Combining Orthogonal Chain-End Deprotections and Thiol–Maleimide Michael Coupling: Engineering Discrete Oligomers by an Iterative Growth Strategy

Article abstract of DOI:10.1002/anie.201706522

Orthogonal maleimide and thiol deprotections were combined with thiol–maleimide coupling to synthesize discrete oligomers/macromolecules on a gram scale with molecular weights up to 27.4 kDa (128mer, 7.9 g) using an iterative exponential growth strategy with a degree of polymerization (DP) of 2ⁿ?1. Using the same chemistry, a “readable” sequence-defined oligomer and a discrete cyclic topology were also created. Furthermore, uniform dendrons were fabricated using sequential growth (DP=2ⁿ?1) or double exponential dendrimer growth approaches (DP=2 2²ⁿ ?1) with significantly accelerated growth rates. A versatile, efficient, and metal-free method for construction of discrete oligomers with tailored structures and a high growth rate would greatly facilitate research into the structure–property relationships of sophisticated polymeric materials.

Full text of DOI:10.1002/anie.201706522

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Accepted Article
Title: Combining Orthogonal Chain End Deprotections and Thiol-
Maleimide Michael Coupling: Engineering Discrete Oligomers
through Iterative Growth Strategy
Authors: Zhihao Huang, Junfei Zhao, Zimu Wang, Fanying Meng,
Kunshan Ding, Xiangqiang Pan, Nianchen Zhou, Xiaopeng Li,
Zhengbiao Zhang, and Xiulin Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706522
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10.1002/anie.201706522
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Combining Orthogonal Chain End Deprotections and Thiol-Maleimide
Michael Coupling: Engineering Discrete Oligomers through Iterative
Growth Strategy
Zhihao Huang[a], Junfei Zhao[a], Zimu Wang[a], Fanying Meng[a], Kunshan Ding[a], Dr. Xiangqiang Pan[a], Prof.
Dr. Nianchen Zhou[a], Prof. Dr. Xiaopeng Li[b], Prof. Dr. Zhengbiao Zhang*[a], Prof. Dr. Xiulin Zhu[a]
Abstract: For the first time, we combined orthogonal maleimide and thiol
deprotections together with thiol-maleimide coupling to synthesize discrete
oligomers/macromolecules on gram scale with molecular weight up to 27.4
kDa (128mer, 7.9 g) via iterative exponential growth strategy with degree of
polymerization (DP) at 2ꢀ-1. By using the same chemistry, a “readable”
sequence-defined oligomer and a discrete cyclic topology were also created.
reactions, such as Suzuki coupling reaction,[8b] Sonogashira reaction,[9a]
Stille reaction,[9b] Buchwald reaction,[8e] Wittig reaction,[9c] copper
8i, 8k, 8l]
catalyzed azide-alkyne cycloaddition (CuAAC) reaction,[8d,
Glaser coupling reaction,[10] esterification,[11] amidation,[9d] and
9e]
etherification[8c,
etc., have been utilized in precision synthesis of
oligomers. Among them, metal-catalyzed coupling reactions are
frequently used owing to the versatility, effectiveness and sometimes
“click-like” manner.[7g, 8d, 8i, 8k] However, metal ions may increasingly
accumulate after many cycles and contaminate target products. This
might yield inaccurate measurements when investigating the structure-
property relationship of the discrete oligomers, limiting their potential
for future applications.
Furthermore, uniform dendrons were fabricated via either sequential growth
ꢂ
(DP = 2ꢀ-1) or double exponential dendrimer growth approach (DP =2ꢁ
-
1) with significantly accelerated growth rate. This work offered a versatile,
efficient and metal-free platform for construction of discrete oligomers with
vast designability and high growth rate, which would greatly facilitate
sophisticated structure-property research as well as applications of precise
polymer-based materials.
Herein, for the first time, we combined the orthogonal chain end
deprotections and thiol-maleimide Michael coupling together as a
versatile approach for the iterative synthesis of a variety of discrete
oligomers, including linear, dendron and cyclic oligomers. The thiol-
maleimide Michael coupling is a well-known and important member of
the “click” reactions.[12] The maleimide group can be readily protected
by furan group, which can be quantitatively deprotected by retro Diels-
I
t is well-documented that the property/function of polymers strongly
relies on their molecular weight, topology and sequence distribution.[1]
Nature creates a variety of biopolymers, such as DNA[2] and proteins[3]
with precisely-defined chain lengths, functional sequence, and
topologies. Since most artificial polymers are polydisperse with various
chemical structures and molecular weights at the molecular level, the
research on structure-property relationship is mainly limited to an
ambiguous and statistical manner.[4] Therefore, it is of great interest for
synthesis of discrete oligomers with uniform chain lengths (i.e.,
monodisperse molecular weight), monomer unit sequences, and
topologies to advance more comprehensive and accurate study of the
structure-property relationship.[5] Driven by this challenge, indeed,
chemists have made enormous efforts to synthesize discrete oligomers
with diverse directions and approaches. Within these pioneering work,[6]
iterative sequential,[7] or exponential[8] growth through terminal
deprotections/transformations and end-to-end couplings,[9] is commonly
used for preparations of discrete oligomers. When building discrete
oligomers, the efficient orthogonal chain terminal deprotections together
with end-to-end coupling reaction are highly desirable for high degree
of polymerization (DP) and scalable preparation. A number of coupling
o
Alder reaction upon heating to 110 C or above.[13] On the other hand,
thiol group[14] was protected by the judiciously selected acetyl group,
which can withstand high temperature up to 110 oC and release a reactive
thiol group in quantitative yield under acidic (or basic) environment or
by using acetyl chloride.[15] Surprisingly, no previous report combined
the deprotections of maleimide and thiol at two terminals for the
subsequent thiol-maleimide coupling in polymers and/or oligomers
synthesis. This work unprecedentedly developed a metal-free, mild and
user-friendly chemistry, i.e., combining orthogonal maleimide and thiol
group deprotections together with the thiol-maleimide coupling reaction,
to prepare discrete oligomers, which are ideal models for accurately
investigating the polymer’s structure-property relationship and provide
potential applications in bio-related or smart polymeric materials with
molecular level precision.
In all the iterative chain growth of this study, the highly efficient
retro Diels-Alder reaction was used to remove the furan protecting group
on the maleimide group, and a hydrolysis reaction was used to remove
the acetyl group on the thiol for the subsequent coupling reactions. As
depicted in Figure 1a, the precursor monomer (US-G1) was first
synthesized with furan-protected maleimide and acetyl-protected thiol
(Scheme S1) for linear oligomers synthesis. Then, repeating the
orthogonal deprotections of two ends followed by thiol-maleimide
Michael coupling cycles (Scheme S2), the linear oligomer’s chain length
propagated exponentially with DP= 2ꢀ-1 to generate 2mer (536.7 Da),
4mer (963.3 Da), 8mer (1,816.5 Da), 16mer (3,522.8 Da), 32mer
(6,935.6 Da), 64mer (13,761.0 Da) and 128mer (27,411.9 Da) (Scheme
S3-S8). Importantly, the chemistry for these discrete oligomers can be
scalable, and dozens of grams of these linear oligomers were obtained.
[a]
Z. Huang, J. Zhao, Z. Wang, F. Ying, K. Ding, Dr. X. Pan, Dr. N.
Zhou, Dr. X. Li, Dr. Z. Zhang, Dr. X. Zhu
State and Local Joint Engineering Laboratory for Novel Functional
Polymeric Materials; Jiangsu Key Laboratory of Advanced
Functional Polymer Design and Application; College of Chemistry,
Chemical Engineering and Materials Science, Soochow University
Suzhou, 215123, China
E-mail: zhangzhengbiao@suda.edu.cn
[b]
Department of Chemistry, University of South Florida, Tampa,
Florida 33620, United States
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For example, 7.9 g of 128mer was afforded with 13.3% isolated yield
over 21 steps from the starting monomer (US-G1, 97.5 g), demonstrating
the high-efficiency of this approach.
The protons of the acetyl protected group at the other chain end were
identified at 2.25 (e) ppm. Based on the integrations of 3.70 (d), 3.12 (c)
and 2.48 (c) ppm arising from the protons of the succiminide thioethers
and the protons (e) of acetyl, the DP of each oligomer was calculated.
The results from 1H NMR were in agreement with those from MALDI-
TOF mass spectrum. These convincing results enabled the orthogonal
deprotections and subsequent thiol-maleimide Michael coupling as an
accessible, robust and scalable platform for the precise preparation of
uniform linear oligomers. In addition to linear oligomers, cyclic ones
were also successfully prepared by the intramolecular ring closure via
thiol-maleimide Michael coupling under high dilution (about 1.1×10-4
M) (Scheme S16). Detailed characterizations, i.e., NMR, SEC and mass
spectrometry, were carried out to confirm the cyclic structure (Figure
S32). The successful fabrication of monodisperse cyclic oligomer would
enable reliable property comparisons between the analogous cyclic and
linear oligomers, since the research on the cyclic polymer have been the
subject of increased study because their cyclic topology imparts upon
them unique physical properties.[16]
The above efficient chemistry, i.e., orthogonal chain terminal
deprotections together with thiol-maleimide coupling reaction, was also
employed for the synthesis of sequence-defined oligomers. An example
was demonstrated here, wherein two precursor monomers were each
incorporated with naphthyl (FS-PI-3, Scheme S10) and alkene groups
(FS-PII-8, Scheme S12). Dimers of FS-PI (Scheme S11) and FS-PII
(Scheme S13) were obtained via one IEG cycle from corresponding
monomers, respectively. FS-PI-MA (removal of furan of FS-PI) and FS-
PII-SH (removal of acetyl of FS-PII) were coupled via thiol-maleimide
Michael type addition to afford FS-L (Figure 3a and Scheme S14). Then,
FS with definite unit sequence was successfully constructed by click
coupling of US-G4-SH with FS-L-MA (Figure 3a and Scheme S15). The
sequence-defined oligomer FS was rigorously characterized by MALDI-
TOF mass spectrometry (upper inset in Figure 3b) and 1H NMR (Figure
S23). Since sulfur-carbon bonds of the succinimide thioether unit
formed in this thiol-maleimide Michael coupling were relatively weak,
the information stored in the sequence-defined oligomer was able to be
“read” or decoded via a tandem mass spectrometry (MS/MS)-based
sequencing methodology with potential applications for data storage and
anti-counterfeiting technologies.[7d, 7j, 17] The decoding of the as-prepared
sequence-defined discrete oligomers was implemented on the tandem
MALDI-TOF/TOF (i.e., MS/MS). The fragmentations of FS affording
the US-G1 unit (unit MW = 213Da), FS-PII (unit MW = 304 Da) and
FS-PI (unit MW = 343 Da) were clearly identified (Figure 3b). Some
fragmentations of the corresponding cleavage owing to the high energy
of laser were also reasonably assigned (Figure S24).
Figure 1. (a) Synthetic route of the discrete oligomers via iterative exponential
growth (IEG). [a]The purity of each generation was confirmed by combining 1H
NMR, SEC trace and MALDI-TOF mass spectrum. [b]Purification was performed
by silica gel column chromatography except that [c]128mer was purified by
fractional precipitation in anhydrous methanol; The isolated yields were
calculated over 3 successive steps (i.e. terminal maleimide deprotection,
terminal thiol deprotection, and intermolecular thiol-maleimide coupling) in each
cycle. (b) SEC traces of 2mer, 4mer, 8mer, 16mer, 32mer, 64mer, and 128mer;
(c) MALDI-TOF mass spectra of 4mer, 8mer, 16mer, 32mer, and 64mer.
The molecular structure of each linear oligomer was further
validated by size exclusion chromatography (SEC, SEC traces of crude
oligomers without purification were shown in Figure S7 in Supporting
Information) and matrix-assisted laser desorption ionization time-of-
flight (MALDI-TOF) mass spectrometry (Figures 1b and 1c). Unimodal
and symmetrical SEC traces as well as the single-peak signal agreeing
with the calculated value of the molecular mass ([M+Na-Furan]+) for
each oligomer in MALDI-TOF mass spectrum confirmed the uniformity
of these structures. MALDI-TOF mass spectrum of 128mer by reflection
mode could not be obtained, and the linear mode resulted in
fragmentations due to its high MW and low ionization efficiency (Figure
S8). Figure 2 showed the 1H NMR spectra of the discrete oligomers from
2mer to 128mer. The resonances for the protons from furan protected
chain terminal could be easily identified at 6.50 (a) and 5.26 (b) ppm.
The versatility and robustness of the above chemistry for building
discrete oligomers was further demonstrated by constructing different
generations of topological oligomers, i.e., dendrons. In this study, the
succinimide thioether groups in US-G2 from thiol-maleimide Michael
addition reaction was facilely reduced to regenerate the vinyl double
bonds, through an addition-elimination process using N-
chlorosuccinimide (DT-1, Scheme S17). [18] Subsequent thiol-maleimide
Michael coupling on maleimide thioether group with thiol-deprotected
US-G1-SH afforded DT-G1 with one branching point (Figure 4a and
Scheme S18). Starting from DT-G1, the uniform oligomer-based
dendrons of DT-G2 and DT-G4 were constructed via double exponential
dendrimer growth (DEDG) strategy[19] with DP =2ꢁꢂ-1 (Figure 4a and
Schemes S19 and S21) by repetitive orthogonal deprotections and thiol-
maleimide Michael additions. Meanwhile, through sequential growth
strategy[20] with DP = 2ꢀ-1, dendron of DT-G3 was prepared from DT-
Figure 2. 1H NMR spectra of 2mer, 4mer, 8mer, 16mer, 32mer, 64mer, and
128mer in CDCl3 (Bruker, 300 MHz, TMS).
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Figure 3. (a) Synthetic route of the sequence-defined oligomer FS. (b) Full interpretation of the MALDI–TOF/TOF mass spectrum of FS fragments using the
LIFT mode (Upper inset: MALDI-TOF mass spectrum of FS acquired in the first TOF unit using Na salt as the cationization agent and DCTB as the matrix).
G2 and DT-G1 (Figure 4a and Scheme S20). The resulting dendron
topologies were characterized by SEC (Figure 4b), MALDI-TOF mass
spectrometry (Figure 4c) and H NMR (Figures S28-S30). The data of
analysis clearly demonstrated the precise constructions of these
topologies. It is noteworthy that these dendron topologies were merely
originated from one starting monomer, US-G1, no other reactant was
needed besides the catalysts or reducing agents. More importantly,
DEDG approach paved an avenue towards highly-branched dendrons in
a significantly accelerated manner.
1
Figure 4. (a) Synthetic route of dendrons DT-G2, DT-G3 and DT-G4, NCS: N-chlorosuccinimide; (b) SEC spectra and (c) MALDI-TOF mass spectra of DT-
G2, DT-G3 and DT-G4 (DT-G4 was destroyed during testing in MALDI-TOF mass spectrometry due to its high MW, the full spectrum with fragmentation peaks
is shown in Figure S31 in Supporting Information).
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As demonstrated, the above chemistry afforded an array of
discrete oligomers, which are perfect samples for accurately exploring
structure-property relationship. Especially, the study of the physical
properties of discrete oligomers with similar chemical structure but
different MWs or topologies is a fundamental topic in polymer science
area. As demonstrated here, the variation of glass transition temperature
(Tg) with inverse MW of these discrete oligomers, including linear and
topological ones, was analyzed based on Flory-Fox equation[21] as in
Figure 5. For both uniform linear oligomers and dendrons, the Tg
gradually increases with increasing the MW (Figure 5a and 5b).
Importantly, the correlation between the MW and Tg matched with
Flory-Fox equation, and the Tg was close to the predicted Tg∞ when MW
reached up to 10,000 Da (Figure 5c). In addition, the linear oligomers
and dendrons ones show almost the same linear correlation plot,
denoting that both Tg∞ and empirical parameter K of Flory-Fox equation
are almost the same values in linear and topological ones with the same
chemical structure, although the concentration of end groups in each
molecules is different in oligomers and dendrons, respectively.
Furthermore, the DSC results indicate that oligomers with polydisperse
MWs obtained from step-growth polymerization via thiol-maleimide
coupling exhibit much broader glass transition[8f] and lower Tg, as
compared with the discrete oligomers having similar MWs (Figure S9).
These differences might probably be attributed to the existence of low-
MW fractions in the polydisperse samples, according to Flory-Fox
equation.[21] Deep insights and comprehensive understanding requires
detail study, providing us further motivations for developing effective
chemistry towards discrete oligomers.
Acknowledgements
This work was supported by the National Science Foundation of China
(21674072 & 21234005), the Priority Academic Program Development
of Jiangsu Higher Education Institutions (PAPD) and the Program of
Innovative Research Team of Soochow University. The authors also
thank Prof. J. L in I. C. S and Prof. Z. J. H in Soochow U. for their helpful
discussions.
Keywords ： thiol-maleimide Michael type addition • discrete
oligomer • iterative growth • dendrimer • sequence defined
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In summary, a versatile, efficient and metal-free chemistry, i.e.,
combining orthogonal deprotections of maleimide and thiol groups
together with thiol-maleimide Michael coupling, was developed for
precisely fabricating discrete oligomers. This efficient coupling
chemistry allows the generation of an unprecedentedly broad library of
discrete oligomers with a range of linear, cyclic, and dendron
architectures. We anticipated that these precisely-defined oligomers
would enable accurate investigation on the structure-property
relationships and advance potential applications of exquisite polymer-
based functional materials.
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10.1002/anie.201706522
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Zhihao Huang, Junfei
Zhao, Zimu Wang,
Fanying Meng, Kunshan
Ding, Dr. Xiangqiang Pan,
Dr. Nianchen Zhou, Dr.
Xiaopeng Li, Dr.
A versatile, efficient and
metal-free chemistry,
combining orthogonal
deprotections of
maleimide and thiol
groups together with
thiol-maleimide Michael
coupling, was firstly
developed for precisely
fabricating discrete
oligomers.
Zhengbiao Zhang*, Dr.
Xiulin Zhu
Page No. – Page No.
Combining Orthogonal
Chain End
Deprotections and Thiol-
Maleimide Michael
Coupling: Engineering
Discrete Oligomers
through Iterative Growth
Strategy
This article is protected by copyright. All rights reserved.