Two Colour Photoflow Chemistry for Macromolecular Design

Article abstract of DOI:10.1002/anie.202003130

We report a photochemical flow setup that exploits λ-orthogonal reactions using two different colours of light (λ₁=350 nm and λ₂=410 nm) in sequential on-line irradiation steps. Critically, both photochemically reactive units (a visi

Full text of DOI:10.1002/anie.202003130

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Accepted Article
Title: Two Colour Photoflow Chemistry for Macromolecular Design
Authors: Matthias Van De Walle, Kevin De Bruycker, James P. Blinco,
and Christopher Barner-Kowollik
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202003130
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Two Colour Photoflow Chemistry for Macromolecular Design
Matthias Van De Walle,[a] Kevin De Bruycker,[a] James P. Blinco*[a] and Christopher Barner-Kowollik*[a]
Abstract: We report a photochemical flow setup that exploits λ-
orthogonal reactions using two different colours of light (λ1 = 350 nm
and λ2 = 410 nm) in sequential on-line irradiation steps. Critically, both
photochemically reactive units (a visible light reactive chalcone and a
UV-activated photo-caged diene) are present in the reaction mixture.
We demonstrate the power of two colour photoflow by the
wavelength-selective end group modification of photo-caged polymer
end groups and the subsequent polymer ring closure driven by a [2+2]
cycloaddition. Importantly, we evidence that the high energy gate
does not induce the visible light reaction of the chalcone, which attests
the true λ-orthogonal nature of the flow reaction system. For the first
time, this study opens the realm of photoflow reactions to λ-orthogonal
photochemistry.
In 1920, Hermann Staudinger postulated that covalent bonds
between repeating monomeric units are the key element in
synthetic high molecular weight molecules.[1] The introduction of
this concept into the field of chemistry and organic synthesis has
laid the foundation of today’s understanding of macromolecules.
Since this discovery, precision macromolecular design has
become
a key field, targeting advanced properties and
applications on a macromolecular level. A large synthetic toolbox
has been established over the last decades, enabling the
selective generation and cleavage of bonds to design novel
polymeric structures.[2] Importantly, not only size, but also polymer
shape and morphology can be finely tuned, with control of these
structural properties being possible utilising a number of different
synthesis methodologies.[3]
Amongst the many systems that have been developed to form
larger molecular entities through covalent bonds, light-driven
reactions have become increasingly popular.[4] Not only can they
be executed under catalyst-free and ambient conditions (reducing
the chance of inducing any side reactions), yet more importantly,
they allow the precise spatial and temporal control over chemical
reactivity.[5] Furthermore, chemical selectivity can be achieved by
tuning the wavelength and light intensity.[6] Moreover,
photoreactions executed in a photoflow system can even further
enhance reactivity, selectivity, reaction control and scalability, and
have been demonstrated to be of critical value in the field of
macromolecular design and organic synthesis.[7]
Through the use of flow setups, spatial control can be readily
achieved with light, as different segments of the reactor tubing can
be irradiated separately at the same time without mutual
interference.[8] Such a strategy allows to induce reactivity of a
reactant mixture at a certain interval of the reactor with one light
source, followed by the initiation of another reaction, independent
of the former process, with a second source.[9] Subsequent
reactions can be triggered with other wavelengths, without
interfering with the former irradiation paths. Therefore, the flow
Scheme 1. Overview of the two-colour photoflow setup. Consecutive
irradiation of the compounds with UV-A light (λ1 = 350 nm) and violet-blue
light (λ2 = 410 nm), respectively, selectively folds the polymeric chains into
macrocycles.
setup can facilitate multi-step processes comparable to a ‘one-pot’
synthesis strategy by allowing controlled and efficient irradiation
of the reactant mixture at all time.[10]
Herein, we introduce a photoflow system that can trigger two
consecutive photochemical reactions with disparate wavelengths
(Scheme 1). The photoligation of o-methylbenzaldehydes (MBA)
in flow has been proven to be very efficient and fast in the
presence of suitable dienophiles such as maleimides.[7d] The
generation of reactive dienes upon irradiation with UV-light is
therefore a very suitable strategy for chain-end modification using
irreversible, light-driven reactions. In addition,
a second
photoreactive system is introduced at both chain ends that can
undergo self-dimerisation, compacting the macromolecular chain
into its corresponding cyclic structure. Importantly, the latter
visible-light-reactive moiety remains unreacted during the first
UV-induced photochemical process under the employed
photoflow setup and can be addressed separately upon
irradiation with visible light. This constitutes a key example of true
λ-orthogonality, where a UV induced photoligation can be
triggered without activating a visible-light-reactive chromophore
that is present in the same reaction mixture.
We developed a [2+2]-cycloaddition system based on pyrene-
chalcones that can be activated with violet-blue light close to 410
nm and is unreactive in its monomeric state upon irradiation with
UV-light (λmax = 350 nm). Pyrene-chalcones (PC) are therefore
ideally suited for the purpose of selective photoligation in
[a]
M. Van De Walle, K. De Bruycker, J. P. Blinco, C. Barner-Kowollik
Centre for Materials Science, School of Chemistry and Physics,
Queensland University of Technology (QUT), 2 George St.,
Brisbane, QLD 4000, Australia.
combination with MBA-systems.
functionalised pyrene-chalcone (PC-OMe) in
A
solution of methoxy-
mixture of
a
E-mail: christopher.barnerkowollik@qut.edu.au; j.blinco@qut.edu.au
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the maxima close between 330 nm and 350 nm remain visible.
Therefore, the dimerisation of PC is not entirely reversible and,
with time, reaches a certain equilibrium (Supporting Information,
Figure S1-2).
In order to assess the λ-orthogonality between the pyrene-
chalcone
photodimerisation
and
the
MBA-maleimide
photoligation, initial small-molecule tests were performed.
Equimolar mixtures of 2-methoxy-4,6-dimethylbenzaldehyde
(MeO-MBA) and maleimide-functional pyrene-chalcone (PC-Mal)
in a mixture of acetonitrile and toluene were irradiated with UV-A
light (λmax
= 350 nm) under inert conditions (Scheme 2).
Experiments were performed in a Luzchem LZC-4V photoreactor
setup (refer to Supporting Information Figure S3). The reaction
was monitored over time via LC-MS (Figure S4). Full conversion
of the starting components over longer irradiation time was
observed in LC, while a new species was simultaneously formed
that was identified via mass spectrometry as the desired Diels-
Alder photoadduct PC-DA with an exact mass of 788.28 Da
([M+Na]+). The stability of the pyrene-chalcone functionality was
confirmed via UV-Vis spectroscopy, as the absorbance profile
showed the presence of the latter moiety (refer to Supporting
Information Figure S5). In addition, 1H-NMR spectroscopy (Figure
S6) revealed that the protons corresponding with the maleimide
moiety and MBA group reacted and that the Diels-Alder adduct
was generated.
As we evidence that both reactions can be executed with clean
product formation, subsequent experiments were performed
combining both reactions to establish λ-orthogonality on the small
molecule level. Equimolar mixtures of MeO-MBA and PC-Mal
were irradiated with UV-light under the same conditions as before,
followed by irradiation with violet-blue light (λmax = 415 nm), while
the UV-light was switched off. It must be noted that the sequence
of irradiation is critical since pyrene-chalcones can undergo
cycloreversion. Cleavage of the covalent bonds can be triggered
with UV-light, similar to the conditions employed for MBA-
maleimide ligation (Scheme 1). Reversing the order of irradiation
might therefore cleave the PC-linkage again, not initiating
macrocyclisation when built onto linear chain ends. The reaction
was again followed via LC-MS measurements and it was
confirmed that both reactions can be executed consecutively
without any purification or intermediate step (Figure S7).
Scheme 2. Reaction of o-methylbenzaldehyde and maleimide triggered by
UV-A light (λmax = 350 nm) in the presence of pyrene-chalcone, resulting
in the corresponding Diels-Alder adduct (top). [2+2]-Cycloaddition of
pyrene-chalcone after irradiation with violet-blue light (λmax = 410 nm)
acetonitrile and toluene was irradiated with a 10 W 415 nm LED
(Scheme 2, Figure S1). UV-Vis spectroscopy confirmed the
reactivity of the conjugated π-system upon irradiation with violet-
blue light. The typical absorbance spectrum of pyrene-chalcone
with a maximum around 390 nm changed into an absorbance
spectrum with two new maxima around 330 nm and 350 nm
(Figure 1b). The new pattern matched with the absorbance
spectrum of pyrene, showing two similar maxima in its
absorbance spectrum. Therefore, we conclude that the
conjugated bond between the pyrene and carbonyl species has
undergone photoreaction. Additionally, 1H-NMR spectroscopy
evidences that the resonances of the protons of the conjugated
system shifted or disappeared and the newly formed resonances
are in good agreement with the formation of a cyclobutane moiety
after [2+2]-cycloaddition (Figure 1a). Notably, the cycloaddition of
pyrene-chalcones is reversible upon irradiation with UV-light. UV-
Vis spectroscopy measurements were performed and the
reversibility over time was analysed (Figure 1b). By increasing the
irradiation time under UV-B light (λmax = 313 nm), the absorbance
peak close to 390 nm becomes more prominent, showing the
reoccurrence of the single pyrene-chalcone species. However,
Figure 1. a) 1H-NMR spectra (DMSO-d6, 600 MHz) of PC-OMe and the corresponding dimer. Upon dimerisation, a shift can be observed for the aromatic
resonances as well as new resonances appearing at 5.15 and 5.35 ppm, identified as the protons of the cyclobutane ring formed after cycloaddition. b) UV-
VIS absorption spectra of PC-OMe and the corresponding dimer. Irradiating the dimer with UV-B light regenerates single PC-OMe over time, as the absorbance
peak at 390 nm becomes more prominent. All spectra are normalised to the isosbestic point at 360 nm.
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As the λ-orthogonality was proven for the two-chromophore
reaction system, the dual-wavelength experimental design was
translated to a photoflow reactor setup (Figure S8). Initially, the
flow parameters for the individual reactions were investigated.
The MBA-maleimide coupling was performed using a self-built
photoflow coil with a residence volume of 1 mL that was wrapped
around a Luzchem UV-A lamp emitting at 350 nm. Full conversion
of the Diels-Alder adduct was achieved at a flow rate of 0.5 mL
min-1 with concentrations close to 0.1 mg mL-1 of crude starting
material. Similarly, the dimerisation of PC-OMe was optimised
using a Vapourtec E2 Flow Reactor with a UV-150 module
equipped with 410 nm LEDs. Using a 5 mL flow coil, full
conversion of the starting compound (1 mg mL-1) was achieved
within 1 minute. We thus conclude that both photo-active systems
can be activated separately in flow, which bodes well for our aim
of establishing a dual colour λ-orthogonal flow system.
used for the photochemical reactions Firstly, PEG (Mn = 2050 g
mol-1) was end-capped with tosylate moieties and subsequently
substituted with MBA functionalities, with an overall yield of 71%.
The product was analysed and confirmed via 1H-NMR
spectroscopy and mass spectrometry (Figure S9-10). The
modified PEG was further employed for photoflow synthesis. It is
critical to keep the concentration of the chains low during the
photoreactions. Indeed, at low concentrations, intramolecular
[2+2]-cycloadditions are favoured when PEG is end-capped with
PC moieties and irradiated with violet-blue light, resulting in the
desired macrocycle. However, when the concentration of
polymers exceeds
a certain level, intermolecular reactions
become more favourable, resulting in larger polymers via
photopolyaddition. To overcome uncontrolled addition into larger
chains, polymer concentrations were kept at 0.025 mg mL-1 for all
photoflow reactions.
A solution of bisMBA-PEG with 2.05
equivalents of PC-Mal in acetonitrile/toluene (3:1) was irradiated
in flow with UV-A light (Figure 2a). The same setup was used as
described before. The reaction progress was monitored via size
exclusion chromatography (SEC). The intermediate product after
λ1-irradiation was analysed. Comparing the size distribution of the
starting compound (bisMBA-PEG) to the distribution of the
obtained flow product shows a shift towards higher hydrodynamic
Subsequently, we translated the dual-wavelength-selective
concept to the macromolecular realm by incorporating the
photoreactive functionalities onto linear polymers to selectively
fold the chains into macrocycles. Poly(ethylene glycol) (PEG) was
chosen as the polymer backbone because of the straightforward
end-group modification and the good solubility in the solvents
Figure 2. a) Reaction scheme of the dual-wavelength photoflow setup. Consecutive irradiation of the starting compounds selectively folds the PEG chains into
macrocycles. b) SEC elugrams of the reaction mixture at each stage of the flow setup (before, after λ1 irradiation and after λ2 irradiation). Starting from bisMBA,
a shift towards higher hydrodynamic volume could be observed upon irradiation with UV-A light (bisPC; λ1, λmax = 350 nm). Consecutive irradiation with violet-
blue light causes the chain to collapse, indicated by a shift back towards smaller hydrodynamic volume (folded cycle; λ2, λmax = 410 nm). c) UV-Vis absorption
spectra after each irradiation step. The absorption spectrum of pyrene-chalcone can be recognised on the end-capped PEG-chain. The spectrum shifts towards
the [2+2]-cycloadduct upon chain folding.
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volume after the photoreaction (Figure 2b). The shift is well in line
with expectations, as introducing new moieties on both ends of
the chains increases the size of the molecule and therefore also
its volume. Additionally, mass spectrometry confirmed the
formation of the new bis-substituted PEG-species (Figure S11).
Subsequently, the pyrene-chalcone end capped polymer was
irradiated with 410 nm LEDs. Again, SEC was employed to
determine the change in size distribution occurring due to the
batch size. The flexibility of the reactor design allows adaptation
towards different chemical photosystems and light sources, as
well as facile expansion with multiple flow coils.
Acknowledgements
irradiation in flow. Specifically,
a
shift towards lower
C.B.-K. acknowledges a Laureate Fellowship from the Australian
Research Council (ARC) enabling his photochemical research
program. Key additional support from the Queensland University
of Technology (QUT) is gratefully acknowledged. The authors
acknowledge the Central Analytical Research Facility (CARF) at
QUT, which is generously supported by the Faculty of Science
and Engineering.
hydrodynamic volume was observed after the second irradiation
compared to the size distribution of the PC end-capped polymer
(Figure 2b). A smaller hydrodynamic volume implies that the
single chains collapsed during irradiation, which was achieved by
covalent bond formation of the respective chain ends. The [2+2]-
cycloaddition reaction therefore effected the intramolecular
cyclisation, resulting in macrocycles. The small side distribution at
lower retention time is the result of minimal polyaddition during
the second irradiation. This was minimalised by employing low
concentrations but could not be prevented entirely as lower
concentrations would require very long reaction times. It was
shown that higher concentrations of polymer significantly increase
the amount of polyaddition product (refer to Supporting
Information Figure S12). In addition, UV-VIS spectroscopy
revealed the presence of the [2+2]-cycloadduct after inducing the
chain folding (Figure 2c).
As additional proof of cyclisation, a third light source was used to
cleave the photo-adduct. As noted earlier, pyrene-chalcones can
undergo cycloreversion, depending on the irradiation wavelength.
Therefore, irradiating the macrocycles with UV-B light results in
the opening of the cyclic structure, regenerating the chalcone-
end-capped PEG linear polymer. The UV-VIS spectra (Figure
S13) of the macrocycles before and after irradiation with UV-B
light indicate that the typical absorption maximum of the pyrene-
chalcone at 390 nm reappeared after irradiation, showing that the
macrocyclic structure can be cleaved again to regenerate linear
PEG chains.
Keywords: flow photochemistry • continuous flow • orthogonal
reactivity • multi-step synthesis • macrocycles
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In conclusion, we introduce a true λ-orthogonal continuous
photoflow system that can initiate multiple reactions. A new [2+2]-
cycloaddition system was developed based on pyrene-chalcones,
triggered upon irradiation with violet-blue light. We demonstrate
that this functionality remains unreacted under UV-A light and can
be reacted orthogonally with MBA-maleimide ligation. By
incorporating o-methylbenzaldehyde functionalities on a small
PEG chain, we show that the polymer can selectively be end-
capped with one light source emitting at 350 nm, and
subsequently cyclised by employing a second light source
emitting at 410 nm – a remarkable example of triggering the high
energy gate without affecting the low energy activated system. To
the best of our knowledge, this is the first multi-step λ-orthogonal
photoflow setup on a macromolecular level. Our system facilitates
multi-step modifications with several photo-induced reactions. In
addition, the flow setup facilitates the scalable synthesis of multi-
step processes by merely increasing the amount of material and
the flow reaction time, without any further modifications or
optimisation. While maintaining efficient and homogeneous
irradiation in photoflow, scaling is significantly more difficult in a
batch process. Increasing light gradients would reduce the
irradiation efficiency, requiring optimisation for each different
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Entry for the Table of Contents
COMMUNICATION
Going
Flow:
orthogonality in
photochemical
reaction
with
True
the
λ-
a
Matthias Van De Walle,
Kevin De Bruycker,
James P. Blinco* and
Christopher Barner-
Kowollik*
system
becomes possible in
a photoflow system,
Page No. – Page No.
able
to
control
Two Colour Photoflow
Chemistry for
Macromolecular
Design
polymer end groups
and topology, based
on
diene
reaction system.
a
photo-caged
and [2+2]
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