Multicomponent Combinatorial Polymerization via the Biginelli Reaction

Article abstract of DOI:10.1021/jacs.6b04425

A multicomponent combinatorial polymerization method has been exploited as a new intersection between combinatorial chemistry, polymer chemistry, and organic chemistry. The tricomponent Biginelli reaction has been employed as a model multicomponent reaction (MCR) to efficiently prepare a library of polycondensates with continuously changed chain structure but different physical properties. The naturally increased reaction modules (monomers) directly doubled the number of polymers in the library, effectively improving the efficiency of polymer preparation. The glass transition temperatures (T_g) of those homologous polymers have been mapped for the first time to predict the T_g values of absent polymer homologues with good to excellent accuracy. Meanwhile, the T_g maps have also been used to reveal the regular change in T_g according to the polymer structure (linking group, monomer chain length, etc.), initially suggesting the academic significance of the multicomponent combinatorial polymerization system. We believe that the current research paves a straightforward way to synthesize new libraries of polymers via MCRs and might prompt the broader study of MCRs in interdisciplinary fields.

Full text of DOI:10.1021/jacs.6b04425

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Communication
Multicomponent Combinatorial Polymerization via the Biginelli Reaction
Haodong Xue, Yuan Zhao, Haibo Wu, Zilin Wang, Bin Yang, Yen Wei, Zhiming Wang, and Lei Tao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04425 • Publication Date (Web): 05 Jul 2016
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Multicomponent Combinatorial Polymerization via the Biginelli
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Haodong Xue, Yuan Zhao, Haibo Wu, Zilin Wang, Bin Yang, Yen Wei, Zhiming Wang, Lei Tao
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Multicomponent Combinatorial Polymerization via the Biginelli Re-
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Haodong Xuea,b, Yuan Zhaoa, Haibo Wua,b, Zilin Wanga, Bin Yanga, Yen Weia, Zhiming Wangb,
Lei Taoa*
a The Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department
of Chemistry, Tsinghua University, Beijing 100084, P. R. China.Department of Chemistry, Tsinghua University, Bei-
jing, 100084, China.
b School of Petrochemical Engineering, Changzhou University, Changzhou, Jiangsu 213164, China.
Supporting Information Placeholder
laboratorial bench and real life. Thus, developing new HTP
ABSTRACT: A multicomponent combinatorial polymeriza-
polymerization systems to get polymers with more molecular
diversity is a challenging subject in methodological investiga-
tion, and has the practical value.
tion method has been exploited as a new intersection be-
tween combinatorial chemistry, polymer chemistry and or-
ganic chemistry. The tri-component Biginelli reaction has
been employed as a model multicomponent reaction (MCR)
to efficiently prepare a library of polycondensates with con-
tinuously changed chain structure but different physical
properties. The naturally increased reaction modules (mon-
omers) directly doubled the number of polymers in the li-
brary, effectively improving the efficiency of polymer prepa-
ration. The glass transition temperatures (Tgs) of those ho-
mologous polymers have been mapped for the first time to
predict the Tg values of absent polymer-homologues with
good to excellent accuracy. Meanwhile, the Tg-maps have
also been used to reveal the regular change of Tg according to
the polymer structure (linking group, monomer chain length
etc.), initially suggesting the academic significance of the
multicomponent combinatorial polymerization system. We
believe current research paves a straightforward way to syn-
thesize new libraries of polymers via MCRs, and might
prompt the broader study of MCRs in interdisciplinary fields.
Recently, Meier et al., synthesized polycondensates via the
tri-component Passerini reaction,26-29 triggering the research
enthuiasm of multicomponent reactions (MCRs) in polymer
chemistry. More and more MCRs including the Passerini,30,31
Ugi,32-35 Biginelli,36-39 Kabachnik-Fields,40-43 Hantzsch,44,45
Mannich46,47 etc. reactions have been reassessed by the pol-
ymer chemists to prepare new polymers. The polymerization
via MCR (MCP) inherits the unique charm of MCRs to offer
more molecular diversity to polymers,35,43 such as the prepa-
ration of six polymers via the Ugi reaction by combinations
of four monomers (two bifunctional, two monofunctional).35
By now, MCP is becoming a new vibrant branch in modern
polymer chemistry.
MCRs contain more than two reaction modules (Scheme
1a), thus are naturally suitable for the HTP synthesis systems.
Herein, we report for the first time a new combinatorial
polymerization system combining the HTP polymerization
and MCP (HTP-MCP) (Scheme 1b).
Combinatorial synthesis is a very powerful strategy to rapidly
prepare libraries of large amount of analogous compounds
(tens to thousands to even millions) by combination of dif-
ferent reactive modules.1-4 As a result, combinatorial synthe-
sis has been applied in many fields, such as peptide synthesis,
drug discovery, catalyst research and material science etc. to
considerably improve the efficiency of synthesis, optimiza-
tion and screening of the target products.5-12 In polymer
chemistry, the concept of combinatorial synthesis has also
been introduced to develop some delicate high-throughput
(HTP) polymerization systems. By different combinations of
analogous monomers, libraries of homologous polymers have
been rapidly prepared in a time and labor saving manner,
thus accelerating the process to achieve proper functional
polymers as the drug carrier, tissure engineering scaffold and
micro-device etc..13-25 Nowadays, HTP polymerization has
been recognized as a potent tool to bridge the gap between
Scheme 1. a) MCR; b) HTP-MCP.
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According to the principle of combinatorial synthesis, the
to monitor the polymerizations. For example, when A2(8),
B2(5) and urea were used as the monomers (Fig. 2a), the
monomer conversion was calculated by comparing the inte-
gral values between the protons on the benzene ring in B2(5)
monomer and the new formed specific Biginelli methine
protons (PhCH, ~ 5.21 ppm) (Fig. S1). The monomer quickly
consumed (~ 90% in 60 min) (Fig. 2b, Fig. S1), and only oli-
gomers formed during that period (Fig. 2c). Afterwards, the
monomer conversion quickly reached the maximum (~ 100%
in 120 min) (Fig. 2b, Fig. S1), and the polymers had rapidly
increased molecular weights at the late stage of the polymer-
ization (Fig. 2c), confirming the mechanism of step-growth
polymerization. The polycondensation almost finished in 10
h while the molecular weigh only slightly increased after 24 h
(Fig. 2c).
amount of polymers is determined by the combination num-
bers of the monomers in HTP polymerization systems.
Therefore, compared to traditional HTP polycondensation
systems which are constructed through two-component cou-
pling reactions, the HTP-MCP system has natural superiority
to prepare more polymers due to the innately increased
monomers. As a concrete example, the famous Biginelli reac-
tion was employed in current research to establish a HTP-
Biginelli polycondensation system (Scheme 2).
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Scheme 2. The HTP-Biginelli polycondensation system.
The tri-component Biginelli reaction contains three reac-
tion modules: aldehyde, ß-ketoester and (thiol)urea (or their
derivatives) to generate dihydropyrimidin-2(H)-one (DHPM)
as the product. Previous research verified the Biginelli reac-
tion a highly efficient polycondensation tool to rapidly pre-
pare poly(DHPM)s,37-39 which have some attractive proper-
ties, such as metal-bonding ability39 or high glass transition
temperature (Tg),37 suggesting MCP a new strategy to realize
new applications of MCRs. In current research, four di-
aldehyde compounds (A2(X)) and eight di-ß-ketoester deriv-
atives (B2(Y)) were used as the monomers, and the HTP-
Biginelli system was constructed by mixing the A2(X) and
B2(Y) monomers via different combinations in the presence
of urea (C(1)) or thiolurea (C(2)) to simultaneously synthe-
size 32 A2(X)B2(Y)C(1) or 32 A2(X)B2(Y)C(2) polymers (Fig. 1a).
Figure 2. a) Reaction conditions: acetic acid as solvent, 100°C,
[A2(8)]/[B2(5)]/[urea]/[MgCl2] = 1/1/3/0.2; b) the conversion
of Biginelli reaction versus time; c) the GPC curves during
1
Biginelli polycondensation; d) H NMR spectrum (DMSO-d6,
400 MHz) of the final A2(8)B2(5)C(1) polymer.
Figure 1. a) The 32 combinations of A2(X) and B2(Y) mono-
mers; b) the experiment scene of HTP-Biginelli polyconden-
sation (32 samples in 35 positions, 3 empty positions).
Through simple precipitation into cold water to remove
the acetic acid and other small molecules (urea, MgCl2 etc.)
and washing with diethyl ether, 32 polymers could be easily
obtained for further analyses. As a typical example, from the
1H NMR spectrum of the purified A2(8)B2(5)C(1) polymer (Fig.
2d), the aldehyde group (10.1 ppm) almost completely disap-
peared, and the characteristic peaks of Biginelli cyclization
product (PhCH: 5.21 ppm, NH: 7.81 ppm, 9.29 ppm) could be
clearly identified. The integral ratio between the PhCH me-
thine and the protons of benzene ring (I5.21/I7.37/I7.91 = 1/2/2) is
consistent with the theoretical value (1/2/2), indicating the
efficient and thorough Biginelli reaction. The molecular
weight of the A2(8)B2(5)C(1) polymer was detected using a
multi-angle laser light scattering (MALLS) detector as Mn, LLS
~ 31000 g/mol (dn/dc: 0.055), thus the polymerization degree
(DP) could be deduced as ~ 32. All polymers have expected
structure (unpresented data) and high molecular weights
The polymerization is highly efficient and easy for opera-
tion due to the robust Biginelli reaction, thus can be easily
carried out in centrifuge tubes in a homothermal shaker (Fig.
1b). According to our previous research,38,39 the polymeriza-
tion condition was chosen as 100°C using acetic acid and
MgCl2 (20% to aldehyde) as the solvent and catalyst, respec-
tively. When urea was used as the third monomer, the molar
ratio of monomers was set as: [A2(X)]/[B2(Y)]/[urea] = 1:1:3,
50% excess urea which can be easily washed out by water
after polymerization was used to ensure the rapid polycon-
densation.
After adding all the monomers, catalyst and solvent, 32
tubes were kept in a shaker (100°C) for 24 h. Samples were
1
taken at different time points for H NMR and GPC analyses
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(Tab. S1), and the MALDI-TOF-MS analysis of oligomer
Similar results (Fig. S5b) were also observed when thio-
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(A2(8)B2(4)C(1) as the model) also indicated the polymer has
designed structure (Fig. S2), confirming the successful con-
struction of HTP system via the Biginelli reaction.
lurea was used (Fig. S7, Tab. S2, S4), and most of the predict-
ed Tg values are found to wonderfully coincide with the ex-
perimental results (δ < 5%), further suggesting the reliability
of this statistical method.
Similarly, when thiolurea was used to repeat the polycon-
densation, the other 32 polymers have been facilely prepared
after 24 h. The polymerization study (A2(8), B2(5), C(2) as
model monmers) also confirms the polycondensation process
(Fig. S3, S4), and all polymers are formed through the Bigi-
nelli polycondensation (containing ~ 17-29% isomer) (Fig.
S3d, A2(8)B2(5)C(2) polymer as an example) and have satis-
fied molecular weights (Tab. S2). Thus, the total number of
polymers has been doubled to 64 by simply changing the
third monomer, suggesting the introducing MCRs into HTP
polymerization a straightforward way to improve the synthe-
sis efficiency.
After collecting the Tg values of those 40 urea contained
polymers (8 × 5 samples), a 3D waved map of Tg versus X&Y
number (Tg-X-Y-C(1)) can be created (Fig. 3b). Similarly, an-
other 3D waved map (Tg-X-Y-C(2)) can also be made with 40
thiolurea contained polymers (Fig. 3c). From both maps, Tg
values have been found to reasonably decrease with in-
creased spacer-length (softer spacer) of the monmers. After
merging those two maps (Fig. 3d), it is clearly to see most of
the urea contained polymers have higher Tg values than their
thiolurea contained counterparts, which was also observed in
our previous research and used to be attributed to the more
rigid urea contained DHPM moiety.45 However, some unex-
pected inversion points can also be observed (Fig. 3d). That
interesting phenomenon should be a result of multiple fac-
tors (type, size and rigidity of the coupling groups; distance
between coupling groups; molecular weights of polymers
etc.), and suggests the limitation of the analysis based on
small amount of samples. Therefore, the HTC-MCP system
which can easily increase the number and diversity of poly-
mer samples should be valuable for more precise analysis and
better understanding of the physical properties of polymers.
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The Tg values of all those 64 polymers were recorded (Tab.
S1, S2) to summerize their changing trend according to pol-
ymer chains. For example, when A2(8), B2(1,2,3,5) and C(1)
were used, the correlation between Tg values (Fig. S5a) and Y
number is found to accord with the exponential decline regu-
larity (Fig. 3a, black points). To test the reasonability of that
regularity, B2(4) monomer was used to polymerize with A2(8)
and urea, and the Tg of obtained A2(8)B2(4)C(1) polymer is
tested as 64.3°C (Fig. 3a, blue point), similar with the pre-
dicted value (60.2°C, Fig. 3a, circle point). Furthermore, all
Tg-Y number curves with different A2(X) were drawn, and a
list of A2(X)B2(4)C(1) polymers were prepared to test the fit-
ting effect (Fig. S6). The relative errors (δ) between expected
and experimental values are in a good to excellent range (~
4-15%) (Tab. S3), preliminary indicating the rationality of
that inductive method. The large deviations (δ > 10%) might
come from the rigid Biginelli ring which limits the move-
ment of the spacers, especially those short spacers.
Conclusions
In summary, a multicomponent combinatorial polymeriza-
tion system has been successfully constructed by the combi-
nation of HTP polymerization and tri-component Biginelli
reaction. After two procedures, 64 polymer homologues were
facilely prepared by changing the reaction modules. The Tg-
maps of those Biginelli polymers have been drawn to predict
the Tg values of unprepared polymers with satisfactory accu-
racy. Meanwhile, some unexpected Tg results have also been
discovered, suggesting the significancy to analysize large
amount of samples, and the value of HTP-MCP system in
polymer science. Considered the isourea, isothiolurea and
mono-substituted derivatives of urea and thiolurea can also
be used as the modules for the Biginelli reaction,48 and a
polycondensate using A2(8), B2(4) and N-methylthiolurea as
the monomers has also been successfully prepared (Fig. S8),
the current HTP-Biginelli polycondensation system has the
potential to be upgraded to further expand the type and
amount of polymers.
Besides the HTP-synthesis, the HTP-analysis is also crucial
to achieve the HTP benefits. Thus, the HTP-MCP system still
has improvement space by ultilizing some advanced analysis
technologies, such as the microfluidic method, or including
functions suitable for HTP-analysis, such as optical property,
stimuli-responsibility, anti-bacterial ability etc.. Furthermore,
synthesis of polymers via MCRs is growing as a hotspot in
polymer chemistry, and many MCRs have been exploited to
prepare elegant polycondensates, this firstly reported HTP-
Biginelli polycondensation system might prompt the devel-
opment of other HTP-MCP systems via different MCRs (Ugi,
Passerini, Mannich, Hantzsch reactions etc.), and will lead to
the appearance of huge amount of homologus MCR polymers
with interesting characters in the foreseeable future.
Figure 3. a) The simulation curve based on the Tgs of
A2(8)B2(1,2,3,5)C(1) polymers (black points), and the compar-
ison between the predicted (circle point) and actual (blue
point) Tg values of A2(8)B2(4)C(1); b) the Tg map of
A2(X)B2(Y)C(1) polymers; c) the Tg map of A2(X)B2(Y)C(2)
polymers; d) the merged Tg maps (blue: A2(X)B2(Y)C(1),
green: A2(X)B2(Y)C(2)).
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NMR and Tg results of polycondensates etc. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(26) Kreye, O.; Toth, T.; Meier, M. A. R. J. Am. Chem. Soc.
2011, 133, 1790.
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*Email: leitao@mail.tsinghua.edu.cn.
Notes
The authors declare no competing financial interests.
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This research was supported by the National Science Foun-
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Multicomponent Combinatorial Polymerization via the Biginelli Re-
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Haodong Xue, Yuan Zhao, Haibo Wu, Zilin Wang, Bin Yang, Yen Wei, Zhiming Wang, Lei Tao
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