A Combined Photochemical and Multicomponent Reaction Approach to Precision Oligomers

Article abstract of DOI:10.1002/chem.201705939

We introduce the convergent synthesis of linear monodisperse sequence-defined oligomers through a unique approach, combining the Passerini three-component reaction (P-3CR) and a Diels–Alder (DA) reaction based on photocaged dienes. A set of oligomers is prepared resting on a Passerini linker unit carrying an isocyano group for chain extension by P-3CR and a maleimide moiety for photoenol conjugation enabling a modular approach for chain growth. Monodisperse oligomers are accessible in a stepwise fashion by switching between both reaction types. Employing sebacic acid as a core unit allows the synthesis of a library of symmetric sequence-defined oligomers. The oligomers consist of alternating P-3CR and photoblocks with molecular weights up to 3532.16 g mol^?1, demonstrating the successful switching from P-3CR to photoenol conjugation. In-depth characterization was carried out including size-exclusion chromatography (SEC), high-resolution electrospray ionization mass spectrometry (ESI-MS) and NMR spectroscopy, evidencing the monodisperse nature of the precision oligomers.

Full text of DOI:10.1002/chem.201705939

A Journal of
Accepted Article
Title: A Combined Photochemical and Multi-Component Reaction
Approach to Precision Oligomers
Authors: Waldemar Konrad, Fabian Raphael Blößer, Katharina Wetzel,
Andreas Boukis, Michael Meier, and Christopher Barner-
Kowollik
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To be cited as: Chem. Eur. J. 10.1002/chem.201705939
Link to VoR: http://dx.doi.org/10.1002/chem.201705939
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A Combined Photochemical and Multi-Component Reaction
Approach to Precision Oligomers
Waldemar Konrad,[a,b] Fabian R. Bloesser,[a,b,c] Katharina S. Wetzel,[c] Andreas C. Boukis,[c] Michael A.
R. Meier,*[c] and Christopher Barner-Kowollik*[a,b]
Abstract: We introduce an avenue for the convergent synthesis of
linear monodisperse sequence-defined oligomers via a unique
approach, combining the Passerini three-component reaction
(P-3CR) and a Diels-Alder reaction based on photo-caged dienes.
Based on a Passerini linker unit carrying an isocyano group for chain
extension via P-3CR and a maleimide moiety for photo-enol
conjugation enabling a modular approach for chain extension.
Monodisperse oligomers are accessible in a stepwise fashion by
switching between both reaction types. Employing sebacic acid as a
core unit allows for the synthesis of a library of symmetric sequence-
defined oligomers. Consisting of alternating P-3CR and photo-blocks
with molecular weights up to 3532.16 g mol-1, the oligomers
demonstrate the successful switching from P-3CR to photo-enol
conjugation. In depth characterization is carried out including SEC,
high resolution mass spectrometry (ESI-MS) and NMR, evidencing
the monodisperse nature of the precision oligomers.
monomer units – at predetermined positions in synthetic
macromolecules are important tools.[2] Historically, the field of
sequence-defined macromolecules emerged with the pioneering
work of Merrifield in the year 1963[3] for which a Nobel prize was
awarded in 1984.[4] The concept was later extended for the
synthesis of precise natural and non-natural peptides,[5]
glycopeptides,[6] oligonucleotides,[7] peptoids[8] and conjugated
oligomers.[9] In addition, dendrimers[10] and exponential growth
strategies[11] significantly enriched the field. Many research
groups introduced different strategies to produce coded
sequence-defined oligomers including single unit monomer
insertions (SUMIs) based on radical processes,[1d, 12] liquid phase
reactions in bulk or flow systems[11a, 13] as well as approaches
using solid templates,[2c, 14] mainly resting on modular insertion of
building blocks or iterative addition of single monomer units,
1k]
summarized in recent reviews.[1j,
Modular chain growth
employing larger sequence-defined building blocks instead of
single monomers for coupling contributes to the overall reaction
efficiency by an accelerated increase of the molecular weight for
each synthetic step. Therefore, modular synthetic concepts
significantly contributed towards a high level of control over
sequence-defined macromolecular formation processes.[2a]
Herein, we extend the synthetic toolbox for preparing
monodisperse multifunctional sequence-defined macromolecules
(i.e. unique according to IUPAC recommendations)[15] by an
approach combining highly efficient methods in an orthogonal
fashion, i.e. the Passerini three component reaction (P-3CR) and
a photochemical reaction relying on a benzaldehyde species
(photo-caged dienes termed photo-enols) as well as maleimides
(Scheme 1).[1f, 2a] Our synthetic strategy is based on P-3CRs and
photo-enols leading to macromolecules consisting of alternating
Passerini and photo-blocks, possibly leading to applications
ranging from bio-conjugation, photoresists, network formation for
NMR orientation media or information storage.[1h, 16]
Naturally occurring key macromolecules, such as DNA or
proteins, feature absolute sequence-definition in their structure,
which is necessary to execute complex biological functions (i.e.
information storage or enzymatic activity) that are vital to life.
Inspired by nature’s precision, the generation of perfectly
monodisperse sequence-defined oligomers and polymers
containing chemical information by coding monomer units into a
predefined order via a simple process, is – for example –
envisaged for data storage materials, molecular bar coding,
biological applications in synthetic enzyme design or precision
network synthesis.[1] Therefore, viable synthetic concepts
featuring simple, scalable and orthogonal strategies for the
accurate placement of functional groups – for instance through
[a]
Waldemar Konrad, Fabian R. Bloesser, Christopher Barner-Kowollik
Macromolecular Architectures
Institut für Technische Chemie und Polymerchemie
Karlsruhe Institute of Technology (KIT)
Photochemistry
Multi-component
Engesserstr. 18, 76131 Karlsruhe, Germany
E-mail: christopher.barner-kowollik@kit.edu
Waldemar Konrad, Fabian R. Bloesser, Christopher Barner-Kowollik
School of Chemistry, Physics and Mechanical Engineering
Queensland University of Technology (QUT)
2 George Street, QLD 4000, Brisbane, Australia
E-mail: christopher.barnerkowollik@qut.edu.au
Fabian R. Bloesser, Katharina S. Wetzel, Andreas C. Boukis, Michael
A. R. Meier
[b]
[b]
Passerini linker
Core Unit
Photo-building block
Laboratory of Applied Chemistry
Institut für Organische Chemie
P-3CR
Karlsruhe Institute of Technology (KIT)
Straße am Forum 7, 76131 Karlsruhe, Germany
E-mail: m.a.r.meier@kit.edu
Further Chain Extension
Photo-block
Photo-block
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Consecutive chain extension starting from a symmetric core unit
employing a multi-component reaction and photochemistry.
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Our here explored synthesis of sequence-defined
macromolecules is based on convergent chain extension starting
from a symmetric core unit via multi-component reactions
followed by a photochemically induced Diels–Alder (DA) reaction,
in which each building block carries functional groups allowing the
respective attachment of Passerini linkers and photo-caged
dienes. Initially, in order to grow oligomers in as few chain
extension steps as possible, a Passerini linker unit 5 (Scheme
2a) was synthesized exhibiting an isocyano functionality, allowing
for further chain extensions via P-3CRs. 5 also bears a maleimide
moiety required for photochemically induced DA reactions. The
targeted Passerini linker was obtained from diisocyanohexane 1,
a maleimide equipped with a carboxylic acid group 2 and lauric
aldehyde 3 in one step by a P-3CR as shown in Scheme 2a. As
Passerini reactions show higher reaction rates and yields in
aprotic, non-polar solvents, all P-3CRs were conducted in DCM.
For the linker formation, DMSO was added to increase the
solubility of the maleimide 2. In order to prevent the reaction of
both isocyano functionalities,
a
fourfold excess of the
diisocyanohexane 1 was employed. Due to extended reaction
Scheme 2. Sequential and modular strategies for the synthesis of sequence-defined oligomers alternatingly consisting of Passerini and photo-blocks. Synthesis of
the α-ω-functionalized Passerini linker 5 in a P-3CR allowing growth of the symmetrical tetramer 7 from sebacic acid 4 as core unit. The tetramer 7 is subsequently
extended with the photo-monomer 8a, a modified photo-monomer 8b and a photo-dimer 7c to afford the functional oligomers equipped with furan capped maleimides
9a and 9c or a terminal carboxylic acid group at both chain ends 9b.
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periods of several days required for the Passerini reaction under
the present conditions, all operations were conducted under
nitrogen atmosphere to prevent the isocyano groups from
degradation. The reaction mixture was stirred for two days at
ambient temperature, resulting in the target compound 5.
Chromatographic purification allowed separation of the target
compound 5 (57 % yield) and partial recovery of the exceeding
precursor 1 (up to 65 %). Introduction of further functional groups
to the Passerini linker is conceivable. However, carboxylic acids,
aldehydes, ketones, amines and isocyanides can be challenging,
as they may compete in a P-3CR or Ugi reaction. The obtained
weight per chain extension step. For the formation of the tetra-
substituted macromolecule 7, similar reaction conditions were
applied according to the synthesis of the Passerini linker 5 using
benzaldehyde 6 for the introduction of a side-chain substituent.
Benzaldehyde 6 was employed in a threefold excess, the linker 5
in a 3.6-fold excess for driving the reaction towards higher yields.
The mixture was stirred in DCM (0.5 M relative to sebacic acid 4)
for three days at ambient temperature to afford the symmetric
tetra-substituted macromolecule 7. Flash chromatography
employing a gradient of cyclohexane/ethyl acetate yielded 67 %
of the desired symmetric sequence-defined oligomer 7 and the
excess of the linker 5 could be recovered (up to 45 %).
linker
5
features three anchor points for consecutive
oligomerizations. First, the isocyano group enables chain
extension via P-3CR. Second, the introduced maleimide moiety –
able to undergo [4+2] DA cycloaddition with ortho-
quinodimethanes – allows chain extension with photo-blocks and
third, a variable alkylic or aromatic side-group can be introduced
to the linker.
The photo-monomer 8a – exhibiting a benzaldehyde moiety
that undergoes photo-enolization upon irradiation as well as a
maleimide for DA-trapping – employed for the current work and
the sequence-defined polymerization has been reported
previously by our team.[2a] In the current study, three different
types of α,ω-functionalized photo-building blocks are employed
for the chain extension after P-3CR: (i) a non-modified monomer
8a exhibiting a photo-caged diene on the one hand side and a
furan caged maleimide on the other; (ii) a modified monomer 8b
equipped with an α-methyl benzaldehyde moiety and a carboxylic
acid in order to conduct chain extension via P-3CR in further
steps; (iii) a photo-dimer 8c functionalized with an α-methyl
benzaldehyde group and a furan protected maleimide. The
maleimide group of monomer 8a offered a facile attachment point
In a subsequent P-3CR, the linker 5 was added to a
symmetrical core unit, i.e. sebacic acid 4, introducing two side-
chain substituents into the growing oligomer on each side in a
single step yielding in the symmetric tetrafunctional
macromolecule 7 as depicted in Scheme 2b. Employing the
bifunctional sebacic acid 4 for the synthesis of linear oligomers
enables bidirectional growth and, thus, the formation of symmetric
macromolecules resulting in a significant increase in molecular
a
b
4
8a
5
7
9a
4
8b
5
7
9b
1,0
1,0
0,5
0,0
0,5
0,0
1,0
102
103
104
102
103
104
Molar Mass [g mol-1]
Molar Mass [g mol-1]
c
d
[9c+3Na]3+
1200.2294
4
5
8c
7
9c
[9c+2Na]2+
1788.8500
0,5
0,0
[9c+4Na]4+
905.9204
102
103
104
500
750 1000 1250 1500 1750 2000 2250 2500
Molar Mass [g mol-1]
m/z
Figure 1. SEC traces (a-c) of the successively synthesized sequence-defined oligomers alternatingly consisting of Passerini and photo-blocks 9a-c illustrating their
successful formation. The core unit sebacic acid 4, the building blocks 5 and 8a-c as well as the tetramer 7 are presented. All SEC traces were recorded in THF.
Full MS spectrum of 9c in the mass range of m/z 500 to 2500 (d) recorded in positive ion mode.
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for a carboxylic acid via base-catalyzed Thia-Michael addition
using mercaptooctanoic acid (refer to the Supporting Information
section 3.2.9, Figure S8 and S9). Prior to the Thia-Michael
addition, deprotection of the furan trapped maleimide was carried
out at 115 °C in vacuum for 24 hours in order to initiate the retro
DA reaction. High vacuum was employed to remove the released
furan from the crude reaction mixture and shift the DA equilibrium
towards cycloreversion. Thia-Michael addition was performed
with triethylamine as a base and mercaptooctanoic acid to afford
8b quantitatively. An efficient way for increasing the molecular
weight of the oligomer is a modular strategy, in which the
symmetric linear molecule is ligated with a previously synthesized
dimer. Therefore, the unmodified photo-dimer 8c was synthesized
exploiting selected transformation of monomer end-groups via
subsequent photo-induced DA together with the monomer unit 8a
bearing a caged maleimide group. In the first instance, the photo-
monomer unit 8a was thermally furan-deprotected on the
maleimide side and the photo-reactive aldehyde functionality was
locked as a dimethyl acetal in order to prevent non-controlled
photo-polymerization of the monomer. The complementary
reactive groups – i.e. the photo-enol moiety of a PEG derived
monomer and the bare thermally deprotected maleimide of 8a –
were allowed to react under irradiation of UV-light at 365 nm
resulting in dimer 8c, which carries a furan-protected maleimide
and a benzaldehyde group itself after converting the labile
dimethyl acetal by acidic hydrolysis to an aldehyde functionality.
results from the necessary purification of the intermediates via
flash chromatography since the Passerini chain extension
requires reactants in excess and the photoreaction demands
equimolar stoichiometry. In addition, the sequence-defined
oligomers require quantitative conversion of the chain ends due
to their bidirectional growth, leading to a certain loss in overall
efficiency. However, in contrast to the report by Zydziak et al., an
intermolecular maleimide-maleimide coupling side reaction under
UV irradiation has not been observed for the preparation of the
herein described building blocks and oligomers.[2a]
The successful formation of the corresponding building blocks
and intermediates was verified by SEC, high resolution Orbitrap
ESI-MS and NMR. All SEC traces of the core unit 4, Passerini
linker 5, tetramer 7, photo-building blocks 8a-c and the final
sequence-defined oligomers 9a-c that are depicted in Figure 1a-
c have been measured using THF as eluent. An increase in
molecular weight (corresponding to a decrease in retention
volume) from the core unit sebacic acid 4 and the respective
building blocks 5 and 8a-c to the consecutive symmetrical
sequence-defined oligomers 9a-c can be observed by inspecting
the SEC traces at each synthetic step of the sequence-defined
macromolecules. The increase in molecular weight and the traces
resulting from the sequential approach confirm the purity and the
success of the successive multi-component reaction and
photochemical synthetic strategy. The molecular weights have
been obtained relative to a polystyrene calibration and the
chromatographically determined dispersities of Đ = 1.01 for the
macromolecules 9a and 9b as well as Đ = 1.03 for 9c are verifying
the monodisperse nature of the synthesized sequence-defined
oligomers 9a-c. It is interesting to note that the SEC trace of 9c
shows a shoulder towards higher molecular weight, leading to a
slight increase of the dispersity going from tetramer to the octamer
(Figure 1c). Further, the trace of 9c appears to be broadened
compared to the traces of 9a and 9b, which may be associated
with the higher interaction of the – in contrast to the Passerini
blocks – more polar photo-monomers incorporated into the
oligomer resulting in an adsorption driven column interaction
leading to signal broadening. However, inspection of the high
resolution ESI-MS spectrum depicted in Figure 1d, only reveals
mass signals associated with macromolecule 9c at
Modular strategies can be employed in order to design
complex sequence-defined macromolecules utilizing building
blocks with different functional groups and thus variation of the
oligomer backbone can be achieved. Here, three photo-building
blocks – i.e. a photo-monomer 8a, a modified photo-monomer 8b
and a photo-dimer 8c – are employed for chain extension, varying
in their chemical structure and therefore diversifying the
composition of the symmetrical sequence-defined oligomers.
Consequently, the photoreaction between the symmetric
Passerini tetramer 7 and the photo-building blocks 8a, 8b and 8c
employing a PL-L lamp (λmax = 365 nm) as irradiation source
leads to the symmetric hexamers 9a (2571.13 g mol-1) and 9b
(2851.52 g mol-1) as well as to the symmetric octamer 9c with a
molecular weight of 3532.16 g mol-1 after only two chain
extension reactions, alternatingly consisting of P-3CR and photo-
blocks (Scheme 2c). An isolated overall yield of 55 % from the
building blocks to the final octamer was achieved. The low yield
m/z = 1788.8500
Δm/z = 0.0016),
([9c+2Na]2+,
m/z = 1200.2294
m/zcalc. = 1788.8516,
([9c+3Na]3+,
m/zcalc. = 1200.2308, Δm/z = 0.0014) and m/z = 905.9188
[9a+Na]+
[9b+2Na]2+
[9c+2Na]2+
a
b
c
[9a+Na]+
calculated
[9b+2Na]2+
calculated
[9c+2Na]2+
calculated
2591 2592 2593 2594 2595 2596 2597 2598 2599 2600 1447
1448
1449
1450
1451
1452
1453 1787
1788
1789
1790
1791
1792
1793
m/z
m/z
m/z
Figure 2. ESI-MS spectra of the oligomers isotopic pattern 9a (a), 9b (b) and 9c (c). The recorded mass spectra shown on top are in excellent agreement with the
calculated isotope pattern of the oligomers (bottom).
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([9c+4Na]4+, m/zcalc. = 905.9204, Δm/z = 0.0016) for the
respective charged sodium adducts, in excellent agreement with
the resolution limits of the employed mass analyzer. The mass
spectrum of 9c clearly indicates monodispersity for the same
compound, as well as the characterization via SEC evidences the
monodisperse character of the synthesized sequence-defined
oligomers 9a-c. In addition, SEC analysis confirms the successful
modular chain extension with an increase of molecular weight with
the addition of each the respective building blocks, which is a total
molecular weight of 1500 g mol-1 for the tetramer 7 and an
increase in molecular weight of 1000 g mol-1 for 8a, 1200 g mol-1
for 8b and 2000 g mol-1 for 8c. Recorded as well as predicted
spectra of 9a-c are depicted in Figure 2. It is interesting to note
that the symmetric hexamer 9b is oxidized during ESI-MS
m/z = 2593.3369 in the ESI-MS spectrum and was assigned to a
sodium adduct of the sequence-defined macromolecule 9a
(m/zcalc. = 2593.3317, Δm/z = 0.0052), a double charged signal
recorded at m/z = 1448.2110 was assigned to the adduct of 9b as
sulfone
Δm/z = 0.0001) and further a double charged species was
detected at m/z = 1788.8500 (m/zcalc. = 1788.8516,
containing
two
sodium
(m/zcalc. = 1448.2111,
Δm/z = 0.0016) associated with 9c containing two sodium counter
ions. The recorded mass spectra of the sequence-defined
oligomers 9a-c shown are in excellent agreement with the
calculated isotopic pattern evidencing the monodisperse
character and the successful synthesis of the multifunctional
sequence-defined macromolecules (full MS spectra of 9a and 9b
can be found in the Supporting Information).
analysis.
A
single charged signal was detected at
46-54
70,71
59,60
24,25
THF
5-8
THF
CHCl3
14,16
32,34
4,9
22,27
40
55
23,26
58,61
19,20
37,38
57,62
12,30
65-67
1
10
28
56
63
64
18
36
3
45
69
13,31
44
2
15
33
11
29
17
35
42,43
21
39
68
41
8
7
6
5
4
3
2
1
0
 [ppm]
Figure 3. 1H-NMR spectrum of the obtained octamer 9c recorded in CDCl3 at 400 MHz. For the signal assignments refer to the depicted structure.
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Additional characterization was carried out via NMR
spectroscopy, with the spectrum of the octamer 9c depicted in
Figure 3 (refer to the Supporting Information Figure S15 and S17
for 9a and 9b). A proton resonance between 6.00-5.84 (64) and
5.04-5.00 ppm (44) was assigned to the chiral methine group
adjacent to the phenyl ring introduced upon formation of the tetra-
substituted oligomer 7 via P-3CR as well as to the methine group
introduced during the Passerini linker 5 formation, as was already
observed for the tetramer 7 (refer to the Supporting Information
for comparison). Successful formation of the isoindole structure
formed upon irradiation of photo-enol in presence of maleimides
evidencing the synthesis of the octamer was confirmed by
resonances detected at 6.00-5.84 (18/36), 3.20-3.06
(19/20/37/38) as well as 2.96-2.88 ppm (21/39) (refer to the NMR
of the photo-dimer 8c in Supporting Information). In addition, the
furan caged maleimide functionality at the chain-ends was verified
by proton resonances at 6.39 (1), 5.17 (2) and 2.77 ppm (3).
Conflict of Interest: The authors declare no conflict of interest.
Keywords: sequence-defined macromolecules
control photochemistry multi-component reactions
convergent
• sequence
•
•
•
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Acknowledgements
C.B.-K. and M.M are grateful to the German Research Council
(DFG) for funding the current study in the context of the SFB 1176
(project A3). C.B.-K. additionally acknowledges the Australian
Research Council (ARC) for a Laureate Fellowship enabling his
photochemical research program as well as key support from the
Queensland University of Technology (QUT). A.B. is grateful for
a Chemie Fonds fellowship from the VCI.
This article is protected by copyright. All rights reserved.

10.1002/chem.201705939
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
The synthesis of multi-functional
Waldemar Konrad, Fabian R.
a
4
8a
5
7
9a
precision
linear macromolecules becomes
possible by fusing a highly efficient
photochemical
component reaction approach
entailing alternating Passerini and
photo-blocks. The growth of the
oligomers is based on a convergent
chain extension concept of sebacic
acid with building blocks on
demand in an orthogonal fashion.
sequence-defined
Bloesser, Katharina S. Wetzel,
Andreas C. Boukis, Michael A. R.
Meier,* and Christopher Barner-
Kowollik*
1,0
0,5
0,0
PASSERINI
and
multi-
Page No. – Page No.
102
103
Molar Mass [g mol-1
104
]
A Combined Photochemical and
Multi-Component Reaction
Approach to Precision Oligomers
PHOTO
CHEMISTRY
This article is protected by copyright. All rights reserved.