Ring opening polymerization of α-amino acid N-carboxyanhydrides catalyzed by rare earth catalysts: Polymerization characteristics and mechanism

Article abstract of DOI:10.1002/pola.25848

Five rare earth complexes are first introduced to catalyze ring opening polymerizations (ROPs) of γ-benzyl-L-glutamate N-carboxyanhydride (BLG NCA) and L-alanine NCA (ALA NCA) including rare earth isopropoxide (RE(OiPr)₃), rare earth tris(2,6-di-tert-butyl-4-methylphenolate) (RE(OAr)₃), rare earth tris(borohydride) (RE(BH₄) ₃(THF)₃), rare earth tris[bis(trimethylsilyl)amide] (RE(NTMS)₃), and rare earth trifluoromethanesulfonate. The first four catalysts exhibit high activities in ROPs producing polypeptides with quantitative yields (>90%) and moderate molecular weight (MW) distributions ranging from 1.2 to 1.6. In RE(BH₄)₃(THF)₃ and RE(NTMS)₃ catalytic systems, MWs of the produced polypeptides can be controlled by feeding ratios of monomer to catalyst, which is in contrast to the systems of RE(OiPr)₃ and RE(OAr)₃ with little controllability over the MWs. End groups of the polypeptides are analyzed by MALDI-TOF MS and polymerization mechanisms are proposed accordingly. With ligands of significant steric hindrance in RE(OiPr)₃ and RE(OAr) ₃, deprotonation of 3-NH of NCA is the only initiation mode producing a N-rare earth metallated NCA (i) responsible for further chain growth, resulting in α-carboxylic-I-aminotelechelic polypeptides after termination. In the case of RE(BH₄)₃(THF)₃ with small ligands, another initiation mode at 5-CO position of NCA takes place simultaneously, resulting in α-hydroxyl-I-aminotelechelic polypeptides. In RE(NTMS)₃ system, the protonated ligand hexamethyldisilazane (HMDS) initiates the polymerization and produces α-amide-I-aminotelechelic polypeptides.

Full text of DOI:10.1002/pola.25848

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Ring Opening Polymerization of a-Amino Acid N-Carboxyanhydrides
Catalyzed by Rare Earth Catalysts: Polymerization Characteristics
and Mechanism
Hui Peng, Jun Ling, Zhiquan Shen
MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering,
Zhejiang University, Hangzhou 310027, China
Correspondence to: J. Ling (E-mail: lingjun@zju.edu.cn) or Z. Shen (E-mail: zhiquan_shen@163.com)
Received 16 August 2011; accepted 26 October 2011; published online 28 November 2011
DOI: 10.1002/pola.25848
ABSTRACT: Five rare earth complexes are first introduced to
catalyze ring opening polymerizations (ROPs) of c-benzyl-L-glu-
tamate N-carboxyanhydride (BLG NCA) and L-alanine NCA
(ALA NCA) including rare earth isopropoxide (RE(OiPr)3), rare
earth tris(2,6-di-tert-butyl-4-methylphenolate) (RE(OAr)3), rare
earth tris(borohydride) (RE(BH4)3(THF)3), rare earth tris[bis(tri-
methylsilyl)amide] (RE(NTMS)3), and rare earth trifluorometha-
nesulfonate. The first four catalysts exhibit high activities in
ROPs producing polypeptides with quantitative yields (>90%)
and moderate molecular weight (MW) distributions ranging
from 1.2 to 1.6. In RE(BH4)3(THF)3 and RE(NTMS)3 catalytic sys-
tems, MWs of the produced polypeptides can be controlled by
feeding ratios of monomer to catalyst, which is in contrast to
the systems of RE(OiPr)3 and RE(OAr)3 with little controllability
over the MWs. End groups of the polypeptides are analyzed by
MALDI-TOF MS and polymerization mechanisms are proposed
accordingly. With ligands of significant steric hindrance in
RE(OiPr)3 and RE(OAr)3, deprotonation of 3-NH of NCA is the
only initiation mode producing a N-rare earth metallated NCA
(i) responsible for further chain growth, resulting in a-carbox-
ylic-x-aminotelechelic polypeptides after termination. In the
case of RE(BH4)3(THF)3 with small ligands, another initiation
mode at 5-CO position of NCA takes place simultaneously,
resulting in a-hydroxyl-x-aminotelechelic polypeptides. In
RE(NTMS)3 system, the protonated ligand hexamethyldisila-
zane (HMDS) initiates the polymerization and produces a-am-
C
V
ide-x-aminotelechelic polypeptides.
2011 Wiley Periodicals,
Inc. J Polym Sci Part A: Polym Chem 50: 1076–1085, 2012
KEYWORDS: a-amino acid N-carboxyanhydride; biopolymers;
end group functionalized polypeptides; rare earth catalysts;
ring-opening polymerization
INTRODUCTION Peptide polymers have many advantages
over conventional synthetic polymers, as they are able to
self-assemble into stable ordered conformations (coils, a-he-
lix, and b-sheet) and hierarchical structures (tertiary and
quaternary structures), which arise from their stereoregular-
ity and precisely arranged sequence of the amino acid. This
ability is the foundation of the biological activity of proteins,
which provide life-giving function.1 Polypeptides are a class
of attractive biomimetic materials. Recently, there has been
interest in developing synthetic routes for preparation of the
natural polymers for applications in biotechnology.2 As a bio-
material with a lot of interesting properties resulting from
well-defined conformational and hierarchical structures,3–5
polypeptides are used in drug delivery,6 tissue engineering,7
biomineralization,8 and nanoscale self-assembly.9,10 Although
these applications are in their infancy period, great potential
is manifested.
synthesis, ring opening polymerization (ROP) of amino acid
N-carboxyanhydride (NCA) is the most used one.11 Ever
since the amino acid NCA monomer is discovered by Leuchs,
great efforts have been made to explore the catalysts to poly-
merize them. Amines (primary amines, secondary amines,
and tertiary amines), alcohols, water, and thiols12 are a class
of metal-free catalysts, among which primary amines and
tertiary amines are the most widely used for their conven-
ience and nontoxic nature. Generally, primary amines pro-
duce polypeptides with low molecular weights (MWs), which
can be controlled by the monomer to catalyst ratio, whereas
tertiary amines yield much higher ones but show little con-
trollability over them. The molecular weight distributions
(MWDs) of the two catalytic systems are usually broad.13,14
Besides, a lot of metal salts and organometallic compounds
are used to catalyze the ROP of NCA including solution of
lithium chloride in N,N-dimethylformamide (DMF), sodium
carbamate, 9-fluorenyl potassium, sodium hydride, sodium
acetate, sodium methoxide, diethylzinc, tributylaluminum,
The synthetic methodology of polypeptide has been explored
over the past decades. Among the methods for polypeptide
Additional Supporting Information may be found in the online version of this article.
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diethylcadmium, tributyltinmethoxide, and so on.15,16 The
MWDs of the polypeptides obtained in these systems are
usually broad arising from the multiple propagation active
centers, heterogeneous character of reaction system and a
variety of side reactions. After 1997, Deming and Lin
reported living ROPs of NCAs by zero-valent nickel and plati-
num complexes. The MWDs of the polypeptides are quite
narrow (MWD < 1.2) and block polypeptides can be conven-
iently synthesized by sequential addition of the two mono-
mers.17–19 In 2007, Cheng et al. reported hexamethyldisila-
zane (HMDS) a controlled polymerization catalyst for NCA.
The MWs of the polypeptides obtained were the expected
ones and the products exhibited low MWDs (MWD ¼ 1.19–
1.26).20 HMDS and its derivatives are further successfully
applied to prepare functionalized polypeptides with narrow
MWDs (MWD < 1.3).21,22 Besides, supramolecular polymer-
ization is achieved by this catalyst.23 Great efforts were also
made to improve the traditional primary amine catalytic sys-
tem and some approaches were elaborated including: high
vacuum techniques,24–26 lowering the reaction tempera-
ture27–29 or the pressure,30 and treating the primary amine
with hydrochloride.31 These methods had the unique advant-
age to allow preparation of copolymers composed of poly-
peptide and nonpolypeptide blocks with well-defined micro-
structures, as amino-terminated polymers are easily
accessible.
oxide, e-caprolactone, lactide, cyclic carbonates, and so on.42
In ROP of NCA, investigations on organometallic catalysts
have been mainly focused on alkali metals, alkaline-earth
metals, and late-transition metals with rare earth metals
being largely overlooked. To the best of our knowledge, only
one paper reported the polymerization of c-stearyl-L-glutame
NCA using tri-component catalyst of neodymium acetylaceto-
nate [Nd(acac)3]- or neodymium tris(2-ethylhexylphospha-
nate) [Nd(P204)3]- with triethylaluminum and water. Rela-
tively high MW (Mw ¼ 8.4 ꢂ 104 Da) polyglutamates with
narrow MWD of 1.22 are produced.43 The promising result
encouraged us to further explore the polymerization behav-
ior in rare earth catalytic systems.
This work investigates ROPs of c-benzyl-L-glutamate NCA (BLG
NCA) and L-alanine NCA (ALA NCA) catalyzed by five rare earth
catalysts, that is, rare earth isopropoxide (RE(OiPr)3), rare earth
tris(2,6-di-tert-butyl-4-methylphenolate) (RE(OAr)3), rare earth
tris(borohydride) (RE(BH4)3(THF)3), rare earth trifluorometha-
nesulfonate (RE(OTf)3), and rare earth tris[bis(trimethylsilyl)
amide] (RE(NTMS)3). They are all high efficient catalysts for
polymerizations of ester monomers such as e-caprolactone,
lactide, and trimethylene carbonate.44–50 Their ligands are
different in sizes and bond types including rare earth–oxygen
bond (REAO), rare earth–borohydride hydrogen bond
(REAHBH3), and rare earth–nitrogen bond (REAN). Their reac-
tion activities toward ROP of NCA are investigated and
discussed in comparison.
Reaction mechanisms of ROP of NCA have received great
attention in the past few years. Two mechanisms, that is, the
normal amine mechanism (NAM) and the activated monomer
mechanism (AMM), have been proposed to ROP of NCA.
Depending on the relative nucleophilicity and basicity, the
catalyst can selectively participate in one of the mechanisms
in a polymerization. Generally, primary amine takes the NAM
route, whereas tertiary amine leads to the AMM.1,32 With the
highlight of the chain end structures, many groups have car-
ried out extensive mechanism studies. Kricheldorf et al.33ꢀ38
revisited the polymerization mechanism of the polypeptides
prepared by traditional catalysts by means of MALDI-TOF
MS. A variety of the chain structures have been identified,
complementing the polymerization mechanisms and dispel-
ling any doubts with any of the NCA issues before. Messman
and coworkers39 rigorously characterized and compared the
end-groups of the poly(O-benzyl-L-tyrosine) prepared under
high-vacuum conditions and glovebox by means of MALDI-
TOF MS, NALDI-TOF MS, and 13C NMR spectroscopy, demon-
strating the advantage of high-vacuum techniques for prepa-
ration of well-defined polypeptides. Using nonaqueous capil-
lary electrophoresis, Giani and coworkers concluded that in
primary amine catalytic system, the NAM is the only possible
initiation pathway and ‘‘dead’’ polymers resulted from
side reactions of the propagating chain ends with DMF
or the NCA. The fractions of the living chains can be greatly
enhanced by decreasing the reaction temperature to
EXPERIMENTAL
Materials
BLG (99.0%, Shanghai Hanhong Chemical, China), L-alanine
(98.5%, Sinopharm Chemical Reagent, China), sodium bis(tri-
methylsilyl)amide (95%, Sigma-Aldrich), sodium borohydride
(96.0%, Sinopharm Chemical Reagent, China), and trifluoro-
methanesulfonic acid (98%, Shanghai Jingchun, China) were
used as received. 2-Propanol was dried by sodium metal and
distilled. Tetrahydrofuran (THF), hexane, and benzene were
refluxed over potassium/benzophenone ketyl before use.
Ethyl acetate was stirred over CaH2 and distilled. DMF was
purified by drying over a mixture of 3 Å and 4 Å molecular
sieves followed by vacuum distillation.
Catalysts Preparation
All catalysts were prepared in Schlenk tubes using vacuum-
line techniques under purified argon. Anhydrous rare earth
chlorides were prepared by heating the mixture of hydrated
rare earth chloride and ammonium chloride under reduced
pressure.51
RE(OiPr)3, RE(OAr)3, RE(BH4)3(THF)3, and RE(OTf)3 were
prepared according to our previous reports.44,45,52,53
RE(NTMS)3 was synthesized according to a reported litera-
ture.54 In a typical example, YCl3 (0.651 g, 3.33 mmol) was
suspended in 25 mL of THF. Then, a THF solution (10 mL)
of sodium bis(trimethylsilyl)amide (1.932 g, 10.0 mmol) was
added dropwise over a period of an hour. This reaction was
stirred at room temperature for 24 h and centrifuged sepa-
rated. The liquid part was evaporated and then extracted
27,28,40,41
ꢁ
0 C.
In the past few years, rare earth compounds have been suc-
cessfully applied to the catalysis of the polymerization of
various monomers including ethyne, isoprene, propylene
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with 30 mL of hexane. The hexane solution was concentrated
and allowed to crystallize. Y(NTMS)3 was obtained as white
needle-like crystals form with a yield of 62%.
Synthesis of c-Benzyl-L-glutamate N-Carboxyanhydride
and L-Alanine N-carboxyanhydride
In a typical procedure, BLG (10.1 g, 42.2 mmol) was sus-
pended in 100 mL of anhydrous THF under argon atmos-
phere. Triphosgene (4.60 g, 15.5 mmol) in 20 mL of THF
was added dropwise over half an hour. The mixture was
allowed to stir for further 2 h and a clear solution was
obtained. The solution was concentrated and precipitated by
anhydrous hexane. After purification by recrystallization
four times from ethyl acetate and hexane, white BLG NCA
crystals (10.37 g, yield ¼ 83%) were obtained. ALA NCA
(yield ¼ 53%) was synthesized in a similar way.
Polymerizations of BLG NCA and ALA NCA
All polymerizations were performed in Schlenk tubes under
argon. In a typical example, BLG NCA (0.396 g, 1.51 mmol)
was dissolved in 3 mL of DMF. Then THF (0.32 mL) solution
of Y(OiPr)3 (0.093 mol/L) was added by syringe. The tube
ꢁ
was sealed and placed in a 40 C oil bath for 24 h. The poly-
mer was isolated by precipitation from methanol containing
5% HCl, washed with methanol, and dried in vacuum (yield
> 95%). Polymerizations of ALA NCA were carried out in
THF for 3 days and precipitated from diethyl ether (yield >
95%).
SCHEME 1 Chemical structures of RE(OiPr)3, RE(OAr)3,
RE(BH4)3(THF)3, RE(NTMS)3, RE(OTf)3, ALA NCA, and BLG
NCA.
Measurements
rare earth–oxygen bonds (REAO). Rare earth metals have a
high affinity to the oxygen atom and tend to be coordinated
by carbonyl group.56,57 RE(BH4)3(THF)3 is a compound with
rare earth–borohydride hydrogen bonds (REAHBH3) charac-
terized as RE[(l2-H)3BH]2[(l2-H)2BH2)] by X-ray diffrac-
tion.48 In contrary to the above two catalysts, this catalyst
MWs and MWDs were determined by gel permeation chro-
matography/multiangle laser light scattering (GPC/MALLS).
The GPC system consisted of a Waters 1515 isocratic high
performance liquid chromatograph pump, two columns of
Styragel (HT3 and HT4), a Wyatt DAWN DSP MALLS detec-
tor, and a Wyatt Opitlab DSP interferometric refractometer.
DMF containing 0.1 mol/L LiBr was used as the eluent with
has
a
relatively small ligand with reduction ability.
ꢁ
RE(NTMS)3 is of special interest, as the trimethylsilyl group
of the ligand can mediate the ROP of NCA.20 Besides,
RE(NTMS)3 has a more basic rare earth–nitrogen bond
(REAN) than the REAO catalysts and a hexamethyldisila-
zanyl ligand with considerable steric hindrance. RE(OTf)3 is
a Lewis acid.58,59 Polymerization of lactones by RE(OTf)3
exclusively proceeds through a cationic mechanism, differing
from the coordination–insertion mechanism of the other
four.56,57
a flow rate of 1.0 mL/min at 60 C. Viscosity average molec-
ular weights (Mv,LSs) were obtained from reduced specific
viscosity using the relationship formulated by Doty et al.55
This method was reported to be reproducible and had an
error within 610%. The viscosities were determined at the
concentration of 0.2 g/100 mL in dichloroacetic acid in
Ubbelohde viscometers at 25 ꢁC. The MALDI-TOF mass
spectra were measured on an Applied Biosystems Voyager
System 4350 with a nitrogen laser (l ¼ 337 nm). All mass
spectra were recorded in the reflection mode with an
acceleration voltage of 20 kV. The irradiation targets were
prepared from trifluoroacetic acid solutions with 2,5-di-
hydroxybenzoic acid as matrix and potassium trifluoro-
acetate as dopant.
The five catalysts are used to catalyze ROP of BLG NCA (Ta-
ble 1). Except RE(OTf)3, the other four catalysts are highly
efficient toward the polymerization of BLG NCA producing
polyBLGs (PBLGs) with high yields. The monomers are com-
pletely consumed within 24 h as shown by FTIR and 1H
NMR. At the same molar ratio of monomer to catalyst
([NCA]/[RE]), the obtained PBLGs have widely different MWs
depending on the catalyst (Table 1). Y(OiPr)3 and Y(OAr)3
produce polypeptides with the highest weight average MWs
of about 1 ꢂ 105 Da, whereas Y(BH4)3(THF)3 yields the mid-
dle one (ꢃ7.5 ꢂ 104 Da). Y(NTMS)3 gives the lowest Mw of
2.9 ꢂ 104 Da. All GPC traces of PBLGs obtained exhibit sym-
metrical and monomodal peaks (Fig. 1) with relatively
RESULTS AND DISCUSSION
RE(OiPr)3, RE(OAr)3, RE(BH4)3(THF)3, RE(NTMS)3, and
RE(OTf)3 are five typical complexes reported to catalyze ROP
of lactone monomers with different activities due to their
electronic and steric effects of the ligands.44–50 Their chemi-
cal structures are shown in Scheme 1. RE(OiPr)3 and
RE(OAr)3 have bulky isopropoxy and phenoxy ligands and
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TABLE 1 Polymerization of BLG NCA catalyzed by single-component rare earth catalystsa
Temp.
(ꢁC)
Yield
(%)
Mb
Mn
Mw
c
c
v,LS
(104 Da)
Run
Catalyst
(104 Da)
(104 Da)
MWDc
1
2
3
4
5
6
a
Y(OiPr)3
Y(OAr)3
Y(BH4)3
40
40
40
40
80
80
98.5
93.2
90.9
94.3
0
9.02
9.11
6.66
2.97
–
6.86
6.85
5.25
2.29
–
10.36
10.53
7.51
2.86
–
1.51
1.54
1.43
1.25
–
Y(NTMS)3
d
Y(OTf)3
d
Sc(OTf)3
37.5
2.19
–
–
–
Polymerization conditions: [BLG NCA]/[Y] ¼ 200, [BLG NCA] ¼ 0.5 mol/L, 24 h in DMF.
Viscosity average molecular weights (Mv,LS).
Determined by GPC/MALLS.
b
c
d
Reaction time was prolonged to 3 days.
narrow MWDs (MWD < 1.6) compared to the one catalyzed
by phenethylamine (MWD > 2.8).13 Y(NTMS)3 produces
PBLG with the narrowest MWD of 1.25. Sc(OTf)3 has low
activity to ROP of BLG NCA, whereas Y(OTf)3, Nd(OTf)3, and
La(OTf)3 are not active at all. This result by RE(OTf)3 is
within our expectation, as the fact that neither radicals nor
cations and acids can initiate ROP of NCA.15
from Y(OiPr)3 and Y(OAr)3. The MWs of PBLGs can be con-
trolled by the [NCA]/[Y] ratios. However, they are higher
than the calculated ones. Y(NTMS)3 produces PBLG with the
lowest MW when the same [NCA]/[Y] is used and exhibits a
linear relationship between Mv,LSs and [NCA]/[Y]. Also, the
effect of rare earth elements is studied as shown in Figure 3.
With the same ligand, rare earth metals including scandium,
yttrium, lanthanum, and dysprosium exhibit similar catalytic
behaviors. In RE(BH4)3(THF)3 and RE(NTMS)3 systems,
yttrium complexes always produce PBLG with the highest
MW than the other three corresponding Sc, La, and Dy
complexes.
Figure 2 shows the dependence of MWs of PBLGs on the
[NCA]/[Y] ratio. Y(OiPr)3 and Y(OAr)3 produce PBLGs with
the highest Mv,LS. In the Y(OiPr)3 system, the MWs are totally
independent on the [NCA]/[Y] ratios and the Mv,LSs are
almost unchanged at the value of 9 ꢂ 104 Da. In Y(OAr)3
system, the MWs are changed slightly within the range of 8
ꢂ 104–10 ꢂ 104 Da with the feeding ratios of [NCA]/[Y]
varying from 50 to 1000. The polymerization features of
these two catalytic systems are similar to that of the strong
base catalyst such as triethylamine,60 which catalyzes ROP of
NCA via the AMM mechanism. Y(BH4)3(THF)3 is different
Figure 4 compares ROPs of BLG NCA at various reaction
temperatures. In Y(OiPr)3, Y(OAr)3, and Y(BH4)3(THF)3 cata-
lytic systems, temperature is a key factor in the MW control
of PBLGs. MWs increase dramatically when the reaction tem-
perature arises from 0 to 40 ꢁC. In the ROPs catalyzed by
Y(NTMS)3, however, the MWs of PBLG are almost independ-
ent with the reaction temperature in the range of 0–60 ꢁC.
FIGURE 1 GPC/MALLS traces of PBLGs prepared by Y(OAr)3 (A
in red, run 2 in Table 1), Y(OiPr)3 (B in blue, run 1 in Table 1),
Y(BH4)3(THF)3 (C in green, run 3 in Table 1), and Y(NTMS)3 (D
in black, run 4 in Table 1).
FIGURE 2 Plots of the viscosity average molecular weights
(Mv,LSs) versus feeding ratios of [BLG NCA]/[Y] in the polymer-
izations of BLG NCA catalyzed by Y(OiPr)3, Y(OAr)3,
Y(BH4)3(THF)3, and Y(NTMS)3.
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lymerization generating polypeptides with amino and car-
boxyl groups at each end.34,37 In this work, MALDI-TOF MS
is applied to analyze the end groups of the polypeptides
prepared by the four rare earth catalysts. ALA NCA is cho-
sen for the study instead of BLG NCA in this section
because the side reaction between the amino end-group
and the ester group of the last amino acid segment in BLG
NCA polymerization61 would complicate the MALDI-TOF
MS results.
The MALDI-TOF mass spectrum of polyALA (PALA) pre-
pared by Y(OiPr)3 is shown in Figure 5. The major peaks
of a and g correspond to a PALA chain with an amino end
(NH2) and a carboxylic end (COOH) (compound I in
Scheme 2). Y(OAr)3 catalyzed PALA shows the same pat-
terns (Supporting Information, Fig. S1). A typical polymer-
ization mechanism with features similar to the tertiary
amine polymerization, AMM mechanism is shown in
Scheme 2. A deprotonation step at 3-NH happens resulting
in a N-rare earth metallated NCA (i) and a molecule of
alcohol or phenol. Complex i attacks at the 5-CO of another
ALA NCA molecule leading to a dimer (ii) with a highly
electrophilic N-acyl NCA end-group and a nucleophilic car-
bamate end group. Further chain growth can proceed
through the carbamate end by attacking at the 5-CO of
another NCA or i, or through the electrophilic N-acyl NCA
end attacked by i or the carbamate end of another ii. After
polymerization, the carboxylic end group is generated dur-
ing the precipitation into moist diethyl ester with the pro-
cess of an attack at 5-CO of N-acyl NCA end group by water
and release of a molecule of CO2.37 The amino end arises
from hydrolysis of the active rare earth carbamate group
followed by releasing CO2. Another two structures are
identified also in both MALDI-TOF spectra of PALAs cata-
lyzed by Y(OiPr)3 and Y(OAr)3 catalysts. One contains an
amino and a hydantoinic ends (II in Scheme 2) and the
other contains a carboxylic and a hydantoic acid ends (III
FIGURE 3 The viscosity average molecular weights (Mv,LSs) of
PBLGs catalyzed by RE(OAr)3 (solid lines), RE(BH4)3(THF)3
(dash lines), and RE(NTMS)3 (dotted lines), in which RE are Sc
(h), Y (*), La (&), and Dy (!).
This may be related to the coordination of the catalyst. The
rare earth–nitrogen bond is much more reactive than REAO
and REAHBH3 bonds, and the energy barrier is relatively
low, resulting in a fast initiation process and high initiation
efficiency at low temperature.
Investigation on end groups of polypeptide is very power-
ful to reveal polymerization mechanisms of NAM or AMM.
Hexylamine, a typical primary amine, is a well-known ini-
tiator for NCA polymerization by NAM mechanism produc-
ing polypeptide chain containing hexyl group of the initia-
tor residue at one end and amino group at the other. N-
Ethyldiisopropylamine, a tertiary amine, initiates AMM po-
FIGURE 4 The effect of temperature to the viscosity average
molecular weights (Mv,LSs) of PBLGs prepared by various rare
earth catalysts: Y(OiPr)3 (A), Y(OAr)3 (B), Y(BH4)3(THF)3 (C), and
Y(NTMS)3 (D). Polymerization conditions: [BLG NCA]/[Y] ¼ 250,
[BLG NCA] ¼ 0.5 mol/L in DMF, 1 day.
FIGURE 5 MALDI-TOF mass spectrum of PALA catalyzed by
Y(OiPr)3. Polymerization conditions: [ALA NCA]/[Y] ¼ 100, [ALA
NCA] ¼ 0.87 mol/L, 25 ꢁC in THF, 3 days.
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in Scheme 2). Product II is first proposed by Bamford and
Block62,63 and Hashimoto and Imanishi64 years ago and
only experimentally demonstrated by Kricheldorf et al.37
recently. Its formation is closely related to i. After the
dimer ii formed, cyclization occurs in competition with
propagation. This cyclized product 3-(rare earth carboxy-
late) hydantoin (iv) attacks the 5-CO of N-acyl NCA end
group of a polymer chain (iii) forming the product II. Prod-
uct III is formed by the addition of a propagating nucleo-
philic carbamate end to the rare earth a-isocyanato carbox-
ylate, which arises from the rearrangement of i, a well-
documented process in the literature.15 No cyclic PALA is
found in our system in contrast to the tertiary amine cata-
lytic system.
The MALDI-TOF mass spectrum of Y(BH4)3(THF)3 catalyzed
PALA is shown in Figure 6. Besides, a-carboxylic-x-aminote-
lechelic PALA (I) [Figs. 6(b,f)] which is formed by the reac-
tion pathway 2 (RP-2) in Scheme 3 similar to that of
RE(OiPr)3 and RE(OAr)3, another major product is identified
as a-hydroxyl-x-aminotelechelic PALA (IV). It is well known
that the borohydride ligand is reductive in ROP of e-caprolac-
tone.48,65 Its reductive ability is also manifested in this poly-
merization producing
a polypeptide chain containing a
hydroxyl end group as shown in the reaction pathway 1 (RP-
1) in Scheme 3. Attacked at 5-CO by RE(BH4)3(THF)3, the
NCA ring opens and inserts into the REAHBH3 bond result-
ing an intermediate [ARE{OC(O)NHCH(CH3)C(O)HBH3}] (v),
in which the HBH3 group immediately interacts with the a-
carbonyl group to form the corresponding rare earth alanine
carbamate derivative [ARE{OC(O)NHCH(CH3)CH2(OBH2)}]
(vi). Polymerization of ALA NCA by vi then proceeds through
the rare earth carbamate attacking at the 5-CO of the mono-
mer resulting in the (1-oxygen)ꢀ(5-acyl) bond cleavage fol-
lowed by release of a molecule of CO2. After termination, a-
hydroxyl-x-aminotelechelic PALA chains are formed. The
hydroxyl end group results from the hydrolysis of the
[ANHCH(CH3)CH2(OBH2)] chain end in water termination.
SCHEME 2 Polymerization mechanism and side reactions of
ROP of ALA NCA catalyzed by rare earth alkoxide and aryloxide
(RE(OR)3, R ¼ iPr or Ar).
FIGURE 6 MALDI-TOF mass spectrum of PALA catalyzed by
Y(BH4)3(THF)3. Polymerization conditions: [ALA NCA]/[Y] ¼ 100,
[ALA NCA] ¼ 0.87 mol/L, 25 ꢁC in THF, 3 days.
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SCHEME 3 Mechanism of ROP of ALA NCA catalyzed by RE(BH4)3(THF)3.
Hydrolysis of the active rare earth carbamate group and
release of CO2 generate an amino group at the other chain
end. This mechanism is similar to NAM. It needs to mention
that RP-1 and RP-2 can switch back and forth, resulting in
monomodal GPC traces and partial control of the MWs.
responsible for further chain growth. Reaction of vii with an
ALA NCA which involves the SiAN bond cleavage and the tri-
methylsilyl (TMS) group transfer generates viii, which con-
tains an active trimethylsilyl carbamate (TMS-CBM) propa-
gating chain end. The following propagation of polypeptide
proceeds through the transfer of TMS group from the termi-
nal TMS-CBM to the incoming NCA monomer until the mono-
mer is completely consumed or the reaction is quenched.
Amide and amino groups are formed by hydrolysis of the
TMS groups. This process is studied in detail by Lu and
Cheng.20,21 Product II is also found in Y(NTMS)3 catalyzed
Figure 7 shows the MALDI-TOF mass spectrum of PALA pre-
pared by Y(NTMS)3. The major peaks are identified as the
product V containing an amide end group and an amino end
group. Its formation is illustrated in Scheme 4. As a strong
base, deprotonation of 3-NH of ALA NCA takes place first
resulting in HMDS (vii) and i. The in situ generated vii is
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tively chosen. In the case of the bulky ligand, isopropyl
(OiPr) and 2,6-di-tert-butyl-4-methylphenyl (OAr) ligands, for
example, the polymerization proceeds exclusively through
mechanism similar to AMM. For a small ligand of HBH3 in
RE(BH4)3(THF)3, its nucleophilicity is manifested and a poly-
merization mechanism similar to NAM takes place in parallel
resulting polypeptides containing hydroxyl end groups. Bis
(trimethylsilyl)amido (NTMS) ligand represents a special
case. The in situ generated HDMS (vii) rather than N-rare
earth metallated NCA (i) initiates most of the monomers
producing a polypeptide chain containing amide end group.
CONCLUSIONS
Five rare earth complexes, that is, RE(OiPr)3, RE(OAr)3,
RE(BH4)3(THF)3, RE(NTMS)3, and RE(OTf)3, are used as sin-
gle component catalyst for the ROP of NCAs. The first four
show high catalytic activities toward the polymerizations and
the produced polypeptides are in high yields (>90%) with
relatively narrow MWDs ranging from 1.2 to 1.6. In each
catalytic system, rare earth elements do not exhibit great dif-
ference. Polymerization features and chain structures of
these catalytic systems are studied in comparison. In
RE(OiPr)3 and RE(OAr)3 catalytic systems, the MWs obtained
are almost independent with the molar ratios of monomer to
catalyst and high MW polypeptides of about 1 ꢂ 105 Da are
produced. MALDI-TOF MS result indicates a a-carboxylic-x-
aminotelechelic polypeptide chain (I) is formed in these sys-
tems and a polycondensation mechanism (Scheme 2) is pro-
posed accordingly. In RE(BH4)3(THF)3 system, the MWs
obtained can be controlled from 2.5 ꢂ 104 to 1 ꢂ 105 Da by
the feeding ratios. By means of MALDI-TOF MS, a a-hydroxyl-
x-aminotelechelic polypeptide chain (IV) is found as the
major product along with I. A nucleophilic ring opening
initiation and chain growth process (RP-1 in Scheme 3) is
proposed to explain its formation. In RE(NTMS)3 catalytic
FIGURE 7 MALDI-TOF mass spectrum of PALA catalyzed by
Y(NTMS)3. Polymerization conditions: [ALA NCA]/[Y] ¼ 100,
[ALA NCA] ¼ 0.87 mol/L, 25 ꢁC in THF, 3 days.
polymerization indicating i is formed. Its formation process
is the same with that of Y(OiPr)3 and Y(OAr)3 catalytic sys-
tems (side reaction (2) in Scheme 2). Y(NTMS)3 system
exhibits good MW controllability and narrow MWD of poly-
peptide as shown in Table 1 and Figure 1. Block polypep-
tides can be also synthesized by sequential addition of NCA
monomers (data not shown).
In NCA ROPs by the four rare earth catalysts, mechanism
similar to AMM always exists. It arises from the strong basic-
ity of the rare earth–ligand bonds, and thus, deprotonation
of 3-NH of NCA is inevitable. Depending on the steric hin-
drance of the ligand, mechanism similar to NAM is selec-
SCHEME 4 Mechanism for ROP of ALA NCA catalyzed by RE(NTMS)3.
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25 Karatzas, A.; Latrou, H.; Hadjichristidis, N.; Inoue, K.;
Sugiyama, K.; Hirao, A. Biomacromolecules 2008, 9, 2072–2080.
system, linear relationship is shown between the MWs and
the molar ratios of monomer to catalyst (Figs. 2 and 3). End
group analysis indicates a a-amide-x-aminotelechelic poly-
peptide chain (V) is formed. This structure is attributed to
the HMDS (vii) initiated polymerization as illustrated in
Scheme 4. Besides, hydantoin-terminated polypeptide chain
(II) is detected as the byproduct in all the catalytic systems.
26 Gitsas, A.; Floudas, G.; Mondeshki, M.; Spiess, H. W.; Alife-
ris, T.; Latrou, H.; Hadjichristidis, N. Macromolecules 2008, 41,
8072–8080.
27 Cottet, H.; Vayaboury, W.; Kirby, D.; Giani, O.; Taillades, J.;
ꢀ
Schue, F. Anal. Chem. 2003, 75, 5554–5560.
ꢀ
28 Vayaboury, W.; Giani, O.; Cottet, H.; Deratani, A.; Schue, F.
Financial supports from the National Natural Science Founda-
tion of China (21174122 and 20804033), Zhejiang Provincial
Natural Science Foundation of China (Y4110115), Special
Funds for Major Basic Research Projects (G2011CB606001),
and the Committee of Science and Technology of Zhejiang Pro-
vice are gratefully acknowledged.
Macromol. Rapid Commun. 2004, 25, 1221–1224.
29 Habraken, G. J. M.; Peeters, M.; Dietz, C. H. J. T.; Koning, C.
E.; Heise, A. Polym. Chem. 2010, 1, 514–524.
30 Habraken, G. J. M.; Wilsens, K. H. R. M.; Koning, C. E.;
Heise, A. Polym. Chem. 2011, 2, 1322–1330.
31 Dimitrov, I.; Schlaad, H. Chem. Commun. 2003, 23,
2944–2945.
32 Ling, J.; Huang, Y. Macromol. Chem. Phys. 2010, 211,
1708–171.
REFERENCES AND NOTES
33 Kricheldorf, H. R.; Lossow, C. V.; Schwarz, G. Macromol.
Chem. Phys. 2004, 205, 918–924.
1 Deming, T. J. Adv. Mater. 1997, 9, 299–311.
2 Deming, T. J. Adv. Polym. Sci. 2006, 202, 1–18.
34 Kricheldorf, H. R.; Lossow, C. V.; Schwarz, G. Macromol.
Chem. Phys. 2005, 206, 282–290.
3 Lu, H.; Wang, J.; Bai, Y.; Lang, J. W.; Liu, S.; Lin, Y.; Cheng,
J. Nat. Commun. 2011, 2, 206.
35 Kricheldorf, H. R.; Lossow, C. V.; Schwarz, G.; Fritsch, D.
Macromol. Chem. Phys. 2005, 206, 1165–1170.
4 Chen, C.; Wang, Z.; Li, Z. Biomacromolecules 2011, 12,
2859–2863.
36 Kricheldorf, H. R.; Lossow, C. V.; Schwarz, G. J. Polym. Sci.
Part A: Polym. Chem. 2005, 43, 5690–5698.
5 Tang, H.; Lee, C.; Zhang, D. J. Polym. Sci. Part A: Polym.
Chem. 2011, 49, 3228–3238.
37 Kricheldorf, H. R.; Lossow, C. V.; Schwarz, G. J. Polym. Sci.
Part A: Polym. Chem. 2006, 44, 4680–4695.
6 Zhang, Z.; Chen, L.; Deng, M. X.; Bai, Y. Y.; Chen, X. S.; Jing,
X. B. J. Polym. Sci. Part A: Polym. Chem. 2011, 49, 2941–2951.
38 Kricheldorf, H. R.; Lossow, C. V.; Schwarz, G. Macromole-
cules 2005, 38, 5513–5518.
7 Yang, C.; Song, B.; Ao, Y.; Nowak, A. P.; Abelowitz, R. B.;
Korsak, R. A.; Havton, L. A.; Deming, T. J.; Sofroniew, M. V.
Biomaterials 2009, 30, 2881–2898.
39 Pickel, D. L.; Politakos, N.; Avgeropoulos, A.; Messman, J.
M. Macromolecules 2009, 42, 7781–7787.
8 Deming, T. J. Prog. Polym. Sci. 2007, 32, 858–875.
ꢀ
40 Vayaboury, W.; Giani, O.; Cottet, H.; Bonaric, S.; Schue, F.
Macromol. Chem. Phys. 2008, 209, 1628–1637.
9 Lin, Y. C.; Kuo S. W. J. Polym. Sci. Part A: Polym. Chem.
2011, 49, 2127–2137.
41 Simo´ , C.; Cottet, H.; Vayaboury, W.; Giani, O.; Pelzing, M.;
Cifuentes, A. Anal. Chem. 2004, 76, 335–344.
10 Cai, C. H.; Zhu, W. J.; Chen, T.; Lin, J. P.; Tian, X. H. J.
Polym. Sci. Part A: Polym. Chem. 2009, 47, 5967–5978.
42 Shen, Z. Q. Front. Chem. China 2006, 1, 247–259.
11 Deming, T. J. J. Polym. Sci. Part A: Polym. Chem. 2000, 38,
43 Hu, X.; Wu, J.; Xu, Z.; Feng, L. Chin. J. Polym. Sci. 2000, 18,
3011–3018.
369–372.
44 Shen, Y.; Shen, Z.; Zhang, Y.; Yao, K. Macromolecules 1996,
29, 8289–8295.
12 Zhang, X. W.; Oddon, M.; Giani, O.; Monge, S.; Robin, J. J.
Macromolecules 2010, 43, 2654–2656.
45 Ling, J.; Shen, Z.; Huang, Q. Macromolecules 2001, 34,
13 Deming, T. J. J. Am. Chem. Soc. 1997, 119, 2759–2760.
7613–7616.
14 Hadjichristidis, N.; Latrou, H.; Pitsikalis, M. Sakellariou, G.
Chem. Rev. 2009, 109, 5528–5578.
46 Ling, J.; Zhang, Y. F.; Shen, Z. Q. Chin. Chem. Lett. 2001,
12, 41–42.
15 Kricheldorf, H. R. a-Aminoacid-N-carboxy-anhydrides and
Related Heterocycles; Springer-Verlag: Berlin, 1987; pp 1–213.
47 Ling, J.; Chen, W.; Shen, Z. Q. J. Polym. Sci. Part A: Polym.
Chem. 2005, 43, 1787–1796.
16 Kricheldorf, H. R. Angew. Chem. Int. Ed. 2006, 45,
48 Guillaume, S. M.; Schappacher, M.; Soum, A. Macromole-
cules 2003, 36, 54–60.
5752–5784.
17 Deming, T. J. Nature 1997, 390, 386–389.
49 Palard, I.; Schappacher, M.; Belloncle, B.; Soum, A.;
Guillaume, S. M. Chem. Eur. J. 2007, 13, 1511–1521.
18 Deming, T. J. J. Am. Chem. Soc. 1998, 120, 4240–4241.
19 Peng, Y. L.; Lai, S. L.; Lin, C. C. Macromolecules 2008, 41,
3455–3459.
50 Zhao, W.; Cui, D.; Liu, X.; Chen, X. Macromolecules 2010,
43, 6678–6684.
20 Lu, H.; Cheng, J. J. Am. Chem. Soc. 2007, 129, 14114–14115.
21 Lu, H.; Cheng, J. J. Am. Chem. Soc. 2008, 130, 12562–12563.
51 Taylor, M. D.; Carter, C. P. J. Inorg. Nucl. Chem. 1962, 24,
387–391.
22 Lu, H.; Bai, Y.; Wang, J.; Gabrielson, N. P.; Wang, Fei.; Lin,
Y.; Cheng, J. Macromolecules 2011, 44, 6237–6240.
52 Wu, G.; Sun, W.; Shen, Z. React. Funct. Polym. 2008, 68,
822–830.
23 Wang, J.; Lu, H.; Kamat, R.; Pingali, S. V.; Urban, V. S.;
Cheng, J.; Lin, Y. J. Am. Chem. Soc. 2011, 133, 12906–12909.
53 Zhu, W. P.; Tong, X. W.; Shen, Z. Q. Chem. J. Chin. Univ.
2007, 28, 1186–1188.
24 Aliferis, T.; Latrou, H.; Hadjichristidis, N. Biomacromolecules
2004, 5, 1653–1656.
54 Bradley, D. C.; Ghotra, J. S.; Hart, F. A. J. Chem. Soc. Dalton
Trans. 1973, 10, 1021–1023.
1084
JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 50, 1076–1085

WWW.POLYMERCHEMISTRY.ORG
ARTICLE
ꢀ
55 Doty, P.; Bradbury, J. H.; Holtzer, A. M. J. Am. Chem. Soc.
1956, 78, 947–954.
61 Fontaine, L.; Menard, L.; Brosse, J. C.; Sennyey, G.; Senet,
J. P. React. Funct. Polym. 2001, 47, 11–21.
56 Ling, J.; Shen, J. G.; Hogen-Esch, T. E. Polymer 2009, 50,
62 Bamford, C. H.; Block, H. J. Chem. Soc. 1961, 4992–
3575–3581.
4995.
57 Liu, J. Z.; Ling, J.; Li, X.; Shen, Z. Q. J. Mol. Catal. A: Chem.
2009, 300, 59–64.
63 Bamford, C. H.; Block, H. J. Chem. Soc. 1961,
4989–4991.
58 Kobayashi, S. Synlett 1994, 689–701.
59 Longbottom, D. Synlett 1999, 2023.
64 Hashimoto, Y.; Imanishi, Y. Biopolymers 1980, 19,
655–668.
60 Blout, E.R.; Karlson, R. H. J. Am. Chem. Soc. 1956, 78,
941–946.
65 Palard, I.; Soum, A.; Guillaume, S. M. Macromolecules 2005,
38, 6888–6894.
WWW.MATERIALSVIEWS.COM
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