,5-dioxopyr-
rolidin-1-yl 2-bromopropanoate (for structure see Scheme 2
linker and maleimide functional polymer (C ). This species
Br
could, however, also simply be a physical adduct that forms
during the ESI process (as is indicated by absence of an
analogue C′ species). Regardless, C occurs in acceptable low
(
1)). In the second step, the so-obtained initiator was then used
in conventional ATRP under standard reaction conditions
Scheme 2 (2)), yielding well-defined polymers (M = 1300 g
Br
Br
(
abundances and does not interfere with the following reaction
steps and indeed disappears in the following reaction steps (see
discussion below). In small quantities, also some proton-
terminated (but yet maleimide-functional) polymer is observed
which stems from disproportion products that was formed
n
−1
mol , Đ = 1.18) with high end group fidelity. In should be
noted that polymers were synthesized with low molecular
weight on purpose in order to enable mass spectrometry
analysis for tracing end group reactions, which is complicated
with higher molecular weights. Polymers with higher molecular
weights could though also be synthesized without problems.
To add a maleimide functionality to the NHS end-functional
polymer, a maleimide linked to a (primary) amine is required.
Therefore, the amino group of aminoethanol was boc-
protected, followed by linking the maleimide via a Mitsunobu
reaction to allow for a high reaction efficiencies. The
Mitsunobo reaction was chosen due its high reaction yields
and overall simplicity to be carried out. Deprotection is in the
last step performed via trifluoroacetic acid (TFA) solution
yielding the associated TFA salt as a white poweder.
during the ATRP process (B ). It should be noted that the
H
spectrum displays a relatively large number of peaks due to the
ammonium salt being able to act as a counterion, thus doubling
the number of peaks visible in the spectrum. Unassignable, low
abundant peaks might hence also stem from different
counterions.
In summary, the NHS synthesis route allows to synthesize
maleimide-functional polymers with overall good success. It
should at this point also be noted that such amine exchange
reactions usually are carried out on much shorter time scale,
which is in the present case hindered by the TFA salt. If the
amine was freed from the salt prior to reaction, reaction times
could probably be reduced to tens of minutes, which in the
present case was, however, not required, since the aim of the
study was only to optimize the later photocycloaddition
reaction.
3.2. Preparation of Maleimide Functionalized Poly-
mer. To exchange the NHS ester by the maleimide linker,
reactions had to be performed in basic environments to free the
amine from the TFA salt (see Scheme 3). Inspection of the
mass spectra given in Figure 1 demonstrates that the end group
exchange is very successful. The most significant peaks in the
spectrum can be clearly assigned. Experimental as well as
theoretical m/z are summarized in Table 1. All NHS-related
3
.3. Alkene−Enone Cycloaddition. With the precursor
maleimide-functional polymers at hand, polymer modification
in the [2 + 2] ene−enone reaction could be targeted.
Therefore, reactions were carried out in a UV batch reactor,
peaks (A ) have almost quantitatively disappeared from the
Br
̈
according to our previous study on Paterno−Buchi con-
spectrum, and the main product is the desired maleimide-
7
jugations. Reactions in batch were successful with comparable
efficiencies (long reaction times, large excess of alkene) as
observed before. We then proceeded quickly to the UV-flow
34
reactor. The reaction efficiency of the [2 + 2] cycloaddition
was mapped for the reaction of the pBA-malemide with a small
model compound (see Scheme 4). 2-Methylpentene (1) and 1-
octene (2) were used to optimize conditions. Since pure
maleimide alkene−enone cycloadditions proceeded in flow
within few minutes, the reaction was tested at a wavelength of
2
54 nm (16 W) for short timespans (1−8 min, regulated by
adjusting the flow rate). Acetonitrile was chosen as a solvent
due to its inertness and low UV-absorption profile. pBA-
maleimide (c = 8 × 10− mol L , M = 1300 g mol ) and
4
−1
−1
n
alkene (10 equiv) in acetonitrile solution were irradiated at 4
°
C. Under these conditions, no reaction was observed with
octene, while the reaction with the secondary alkene, 2-
methylpentene, yielded 45% cycloadduct. Increase in yield by
choosing higher reaction times failed due to the onset of
polymer degradation. ESI-MS spectra of the degrading
materials can be found in the Supporting Information.
This result is somewhat surprising. Even though a reduction
of reaction efficiency must be expected when switching from
small molecules to polymer systems, these results are in large
Figure 1. NHS end group exchange of pBA end groups by maleimide
linker as monitored by high-resolution ESI-MS. Peaks marked with “x”
could not be assigned to any species.
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Table 1. Experimental and Theoretical m/z Values for the Peaks Identified in the Spectrum Given in Figure 1 (Main Products
Are Marked in Bold)
symbol
end group 1
end group 2
DP
ion
m/ztheory
m/zexp
ABr
BBr
BH
NHS
Br
Br
H
9
9
Na+
1552.790
1577.822
1499.911
1567.815
1489.904
1589.797
1552.791
1577.822
1499.916
1567.820
1489.909
1589.797
+
maleimide
maleimide
maleimide
maleimide
dimer
Na
+
10
8
Na
+
B′Br
B′H
CBr
Br
H
C H N O
6 9 2 2
+
9
C H N O
6
9
2
2
Br
8
Na+
Scheme 4. [2 + 2] Photoinduced Alkene−Enone Polymer Cycloaddition in Flow in the Presence of the Thioxanthone
Photosensitizer TXS
contrast to our previous findings. A shift in maleimide
absorption to form the triplet state cannot be the reason for
the loss in reactivity since the polymer displays an almost
unchanged UV absorption at 275 nm for the maleimide when
bound to the polymer. To enforce the reaction, the flow
experiments were thus repeated employing a stronger UV-lamp
Table 2. Conjugation Yields (Conversion of Maleimide) for
the UV Cycloaddition of pBA-Maleimide at c = 8 × 10−
4
pBA
mol L− in the Presence of a 10 times Excess of Alkene under
Variation of the Photosensitizer Concentration TXS at a
Fixed Residence Time of 1.1 min in the UV-Flow Reactor
1
yield[2+2]/%
(
3
400 W) with then also higher light emission wavelength (λ =
65 nm) to avoid potential absorption of light by the acrylate
mol %TXS
octene
2-methylpentene
a
a
polymer itself. With the 400 W light source, residence times
above 2 min resulted in heavy degradation of the polymer, as
evidenced by mass spectrometry and THF-SEC.
0
≈49
55
−
−
−
3
2
1
a
10
10
10
1
48
35.0
41.8
69.4
>95
Therefore, the reaction time was reduced to the residence
53.4
71.4
>95
time where no degradation was yet, or at least not significantly
−
1
observed (1.1 min, flow rate of 10 mL min ). With
thioxanthone (TXS, λmax = 378 nm), known to act as a
10
a
Polymer degradation observed.
42
photosensitizer for alkene−enone cycloadditions, further
experiments were performed at this short residence time
result in significant yields on the time scale. The acceleration of
the reaction is thus a result of the combined action of TXS and
the flow processing, not just of one of both.
(
note that low residence times are equivalent to high flow rates
and thus fast synthesis of materials at large scale). TXS absorbs
43
light efficiently and transfers the energy to the maleimide.
Interestingly, the presence of small amounts of sensitizer
does not lead to quantitative conversion but still significantly
reduces the occurrence of photodegradation. TXS thus serves a
double purpose in the reaction as photocatalyst, but also in
preventing unwanted side reactions. From roughly 0.1 mol %
on, increasing yields are observed for the [2 + 2] cycloaddition,
also allowing to couple 1-octene, which showed no activity in
the flow reactor before. Reaching 10 mol % of TXS compared
to polymer, practically quantitative conversion to the desired
product is observed. It should be noted that 10% is a
comparatively high amount for a catalyst, but in view of the
high mass of the polymers, absolute amounts are comparatively
small. Yet, removal of the sensitizer after reaction is required,
The UV−vis spectra of the pBA-maleimide and TXS are given
in the Supporting Information. Again, the use of TXS was
tested toward the conjugation of the primary and secondary
alkene 1 and 2. The concentration of TXS was varied from 0 to
1
0 mol % according to the polymer alongside a 10-fold excess
−4
of alkene (polymer concentrations are typically low, 8 × 10
−
1
mol L ); thus, TXS concentrations as well as alkene
concentrations are still in a reasonable level. As is evident
from Table 2, the yield of reaction increased significantly from
0
and 50%, respectively, to almost quantitative conversion for
both alkenes. It must thereby be noted that usage of the same
TXS concentration in a batch [2 + 2] cycloaddition did not
5
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dx.doi.org/10.1021/ma500751j | Macromolecules 2014, 47, 5578−5585

Macromolecules
Article
5
1
which can be achieved by precipitation for most polymers. The
difference between the reaction with and without TXS is
depicted in Figure 2 for the less active 1-octene as reaction
photosplitting. Thus, in our setup, photosplittinghere then
a desired reactioncan take place. Regarding polymer
dimerization, we detected indeed a slight increase in molecular
weight after the flow reaction from 1300 up to 1750 g mol−
with, however, unchanged polydispersity. Rise of a shoulder in
1
5
2
the distribution as should be expected when coupling occurs
is not observed, and the change in M may be attributed to the
n
limited reproducibility of SEC as well as to the fact that a
changed end group does at such short chain lengths
significantly alter the hydrodynamic volume. Additionally,
ESI-MS did not show any species affiliated to a maleimide
polymer dimer of two polymer chains; neither single nor
double charged. It is thus hypothesized thatshould a dimer
be formed during the flow reactionimmediate cleavage
occurs due to the presence of high-energy light (<250 nm),
which cleaves the maleimide dimer but not the desired alkene−
enone product. Absence of dimerization products was observed
in all reactions carried out.
3
.4. Approaching Equimolarity. In the tests with TXS,
excesses of the alkene were still employed. While reaction
outcomes were already satisfactory, it is also interesting to test if
the amount of alkene can be reduced to increase the economic
efficiency of the reaction. In principleif reactions could be
carried out under equimolar conditions (as seen with small
molecules in flow even in absence of TXS)also polymer−
polymer conjugation would become available for block
copolymer synthesis. Thus, the content of the secondary
alkene was systematically varied in the presence of 10 mol % of
TXS under otherwise unchanged flow conditions. The amount
of alkene was varied between 10 and 1 equiv (see Table 4).
Figure 2. ESI-MS spectrum of the pBA-maleimide [2 + 2]
cycloaddition product from reaction in flow with 10 equiv of octene
under irradiation at 365 nm (400 W) with (10 mol %) and without the
photosensitizer TXS for 1.1 min residence time at 4 °C.
partner. ESI-MS spectra for the reaction with 0 and with 10 mol
%
are overlapped, showing clearly the degradation that occurs
in absence of TXS and the almost pristine end group
distribution that is achieved in the presence of it. A list of m/
z for the individual peaks is given in Table 3. Peaks in the
spectra that were unassignable (degradation products) are
marked with a cross. An according spectrum and mass table for
the secondary alkene is given in the Supporting Information.
Table 4. Overview of the Reaction Yields As Determined by
ESI-MS for the Photoinduced Cycloaddition between pBA-
Maleimide and 2-Methylpentene under Variation of the
a
Alkene Content
An interesting remark is that the species C that (seemingly)
entry
equiv 2-methylpentene
yield[2+2]/%
Br
was present after the (non-UV) reaction of the NHS-functional
pBA has practically vanished after the reaction in the presence
of TXS, indicating that it was indeed a measurement artifact.
However, even if was a physically present species, its
disappearance could be explained. As was demonstrated nicely
before, maleimdies also form dimers in a photocycloaddition.
These reactions are, however, reversible when irradiated at
wavelengths below 250 nm. A study of Horie et al. examined
the formation of maleic anhydride photodimers in a micro-
reactor and found that by installing a pyrex glas filter (UV
cutoff at 280 nm) in front of the UV lamp allowed to avoid
1
2
3
4
5
6
10
8
≥95
≥95
≥90
≥85
≥90
≥85
6
4
2
5
0
1
a
Note that ESI-MS is not fully quantitative but allows for reasonable
assessment of reaction yields for end group modifications.
Table 3. Overview of the Species Detected in ESI-MS (See Figure 2) for the Photoinduced Cycloaddition between pBA-
Maleimide and Octene with and without TXS (Main Product Observed Is Given in Bold)
symbol
end group 1
end group 2
DP
ion
m/ztheory
m/zexp
BBr
maleimide
maleimide
maleimide
maleimide
“dimer”
Br
9
10
8
Na+
Na+
1577.822
1499.911
1567.815
1489.904
1589.797
1433.780
1483.953
1467.566
1517.740
1567.912
1577.822
1499.916
1567.820
1489.909
1589.797
1433.773
1483.944
BH
H
+
+
B′Br
B′H
CBr
Br
C H N O
6 9 2
2
2
H
9
C H N O
6
9
2
Br
8
Na+
+
DBr
DH
[2 + 2]
Br
8
Na
+
[2 + 2]
H
9
Na
+
EBr,Br
EBr,H
EH,H
dimerization
dimerization
dimerization
Br,Br
Br,H
H,H
7
Na
+
8
Na
+
9
Na
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Macromolecules
Article
Reactions show that high conversions are observed in the full
concentration range. However, a minimum excess of 6 equiv is
required to reach truly complete conversion, virtually showing
no residues of the starting material. Therefore, all further
experiments were performed with at least 5 equiv of alkene to
ensure the quantitative conversion of the maleimide-functional
polymer. It should still be noted that also under equimolar
conditions maleimide conversions above 80% are obtained.
While this efficiency is not sufficient to reach polymer−polymer
conjugation, it is still in good agreement with methods such as
UV-induced radical thiol−ene reactions. Hence, the mal-
eimide alkene−enone photocycloaddition represents a highly
efficient conjugation method that is certainly applicable in side-
chain modifications as well as grafting-to or cross-linking
reactions. Studies focusing on these aspects are currently under
way in our laboratories.
Table 5. Yields of the Photocycloaddition Reaction in Flow
of pBA-Maleimide with the Functional Alkenes Given in
Scheme 4 with cpBA = 5 × 10− mol L in the Presence of 0.1
equiv of Photosensitizer TXS, Irradiation at 365 nm (400
W), and a Residence Time of 1.1 min at 4 °C
4
−1
alkene
equiv TXS
equiv alkene
yield[2+2]/%
2
1
-methylpentene
-octene
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
4
5
5
5
5
5
5
≥95
≥95
≥95
COE
53
allylamine
buten-3-ol
allyl ethyl ether
styrene
≥85
≥90
24
a
triallyl cyanurate
1
80
a
3 equiv when number of functional groups is compared.
3
.5. [2 + 2] UV Cycloadditions with Functional
Alkenes in Flow. Neither octene nor 2-methylpentene carries
a dedicated functional group that may be used in later
applications. Thus, also alkenes bearing various functionalities
were tested (see Scheme 4). Tested were cyclooctene 3,
allylamine 4, buten-3-ol 5, allyl ethyl ether 6, styrene 7, and
triallyl cyanurate 8. Alkene 8 carries three functional alkene
groups and could act as a potential cross-linker or anchor point
for further conjugation reactions. These alkenes were chosen to
represent a broad range of functionalities in order to test for
functional group tolerance of the reaction.
All reactions with the alkenes given in Scheme 4 were
performed according to the conditions that were optimized
with the alkenes 1 and 2. The cyclic alkene 3 allowed likewise
for yields of above 95% cycloadduct. Allylamine 4 seems not to
undergo an alkene−enone cycloaddition; none of the peaks
detected in ESI-MS could be assigned to a known species.
Alkene 5, an alcohol, is associated with a maximum yield of
times of close to a day in batch, quantitative conversion of the
starting material is observed after little over a minute reaction
time.
Maleimide end-functional poly(butyl acrylate) was synthe-
sized (in batch) via an activated ester pathway utilizing a NHS
functional ATRP initiator.
The [2 + 2] cycloadditions between the maleimide end
group and unfunctionalized alkenes were performed in a
custom-made UV flow reactor. After optimization of reaction
conditions, excellent end group conversions were observed
when 10 mol % of the photosensitizer TXS was employed
alongside a moderate excess of the alkene component. Reaction
times are very short, allowing for complete conversion of the
maleimide in roughly 1 min. Using the same methodology, also
functional alkenes were introduced and conjugated to the
polymers, allowing to ligate alcohols, ethers, and multifunc-
tional allyl compounds in satisfactory yields.
Overall, the reaction shows very high efficiency when carried
out in flow. Under these conditions, similar efficiencies are
reached as compared to classical UV-initiated (radical) thiol−
ene. In future, the [2 + 2] cycloadditions may thus equally find
application for polymer modifications in a similar domain when
compared to thiol−ene chemistries.
8
5% while the ether-containing alkene 6, allowed to reach
yields above 90%. In both cases, quantitative conversion may be
reached by increasing the equivalents of the reactant. Styrene 7
did not add to the maleimide in a sufficient rate. Only 24% of
the expected [2 + 2] cycloadduct was formed. The 3-armed
alkene 8 formed a [2 + 2] adduct (≈80%) successfully with
only one of the potential alkene groups being attached. The
further possible double or triple addition of maleimide polymer
were not detected in any significant quantity. All alkenes 1−8
showed after irradiation a slight increase of number-average
molecular weight from 1300 to 1700 g mol . As noted above,
this can be attributed to SEC calibration variation and to the
fact that the mass of the chains is in the cycloaddition indeed
increased. All ESI-MS spectra for the polymers obtained are
displayed in the Supporting Information. Compared to our last
study dealing with the same [2 + 2] cycloaddition, between
unbound maleimide and alkenes 1−8, similar trends as
described in here were observed with regards to the success
of the individual reactions with respect to its functional group
tolerance. Compared to the polymer end group modification in
7,34
ASSOCIATED CONTENT
Supporting Information
NMR spectra of the synthesized compounds and ESI-MS
spectra of the modified polymers. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
−1
*
S
34
AUTHOR INFORMATION
Corresponding Author
*Tel +32 (11) 26 8318; Fax +32 (11) 26 8399; e-mail thomas.
junkers@uhasselt.be (T.J.).
■
Notes
the batch Paterno−Bu
̈
chi reaction, also similar trends are
observed (less efficiency with allylamine and butenol).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
4
. CONCLUSION
Financial support in the framework of the Hercules foundation
for funding in the framework of the project “LC-MS@
UHasselt: Linear Trap Quadrupool-Orbitrap mass spectrom-
eter” is gratefully acknowledged. The authors also thank
additional financial support from UHasselt BOF funds in the
form of a PhD scholarship for M.C.
The successful implementation of UV-induced alkene−enone
cycloaddition of alkenes with maleimide-functional polymers in
a continuous flow reactor was demonstrated. Compared to the
previously studied batch reactions of similar type, a largely
increased reaction efficiency is observed. Instead of reaction
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(
37) Wenn, B.; Conradi, M.; Carreiras, A.; Haddleton, D.; Junkers, T.
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