Are N-substituted glycine N-thiocarboxyanhydride monomers really hard to polymerize?

Article abstract of DOI:10.1002/pola.28402

N-Substituted glycine N-thiocarboxyanhydrides (NNTAs) are promising cyclic monomers to synthesize polypeptoids with the advantages of easier preparation and higher stability during purification and storage than N-substituted glycine N-carboxyanhydrides (NNCAs). NNTAs were commonly considered too stable to polymerize for their low reactivity. In this contribution, we report controlled polymerizations of N-ethylglycine NTA (NEG-NTA) and sarcosine NTA (Sar-NTA) using primary amines as initiator under proper polymerization conditions. The controllability has been fully supported by ¹H NMR end group analyses, MALDI-ToF mass spectra, kinetic data, block copolymerizations by sequential monomer addition, and low polydispersities (1.14–1.17) of polypeptoids. Variation of the [NNTA]/[initiator] ratio allows well control of the molar mass, and degrees of polymerization (DPs) up to 287 can be reached for poly(N-ethylglycine) or DPs up to 262 for polysarcosine. NNTAs exhibit excellent activity and they are potential to synthesize polypeptoids with controllable polymerization.

Full text of DOI:10.1002/pola.28402

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Are N-Substituted Glycine N-Thiocarboxyanhydride Monomers
Really Hard to Polymerize?
Xinfeng Tao,1 Botuo Zheng,1 Hans R. Kricheldorf,2 Jun Ling1
1MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering,
Zhejiang University, Hangzhou 310027, China
2
€
Institut fur Technische und Makromolekulare Chemie, Bundestrase 45, Hamburg D-20146, Germany
Correspondence to: J. Ling (E-mail: lingjun@zju.edu.cn)
Received 18 September 2016; accepted 16 October 2016; published online 00 Month 2016
DOI: 10.1002/pola.28402
ABSTRACT: N-Substituted glycine N-thiocarboxyanhydrides (NNTAs)
are promising cyclic monomers to synthesize polypeptoids with
the advantages of easier preparation and higher stability during
purification and storage than N-substituted glycine N-carboxyan-
hydrides (NNCAs). NNTAs were commonly considered too sta-
ble to polymerize for their low reactivity. In this contribution, we
report controlled polymerizations of N-ethylglycine NTA (NEG-
NTA) and sarcosine NTA (Sar-NTA) using primary amines as ini-
tiator under proper polymerization conditions. The controllability
has been fully supported by 1H NMR end group analyses,
MALDI-ToF mass spectra, kinetic data, block copolymerizations
by sequential monomer addition, and low polydispersities (1.14–
1.17) of polypeptoids. Variation of the [NNTA]/[initiator] ratio
allows well control of the molar mass, and degrees of polymeri-
zation (DPs) up to 287 can be reached for poly(N-ethylglycine) or
DPs up to 262 for polysarcosine. NNTAs exhibit excellent activity
and they are potential to synthesize polypeptoids with controlla-
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ble polymerization. 2016 Wiley Periodicals, Inc. J. Polym. Sci.,
Part A: Polym. Chem. 2016, 00, 000–000
KEYWORDS: block copolymers; controlled polymerization; N-
substituted glycine N-thiocarboxyanhydrides; N-thiocarboxyanhy-
drides; polypeptoids; primary amine; ring-opening polymerization;
water-soluble polymers
development of such methods are sure to have great impact on
the polypeptoid science and technology.
INTRODUCTION Taking the advantages of high reactivity and
productivity, ring-opening polymerization (ROP) of N-substitut-
ed glycine N-carboxyanhydrides (NNCAs) is the most efficient
method to synthesize polypeptoids.1–5 Recently, many efforts
have been paid on NNCAs to achieve their living polymeriza-
tions using different initiators.6–10 Zhang and coworkers
reported N-heterocyclic carbenes (NHCs)-mediated living
polymerization of NNCAs to prepare cyclic homo- and block-
polypeptoids, and investigated the mechanism detailedly.6,9 Lux-
enhofer and coworkers carried out living ROP of NNCAs initiat-
ed by primary amines,7,8 as well as surface-initiated11 and solid
support-initiated12 polymerizations, to synthesize homopoly-
peptoids, diblock and multiblock copolypeptoids. However,
NNCAs have an inherent disadvantage of high sensitivity to
moisture and heat.13 They have to be synthesized and stored in
extremely anhydrous and anaerobic environment. Moreover,
NNCAs require very careful purification before use, sublimation
for instance, as impurities significantly affect the living charac-
teristics of NNCA polymerization.14–16 Therefore, more stable
monomers and easier synthetic approach for preparing
polypeptoids have been strongly desired, and successful
N-Substituted glycine N-thiocarboxyanhydrides (NNTAs),
the thio-analogues of NNCAs, are much more stable mono-
mers for polypeptoids synthesis with the potential of large-
scale production.3–5 All the monomer synthesis and purifi-
cation can be operated in the open air. It is much easier to
prepare and store NNTAs with high purity than NNCAs,
which also benefits the controllability in polymerization
due to fewer side reactions. Although NTA monomers have
been discovered since 1950s,17–19 researches of their
polymerizations are very limited,20–23 not to mention
living/controlled polymerizations. Our early study of sarco-
sine NTA (Sar-NTA) polymerization concludes that Sar-NTA
had a much slower polymerization rate than the correspond-
ing sarcosine NCA and they were too inactive to prepare
moderate molar mass polypeptoids, that is, low yields <50%
and limited molecular weights (MWs) <5 kg/mol.22,23 This
can be a reason why NNTAs were widely ignored in the past
decades.
Additional Supporting Information may be found in the online version of this article.
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ethylamine (26.41 g, 0.410 mol) were added to 450 mL H2O.
After stirred at 25 8C for 24 h, 10 M hydrochloric acid
(200 mL) was added. The reaction mixture was refluxed for
12 h. Then the solvent was concentrated. The yellow crude
product was recrystallized in methanol/ethyl ether to obtain
white crystals (34.05 g, yield 59.5%). 1H NMR (DMSO-d6/TMS)
d: 1.18 ppm (t, 3H, ACH3), 2.93 ppm (q, 2H, ACH2CH3), 3.79
ppm (s, 2H, ACH2COOH), 9.32 ppm (s, 2H, ANHÁHClA), 13.25
ppm (br, 1H, ACOOH).
Synthesis of N-ethylglycine NTA (NEG-NTA)
SCHEME 1 Polymerization of N-substituted glycine NTA
initiated by primary amines. [Color figure can be viewed at
wileyonlinelibrary.com]
N-Ethylglycine hydrochloride (35.49 g, 0.254 mol), S-ethoxy-
thiocarbonyl mercaptoacetic acid23 (45.77 g, 0.254 mol) and
NaOH (30.51 g, 0.763 mol) were dissolved in 400 mL water
and reacted for 72 h at 30 8C with stirring. Then the reaction
mixture was acidified by concentrated hydrochloric acid. The
product N-ethoxythiocarbonyl-N-ethylglycine was extracted
with chloroform. The organic phase was washed with aque-
ous citric acid (5 wt %), and concentrated under reduced
pressure after drying over Na2SO4. The remaining product
was dissolved in 150 mL dry chloroform in an argon atmo-
sphere. PBr3 (30 mL, 0.316 mol) was added dropwise in 15
min at 0 8C. The reaction mixture was stirred for additional
10 min at 0 8C and 1 h at room temperature. After washed
by saturated solution of NaHCO3 and deionized water, the
chloroform solution was dried with MgSO4 and concentrated
in vacuum. The crude product was purified by column chro-
matography (ethyl acetate: petroleum ether 5 1:6). Light yel-
low oil was obtained (13.3 g, yield 36.1%) and stored under
Very recently, we found that NNTA monomers were not that
inert.24–27 We improved Sar-NTA polymerization by using
highly reactive rare earth borohydrides25 and specially-
designed amine-terminated polymers24,26 as initiators to
produce PSars and its copolymers with quantitative yields,
-
predictable high MWs, and low polydispersity indices (D).
However, the mechanism of rare earth borohydrides-mediated
ROP of NNTAs is still unclear,25 which limits the further modifi-
cation of the polypeptoid end-groups. Moreover, amine-
terminated macroinitiators are not easily available and the
products are confined to block copolymers.
In this contribution, we successfully produce polypeptoids
-
with degrees of polymerization (DP) up to 287 and D of 1.14
from controlled NNTA polymerization using small molecular
primary amines, for instance, benzylamine and hexylamine, as
initiator in proper polymerization conditions (Scheme 1), and
suggest a new opinion that NNTA monomers can be active
enough with carefully design of polymerization conditions.
Compared with our previous work,25 small molecular primary
amines are more available initiators with the advantages of
metal-free and definite end-group of the products, which is
promising for block copolypeptoids synthesis and end-group
modification for further biomedical applications.
1
argon atmosphere. H NMR (CDCl3/TMS) d: 1.25 ppm (t, 3H,
ACH3), 3.60 ppm (q, 2H, ACH2CH3), 4.20 ppm (s, 2H,
ACH2COA). 13C NMR (CDCl3/TMS) d: 12.57 ppm (CH3CH2A),
38.96 ppm (CH3CH2A), 59.32 ppm (ACH2COA), 164.40 ppm
(ANCOSCOA), 194.18 ppm (ANCOSCOA). ESI-MS: 146.11
m/z ([NEG-NTA]ÁH1). ELEM ANAL: C, 41.06%; H, 4.91%; N,
9.54% (Theoretical value: C, 41.36%; H, 4.86%; N, 9.65%).
Polymerization of NEG-NTA and Sar-NTA
Initiated by Primary Amines
All polymerizations were performed using Schlenk technique
and all polymerization tubes were predried and purged with
argon.
EXPERIMENTAL
Materials
Sarcosine (98%, Energy Chemical, China), ethylamine (70 wt
% aqueous solution, Energy Chemical, China), glyoxylic acid
(50 wt % aqueous solution, Energy Chemical, China), phos-
phorous tribromide (99%, Energy Chemical, China), hexyl-
amine (99%, Aldrich), and trioxymethylene (991%, Acros)
were used as received. Tetrahydrofuran (THF) was refluxed
before use over potassium/benzophenone ketyl. Acetonitrile
was stirred over CaH2 and distilled. Benzylamine was stirred
over CaH2 and followed by distillation under reduced pres-
sure. Sar-NTA was prepared according to the procedure
(Supporting Information Scheme S1 and Figure S1) described
in literature23 and our previous report.25
As a typical homopolymerization, NEG-NTA (0.382 g, 2.63
mmol) was dissolved in 4.6 mL dry THF, followed by
0.64 mL benzylamine in THF solution (0.2040 mol/L). The
tube was sealed and placed in a 60 8C oil bath for 24 h. The
polymer was isolated by precipitation from diethyl ether and
dried in vacuum (0.228 g, 95.9%).
Sar-NTA (0.431 g, 3.29 mmol) was dissolved in 6.4 mL dry ace-
tonitrile, followed by 0.16 mL benzylamine in acetonitrile solu-
tion (0.2023 mol/L). The tube was sealed and placed in a 60 8C
oil bath for 24 h. The polymer was isolated by precipitation
from diethyl ether and dried in vacuum (0.226 g, 95.3%).
Synthesis of N-ethylglycine hydrochloride
An amount of 50 wt % aqueous solution of glyoxylic acid
(121.42 g, 0.820 mol) and 70 wt % aqueous solution of
As a typical block copolymerization, NEG-NTA (0.533 g, 3.67
mmol) was dissolved in 6.9 mL dry acetonitrile, followed by
0.44 mL benzylamine in acetonitrile solution (0.2055 mol/L).
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TABLE 1 Polymerization of N-Substituted Glycine NTA Initiated by Benzylaminea
b
c
d
Mn theo
Mn NMR
Mn SEC
d
-
Sample
Monomer
[M]0/[BnNH2]0
Yield (%)
(kg/mol)
DPc
(kg/mol)
(kg/mol)
D
1
NEG-NTA
NEG-NTA
NEG-NTA
NEG-NTA
NEG-NTA
NEG-NTA
NEG-NTA
Sar-NTA
Sar-NTA
Sar-NTA
Sar-NTA
Sar-NTA
Sar-NTA
20
95.9
>99
>99
>99
>99
97.7
87.1
88.6
90.0
94.4
95.3
97.8
90.1
1.7
21
1.9
5.4
1.12
1.16
1.16
1.15
1.13
1.17
1.14
1.13
1.15
1.16
1.22
1.31
1.28
2
40
3.5
41
3.6
8.4
3
60
5.2
64
5.6
11.2
14.6
18.5
28.2
40.9
4.2
4
80
6.9
78
6.7
5
100
200
370
20
8.6
97
8.4
6
16.7
27.5
1.4
198
287
19
17.0
24.5
1.5
7
8
9
40
2.7
40
3.0
6.3
10
11
12
13e
60
4.1
59
4.3
7.8
100
180
420
6.9
97
7.0
9.0
12.6
27.0
156
262
11.2
18.7
10.2
12.3
a
c
Polymerization conditions: [M]0 5 0.5 mol/L, 24 h at 60 8C, THF and acetoni-
As determined by 1H NMR.
As determined by SEC.
As polymerized for 48 h.
d
e
trile were used as the solvents for NEG-NTA and Sar-NTA, respectively.
b
Theoretical Mn,
Mn,theo 5 [M]0/[BnNH2]0 3 yield 3 MW of repeat
units 1 MW of initiator.
The tube was sealed and placed in a 60 8C oil bath. After
24 h, NEG-NTA was consumed (confirmed by H NMR analy-
spectra were recorded on a Bruker Avance DMX 400 spectrom-
eter (1H: 400 MHz and 13C: 100 MHz) with DMSO-d6 or CDCl3
as solvent and tetramethylsilane (TMS) as internal reference.
Matrix-assisted laser desorption ionization-time of fight
(MALDI-ToF) mass spectra were collected on a Bruker Ultra-
FLEX MALDI-ToF mass spectrometer in the reflector mode.
2,5-Dihydroxybenzoic acid (DHB) was used as matrices and
potassium trifluoroacetate was used as the cationic agent.
Electrospray ionization mass spectrometry (ESI-MS) spectrum
was measured by LCQ DECA XP MAX (Thermo) Liquid
Chromatograph Mass Spectrometer. Elemental analysis was
measured by varioMICRO CUBE (Elementar Analysensysteme
GmbH) elementar analyzer.
1
sis), and 3.5 mL solution was removed from the reaction
mixture for the analytical investigations of the first block.
Then Sar-NTA (0.501, 3.82 mmol) was added to the reaction
mixture of the first block. Additional 24 h the reaction mix-
ture was stirred. The polymer was isolated by precipitation
from diethyl ether and dried in vacuum (0.377 g, 87%).
Polymerization Kinetics
Polymerization kinetics of NEG-NTA were measured at 60 8C
with a feed molar ratio ([NEG-NTA]0/[benzylamine]0) of 20 in
sealed tubes using THF as solvent, benzylamine as initiator and
trioxymethylene as internal standard. 1H NMR spectra (500
MHz) were collected every 1 h by taking a small amount of reac-
tion mixture and dissolving in DMSO-d6. Monomer conversions
were calculated from the relative integration of the ethylene
proton resonance of NEG-NTA and trioxymethylene. Polymeri-
zation kinetics of Sar-NTA were measured at the same condi-
tions with a feed molar ratio ([Sar-NTA]0/[benzylamine]0) of 75
and acetonitrile as solvent. 1H NMR spectra were collected with
an interval of 10–30 min.
RESULTS AND DISCUSSION
We synthesized N-ethylglycine NTA (NEG-NTA) through a
phosgene-free method as shown in Supporting Information
Scheme S2, a novel NNTA monomer prepared for the first time,
whose polymer, that is, poly(N-ethylglycine) (PNEG), had an
excellent solubility in water and common organic solvents such
as THF, dioxane, chloroform, ethyl acetate, etc.7,28,29 Meanwhile,
PNEG was a rising biocompatible material promising for bio-
medical applications.28,29 The structure of NEG-NTA is well
characterized by ESI-MS spectrometry, elemental analysis and
NMR spectra (Supporting Information Figure S2–S5). NEG-NTA
polymerizations were carried out in THF at 60 8C initiated by
benzylamine with various feed molar ratios changing from 20 to
370 (sample 1–7 in Table 1). Quantitative yields (> 95%) were
achieved in all polymerizations and DPs agreed well with the
design when the feed molar ratios of [NEG]0/[BnNH2]0
were below 200, which demonstrated that NEG-NTA had a
well-controlled polymerization under optimal conditions. PNEG
Measurements
Molecular weights (MWs) and polydispersity indices (D) were
-
determined by size-exclusion chromatography (SEC), which
consisted of a Wyatt series 1500 HPLC pump, a Wyatt Opitlab
T-rEX interferometric refractometer (RI) and two MZ-Gel
SDPlus columns of 102 Å 10 lm and 104 Å 10 lm. N,N-
dimethylformamide (DMF) containing 0.05 mol/L LiBr and
2& (v/v) triethylamine was used as eluent with a flow rate of
0.8 mL/min at 50 8C, and commercial polystyrenes were used
as calibration standards. Nuclear magnetic resonance (NMR)
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FIGURE 1 MALDI-ToF mass spectra of sample 1 (A) and 8 (D) with zoom-in views (B and E) and the corresponding polypeptoid
structures (C and F). [Color figure can be viewed at wileyonlinelibrary.com]
-
with an absolute Mn of 24.5 kg/mol (D 51.14), that is, DP of
287 was obtained shown as sample 7 in Table 1. It is worthy of
mentioning that DP of 287 is also regarded as a long chain in
NCA polymerization. A monomodal profile of PNEG in MALDI-
ToF mass spectrum [Fig. 1(A–C)] reveals benzyl and amino end
groups, which is in accordance with normal amine mechanism
(NAM; Supporting Information Scheme S3).23,30,31 All protons
in PNEG are assigned in 1H NMR spectrum as reported [Fig.
2(A)].7 The DPs of the obtained PNEGs are calculated from
signals Ha with He in 1H NMR, consistent well with the feed molar
ratios based on single-site initiation by benzylamine. All SEC
traces (Fig. 3) of PNEGs 1-7 are monomodal and symmetrical
-
with narrow MW distribution, that is, D between 1.12 and 1.17,
even [NEG]0/[BnNH2]0 rising to 370. Samples 3-5 show high MW
shoulders in SEC, which is attributed to nonoptimized SEC condi-
tions and polymer aggregations in solvents (see below), as also
observed in some cases of NNCA polymerizations.6,7,32–34 Mns
measured by SEC ranging from 5.4 to 40.9 kg/mol demonstrate
FIGURE 2 1H NMR spectra of samples 1 (A) and 10 (B) in DMSO-d6
FIGURE 3 SEC traces of PNEG samples 1-7. [Color figure can
(*: water). [Color figure can be viewed at wileyonlinelibrary.com]
be viewed at wileyonlinelibrary.com]
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With the help of the exciting results above, we realize that
polymerizing NNTA in good solvents, that is, good solubility
for polymer and no side reaction, are essential. Therefore,
searching a suitable solvent is the key to achieve controlled
polymerization of Sar-NTA. THF and dioxane are usual reac-
tion media for NCA polymerization22,35–37 but not suitable in
the case of Sar-NTA. The poor solubility of PSar in them
leads to uncontrolled polymerization and limitation of DP
below 100 due to heterogeneous reactions.23–25 However,
most good solvents for PSar, such as DMF, N,N-dimethylace-
tamide, dimethylsulfoxide (DMSO), and N-methyl pyrrolidone
(NMP), result in uncontrollable Sar-NTA polymerization at
60 8C producing PSar with low MWs and low yields (< 30%)
because they alone initiate NNTA polymerization and cause
chain transfer.
FIGURE 4 Kinetic plots of the polymerization of NEG-NTA in
THF (R2 5 0.998) and Sar-NTA in acetonitrile (R2 5 0.998) initiat-
ed by benzylamine in sealed tube ([M]0 5 0.5 mol/L, [NEG]0/
[BnNH2]0 5 20, [Sar]0/[BnNH2]0 5 75, 60 8C). [Color figure can be
viewed at wileyonlinelibrary.com]
Fortunately, we found that acetonitrile was an appropriate
polymerization medium for Sar-NTA25 and also applied in
Sar-NCA polymerization.38,39 Therefore, polymerizations of
Sar-NTA initiated by benzylamine were carried out in aceto-
nitrile at 60 8C (Table 1). All polymerizations exhibited high
yields (>88%) with various feed molar ratios of [Sar]0/
[BnNH2]0 ranging from 20 to 420 (sample 8–13 in Table 1)
within 24 h (sample 13 for 48 h). The PSar polymers with
quantitative benzyl chain-end are confirmed by MALDI-ToF
and NMR analyses [Figs. 1(D–F) and 2(B)], indicating the
NAM mechanism of NTA polymerization in absent of side
reactions (Supporting Information Scheme S3). The DPs of
the obtained PSars are consistent well with the feed molar
ratios based on single-site initiation by the benzylamine at
low molecular weight range ([Sar]0/[BnNH2]0 < 100), indi-
cating the good controllability of the polymerization. When
[Sar]0/[BnNH2]0 is higher than 180 (sample 12 in Table 1),
the NMR-based DPs become smaller than the theoretical val-
ues, and the deviation is pronounced when [Sar]0/[BnNH2]0
ratio is 420. The largest absolute Mn of PSar (sample 13 in
Table 1) reaches 18.7 kg/mol, that is, DP of 262, which is
comparable to many products obtained in Sar-NCA polymeri-
zation. It is a great improvement compared with Sar-NTA
that calibration with polystyrene overestimates the real Mn of the
polypeptoids products due to the higher hydrodynamic volume
of these polar polymers.
Furthermore, polymerization kinetics of NEG-NTA were mea-
sured at 60 8C with a feed molar ratio of 20 ([NEG]0/
[BnNH2]0) in sealed tube using THF as solvent, benzylamine as
initiator and trioxymethylene as internal standard. The plots of
ln(M0/Mt) vs. time appear linear up to relatively high mono-
mer conversions (ꢀ80%), supporting pseudo-first order kinet-
ics with regard to monomer (Fig. 4), differing from the
acceleration at high conversion of rare earth borohydrides sys-
tem.25 The result indicates constant concentration of chain
propagation active species and living character of NEG-NTA
polymerization, in spite of the much smaller apparent propa-
gating rate (1.50 3 1023 L mol21 s21) than that of NEG-NCA
polymerization under the same monomer concentration and
higher feed molar ratio of 50 (8.54 3 1023 L mol21 s21, 20 8C
in benzonitrile) as reported.7
Hexylamine-initiated polymerizations of NEG-NTA were also
conducted in THF at 60 8C to produce PNEG with high yields
(>86%), controlled MWs and narrow MW distribution
(1.14–1.23; Supporting Information Table S1). The structure
of the products is well confirmed by the 1H NMR spectrum
(Supporting Information Figure S6). The MALDI-ToF mass
spectrum of PNEG sample S1 reveals a monomodal distribu-
tion without shoulders (Supporting Information Figure S7)
though its SEC profile (Supporting Information Figure S8)
shows a high MW shoulder. Therefore, we attributed the
high MW shoulder to nonoptimized SEC conditions and poly-
mer aggregations in solvents rather than side reactions,
which was also observed in our previous work of copolypep-
toids.27 The MALDI-ToF mass spectrum supports that the
polymerizations undergo NAM. In summary, polymerizations
of NNTA initiated by primary amines exhibit a much better
controllability than our previous work of rare earth borohy-
drides initiators, since the latter produce polypeptoids with
FIGURE 5 SEC traces of PSar samples 8–13. [Color figure can
25
-
be viewed at wileyonlinelibrary.com]
moderate D (1.3–1.5) and indefinite end-group.
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TABLE 2 Synthesis of Block Copolypeptoids in Acetonitrile Initiated by Benzylaminea
Sample
Feed molar ratio
[Sar]/[NEG]/[I]
First block
Final product
DPb
21
Mn (kg/mol)c
D
Compositionb
Mn (kg/mol)c
c
c
-
-
D
14
20/55/1
4.3
1.09
Bn-PSar21-b-PNEG50
8.9
1.18
1.24
[NEG]/[Sar]/[I]
40/80/1
15
38
6.5
1.12
Bn-PNEG38-b-PSar78
13.3
a
b
c
The first block was polymerized at 60 8C for 24 h with [M]0 5 0.5 mol/L,
and the second block was polymerized at 60 8C for additional 24 h.
As determined by 1H NMR.
As determined by SEC.
polymerizations in dioxane, not a solvent as good as acetoni-
trile for PSar, where the DPs were less than 80.23,24 Slight
gels were observed during the Sar-NTA polymerization
in acetonitrile when [Sar]0/[BnNH2]0 was higher than 100,
which was responsible for the deviation of DP and the
broadening of MW distribution (from 1.13 to 1.31). Acetoni-
trile is not an ideal solvent for PSar with higher MW. All SEC
traces of the products are monomodal and symmetrical with
narrow MW distribution (Fig. 5). We also carried out poly-
merization kinetics of Sar-NTA at 60 8C with a feed molar
ratio of 75 ([Sar]0/[BnNH2]0) in sealed tube using acetonitrile
as solvent. The plots of ln(M0/Mt) vs. time appear linear up to
high monomer conversions (>90%; Fig. 4), indicating pseudo-
first order kinetics with regard to monomer and constant
concentration of chain propagation active species and living
character of Sar-NTA polymerization. Sar-NTA shows a much
faster polymerization rate (31.67 3 1023 L mol21 s21) than
NEG-NTA due to the smaller substituent on the chain-end of
secondary amine and higher solvent polarity of acetonitrile
than THF.7,9 The polymerization rate is even comparable with
Sar-NCA polymerization under the same monomer concentra-
tion and a feed molar ratio of 50 (28.78 3 1023 L mol21 s21
,
20 8C in NMP) as reported,7 which indicates NNTA also can
be reactive enough under proper conditions. Thus, we have
distinctly improved Sar-NTA polymerization by simply replac-
ing the solvent of dioxane with acetonitrile and increasing the
temperature of 20 8C to 60 8C.
Block copolypeptoids were prepared to further verify the con-
trollability of the NNTA polymerization. Bn-PSar-b-PNEG and
Bn-PNEG-b-PSar were successfully synthesized by changing
monomer feeding sequence (Table 2). In consideration of the
solubility of the whole diblock copolymer chains, acetonitrile
was selected since it was good solvent for both PSar and PNEG.
A polymerization of the first block ([M1]0/[BnNH2]0 5 20 or
40) was conducted at 60 8C for 24 h to reach quantitative
monomer conversion as monitored by 1H NMR. A batch of the
second monomer ([M2]0/[BnNH2]0 5 55 or 80) was subse-
quently added and allowed for further chain propagation. SEC
traces exhibit MW increases from the first blocks to the corre-
sponding block copolymers as shown in Figure 6. Both signals
1
of Sar and NEG units are observed in H NMR spectra of the
final products (Supporting Information Figure S9 and S10).
DPs of the first block and final products calculated by NMR
meet the feed molar ratio quite well. Accordingly, the composi-
tions of the two copolypeptoids are calculated as Bn-PSar21-b-
PNEG50 (sample 14) and Bn-PNEG38-b-PSar78 (sample 15). It
is the first report of block copolypeptoids synthesized from
NNTA monomers.
CONCLUSIONS
In summary, we achieved primary amine-initiated controlled
polymerizations of NNTA by optimizing the polymerization
conditions, especially using ideal reaction media and high tem-
perature. For instance, controlled polymerizations of NEG-NTA
were carried out in the good solvent THF at 60 8C with quanti-
-
tative yield (>95%) and low D (1.12–1.17) even at high feed
molar ratios. PNEG with an absolute Mn of 24.5 kg/mol
FIGURE 6 A: SEC traces of the first block (a) and final product
(b) of Bn-PSar-b-PNEG (sample 14). B: SEC traces of the first
block (c) and final product (d) of Bn-PNEG-b-PSar (sample 15).
[Color figure can be viewed at wileyonlinelibrary.com]
-
(DP 5 287, D 5 1.14) was synthesized, which was comparable
to those prepared from NEG-NCA by amine initiator. In the
case of Sar-NTA, benzylamine-mediated polymerizations were
6
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POLYMER SCIENCE
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ARTICLE
14 T. Aliferis, H. Iatrou, N. Hadjichristidis, Biomacromolecules
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medium at 60 8C. In this way, PSars with predictable MWs
from 1.5 to 18.7 kg/mol were obtained. Kinetic study and
block copolypeptoid synthesis further confirm the controllabil-
ity of primary amine-initiated polymerization of NNTA. We
afford a positive model of NNTA controlled polymerization and
develop a versatile and practical synthetic method to prepare
high-MW polypeptoids. These findings pave the way for con-
trollable syntheses of polypeptoids from NNTAs. NTA-
approach deserves further intensive effort of investigations.
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