Visible Light-Induced Ligation via o-Quinodimethane Thioethers

Article abstract of DOI:10.1021/jacs.8b08343

We introduce a photocaged diene system (o-quinodimethane thioethers) based on o-methylbenzaldehydes (o-MBAs) that can be activated with visible light. The pioneered system is accessible in a single step from commercially available starting materials in ex

Full text of DOI:10.1021/jacs.8b08343

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Article
Visible Light Induced Ligation via o-Quinodimethane Thioethers
Florian Feist, Jan P. Menzel, Tanja Weil, James P. Blinco, and Christopher Barner-Kowollik
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08343 • Publication Date (Web): 23 Aug 2018
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Journal of the American Chemical Society
Visible Light Induced Ligation via o-Quinodimethane Thioethers
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§
Florian Feist,† Jan P. Menzel,† Tanja Weil,*§ James P. Blinco*† and Christopher Barner-Kowol-
lik*†‡
†School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology (QUT), 2 George
Street, Brisbane, QLD 4000, Australia
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§Max Plank Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
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‡Macromolecular Architectures, Institut fꢀr Technische Chemie und Polymerchemie, Karlsruhe Institute of Technol-
ogy (KIT), Engesserstr. 18, 76131 Karlsruhe, Germany
SUPPORTING INFORMATION PLACEHOLDER
bioorthogonality, specific limitations apply when these reac-
tions are employed. For example, nitrile imines react with var-
ABSTRACT: We introduce a photocaged diene system (o-
quinodimethane thioethers) based on o-methylbenzaldehydes (o-
ious functional groups (including amines, thiols, carboxylic
MBAs) that can be activated with visible light. The pioneered sys-
tem is accessible in a single step from commercially available start-
acids and heterocycles) limiting their chemical selectivity.17
Thus, the development of reactions with exceptional selectiv-
ity and mild trigger wavelength remains critically important.
To date, the majority of the established photoinduced ligation
reactions require UV light. For several applications such as
coupling of photosensitive entities or chemistry in living cells,
the use of UV-light constitutes a formidable barrier.18 Shifting
the absorption and reactivity of photoreactive molecules into
the visible range while preserving orthogonality and biocom-
patibility, though avoiding potentially toxic transition metal
catalysts, constitutes a key aim in contemporary photochem-
istry.19-21
ing materials in excellent yields. Variable synthetic handles can be
attached to the photocaged diene, often without elaborative protect-
ing group chemistry. Full conversion of various o-methylbenzalde-
hydes to the Diels-Alder adduct is achieved in the presence of ma-
leimides under catalyst free conditions triggered by visible light ir-
radiation with LEDs under flow conditions. Unlike the previously
reported UV-induced ligation of o-quinodimethanes, the reaction
can be conducted both in organic solvents and aqueous solution.
We further demonstrate the ability of the photo-caged dienes to li-
gate two polymer blocks by visible light. The [4+2] nature of the
reaction makes it a powerful orthogonal ligation platform.
Despite considerable research efforts, only few of the known
efficient UV-photoligations have been adapted for visible light
activation. For example, the NITEC reaction was shifted to 405
nm by the attachment of a terthiophene unit to the 2-position
of the tetrazole.18, 22
INTRODUCTION
The click chemistry concept introduced by Kolb, Finn and
Sharpless, has emerged as a pivotal tool in contemporary small
molecule synthesis as well as polymer chemistry. The concept
focuses on function and properties rather than on complex
multi-step synthesis.1 The hypothesis that functional mole-
cules can be obtained by combining molecular building blocks
with highly efficient ligation reactions has been amply demon-
strated in the following years in countless studies, especially
in the field of bio-2 and polymer chemistry.3,4
Light induced click reactions critically enhance the concept
with spatio-temporal control.5 In contrast to reactions requir-
ing a catalyst, for instance the photochemical reduction of
Cu(II) to Cu(I) catalysing a copper-mediated azid alkyne cou-
pling (CuAAC),6 photo-click reactions only involve two sub-
strates allowing for the highest possible control over the reac-
tion. Photochemical patterned surface functionalization,7
conjugation of biomolecules8 and macromolecules, 3D stereo-
lithography,9-10 light induced folding of single-chain nanopar-
ticles,11-12 as well as reactions in living cells2 are among the var-
ious applications of such reactions. Bioorthogonal ligations re-
quire an exceptional level of efficiency and chemical selectiv-
ity resulting in minimal interference with existing biological
components. Reactions that perform well in vivo can therefore
be considered the gold-standard of click reactions.13-14 Espe-
cially the photochemically controlled strain-promoted azide
alkyne coupling (photo-SPAAC) and the 1,3-dipolar cycloaddi-
tion between a nitrile imine generated from a tetrazole under
light irradiation and an alkene (Nitrile Imine mediated Te-
this work
previous work
conversion
1
1x103
0
450
300
350
400
/ nm
Scheme 1: (Top) Structural overview of the red-shifted o-QDMs of the
current study (red) and the most recent state-of-the-art o-QDMs
(blue). In the present study, transformations are carried out in photo-
flow. (Bottom) Red-shifted UV-VIS absorption spectrum of o-MBAs
and wavelength-resolved fractional conversion using a tunable laser
and constant photon count (30 µmol, for details refer to the Support-
ing Information section 1.9), shown on the example of species A1 (see
Scheme 2) recorded in DCM. The visible range of the spectrum is de-
picted using the RGB-equivalents of the corresponding wavelength.
trazole Ene Cycloaddition, NITEC) are both often considered
The use of conjugated π-systems to shift the absorption and
reactivity from the UV to the visible-region was successfully
15-16
to be bioorthogonal.2,
However, despite their asserted
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demonstrated in azirines, acylsulfides and styryl-com-
To activate a photoreactive compound with visible light, the
molecule must possess two key properties. First, visible light
must be absorbed and a reactive intermediate with a lifetime
suitable for a chemical reaction must be formed. Second, the
photochemically generated intermediate needs to selectively
react with the target substrate. Here, we address these re-
quirements by simply replacing oxygen with sulfur (Scheme
1), lowering the energy gap for the π-π* transition that leads
to the formation of o-QDMs. In addition to the red-shift in
absorption, the thioether moiety might also enforce a favour-
able conformation to enable the excited-state intramolecular
proton transfer (ESPIT)37, 39 that takes place during o-QDM
formation. Such an ortho-effect was for instance studied in de-
tail for the Bergman-cyclisation.42 Furthermore, the n-donor
properties of the thioether group might contribute to the nu-
cleophilicity of the formed o-QDMs enabling an efficient
Diels-Alder cycloaddtion with electron deficient enes.
pounds.23-25
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The photochemically induced generation of reactive dienes,
for instance o-QDMs or naphtoquinon-3-methides (o-
MQMs)15,26 and their subsequent (hetero)-Diels-Alder reac-
tion with electron deficient enes is one of the most important
strategy for photoclick ligations. These find wide-spread ap-
plications in, for example, the synthesis of sequence-defined
macromolecules,27 single-chain folding,28-30 surface function-
alization,31 light-induced assembly of nanostructures,32 and
photoresists for 3D direct laser writing.9-10 Recently, the wave-
length-dependency of o-QDMs formed from an o-methyl ben-
zaldehyde (o-MBA) and its subsequent Dieles-Alder reaction
was explored in detail. Underpinned by time-dependent den-
sity functional theory (TD-DFT) calculations this investiga-
tion allowed for an in-depth understanding of the mechanism
and photo-physical properties of the reaction.33 A large num-
ber of synthetically valuable transformations including light-
induced reactions based on o-QDMs have been reported,34 in-
cluding various organocatalytic strategies to for enantioselec-
tive trapping of o-QDMs.35 Especially the generation of hetero
aza-o-xylylenes (heteroatom analogue o-QDMs) was repeat-
edly used to enable elegant syntheses of complex structural
motifs.36-39 To the best of our knowledge, there is only one re-
port that indicates the formation of o-QDMs using visible
light: Furukawa and coworkers reported in 1993 that 8,13-di-
hydrobenzo[g]naphtho[1,8-bc][1,5]di-selenonine form o-
QDMs under exposure of ambient laboratory light.40 This in-
teresting reaction forms naphtho[1,8-cd][1,2]diselenole in stoi-
chiometric quantities, thus requiring chromatographic purifi-
cation. Critically, it involves toxic organoselenium com-
pounds and can thus not be considered a viable (bio)-ligation
strategy.
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The synthesis of non-functionalized model o-MBAs and o-
MBAs functionalized with linker groups was achieved via lit-
erature adapted one-step procedure from commercially avail-
able 2-fluoro-6-methylbenzaldehyde 1.43 The optimization of
°
the reaction conditions suggests that 85 C and 12 h reaction
time leads to full conversion in all cases indicated by the ab-
sence of 19F-NMR resonances. The desired products were ob-
tained in excellent isolated yields of 83-97 % (for detailed an-
alytical information refer to the Supporting Information sec-
tion, Figs. S4-S25). The synthetic strategy represents a consid-
erable advantage over previously reported functional o-MBAs
that are only accessible in a 3-step procedure for hydroxyl-ter-
minated systems and a 4-step procedure for carboxy-termi-
nated variants with low yields (25 and 14%, respectively).31, 41
Critically, compared to other visible light photosystems that
often require laborious synthesis especially when chromo-
phores are attached to the photoreactive entity, the herein es-
tablished synthesis is simple and versatile.18, 23-25
The UV-VIS absorption spectra of the three model-com-
pounds A1, A2, and A3, depicted in supporting Fig. S64 indi-
cate an π-π* transition absorption maximum between 350-360
nm tailing into the visible region (refer to the zoom between
390-450 nm). Compared to the previously reported o-MBAs
PE1 and PE231, 41 (Scheme 2, Fig S64, SI) featuring an π-π* tran-
sition at approximately 320 nm, our new compounds are red-
shifted by close to 40 nm in their absorption. Aryl-aryl thi-
oether A2 shows the strongest tailing into the visible region.
In an action plot, the conversion of a photoreactive molecule
is probed at a constant photon count at different monochro-
matic wavelengths. For the o-MBA UV-only active PE2, Men-
zel et al.33 recorded an action plot, demonstrating that the
compound still shows some very limited photoreactivity up to
390 nm. Assuming the new red-shifted compounds show a
similar wavelength-dependent behaviour, we expected that
the new compounds would be reactive under visible light ir-
radiation. Since the structure of the transient o-QDM is rather
similar to the previously reported molecule PE2, we envisaged
that trapping with a suitable dienophile would be comparably
efficient. We thus herein assess the photoligation of model-
compounds A1, A2 and A3 by trapping their transient o-QDM
species with dienophile B1 at max= 410 nm (LED, emission
spectra shown in the SI, Figure S1) in a photoflow reactor with
a retention time of 10 min at 20 °C. Alkyl-arylthiother A1 was
quantitatively converted to product C1 in the presence of
dienophile B1 and Aryl-aryl thioether A2 also quantitatively
The current contribution provides a simple to access visible
light induced [4+2] ligation technology platform, shifting the
wavelength of activation well into the visible light regime up
to 430 nm via a simple oxygen/sulfur exchange within the o-
MBA’s structure (refer to Scheme 1).
RESULTS and DISCUSSION
Scheme 2: (Top) Synthesis and isolated yields of red-shifted o-MBAs
A1-A3 and various other herein prepared o-MBAs with attached linker
groups by reaction of 2-fluoro-6-methyl benzaldehyde 1 with the re-
spective thiol. (Bottom) Structures of literature reported state-of-the-
art o-MBAs PE 1 (2-((10-hydroxydecyl)oxy)-6-methylbenz-aldehyde)
and PE 2 (4-((2-formyl-3-methylphenoxy)methyl)benzoic acid).31, 41
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afforded the cycloadduct C2 under identical conditions (Fig-
along with the desired cycloaddition. Critically, A1 and A2
were also quantitatively converted to cycloadducts C1 and C2
using a max= 430 nm LED, albeit with a longer retention time
of 20 min (emission spectra of the LEDs and overlay with UV-
VIS spectra of o-MBAs A1-A3, SI Fig. S65). The NMR spectra
after irradiation at 365 nm, and 430 nm – again without any
further purification – are depicted in supporting Figures Figs.
S45-S46.
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8
ure 1, for additional spectroscopic data refer to the Supporting
Information Figs. S28 to S29). Note that the spectra shown in
Figure 1 were obtained without any purification and result ex-
clusively from merely removing the solvent. However, benzyl-
arylthioether A3 did not react selectively to the desired cy-
cloadduct C3. Thus, the NMR-spectra after irradiation of A3 in
presence of B1 show not only the new resonances for the cy-
cloadduct C3 but also new signals between 10 and 11 ppm. We
assume that either α-cleavage or α-H abstraction takes place
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/ ppm
/ ppm
Figure 1 (Top) Reaction between o-MBAs A1-A3 and B1 to form cycloadducts C1-C3 under visible light irradiation (LED-emission
spectra refer to supporting Figs. S1). (Bottom) 1H-NMR spectra obtained of A1, C1, A2, C2 with assigned resonances. No purification
was carried out for C1 and C2, indicating the extremely high selectivity of the photoligation. A3 forms non-selective products with
B1. Detailed analytical information for all compounds depicted in Fig. 1 can be found in the supporting Figs. S4-S9 and S26-S29.
In addition to the photoflow experiments, batch-experiments
with a tunable laser, in order to precisely determine the max-
imum wavelength for visible light activation of substrate A1
were performed. This was achieved through irradiation of
samples at 360, 390, 420, 440 and 450 nm with the same num-
ber of photons in deuterated acetonitrile (ACN) with equimo-
lar stoichiometry. The conversion was determined via H-
NMR. The resulting wavelength-resolved action plot is in-
cluded in Scheme 1 above (for the detailed NMR spectra refer
to the Supporting Information Fig. S44).
To examine the performance of the reaction at different wave-
lengths, retention times and solvents, we performed experi-
ments using substrate A4 as it ionizes well during ESI mass
spectrometry and is therefore ideal for additional LC-MS anal-
ysis. In addition, A4 is soluble in most common solvents. Cy-
cloadduct C4 was obtained in high purity without any purifi-
cation in preparative scale after irradiation of A4 in the pres-
ence of a slight excess (1.10 eq.) of B1 with 410 nm in acetoni-
trile after a flow retention time of 20 min (refer to Figure 2).
The results for the flow-experiments of A4 and B1 are collated
in Table 1. The corresponding 1H-NMR-spectra, LC-MS traces
and mass spectra can be found in the Supporting Information
section (Figs. S 10-11, 30-31, 47-51, 54-55, 59-61). For acetonitrile
and toluene, we observed product formation with the highest
2,3,4,5,14
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16
6,10,15
13
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11
7
12
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10
2
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3
11
7,8
9
1
11
10
9
8
7
6
5
4
3
2
1
0
/ ppm
Figure 2: (Top) Photoligation in acetonitrile of A4 and B1 to form cy-
cloadduct C4, 1H-NMR spectrum of A4 (bottom) and the photoprod-
uct C4 (middle). Detailed analytical information for all compounds
depicted in Fig. 2 can be found in the supporting Figs. S10-S11, S30-S31
and S54-S55
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selectivity towards C4 , including its potentially formed stere-
One of the key attractive features of our new class of visible
light reactive o-MBAs is the ability to conduct the photoliga-
tion in aqueous media, which opens considerable avenues for
bioorthogonal ligation. In Fig. 3, the reaction between the wa-
ter soluble ‘hexaethylene glycol-o-MBA’ A4 and the water sol-
uble ‘hexaethylene glycol-maleimide’ B2 under flow condi-
tions and irradiation with UV and visible light is explored. Sur-
prisingly, the new red-shifted o-MBA reacts well in a mixture
of 0.1 M PBS/water 50:50 v/v, typically used in bioligations. 1H-
NMR and LC-MS indicate close to quantitative conversion and
selectivity using equimolar amounts of the starting materials.
1
2
3
4
5
6
7
8
oisomers. Stereoisomerism leads to more complex NMR and
LC-MS spectra, although for a ligation technique the stereo-
chemistry of the formed link is not critical under most circum-
stances. We additionally investigated the ligation in DMF and
DMSO, where the previously reported o-MBAs31, 41 performed
very poorly, limiting the substrate scope for photoinduced li-
gations considerably. In contrast, we observed ligation, alt-
hough the perfect endo-selectivity found in dichloromethane
(Figure 1), acetonitrile and toluene (Table 1) was reduced in
DMF. We identified a minor side-product (not exceeding 10%
in the worst case) in less favorable solvents such as DMF and
DMSO formed by oxidation, consuming the residual oxygen
in the reaction solution after deoxygenation by saturation
with N2. Identification of ox-A4 was possible by comparing
NMR and LC-MS spectra of a purposeful synthesized ox-A4 by
oxidation of A4 with sodium periodate in EtOH/H2O. The an-
alytical data for ox-A4 is given in Figs. S38-39 and S58 in the
Supporting Information.
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RT= 6.6-8.4
434.2216
[A4 +NH4]
+
max410 nm,  = 20
max365 nm,  = 10
B2 + A4
A4
C5
B2
RT= 15.0-15.35
379.2064
[B2 +NH4]
+
RT= 12.6-13.4
795.3910
+
[C5 +NH4]
406.7118
[C5 +NH4]2
2+
Scheme 3: Main ligation products endo-rac-C4 and exo-rac-C4 as well
as minor side-product identified during the photoinduced Diels-Alder
reaction of A4 and B1 in DMF and DMSO.
400 500 600 700 800
6
7
8
9
10 11 12 13 14 15
m/z
retention time / min
Figure 3: (Top) Aqueous photoinduced ligation between A4 and B2
affording cycloadduct C4 at 365 and 410 nm (max) in in a continuous
flow reactor with 10 and 20 min retention time, respectively. (Bottom,
left) LC-traces (UV-detection at 215 nm). Note that B2 elutes broadly
under the elution conditions required for optimized product elution.
(Bottom, right) Accumulated mass spectra from the LC-traces with
the accumulated area marked in grey and annotated masses for the
Table 1: Flow photoligation experiments using A4 and B1 in different
solvents. LED-irradiation wavelengths (max), retention time (τ), Xa
1
conversion evaluated via H-NMR (based on the aldehyde-resonance
numbered 11 within the starting material vs. the α-hydroxy-resonance
11 of the product, refer to Fig. 2). Xb conversion evaluated via LC-MS
(UV-detection at 254 nm). endo-rac-C4/exo-rac-C4 ratio of the endo
and exo-cycloadduct depicted in Scheme 3.
1
most abundant ions. Detailed analysis of the mass spectra and H-
Xa
Xb
endo-rac-C4/ ox-A4
NMR can be found in Supporting Information Figs. S52 and S56.
max
τ
Solvent [nm] [min] [%]
[%]
exo-rac-C4
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
76:24
75:25
80:20
65:35
65:35
70:30
67:23
>99:1
>99:1
>99:1
>99:1
[%]
<1
0
0
0
0
0
0
0
0
2
3
1
8
2
1
In a subsequent step, we explored the reactivity of our red-
shifted o-MBAs towards alternative dienophiles. Of particular
interest are those that also constitute mediating agents for re-
versible deactivation radical polymerization (RDRP). A partic-
ularly attractive reagent is cyanoisopropyldithiobenzoate
(CPDB, B3), which is a versatile controlling entity for a wide
monomer range during reversible addition fragmentation
chain transfer (RAFT) polymerization.44-45 B3 was converted
to cycloadduct C6 in ACN under equimolar conditions with
visible light irradiation at 410 nm at a retention time of 20 min.
Figure 4 shows the LC-MS traces of the A4 and C6 as well as
the associated high resolution ESI spectra, attesting the effi-
ciency of the phototransformation (isolated yield 91%, refer to
the Supporting Information for an in-depth discussion of the
associated spectra, Figs. S32-33, S57). Ligation at 410 nm is a
critical improvement over the current state-of-the-art re-
ACN
365
410
410
430
430
10
10
20
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20
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10
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100
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99
78
-
33
58
-
17
-
Toluene 365
410
430
430
365
365
410
410
410
430
430
DMF
ported by Oehlenschlaeger et al., who employed 320 nm (max
)
to afford the cycloadduct.46
36
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47
28
2
3
7
1
Given that B3 is a RAFT agent, it is mandatory to assess the
visible light ligation of two disparate polymer blocks present
in equimolar ratios (end groups) in flow. We thus prepared P1,
a poly(-caprolactone) carrying our red-shifted o-MBA struc-
ture, and P2, a poly(methyl methacrylate). Figures 5 illustrates
DMSO 365
-
-
-
-
365
410
430
20
20
20
10
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the size exclusion chromatography (SEC) traces of P1 and P2
important for its applicability in bioligations. Further, we
demonstrate the visible light [4+2] ligation in various solvents
including ACN, toluene, dichloromethane (DCM) as the most
suitable systems, while DMSO and DMF allow the reaction to
proceed, albeit at lower reaction rates. Finally, the visible light
activation of o-MBA-thioethers was employed for the ligation
of two disparate polymer strands. The herein introduced new
class of visible light photochemical ligation agents thus repre-
sents a simple to access, versatile and efficient tool for diverse
synthetic scenarios. In addition, red-shifted catalyst-free liga-
tion is essential for establishing -0rthogonal reaction sys-
tems47-48 required for multi-material 3D laser lithography.49
1
2
3
4
5
6
7
8
as well as the ligation product P1-P2, clearly evidencing the
formation of the block copolymer structure at higher elution
volumes. Note that the ring opening process employed for the
formation of P1 limits the initial dispersity of the starting pol-
ymer.
RT= 14.8-15.45
434.2216
[A4 +NH4]
+
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max410,  20 min
A4 + B3
RT= 17.3-18.2
A4
C6
ASSOCIATED CONTENT
655.2537
[C6 +NH4]
+
Supporting Information
Materials, Instrumentation, Synthetic procedures, Supporting
Spectroscopic Data. The Supporting Information is available
free of charge on the ACS Publications website.
AUTHOR INFORMATION
400 500 600 700 800
14
15
16
17
18
m/z
retention time / min
Corresponding Authors
Figure 4: (Top, left) Reaction scheme of o-MBA A4 and dithioester B3
forming cycloadduct C6. (Right) UV-detector traces (254 nm detec-
tion wavelength) of A4 and C6, respectively.
weil@mpip-mainz.mpg.de
j.blinco@qut.edu.au
christopher.barnerkowollik@qut.edu.au,
christopher.barner-kowollik@kit.edu
Additionally shown in Figure 5 are the UV/Vis spectra of P1
and P1-P2, clearly reveal that the n-* transition associated
with the thiocarbonlythio chain terminus of P2 disappears,
leading to a non-colored reaction product. The ability of our
red-shifted o-MBAs to ligate polymer chains demonstrate the
applicability of our system for complex polymer construction.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
C.B.-K. acknowledges funding from the Australian Research
Council (ARC) in the form of a Laureate Fellowship enabling
his photochemical research program as well as key support
from the Queensland University of Technology (QUT). C.B.-
K. and J. B. acknowledge support via an ARC Discovery project
targeted at red-shifting photoligation chemistry. F. F. grate-
fully acknowledges the ARC for a PhD Fellowship. This work
was enabled by use of the Central Analytical Research Facility
hosted by the Institute for Future Environments at QUT. T.W.
acknowledges support from the European Research Council
(ERC) via a Synergy Grant (319130-BioQ). The authors thank
Dr. David Y. W. Ng (MPIP) for fruitful discussions and com-
ments on the manuscript.
P1 Mn = 2500 g mol-1 Đ = 1.28
1.0
0.5
0.0

P1 + P2 (before irradiation)
P1-P2
P2 Mn
P1-P2 Mn = 8300 g mol-1 Đ = 1.27
= 6700 g mol-1 Đ = 1.19
1.0
0.5
0.0
n
450
475
500
525
550
575
20 21 22 23 24 25 26 27 28 29 30 31 32
300
350
400
450
/ nm
500
550
600
elution volume / mL
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