Controlled ring-opening polymerization of α-amino acid N-carboxy-anhydride by frustrated amine/borane Lewis pairs

Article abstract of DOI:10.1039/c7cc01440f

In this communication, we presented a novel strategy to control the ROP of α-amino acid N-carboxy-anhydrides using the concept of frustrated Lewis pairs (FLPs). An FLP intermediate containing an interaction between the bulky borane Lewis acid and the amine groups of the propagation chain end is essential to accomplish the polypeptide synthesis with well-defined structures under mild conditions.

Full text of DOI:10.1039/c7cc01440f

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Controlled Ring-Opening Polymerization of α-amino acid N-
carboxy-anhydride by Frustrated Amine/Borane Lewis Pairs
Hongyuan Zhang,a Yanzhao Nie, a Xinmei Zhi, a Haifeng Dub, Jing Yang, a,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
the particularly robust and orthogonal LA and LB reactivity, the
chemistry of FLP provides a powerful approach for a wide range of
transformations.8 Notably, FLPs have also been successfully
employed for the polymerization catalysis.9,10 For example, Chen
and coworkers developed novel polymerization methods with FLPs
for conjugated polar alkenes including linear and cyclic acrylic
monomers.9a-c,11 Bourissou’s group lately reported a controlled ROP
In this paper, we presented a novel strategy to control ROP of α-
amino acid N-carboxy-anhydrides using the concept of frustrated
Lewis pairs (FLPs). An FLP intermediate containing an interaction
between the bulky borane Lewis acid and the amine groups of the
propagation chain end is essential to accomplish the polypeptide
synthesis with well-defined structures under mild conditions.
of lactide and ε
-caprolatone with Zn(C6F5)2-based Lewis pairs.12 In
Synthetic polypeptides consisting of α-amino acids are a class of
important biomaterials, which are extensively applied in drug and
gene delivery, tissue engineering, biosensors.1 Generally, primary
amines can initiate the ring-opening polymerization (ROP) of N-
carboxy-anhydrides (NCAs) to afford polypeptides with high
molecular weight by normal amine mechanism (NAM). However,
uncontrolled molecular weight and broad molecular weight
distribution are usually obtained due to the side reactions. In 1997,
Deming and co-workers developed transition metal complexes as
active species to successfully control the ROP of NCA monomers by
the way of end-group protection.2 Schlaad and co-workers utilized
amine hydrochloride salts as initiator to avoid the formation of NCA
anions and inhibit the side reactions.3 Recently, several interesting
approaches for the controlled NCA polymerization have been
developed by employing new initiators4 (hexamethyldisilazanes,
trifluoroboranes, heavy metal catalysts, secondary amine-assisted
primary amines, and thiourea/amine initiation system), or by tuning
the reaction conditions,5 such as high vacuum, low temperature,
nitrogen flowing and so on. Despite these advances, it is still of high
interest to explore new polymerization pathways to achieve the
well-defined synthesis of polypeptides.
view of their cooperatively activating the monomer and
participating in chain initiation as well as chain propagation, it is
envisioned that FLPs may provide unprecedented opportunity for
the polypeptide synthesis. However, to the best of our knowledge,
the controlled ROP of NCA monomer mediated by FLPs has been
less reported.
In conjunction with the advantages of FLPs and the
characteristics of NCA polymerization, herein, we wish to put
forward a novel strategy to realize the controlled ROP of NCAs. As
shown in Scheme 1, the Lewis base (LB) in FLPs is supposed to still
keep its nucleophilicity to initiate NCA monomer polymerization.
During the polymerization, the bulky Lewis acid (LA) can capture the
ω-amine end of propagating chain to form a new FLP intermediate,
which will efficiently restrain the side reactions. This resulting FLP
intermediate will further attack other monomers to realize the
chain growth. The slowed-down propagation of the polymer chain
will ensure a controlled polymerization. In this context, we describe
our efforts on the controlled ROP of NCAs mediated by the FLPs of
bulky boron Lewis acid and aromatic amine for the synthesis of
well-defined polypeptide (Scheme 2).
Since the seminal works of Stephan6, the chemistry of frustrated
Lewis pairs (FLP) attracts an explosive level of interest in the past
decade.7 An FLP can be defined as a non-classical Lewis pair of a
bulky Lewis acid (LA) and a bulky Lewis base (LB) to sterically
preclude from forming stable classical LA-LB adducts (CLAs). Due to
The polymerization of γ-benzyl-L-glutamate (Glu-NCA) initiated by
aniline was initially investigated in N,N-dimethylformamide (DMF),
tetrahydrofuran (THF) and dichloromethane (DCM) in the absence
of Lewis acid (Table 1, runs 1-3), respectively. Under identical
conditions (25 oC, [Glu-NCA] = 0.50 M and M/I = 50/1), the
LA
LA
LA
a.State Key Laboratory of Chemical Resource Engineering, Beijing Key Laboratory of
Bioprocess, College of Life Science and Technology, Beijing University of Chemical
Technology, Beijing 100029, China. Email address: yangj@mail.buct.edu.cn
b.Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China.
Electronic Supplementary Information (ESI) available: [Experimental details as well
as supporting data including NMR data, kinetic experiment data and GPC profiles
of obtained polypeptides]. See DOI: 10.1039/x0xx00000x
R
NH
O
O
O
O
O
initiation
O
O
NH2
R
O
H
+
NH
NCA
N
NH2
Chain Growth
on the FLP Side
LB
LB
R
LB
R
O
R
FLP
FLP'
FLP''
Scheme 1. Proposed Lewis pairs involved in the ROP of Glu-NCA.
J. Name., 2013, 00, 1-3 | 1
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but the broad Ð of the final polymer (1.63) demonstrated that the
polymerization process was still uncontrolled. It was found that the
bulky Lewis acid Fmes2BF itself cannot initiate the polymerization of
Glu-NCA (Table 1, run 4). When a FLP of aniline and Fmes2BF (1/1,
molar ratio) was employed for the polymerization of Glu-NCA in
DMF or THF, extremely low conversions were still obtained (Table 1,
runs 5 and 6). Using DCM as solvent, the polymerization time was
extended to 8 h with a 99% monomer conversion. However, to our
pleasure, the Ð of the obtained polymer was significantly decreased
to 1.28, and the measured Mn was very close to the calculated one
(Table 1, run 7). Under the same condition, the combination of
B(C6F5)3 and aniline was inert for the Glu-NCA polymerization (Table
1, run 8), which was possibly due to the diminished nucleophilicity
of aniline by a strong interaction with LA (Figure S3). When
Fmes2BH was subjected to the polymerization of Glu-NCA with
aniline, only a 60% monomer conversion with a broad Ð (1.53) was
obtained after a 12 h polymerization (Table 1, run 9).
Scheme 2. The chemical structures of Lewis acids, Lewis bases and
monomers used in this study.
polymerization in DMF or THF exhibited a relatively lower activity
(nearly 100% monomer conversion for 14 h). The obtained much
higher molecular weight (Mn) than the calculated ones, and the
broad molecular weight distribution (Ð) (>1.80) indicate that the
polymerization in these two solvents is very complex. When the
solvent was changed to DCM, a less polar and non-coordinating
solvent, the polymerization can be completed in 1 h (run 3). The
Subsequently, the molar ratio of Fmes2BF to aniline was studied
for the polymerization. Reducing the amount of Fmes2BF to 0.5 or
0.75 resulted in a more rapid polymerization with a slightly higher Ð
value (Table 1, runs 7 vs 10 and 11). However, when a higher
loading of Fmes2BF was employed in the range of 1.25-2.0, a slower
4
4
measured Mn (1.42×10 ) was close to the calculated one (1.10×10 ),
Table 1. ROP of Glu-NCA and Lys-NCA initiated by FLP.
b
-4 c
-4 d
Run
Solvent
LA
LB
Mon
[M]:[LB]:[LA]a Time (h)
Ðd
1.81
1.92
1.63
—
Conv. (%)
>99
M
×10
M
×10
n, cal
n, mea
1
2
DMF
THF
—
Ani
Ani
Ani
—
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
Glu-NCA
50:1:0
50:1:0
14
14
1
1.10
2.78
—
>99
>99
0
1.10
1.10
—
1.87
1.42
—
3
DCM
DCM
DMF
THF
—
50:1:0
4
Fmes2BF
Fmes2BF
Fmes2BF
Fmes2BF
B(C6F5)3
Fmes2BH
Fmes2BF
Fmes2BF
Fmes2BF
Fmes2BF
50:0:1
14
12
12
8
5
Ani
Ani
Ani
Ani
Ani
Ani
Ani
Ani
Ani
Ani
50:1:1
8
0.09
—
1.30
—
1.26
—
6
50:1:1
0
7
DCM
DCM
DCM
DCM
DCM
DCM
DCM
50:1:1
>99
0
1.10
—
1.19
—
1.28
—
8
50:1:1
12
12
3
9
50:1:1
60
>99
>99
91
74
0.66
1.10
1.10
1.00
0.81
0.77
0.97
1.01
0.93
0.86
1.53
1.36
1.34
1.27
1.23
10
11
12
13
50:1:0.5
50:1:0.75
50:1:1.25
50:1:1.5
6
10
12
14
15
DCM
DCM
Fmes2BF
Fmes2BF
50:1:2
50:1:1
18
10
66
90
0.72
0.96
0.75
1.16
1.22
1.25
p-MeO- Glu-NCA
Ani
16
17
18
DCM
DCM
DCM
Fmes2BF
Fmes2BF
Fmes2BF
p-Br-Ani Glu-NCA
50:1:1
50:1:1
50:1:1
12
9
75
0.82
0.96
1.31
0.64
1.01
1.19
1.29
1.24
1.22
BA
Glu-NCA
Lys-NCA
>99
Ani
5
>99
a Indicating that the molar ratio of monomer (Glu-NCA), Lewis base (LB) and Lewis acid (LA). b Determined by monitoring the change of the
c
d
NCA anhydride absorption peak at 1785 cm-1 in FT-IR spectroscopy. Calculated by [Glu-NCA]/[LB]× (MNCA-44)×monomer conversion.
Determined by gel-permeation chromatography (GPC) in THF as eluent, Ð represents molecular weight distribution.
2 | J. Name., 2012, 00, 1-3
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polymerization was observed but with relatively lower Ð values
(Table 1, runs 7 vs 12-14). It is indicated that more Lewis acid
ensured more effective interaction with the ω-amino end to lead a
slow-down propagation of the polymer chain and
a better
controllability of the polymerization. The Glu-NCA monomer
conversion at various ratios of Fmes2BF to aniline was monitored in
situ by IR at fixed time intervals (1 minute, Figure S4). As a result,
the observed polymerization rate (Kobs) calculated from the slopes
of the straight lines was decreased from 0.036 min-1 to 0.0036 min-1
upon increasing Fmes2BF loading from 0.5 to 1.5 in the system
(Figure S5). In addition, when polymerization was catalyzed by the
molar ratio of Fmes2BF and aniline with 1 to 1, it was found that an
increase in Mn of the polymer was well linearly correlated to the
enhancement of monomer conversion (Figure S6 and S7). The slight
changes of molecular weight distribution between 1.12 and 1.28
clearly suggest that the FLP-mediated polymerization is controlled.
Next, several aromatic amines instead of aniline were used as
initiators for the FLP-mediated polymerization of Glu-NCA. For
example, with the use of more nucleophilic p-methoxylaniline (p-
MeO-Ani) and Fmes2BF, the ROP of Glu-NCA proceeded smoothly to
afford a 90% conversion in 10 h with a comparatively narrow Ð
(1.25) (Table 1, run 15). When p-bromoaniline (p-Br-Ani) was
combined with Fmes2BF, the obtained Ð value was dramatically
decreased from 1.64 (in the absence of Fmes2BF, Table S1, run 2) to
1.29 (Table 1, run 16). Benzylamine (BA) is one of the widely used
initiators in the ROP of NCA. When BA itself initiated Glu-NCA to
polymerize, nearly a 100% monomer conversion was obtained in
only 1 h with the Ð value of 1.37 (Table S1, run 3). In contrast, the
combination of Fmes2BF and BA gave a better Ð value of 1.24
despite that the polymerization time was extended to 9 h (run 17,
Table 1). Additionally, the FLPs of aniline and Fmes2BF were
examined for the polymerization of other NCA monomer such as
Lys-NCA. As a result, 1.19×104 of molecular weight with a relatively
narrow Ð was obtained after a 5 h polymerization (run 18, Table 1).
To have a better insight into the FLP-catalyzed polymerization of
Glu-NCA, 11B NMR was utilized to monitor the polymerization
process. The boron signal of free Fmes2BF appeared at 45.6 ppm
(Figure 1). With adding aniline into Fmes2BF in DCM with the molar
ratio of 1 to 1, the boron signal shifted to 4.91 ppm,13 which was
attributed to the interaction between boron Lewis acid and amine
Lewis base. The obtained experimental results indicate that aniline
can still trigger the polymerization of Glu-NCA, although its
nucleophilicity was weakened by the interaction with Lewis acid.
When Glu-NCA was added into the FLP system with molar ratio of 5
to 1, the boron signal appeared around 5.50 ppm during the
polymerization (Figure 1). To determine the chemical shift of boron
atom resulting from the interaction of Fmes2BF with the amine end
of the propagation chain, α-amino-β-benzyl ester-L-aspartamyl
aniline (Comp 2) was synthesized according to the synthesis route
in Scheme S1 [the preparation of α-amino-γ-benzyl ester-L-glutamyl
aniline (Comp 1) was failed due to the side reaction of lactam].
When Comp 2 with free amino group was added into Fmes2BF
solution with molar ratio of 1 to 1, the boron signal distinctly
6 h
2 h
Fmes2BF+aniline+Glu-NCA
0 h
Fmes2BF+aniline
Fmes2BF
60
50
40
30
20
10
0
-10
Chemical shift (ppm)
Figure 1. 11B NMR spectra of Fmes2BF, Fmes2BF and aniline systems
with molar ratio of 1 to 1, and Fmes2BF, aniline and Glu-NCA
systems with molar ratio of 1 to 1 to 5.
appeared at 5.60 ppm (Figure S9). In contrast, when Boc-protecting
Comp 2 was added into the Fmes2BF solution, the chemical shift of
boron (46.2 ppm) kept unchanged, indicating there no interactions
involved between Fmes2BF and Boc-protecting Comp 2. These
results support that Fmes2BF can interact with the end amino group
of the propagation chain to form FLP intermediates.
The ROP process was also investigated by 1H NMR technology.
For the polymerization with aniline and Glu-NCA at the molar ratio
of 1 to 5, the characteristic peaks of monomer at 6.45 ppm (e) and
4.37 ppm (f) were gradually diminished (Figure S10A). Concurrently,
the methine signal (f’) on the polymer backbone was obviously
enhanced. Notably, with the amino signal (a) of aniline vanishing at
3.70 ppm, a new proton peak (a’) appeared at 3.06 ppm. Addition
of trifluoroacetic anhydride (TFAA) into the polymerization system,
the peak at 3.06 ppm was immediately disappeared, which was
therefore assigned as the N-H signal at the polymer chain end via
ROP. However, for the polymerization system with Fmes2BF and
Scheme 3. Proposed mechanism for ROP of NCA controlled by FLP.
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Messman, Macromolecules, 2009, 42
, 7781. (d) W.
aniline, the amino signal of aniline at 3.70 ppm was not observed at
the initiation stage due to the interaction of aniline with Fmes2BF
leading to its chemical shifting (Figure S10B). Moreover, the signal
at 3.06 ppm for the end amino generated via ROP was also not
detected in the polymerization process due to a similar reason.
Based on the aforementioned results, a probable polymerization
pathway is outlined in Scheme 3. Aniline and Fmes2BF form a FLP
due to the steric hindrance, which will keep the nucleophilicty of
aniline to initiate Glu-NCA polymerization. After initiation, Fmes2BF
Lewis acid captures the end amino group of the propagation chain
to generate a new FLP-intermediate, which will further attack NCA
monomer to realize the propagation. Although the initiation rate is
also slowed down by FLP, the significant decrease of propagation
rate by forming new FLP-intermediates largely enhances the
controllability of the Glu-NCA ROP.
Vayaboury, O. Giani, H. Cottet, A. Deratani, F. Schue,
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a novel strategy supported by an original
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9
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Acknowledgement
This work was supported by National Natural Science Foundation of
China (NSFC, Grant No. 21174013; 21374005), the New Century of
Ministry of Education (NCET-12-0754), Beijing National Laboratory
for Molecular Sciences (BNLMS20150127).
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TOC:
An FLP intermediate formed through the bulky borane Lewis acid and the amine
groups of the propagation chain end controlled the ring-opening polymerization of
α-amino acid N-carboxy-anhydride monomers.