Two tandem multicomponent reactions for the synthesis of sequence-defined polymers

Article abstract of DOI:10.1007/s11426-015-5448-0

Multicomponent polymerizations have become powerful tools for the construction of sequence-defined polymers. Although the Passerini multicomponent reaction has been widely used in the synthesis of sequence-defined polymers, the tandem usage of the Passerini multicomponent reaction and other multicomponent reactions in one-pot for the synthesis of sequence-defined polymers has not been developed until now. In this contribution, we report the tandem usage of the Passerini three-component reaction and the three-component amine-thiol-ene conjugation reaction in one pot for the synthesis of sequence-defined polymers. The Passerini reaction between methacrylic acid, adipaldehyde, and 2-isocyanobutanoate was carried out, affording a new molecule containing two alkene units. Subsequently, an amine and a thiolactone were added to the reaction system, whereupon the three-component amine-thiol-ene conjugating reaction occurred to yield a sequence-defined polymer. This method offers more rapid access to sequence-defined polymers with high molecular diversity and complexity.

Full text of DOI:10.1007/s11426-015-5448-0

SCIENCE CHINA
Chemistry
January 2015 Vol.58 No.1: 1–7
doi: 10.1007/s11426-015-5448-0
• ARTICLES •
· SPECIAL TOPIC · Progress in Synthetic Polymer Chemistry
doi: 10.1007/s11426-015-5448-0
Two tandem multicomponent reactions for the synthesis of
sequence-defined polymers
Lu Yang1, Ze Zhang1, Bofei Cheng1, Yezi You1, Decheng Wu2 & Chunyan Hong1*
1Key Laboratory of Soft Matter Chemistry, Chinese Academy of Sciences; Department of Polymer Science and Engineering, University of
Science and Technology of China, Hefei 230026, China
2Beijing National Laboratory for Molecular Sciences; State Key Laboratory of Polymer Physics & Chemistry; Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, China
Received April 12, 2015; accepted April 22, 2015
Multicomponent polymerizations have become powerful tools for the construction of sequence-defined polymers. Although
the Passerini multicomponent reaction has been widely used in the synthesis of sequence-defined polymers, the tandem usage
of the Passerini multicomponent reaction and other multicomponent reactions in one-pot for the synthesis of sequence-defined
polymers has not been developed until now. In this contribution, we report the tandem usage of the Passerini three-component
reaction and the three-component amine-thiol-ene conjugation reaction in one pot for the synthesis of sequence-defined poly-
mers. The Passerini reaction between methacrylic acid, adipaldehyde, and 2-isocyanobutanoate was carried out, affording a
new molecule containing two alkene units. Subsequently, an amine and a thiolactone were added to the reaction system,
whereupon the three-component amine-thiol-ene conjugating reaction occurred to yield a sequence-defined polymer. This
method offers more rapid access to sequence-defined polymers with high molecular diversity and complexity.
multicomponent polymerizations, multicomponent reaction, sequence-defined polymers, Passerini reaction
rectly undergo the next in situ reaction, thereby selectively
1 Introduction
affording complicated structures [4,8]. The Passerini reac-
tion is a multicomponent reaction involving a carboxylic
acid, an isocyanide, and an aldehyde. This reaction has
many advantages, such as mild reaction conditions, high
efficiency, functional group tolerance, and atom economy
[8,26]. Since Meier first introduced the use of the Passerini
multicomponent reaction for the synthesis polymers, Pas-
serini reactions have been extensively used in the synthesis
of sequence- defined polymers. For example, Meier et al. [8]
combined the Passerini three-component reaction and olefin
metathesis for the preparation of poly[1-(alkyl car-
bamoyl)alkyl alkanoates], a new class of polyesters with
amide moieties in the side chain, from renewable resources.
Li et al. [23] reported a facile method for the synthesis of
multiblock copolymers consisting of poly(ethylene glycol)
(PEG) and poly(esteramide) segments with defined side
The development of efficient methods for the synthesis of
polymers with novel structures and unique properties is of
great academic significance and industrial implication
[1–11]. There are numerous synthetic strategies that can
control the topological [12–20] and sequence structures of
polymers [16,21–23]. Among these strategies, multicom-
ponent reactions have become powerful tools for the fabri-
cation of macromolecules with controlled sequences be-
cause of their high efficiency, functional group tolerance,
atom economy, and step economy [24–28]. Multicomponent
reactions are performed in one pot and occur in a specific
order. They do not require the isolation of intermediates,
and reactive intermediates formed in the first step can di-
*Corresponding author (email: hongcy@ustc.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2015
chem.scichina.com link.springer.com

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Lu et al. Sci China Chem January (2015) Vol.58 No.1
group sequences via multicomponent polymerization based
on the Passerini reaction. On the other hand, the multicom-
ponent reaction between a thiolactone, an amine and an al-
kene, which is an amine-thiol-ene conjugation, can be car-
ried out with high efficiency under mild conditions. The
reaction has high functional group tolerance as evidenced
by Du Prez’s [29–32] and our experiments [25,33,34], and
is therefore a very promising method for the synthesis of
functional and sequence-controlled polymers.
and a Precision Detectors PD2020 Light Scattering (LS)
Detector. LiBr/ DMF solution (0.1%) with a flow rate of 1.0
mL/min was used as the eluent. The molecular weights were
calibrated against polystyrene standards. Mass spectrum
analysis was performed by using a liquid chromatography-
mass spectrometry (LC-MS) instrument (LTQ Orbitrap XL,
Thermo Scientific, USA). The system was equipped with an
electrospray ionization (ESI) source, and MS data were
processed using Xcalibur software (2.1.0 SP1 build 1160).
We envisaged that the Passerini three-component reac-
tion and the three-component amine-thiol-ene conjugation
reaction between a thiolactone, an amine and an alkene can
be carried out in tandem in one pot because the reactions
require similar reaction conditions, do not require any cata-
lyst, and proceed with high efficiency. The two tandem
multicomponent reactions would more rapidly afford
sequence-defined polymers with more components, diver-
sity and functionality.
2.3 Synthesis
2.3.1 Synthesis of N-acetylhomocysteine thiolactone
DL-homocysteine thiolactone hydrochloride (3.07 g, 20
mmol) was mixed with triethylamine (9.70 g, 96 mmol) in
dichloromethane (50 mL) in ice bath, to form a suspension.
Acetyl chloride (2.36 g, 30 mmol) was added dropwise over
30 min. The solution was stirred overnight at room temper-
ature. Subsequently, the reaction mixture was diluted with
dichloromethane (20 mL), filtered, washed with brine (30
mL×2), and extracted with dichloromethane (40 mL×2).
The organic layer was dried with anhydrous Na2SO4. The
product was further purified by silica gel column chroma-
tography using ethyl acetate as the eluent. The yield was
2 Experimental
2.1 Materials
N,N-dimethyl-1,3-propanediamine (DMPDA, 99%), meth-
acrylic acid (99%), 1-butanethiol (99%) and sodium perio-
date (98%) were purchased from Alfa Aesar (USA).
DL-homocysteine thiolactone hydrochloride (99%), acetyl
chloride (98%), and 4,7,10-trioxa-1,13-tridecanediamine
(97%) were purchased from Sigma-Aldrich (USA). Allyl
chloroformate (98%), adipoyl chloride (98%) and 1,2-cyclo-
hexanediol (98%) were purchased from TCI. Triethylamine
(99.5%) and 2,2-dimethoxy-2-phenylacetophenone (DMPA,
99%) were purchased from Aladdin (USA). Ethyl isocy-
anoacetate (99%) was purchased from Adamas-beta (China).
DMSO-d6 (99.8 atom% D) and chloroform-d (99.8 atom%
D) were purchased from J&K (China). Anhydrous sodium
sulfate (99%), sodium hydroxide (96%), n-hexane (97%),
ethyl acetate (99.5%), methanol (99.7%), dichloromethane
(99.5%), 1,4-dioxane (99%) and anhydrous diethyl ether
(99.7%) were purchased from Sinopharm Chemical Reagent
Co. Ltd. (SCRC, China). Tetrahydrofuran (SCRC, 99%)
was purified by distillation. Other reagents were used as
received.
1
65%. H NMR (300 MHz, CDCl3): δ 1.931 (m, 1H), 2.029
(s, 3H), 2.895 (m, 1H), 3.301 (m, 2H), 4.527 (m, 1H), 6.171
(s, 1H).
2.3.2 Synthesis of N-(allyloxy)carbonylhomocysteine thi-
olactone
DL-homocysteine thiolactone hydrochloride (3.07 g, 20
mmol) was added to a suspension of NaHCO3 (8.42 g, 100
mmol) in 1,4-dioxane/H2O (1:1, v/v, 50 mL), and the mix-
ture was stirred for 30 min. Subsequently, a solution of allyl
chloroformate (4.85 g, 40 mmol) in 1,4-dioxane (5 mL) was
added over 20 min. After the reaction mixture was stirred
overnight at room temperature, the reaction mixture was
washed with brine (100 mL) and extracted with ethyl ace-
tate (150 mL×3). The organic layer was dried with anhy-
drous Na2SO4. The product was further purified by silica gel
column chromatography using CH2Cl2/MeOH (49:1, v/v) as
the eluent. The yield was 47%. 1H NMR (300 MHz, CDCl3):
δ 2.018 (m, 1H), 2.886 (m, 1H), 3.299 (m, 2H), 4.338 (m,
1H), 4.583 (d, 2H), 5.216–5.353 (m, 3H), 5.930 (m, 1H).
2.2 Characterizations
2.3.3 Synthesis of N,N-bis(2-oxotetrahydrothiophen-3-yl)
adipamide
All NMR spectra were recorded on a Bruker AV300 NMR
(Germany) spectrometer (resonance frequency of 300 MHz
DL-homocysteine thiolactone hydrochloride (6.1 g, 40
mmol) was added to a suspension of NaHCO3 (13.44 g, 150
mmol) in 1, 4-dioxane/H2O (2:1, v/v, 120 mL), and the
mixture was stirred for 30 min. After adipoyl chloride (3.4 g,
18.5 mmol) was added dropwise over 30 min, the mixture
was stirred overnight at room temperature. After filtration,
the residue was dissolved in water (250 mL). The product
1
for H and 75 MHz for 13C) operated in the Fourier trans-
form mode. Molecular weights and molecular weight poly-
dispersity indices (PDIs) were measured with a Size Exclu-
sion Chromatography (SEC) instrument (Waters, USA).
The system was equipped with a PL-RI Differential Refrac-
tive Index (DRI) detector, PL-BV 400RT Viscometer (Visc)

Lu et al. Sci China Chem January (2015) Vol.58 No.1
3
was obtained as a white powder by filtration and dried in
vacuum. Yield was 16%. 1H NMR (300 MHz, DMSO-d6): δ
1.488 (s, 4H), 2.108 (m, 6H), 2.382 (m, 2H), 3.316 (m, 4H),
4.586 (m, 2H), 8.165 (d, 2H).
2.3.4 Synthesis of adipaldehyde
NaIO4 (13.85 g, 65 mmol) in hot water (60 mL) was added
to silica gel (50 g) and stirred vigorously. Subsequently, a
solution of 1,2-cyclohexanediol (5.81 g, 50 mmol) in
CH2Cl2 (250 mL) was added dropwise to the suspension,
and the reaction was stirred for 24 h at room temperature.
The mixture was filtered, and the silica gel was washed with
CH2Cl2 three times. Adipaldehyde was obtained as colorless
1
oil after the removal of CH2Cl2. The yield was 75%. H
NMR (300 MHz, CDCl3): δ 1.663 (m, 4H), 2.486 (m, 4H),
9.786 (s, 2H).
2.4 Two tandem multicomponent reactions in one pot
Methacrylic acid (86.0 mg, 1.0 mmol), adipaldehyde (57.0
mg, 0.50 mmol) and ethyl isocyanoacetate (135.0 mg, 1.2
mmol) were dissolved in CH2Cl2 (1 mL) and stirred at room
temperature for 24 h. Subsequently, N,N-bis(2-oxotetrahyd-
rothiophen-3-yl) adipamide (172.0 mg, 0.50 mmol) and
N,N-dimethyl-1,3-propanediamine (122.0 mg, 1.2 mmol) in
THF (4 mL) were added to the solution. After an additional
48 h at 40 °C, the polymer was isolated by precipitation in
excess diethyl ether and dried under vacuum.
Methacrylic acid (86.0 mg, 1 mmol), adipaldehyde (57.0
mg, 0.5 mmol) and ethyl isocyanoacetate (135.0 mg, 1.2
mmol) were dissolved in CH2Cl2 (1 mL) and stirred at room
temperature for 24 h. Subsequently, thiolactone (N-acetylh-
omocysteine thiolactone or N-(allyloxy) carbonylhomocys-
teine thiolactone, 1.0 mmol), 4,7,10-trioxa-1,13-tridecane-
diamine (110.0 mg, 0.5 mmol), and triethylamine (10 mg,
0.1 mmol) in THF (4 mL) were added to the reaction system.
After an additional 48 h at 40 °C, the polymers were isolat-
ed by precipitation in excess diethyl ether and dried under
vacuum.
Scheme 1 Outline of the synthesis of a sequence-controlled polymer via
tandem multicomponent reactions.
reactions in one pot. The Passerini three-component reac-
tion between methacrylic acid, adipaldehyde and ethyl iso-
cyanoacetate was carried out in CH2Cl2 at room temperature,
and NMR spectroscopy was used to follow the progress of
reaction, as shown in Figure 1. The Passerini three-compo-
nent reaction involves a trimolecular reaction between the
isocyanide, the carboxylic acid, and the aldehyde in a se-
quence of nucleophilic additions. After the nucleophilic
additions, the chemical shift of the CH2 unit (h) in adipal-
dehyde changes from 2.42 to 1.91 ppm, the chemical shift
of the CH2 unit (d) in ethyl isocyanoacetate changes from
4.25 to 4.19 ppm, and the chemical shifts of the methacrylic
unit (b, a) change from 2.00, 5.58, 6.16 to 1.95, 5.61, 6.20
ppm, respectively, as shown in Figure 1(A). Based on inte-
gral values, the acid conversion reaches 94.6% after 24 h. In
the 13C spectra, after reaction for 24 h, the peaks for the
carbons of Nos. 10, 11 and 12 in adipaldehyde almost com-
pletely move from 202.5, 43.3, 21.3 to 73.8, 31.7, 24.1 ppm,
respectively. The chemical shifts of carbons Nos. 5 and 6 in
ethyl isocyanoacetate change from 163.7, 63.1 to 170.1,
41.0 ppm, respectively, and the peak of the methacrylic unit
(4) almost completely moves from 171.0 to 166.0 ppm, as
shown in Figure 1(B). All of these results indicate that the
Passerini three-component reaction between methacrylic
acid, adipaldehyde, and ethyl isocyanoacetate in situ forms
an intermediate molecule with two alkene units in a very
high yield.
3 Results and discussion
The tandem Passerini three-component reaction and three-
component amine-thiol-ene conjugation reaction are out-
lined in Scheme 1. First, the Passerini three-component re-
action between methacrylic acid, adipaldehyde and ethyl
isocyanoacetate produced a new molecule with an alkene
unit at both ends. Subsequently, a thiolactone and an amine
were added to the reaction system. The amine can ring-open
the thiolactone to give a thiol-containing molecule, which
can immediately react with 4,7,14,17-tetraoxo-3,18-dioxa-
6,15-diazaicosane-8,13-diyl bis(2-methylacrylate) (formed in
the Passerini three-component reaction), thereby forming a
sequence-defined polymer via two tandem three component
Du Prez’s and our investigations have shown that pri-
mary amines do not react with the electron-deficient carbon-

4
Lu et al. Sci China Chem January (2015) Vol.58 No.1
carbon double bond of methacrylate without a catalyst.
However, primary amines are able to ring-open a cyclic
thiolactone, thereby releasing a thiol, whereas secondary
and tertiary amines do not perform this reaction [25,31,35].
On the other hand, the thiol can react with methacrylate
very efficiently in the presence of a nucleophile such as a
tertiary amine [35,36]. Therefore, N,N-bis(2-oxotetrahy-
drothiophen-3-yl) adipamide and N,N-dimethyl-1,3-pro-
panediamine (DMP-DA) were added to the completed Pas-
serini three-component reaction system. We expected that
the following would happen: DMPDA does not react with
methacrylate [25], but it causes the ring-opening of
N,N-bis(2-oxotetrahydrothiophen-3-yl) adipamide to give a
thiol-intermediate. The latter is very likely to react with the
double bond of methacrylate via a Michael addition reaction,
thereby producing a sequence-defined polymer, as shown in
Scheme 1 and Figure 2.
spectrum, the conversion of the double bond of methacry-
late reaches ~95% after 48 h. We also used SEC to trace the
sequence-defined polymer obtained after performing the
amine-thiol-ene conjugation for 48 h. The corresponding
sequence-defined polymer has a molecular weight of 13.7
kDa and a polydispersity of 3.1, as shown in Figure 2(C).
Moreover, these tandem three-component reactions can
be extended to prepare sequence-defined polymers with
functional side units (such as a clickable alkene unit) as
shown in Scheme 2. When N-(allyloxy) carbonylhomocys-
teine thiolactone and 4,7,10-trioxa-1,13-tridecanediamine
are used in the second multicomponent amine-thiol-ene
conjugation reaction, the sequence-defined polymer formed
has clickable alkene side units as shown in Scheme 2. The
sequence-defined polymer with clickable alkene side unit
obtained via two tandem multicomponent reactions has a
molecular weight of 49.8 kDa and polydispersity of 2.03
after a reaction time of 48 h, as shown in Figure 3. It should
be noted that, although the alkene units can readily react
with thiols via a radical-mediated thiol-ene click reaction,
here the thiol-intermediate does not react with the alkene
side units because there is no radical source in the three-
component polymerization system [33,36]. As shown in
Figure 4, it is very clear that the signals for the alkene unit
at 5.8 and 5.2 ppm survive after reaction for 48 h. These
clickable alkene side units can be used as reacting units for
the modification of the sequence-defined polymer via thiol-
ene click reaction. Here we used benzene thiol as a model
molecule to modify the polymer. It is clear that all of the
signals arising from the benzene thiol molecule appear in
the sequence-defined polymer after modification.
The thiol unit is very reactive toward the carbon–carbon
double bond of the methacrylate unit [36,37]. In the Mi-
chael addition based thiol-ene click reaction, a proton is
abstracted from the thiol unit to give a thiolate anion. The
thiolate anion is generally a strong nucleophile, and it read-
ily adds to the electron-deficient carbon-carbon double bond
of methacrylate, yielding a carbon-centered anionic inter-
mediate. The latter can abstract a hydrogen to yield a thi-
oether as the product, as shown in Scheme 1 [36]. The sig-
nals due to the methylene unit of methacrylate (at 5.7, 6.2
ppm) are very weak in 48 h, as shown in Figure 2. Addi-
tionally, the peaks at 135 and 127 ppm for the carbons in-
volved in the C=C double bond of methacrylate almost shift
to 40 (j) and 35 (l) ppm as shown in the 13C NMR spectrum
1
(Figure 2(B)). Based on the integral values in the H NMR
Figure 1 1H NMR (A) and 13C NMR (B) spectra in CDCl3 regarding the Passerini three-component reaction between methacrylic acid, adipaldehyde, and
ethyl isocyanoacetate at different reaction times. * is CH2Cl2.

Lu et al. Sci China Chem January (2015) Vol.58 No.1
5
Figure 2 1H NMR (A) and 13C NMR (B) spectra in CDCl3 and SEC trace (C) of the polymer obtained via two tandem multicomponent reactions.
Figure 3 SEC trace of the sequence-defined polymer with clickable
alkene side units obtained via two tandem multicomponent reactions.
4 Conclusions
In summary, we have reported a strategy consisting of tan-
dem two multicomponent reactions for the synthesis of se-
quence-controlled polymers. Moreover, the novel multi-
component reactions can be extended to multicomponent
polymerizations for the preparation of a series of sequence-
Scheme 2 Outline of the synthesis of a sequence-controlled polymer with
functional side units.

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Lu et al. Sci China Chem January (2015) Vol.58 No.1
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