Polymerization of α-amino acid N-carboxyanhydrides catalyzed by rare earth tris(borohydride) complexes: Mechanism and hydroxy-endcapped polypeptides

Article abstract of DOI:10.1002/pola.26077

In this work, rare earth tris(borohydride) complexes, Ln(BH ₄)₃(THF)₃ (Ln = Sc, Y, La, and Dy), have been used to catalyze the ring-opening polymerization of γ-benzyl-L-glutamate N-carboxyanhydride (BLG NCA). All the catalysts show high activities and the resulting poly(γ-benzyl-L-glutamate)s (PBLGs) are recovered with high yields (≥90%). The molecular weights (MWs) of PBLG can be controlled by the molar ratios of monomer to catalyst, and the MW distributions (MWDs) are relatively narrow (as low as 1.16) depending on the rare earth metals and reaction temperatures. Block copolypeptides can be easily synthesized by the sequential addition of two monomers. The obtained P(γ-benzyl-L-glutamate- b-μ-carbobenzoxy-L-lysine) [P(BLG-b-BLL)] and P(γ-benzyl-L-glutamate-b- alanine) [P(BLG-b-ALA)] have been well characterized by NMR, gel permeation chromatography, and differential scanning calorimetry measurements. A random copolymer P(BLG-co-BLL) with a narrow MWD of 1.07 has also been synthesized. The polymerization mechanisms have been investigated in detail. The results show that both nucleophilic attack at the 5-CO of NCA and deprotonation of 3-NH of NCA in the initiation process take place simultaneously, resulting in two active centers, that is, an yttrium ALA carbamate derivative [H₂BOCH ₂(CH)NHC(O)OLni￡] and a N-yttriumlated ALA NCA. Propagation then proceeds on these centers via both normal monomer insertion and polycondensation. After termination, two kinds of telechelic polypeptide chains, that is, α-hydroxyl-ω-aminotelechelic chains and α-carboxylic-ω-aminotelechelic ones, are formed as characterized by MALDI-TOF MS, ¹H NMR, ¹³C NMR, ¹H-¹H COSY, and ¹H-¹³C HMQC measurements. By decreasing the reaction temperature, the normal monomer insertion pathway can be exclusively selected, forming an unprecedented α-hydroxyl-ω-aminotelechelic polypeptide.

Full text of DOI:10.1002/pola.26077

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Polymerization of a-Amino Acid N-Carboxyanhydrides Catalyzed
by Rare Earth Tris(borohydride) Complexes: Mechanism and
Hydroxy-Endcapped Polypeptides
Hui Peng,1 Jun Ling,1 Yinghong Zhu,2 Lixin You,1 Zhiquan Shen1
1Department of Polymer Science and Engineering, MOE Key Laboratory of Macromolecular Synthesis and Functionalization,
Zhejiang University, Hangzhou 310027, People’s Republic of China
2College of Chemical Engineering and Materials, Zhejiang University of Technology, Hangzhou 310014,
People’s Republic of China
Correspondence to: J. Ling (E-mail: lingjun@zju.edu.cn)
Received 13 January 2012; accepted 21 March 2012; published online
DOI: 10.1002/pola.26077
ABSTRACT: In this work, rare earth tris(borohydride) com-
plexes, Ln(BH4)3(THF)3 (Ln ¼ Sc, Y, La, and Dy), have been
used to catalyze the ring-opening polymerization of c-benzyl-L-
glutamate N-carboxyanhydride (BLG NCA). All the catalysts
show high activities and the resulting poly(c-benzyl-L-gluta-
mate)s (PBLGs) are recovered with high yields (ꢀ90%). The
molecular weights (MWs) of PBLG can be controlled by the
molar ratios of monomer to catalyst, and the MW distribu-
tions (MWDs) are relatively narrow (as low as 1.16) depending
on the rare earth metals and reaction temperatures. Block
copolypeptides can be easily synthesized by the sequential
addition of two monomers. The obtained P(c-benzyl-L-gluta-
mate-b-e-carbobenzoxy-L-lysine) [P(BLG-b-BLL)] and P(c-ben-
zyl-L-glutamate-b-alanine) [P(BLG-b-ALA)] have been well
characterized by NMR, gel permeation chromatography, and
differential scanning calorimetry measurements. A random
copolymer P(BLG-co-BLL) with a narrow MWD of 1.07 has
also been synthesized. The polymerization mechanisms have
been investigated in detail. The results show that both nucleo-
philic attack at the 5-CO of NCA and deprotonation of 3-NH of
NCA in the initiation process take place simultaneously,
resulting in two active centers, that is, an yttrium ALA carba-
mate derivative [H2BOCH2(CH)NHC(O)OLnA] and a N-yttrium-
lated ALA NCA. Propagation then proceeds on these centers
via both normal monomer insertion and polycondensation.
After termination, two kinds of telechelic polypeptide chains,
that is, a-hydroxyl-x-aminotelechelic chains and a-carboxylic-
x-aminotelechelic ones, are formed as characterized by
MALDI-TOF MS, 1H NMR, 13C NMR, 1H–1H COSY, and 1H–13
C
HMQC measurements. By decreasing the reaction tempera-
ture, the normal monomer insertion pathway can be exclu-
sively selected, forming an unprecedented a-hydroxyl-x-
C
V
aminotelechelic polypeptide.
2012 Wiley Periodicals, Inc. J
Polym Sci Part A: Polym Chem 000: 000–000, 2012
KEYWORDS: a-amino acid N-carboxyanhydride; biopolymers;
catalysts; polypeptides; rare earth catalysts; ring-opening
polymerization
INTRODUCTION Polypeptides are a class of important bioma-
terials in drug delivery,1,2 tissue engineering,3 and nanoscale
self-assembly.4 The most important method for polypeptide
synthesis is the ring-opening polymerization (ROP) of amino
acid N-carboxyanhydrides (NCAs).5 After the discovery of
NCA monomers by Leuchs, catalysts used to polymerize
them have been received great attention.6,7 They are mainly
categorized into three classes. (1) Amines (primary amines,
secondary amines, and tertiary amines), alcohols, thiols,8 and
water are metal-free catalysts among which primary and ter-
tiary amines are the most widely used, so far, for their easily
accessible reasons. In general, primary amine is good for
preparing low-molecular weight (MW) polypeptides with the
MWs close to the theoretical ones. Tertiary amine, in the
contrary, produces soluble polypeptides with extremely high
MWs.9 The MW distributions (MWDs) are reported as broad
as 2.810 and even bimodal.11 (2) Metal salts and organome-
tallic compounds are another class of catalysts. During the
past few years, some metallic compounds were developed
for ROP of NCA, for instance, solution of lithium chloride in
N,N-dimethylformamide (DMF), sodium carbamate, 9-fluore-
nyl potassium, sodium hydride, sodium acetate, sodium
methoxide, diethylzinc, tributylaluminum, diethylcadmium,
and tributyltinmethoxide.6,9 These polymerizations, however,
were plagued by a variety of side reactions which resulted in
the uncontrolled MWs and broad MWDs. (3) Zero-valent
nickel complex bipyNi(COD) (bipy ¼ 2,20-bipyridyl, COD ¼
1,5-cyclooctadiene) reported by Deming realized living
Additional Supporting Information may be found in the online version of this article.
C
V
2012 Wiley Periodicals, Inc.
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polymerization of NCAs and facile block polypeptide synthe-
sis.12,13 In 2007, Cheng and coworkers11,14,15 used hexame-
thyldisilazane and its derivatives as the initiators for con-
trolled polymerization of NCAs. The MWs of polypeptides
obtained were found to be close to calculated values and
MWDs were narrow. Recently, some methods have been
reported to improve the primary amine systems, including
high-vacuum techniques,16–18 decreasing the reaction tem-
perature19–21 and pressure,22 and treating the primary amine
with hydrochloride.23 Besides exploring new catalysts, great
progress has also been made on the mechanisms of NCA po-
lymerization by Kricheldorf et al.,24–26 Messman and co-
workers,27 and our group28 with some aspects still unclear.
ing 100 mL anhydrous THF under argon. Triphosgene (4.60
g, 15.5 mmol), dissolved in 20 mL anhydrous THF, was
added dropwise into the BLG/THF solution during 30 min.
The reaction was left to proceed for a further 2 h under ar-
gon atmosphere until a clear solution was obtained. The so-
lution was concentrated and poured into anhydrous hexane.
The crude white precipitate was purified by recrystallization
four times using a mixture of ethyl acetate and hexane
resulting in BLG NCA in crystalline form (10.37 g, 83%).
1H NMR (CDCl3, 500 MHz): d ¼ 7.3–7.4 (m, 5H, ArH), 6.72
(s, 1H, NH), 5.13 (s, 2H, C6H5CH2A), 4.38 (dd, 1H, a-CH),
2.58 (t, 2H, b-CH2), 2.27 (m, 1H, c-CH), and 2.11 (m, 1H,
c-CH).
The organometallic catalysts for ROP of NCA are mainly
focused on alkali-, alkaline-earth-, and late-transition metals.
Rare earth metal compounds are nearly unexplored in poly-
peptide synthesis while they are well-known catalysts in ROP
of lactones, lactides, and cyclic carbonates.29–36 To the best of
our knowledge, only one paper reported the polymerization
of c-stearyl-L-glutamate NCA initiated by rare earth catalyst.
Triple component catalytic system of neodymium acetylaceto-
nate [Nd(acac)3] or neodymium tris(2-ethylhexylphosphonate)
[Nd(P204)3] together with triethylaluminum and water pro-
duced high-MW polyglutamates with relatively narrow
MWDs.37 As organometallic catalyst has its advantages over
the conventional catalytic systems on the propagating chain-
end control,5,10 and rare earth compound shows a promising
result to NCA polymerization, we performed the study of ROP
of NCAs by rare earth metallic catalysts.
The BLL NCA (76%) and ALA NCA (53%) were synthesized
following similar procedures. BLL 1H NMR (CDCl3, 500
MHz): d ¼ 7.3–7.4 (m, 5H, ArH), 7.01 (s, 1H, ring NH), 5.10
(s, 2H, C6H5CH2A), 4.96 (s, 1H, side chain NH), 4.26 (dd, 1H,
a-CH), 3.20 (m, 2H, NCH2), 1.80–1.95 (m, 2H, b-CH), and
1.56–1.40 (m, 4H, ANHCH2CH2CH2CH2A). ALA 1H NMR
(CDCl3, 500 MHz): d ¼ 6.30 (s, 1H, NH), 4.42 (q, 1H, ACH),
and 1.58 (d, 3H, ACH3).
Synthesis of the Catalysts Ln(BH4)3(THF)3
Ln(BH4)3(THF)3 (Ln ¼ Sc, Y, La, and Dy) were prepared
using literature procedures29 and our previous report.38 For
example, YCl3 (1.040 g, 5.3 mmol), NaBH4 (0.643 g, 16.9
mmol), and THF (50 mL) were mixed and the suspension
was allowed to stir at 60 ꢁC for 48 h. After centrifugation
separation, the liquid was allowed to crystallize and dried in
dynamic vacuum (yield ¼ 63%).
In this article, we report rare earth tris(borohydride)
[Ln(BH4)3(THF)3] complex as the first homogeneous single-
component catalyst to polymerize NCAs. The strong coordi-
nation ability of rare earth metals and the reductivity of the
ligand with the rare earth metal-borohydride hydrogen bond
(Ln-HBH3) are of our interest in NCA polymerization. Poly-
merization features were presented and polymerization
mechanism was detailedly studied. Further, based on this
mechanism, a strategy to synthesize an unprecedented a-
hydroxyl-x-aminotelechelic polypeptide was developed.
1H NMR (CDCl3, 400 MHz): d ¼ 4.06 (t, 12H, AOCH2A), 1.97
(m, 12H, AOCH2CH2A), and 0.55 (q, 12H, ABH4).
Polymerization of BLG NCA
All polymerizations were performed in Schlenk tubes under
argon. In a typical polymerization, a mixture of BLG NCA
(0.418 g, 1.59 mmol) in
3 mL DMF and 0.30 mL
Y(BH4)3(THF)3 (0.1034 mol/L in THF) was sealed in a tube
and placed in a 40 ꢁC thermostated oil bath for 24 h. The
produced polymer was isolated by precipitation from metha-
nol containing 5% HCl, washed with methanol, and dried in
vacuum (yield ¼ 87.6%).
EXPERIMENTAL
Materials
c-Benzyl-L-glutamate (BLG) (99.0%, Shanghai Hanhong
Chemical, China), e-carbobenzoxy-L-lysine (BLL) (98.5%,
Shanghai Hanhong Chemical), L-alanine (ALA) (98.5%, Sino-
pharm Chemical Reagent, China), and sodium borohydride
(96.0%, Sinopharm Chemical Reagent) were used as
received. Tetrahydrofuran (THF) and hexane were refluxed
over potassium/benzophenone ketyl before use. Ethyl acetate
was stirred over CaH2 and distilled. DMF was purified by
drying over 4 Å molecular sieves followed by vacuum distil-
lation. Dimethyl sulfoxide (DMSO) was stirred over CaH2 and
vacuum distilled.
Polymerization of ALA NCA
In a typical polymerization, ALA NCA (0.204 g, 1.77 mmol)
was first dissolved in 2 mL THF; 0.20 mL Y(BH4)3(THF)3
(0.0860 mol/L in THF) was then added by syringe. The tube
was sealed and placed at room temperature for 3 days. The
produced polymer was isolated by precipitation from diethyl
ether (yield >99%).
Copolymerization of NCAs
For the synthesis of random copolypeptides, BLG NCA (0.224
g, 0.852 mmol) and BLL NCA (0.151 g, 0.494 mmol) were
dissolved in 4 mL DMF; 0.18 mL of Y(BH4)3(THF)3 (0.0366
mol/L in THF) was then added by syringe. The tube was
sealed and the reaction was performed at room temperature
Synthesis of BLG NCA, BLL NCA, and ALA NCA
In a typical procedure, BLG (10.1 g, 42.2 mmol) was charged
into a 250 mL round bottom Schlenk flask followed by add-
2
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TABLE 1 Polymerizations of BLG NCA Catalyzed by Ln(BH4)3(THF)3 (Ln 5 Sc, Y, La, and Dy)a
Mtheo. (104 Da)
Mn (104 Da)
MWDc
b
c
Run
Catalyst
[M]/[Ln]
Temp. (ꢁC)
Yield (%)
1
2
3
4
5
6
7
8
a
Y(BH4)3
Y(BH4)3
Y(BH4)3
Y(BH4)3
Y(BH4)3
Sc(BH4)3
La(BH4)3
Dy(BH4)3
51
198
40
40
40
25
0
87.6
90.9
92.0
89.7
65.5
98.0
89.5
90.1
c
0.33
1.27
7.81
2.65
1.90
1.57
1.35
1.15
2.01
5.25
8.62
5.21
3.09
3.51
4.98
5.68
1.51
1.43
1.32
1.31
1.18
1.65
1.29
1.16
1,163
404
397
219
40
40
40
206
175
Reaction conditions: [BLG NCA] ¼ 0.5 mol/L, 24 h in DMF.
Mtheo. ¼ [molar mass(BLG NCA)ꢃ44] ꢂ ([M]/[Ln]/3) ꢂ yield.
Determined by GPC/MALLS in DMF containing 0.1 mol/L LiBr
b
at 60 ꢁC (dn/dc ¼ 0.104 mL/g).
for 36 h. The polymer was isolated by precipitation from
diethyl ether (yield ¼ 71.6%).
rimetry (DSC) analyses were performed on a Perkin Elmꢁer
Pyris 1 instrument. Samples were heated from -50 to 150 C
at a rate of 10 C/min under a nitrogen purge, quenched to -
ꢁ
For the synthesis of block copolypeptides, BLG NCA (0.405 g,
1.54 mmol) was first dissolved in 3 mL DMF, and 0.20 mL
Y(BH4)3(THF)3 (0.0366 mol/L in THF) was then added by
syringe. The tube was sealed and the reaction was per-
formed at room temperature for 24 h to ensure complete
conversion of the monomers [monitored by Fourier trans-
form infrared spectra (FT-IR)]. Then, 1.8 mL of the reaction
mixture was withdrawn from the tube and precipitated from
diethyl ether (yield ¼ 87.2%) for the analysis of first block.
BLL NCA (0.173 g, 0.565 mmol) dissolved in 1.6 mL DMF
was then added to the reaction mixture and the polymeriza-
tion of the second block was complete after 72 h. The prod-
uct was isolated by precipitation into diethyl ether (yield ¼
94.8%). Block polypeptides of BLG NCA and ALA NCA were
prepared in a similar way.
50 ꢁC and subjected to a second scan. The first and second
thermo-scanning curves were recorded. The MALDI-TOF
mass spectra were measured on an Applied Biosystems Voy-
ager System 4350 equipped with a nitrogen laser (k 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 hexafluoroisopropyl alcohol solutions
with 2,5-dihydroxybenzoic acid as matrix and potassium tri-
fluoroacetate as dopant. ESI-MS was measured on a Varian
500 mass spectrometer. The FT-IR were recorded on a
Bruker VECTOR 22 spectrometer either in Nujol mull or neat
using KBr plates.
RESULTS AND DISCUSSION
Polymerization Features
The homoleptic trivalent rare earth metal borohydride com-
plexes Ln(BH4)3(THF)3 (Ln ¼ Sc, Y, La, and Dy) are efficient
catalysts for ROP of BLG NCA. Table 1 summarizes the
results of the polymerizations performed in DMF for 24 h. In
general, the polymer poly(c-benzyl-L-glutamate) (PBLG) was
recovered in about 90% yield. The monomer was completely
consumed within 24 h as proved by FT-IR and 1H NMR.
PBLG with the MWs ranging from 2 ꢂ 104 to 9 ꢂ 104 Da
and relatively narrow MWDs (1.32–1.51) could be prepared
by varying the molar ratios of monomer to catalyst (runs 1–
3 in Table 1), in contrast to the strong-base catalyst such as
triethylamine which showed no controllability to the MWs.39
MWs and MWDs also depend on the reaction temperature.
Low temperature inclined to produce polypeptides with low-
MWs and narrow MWDs. At 0 ꢁC (run 5 in Table 1), PBLG
with MW of 31 KDa and MWD of 1.18 was obtained. How-
ever, the experimental MW is deviated from the theoretical
one, this may be related to the difference of the three BH4
ligands.29 Four rare earth tris(borohydride) complexes, that
is, Ln(BH4)3(THF)3, (Ln ¼ Sc, Y, La, and Dy), were used as
initiators of BLG NCA. At comparable monomer to catalyst
molar ratios (runs 2, 6, 7, and 8 in Table 1), Sc(BH4)3(THF)3
produced PBLG with the lowest MW (3.5 ꢂ 104 Da) and the
broadest MWD (MWD ¼ 1.65). The other three catalysts
Reaction of ALA NCA With Y(BH4)3(THF)3
A Y(BH4)3(THF)3/THF solution (0.0861 mol/L, 10 mL, 0.861
mmol) was stirred at room temperature. ALA NCA (0.300 g,
2.601 mmol) dissolved in 2-mL THF was then added drop-
wise. A white precipitate rapidly appeared in a colorless so-
lution accompanied with gas evolution. After 1 day, the solu-
tion was filtered and the resulting white powder was
washed thoroughly with THF for two times and finally dried
in vacuum. The white solid (yield ¼ 83%) was analyzed by
ESI-MS, FT-IR, and 13C NMR.
Measurements
NMR spectra were recorded on a Bruker Avance DMX 500
spectrometer (1H: 500 MHz, 13C: 125 MHz) using CDCl3/tri-
fluoroacetic acid (CF3COOH) (v:v ¼ 3:1), CF3COOD or DMSO-
d6 as solvent and tetramethylsilane, or CF3COOH as internal
reference. MWs and MWDs were determined by gel permea-
tion chromatography/multiangle laser light scattering (GPC/
MALLS) which consisted of a Waters 1515 isocratic high-per-
formance liquid chromatograph pump, a Wyatt DAWN DSP
MALLS detector, a Wyatt Opitlab DSP interferometric refrac-
tometer, and two columns of Styragel (HT3 and HT4). DMF
containing 0.1 mol/L LiBr was used as the eluent with a
ꢁ
flow rate of 1.0 mL/min at 60 C. Differential scanning calo-
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TABLE 2 Block and Random Copolymerizations of NCAs Catalyzed by Y(BH4)3(THF)3.a
d
nII/nI
Time
(day)
Yield
(%)
nII/nIc
Mtheo.
(104 Da)
Mn
(104 Da)
MWDd
b
Run
MI/MII
[MI]/[Y]
(feed)
(product)
1
2
3
4
BLG NCA/BLG NCA
BLG NCA/BLL NCA
BLG NCA/ALA NCA
BLG NCA/BLL NCA
200
210
413
129
1.11
0.92
0.61
0.58
1þ3
1þ3
1þ3
1.5
95.0
94.8
89.3
71.6
–
1.39/2.93
1.45/3.05
–
2.19/4.41
2.58/3.87
–
1.30/1.23
1.20/1.14
–
0.92
0.69
0.54
0.89
2.57
1.07
c
BLG NCA: c-benzyl-L-glutamate N-carboxyanhydrid; BLL NCA: e-carbo-
benzoxy-L-lysine N-carboxyanhydride; ALA NCA: L-alanine N-
carboxyanhydride.
Calculated from 1H NMR spectra of products from the integration (Int.)
ratios Int.PBLL/Int.PBLG using the methine groups (COCHRNH, d ¼ 4.61
ppm for PBLG and d ¼ 4.41 ppm for PBLL) and [Int.PALA/3]/[Int.PBLG/2]
using the methyl group and benzyl group (CH3CH, d ¼ 1.47 ppm for
PALA and C6H5CH2, d ¼ 5.07 ppm for PBLG).
a
Reaction conditions: [BLG NCA] ¼ 0.5 mol/L, 25 ꢁC in DMF.
b
Feeding mode: sequential addition (runs 1–3) and simultaneous addi-
d
tion (run 4).
Determined by GPC/MALLS in DMF containing 0.1 mol/L LiBr at 60 ꢁC.
produced PBLGs with similar MWs but different MWDs rang-
ing from 1.16 to 1.43. This result may be related to the dif-
ferences of atom radius and electronic structures of rare
earth metals.
mer [P(BLG-b-BLL)] also exhibited the liquid crystalline
phase transition at a slightly lower temperature (TLC ¼ 102
ꢁC) with a smaller enthalpic change than PBLG homopoly-
mer. This is because the a-helical conformation of PBLG seg-
ments was partially affected by PBLL and the liquid crystal-
Block and random copolypeptide can also be synthesized by
Y(BH4)3(THF)3 as shown in Table 2. After the first block po-
lymerization was completed, the second batch of NCA mono-
mer including BLG NCA, BLL NCA, and ALA NCA was added
(runs 1–3 in Table 2). The products were submitted to 1H
NMR (Fig. 1) and GPC (Fig. 2) analyses to test the formation
of the block copolymers. As shown in Figure 2, obvious GPC
MW increases were seen while the peaks remained mono-
modal. More convincing evidence for the formation of the
block polypeptide comes from P(c-benzyl-L-glutamate-b-ala-
nine) [P(BLG-b-ALA)]. Polyalanine (PALA) is a polypeptide
hardly soluble in common organic solvents. With a certain
length of PALA segments relative to PBLG (ꢀ8.4 wt %),
P(BLG-b-ALA) becomes insoluble.40 After adding ALA NCA
into a completed Y(BH4)3(THF)3-catalyzed PBLG polymeriza-
tion mixture, the block copolymer P(BLG-b-ALA) precipitated
as expected. The isolated precipitate was suspended in THF,
a good solvent for PBLG, and sonicated for 40 min to remove
the possible homopolymers of PBLG. The THF-insoluble poly-
line phase transition process occurred at
a
lower
temperature. As expected, no liquid crystalline phase transi-
tion was observed for the random copolymer P(BLG-co-BLL),
suggesting the a-helical conformation of PBLG was disrupted
due to the random distribution of PBLL segments.
Mechanistic Aspects
ALA NCA instead of BLG NCA has been selected in mechanis-
tic study due to the following three reasons. First, PALA has
a simple and characteristic chemical structure. Thus, well-
resolved NMR signals are expected. Second, the side reaction
between the amino end group and the ester group of the
last amino acid segment which is well known in BLG NCA
polymerization43 is absent in ALA NCA polymerization.
Third, PALA precipitates during the polymerization process,
resulting in low-MW polypeptide which is convenient for
MALDI-TOF MS and NMR analyses.
Initiation Process of Polymerization of ALA NCA by
Y(BH4)3(THF)3
1
mer was analyzed by H NMR [Fig. 1(C)]. Both peaks related
Upon reaction of the first three ALA NCA molecules with
Y(BH4)3(THF)3, all possible products are outlined in Scheme
1 corresponding to the reactions at four reactive sites of a
NCA molecule. First, the Y(BH4)3(THF)3 may initiate a nucle-
ophilic attack at the 2-CO group of ALA NCA, leading to a
borane-(S)-2-formamidopropionate which either loses the
borane molecule immediately forming the yttrium (S)-2-for-
mamidopropionate (Product I) or is reduced by borane form-
ing the yttrium (S)-2-methylamidopropionate (Product II).
However, it is need to note that this process is quite less
possible for the reason that 2-CO is less reactive compared
with 5-CO as reported by Kricheldorf.9 Second, a deprotona-
tion could occur at the 3-NH position which is typical in the
presence of strong bases.9 The formed N-yttriumlated ALA
NCA could be subject to a fast rearrangement resulting in an
yttrium a-isocyanato carboxylate (Product III). This is well
known for NCA anions and transition metallated NCAs.9
Third, deprotonation of 4-CH might be taken into account
although this initiation step is less favorable due to the
to PBLG and PALA segments were resolved and identified,
indicating a truly block copolymer was produced. After evap-
oration, no residue was left in the THF-soluble part indicat-
ing that all of the PBLG chain ends initiated the ALA NCA.
Random copolymer of BLG NCA and BLL NCA was also pre-
pared by Y(BH4)3(THF)3 (run 4 in Table 2). The 1H NMR of
the copolypeptide showed the presence of both components
[Fig. 1(B)], and the calculated molar ratio of BLG to BLL
units was very close to the feed ratio. GPC trace [Fig. 2(C)]
exhibited a mono-modal peak with a narrow MWD of 1.07.
Figure 3 summarized the DSC curves of block and random
copolymers as well as homopolymers. A small liquid crystal-
line phase transition peak at 109 ꢁC (TLC) was observed for
PBLG homopolymer. This transition which was irreversible
and only occurred during the first heating run was attrib-
uted to an irreversible change from a 7/2 to a 18/5 a-helical
conformation of PBLG.41,42 At higher temperature, no other
transition was observed until its degradation.42 Block poly-
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FIGURE 1 1H NMR spectra of P(BLG-b-BLL) (A) in CDCl3/CF3COOH (run 2 in Table 2), P(BLG-co-BLL) (B) in CDCl3/CF3COOH (run 4
in Table 2), and P(BLG-b-ALA) (C) in CF3COOD (run 3 in Table 2).
lower acidity of the 4-proton. However, it has been shown
that L-NCAs may undergo racemization in the presence of
strong base9 indicating some acidity of the 4-proton. After
deprotonation of 4-CH, if possible, the C-yttriumlated ALA
NCA might rearrange into an yttrium ketenyl carbamate
(Product IV). Last, nucleophilic attack at the 5-CO is also a
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2-CO. The reduced frequency of 2-CO compared with 5-CO is
caused by the nitrogen electron pair delocalized on to the 5-
CO. This assignment has been demonstrated by Kricheldorf.9
The spectrum of Y(BH4)3(THF)3 [Fig. 5(B)] displays three
bands corresponding to the m(BAHterminal
) (2450–2430
cmꢃ1), m(BAHbridging) (2230–2110 cmꢃ1), and d(BAH) (1119
cmꢃ1), as found in the literature for rare earth metallic boro-
hydride complexes of La, Nd, and Sm.30 Figure 5(C) shows
the FT-IR spectrum of the reaction with 1 equiv of the yt-
trium complex. The disappearance of the absorption bands
corresponding to HBH3 groups indicates the cleavage of the
BAH bonds in Y(BH4)3(THF)3 during the initiation process.
The 2-CO band of ALA NCA ring shifts toward lower frequen-
cies (1747 cmꢃ1) compared with monomer ALA NCA [Fig.
5(A)]. It is attributed to the formation of the N-yttriumlated
ALA NCA with the increasing electronegativity of the nitrogen
atom after being yttriumlated. The N-yttriumlated ALA NCA
undergoes a rearrangement into yttrium a-isocyanato carboxy-
late according to the detection of stretching vibrations of iso-
cyanate group44 (2391 cmꢃ1) and yttrium carboxylate (1580
cmꢃ1) group. Evidence of V0 is provided by the CO band of
the amide group located at 1648 cmꢃ1 together with the CO
band of yttrium carbamate group residing at 1580 cmꢃ1
which is overlapped with yttrium carboxylate.
FIGURE 2 GPC traces of PBLG (A) (run 1 in Table 2), P(BLG-b-
BLL) (B) (run 2 in Table 2), and P(BLG-co-BLL) (C) (Run 4 in Ta-
ble 2), determined in DMF containing 0.1 mol/L LiBr at 60 ꢁC.
potential reaction pathway (RP), after which the resulting in-
termediate [AY{OC(O)NHCH(CH3)C(O)HBH3}] is immediately
reduced by the adjacent HBH3 group forming the corre-
CF3COOD was used as the solvent for a better NMR resolu-
tion. The 13C NMR spectrum of the carbonyl groups of the
acidolysis product is shown in Figure 6 with all 13C signals
of carbonyl groups of IIIF and V0F well resolved. Both Prod-
ucts III and V0 react with CF3COOD yielding corresponding
Products IIIF and V0F, respectively. The chemical shifts of the
carbonyl groups of IIIF are assigned according to the model
compound hexyl isocyanate (Supporting Information Fig. S1).
sponding
yttrium
ALA
carbamate
derivative
[AY{OC(O)NHCH(CH3)CH2(OBH2)}] (Product V). This reduc-
tion by the HBH3 group has been well studied in the polymer-
ization of e-caprolactone catalyzed by Ln(BH4)3(THF)3.29–31
Alternatively,
BH3
could
be
lost
by
forming
[AY{OC(O)NHCH(CH3)CHO}] (Product VI). To understand the
initiation mechanism of the polymerization and to determine
which kinds of the compounds are initially formed, we per-
formed the reaction of ALA NCA with equivalent
Y(BH4)3(THF)3 and analyzed the products by ESI-MS, FT-IR,
and 13C NMR.
The above results indicate that only 3-NH and 5-CO are
involved in the initiation step. We further used the equiva-
lent reaction product to initiate ROP of BLG NCA. As
expected, it polymerized BLG NCA in quantitative yield
(95%). The fragment originating from Product V0 is clearly
identified in 1H NMR spectrum of the produced PBLG
The reaction mixture of ALA NCA with one equivalent of
Y(BH4)3(THF)3 was dissolved in anhydrous DMSO and ana-
lyzed by ESI-MS (Fig. 4) with minimum exposure to air. Major
peaks were identified corresponding to structures III and V0.
Product III results from the reaction at the 3-NH of ALA NCA
as shown in Scheme 1. Product V0 is a trimer of PALA formed
by addition of two ALA to compound V (Scheme 1). During
negative ionization in ESI-MS, the initially formed compound
V00 releases a CO2 molecule forming into the Product V0, a
well-documented process.9 These results indicate that both
3-NH and 5-CO of ALA NCA are involved in the initiation
process and rules out the other potential reactions shown in
Scheme 1. Because of the higher energy barrier of deprotona-
tion at 3-NH relative to nucleophilic attack at the 5-CO of an
ALA NCA,9 the ring-opening process at the 5-CO group is
faster than the deprotonation at 3-NH resulting in the com-
petitive products of ALA trimer V0 and unimer of III.
Formation of III and V0 is further supported by FT-IR analy-
ses (Fig. 5). Two characteristic stretching vibrations of ALA
NCA anhydride can be distinguished in Figure 5(A) with the
frequency at 1839 cmꢃ1 assigned to 5-CO and 1778 cmꢃ1 to
FIGURE 3 DSC thermograms of PBLG (A), P(BLG-b-BLL) (B),
P(BLG-co-BLL) (C), and PBLL (D).
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SCHEME 1 Possible mechanisms for the initiation process of ALA NCA polymerization catalyzed by Y(BH4)3(THF)3.
(Fig. 7), implying compound V0 is the active initiation species
responsible for further chain growth. The N-yttriumlated
ALA NCA (Product III) which is also expected to initiate a
polymerization will be discussed below.
molar ratio of monomer to catalyst of 30. The MALDI-TOF
MS result of the produced PALA is shown in Figure 8. Two
populations of polymers corresponding to the chemical
structures of A and B are resolved. All polymers contain an
amino group at one end and either a hydroxyl (structure A)
or carboxyl group (structure B) at the other. The adjacent
peaks of each population have the margin of 71 Da corre-
sponding to an ALA repeating unit.
Propagation Process of the Polymerization of ALA NCA
in the Presence of Y(BH4)3(THF)3
It is well known that two different reaction mechanisms are
adopted during ROP of NCA, that is, the normal amine mech-
anism (NAM) and the activated monomer mechanism
(AMM), depending on the relative nucleophilicity and basic-
ity of the initiator. Identification of the end groups can dis-
tinguish the mechanism. Primary amine, hexylamine for
example, a well-known catalyst for NAM, produces a poly-
The end groups of PALA are further demonstrated by NMR.
Thus, 1H NMR, 13C NMR, 1H–1H COSY, and 1H–13C HMQC
spectra of PALA are illustrated in Figures 9 and 10 and Sup-
porting Information S2 and S3, respectively, with full assign-
ments. NMR analyses of PALA reveal three distinct chain
ends, that is, carboxyl groups, amino groups, and hydroxyl
groups. Among the three end groups, hydroxyl end group
(HOCH2CH(CH3)NHA) is well resolved and the whole set sig-
nals (Hc, Hf, Hg1, Hg2, Hc–Hf, Hc–Hg1, Hc–Cc, Hf–Cf, Hg1–Cg,
Hg2–Cg, Cc, Cf, and Cg) can be observed unambiguously.45
This set signals are due to Ln(BH4)3(THF)3-catalyzed PALA
as they are absent in water- or tertiary amine-catalyzed
PALA [Fig. 9(B,C)]. The signals of carboxyl end group and
peptide chain containing
a hexyl end and amino end
groups,24 whereas N-ethyldiisopropylamine, a tertiary amine,
initiating ROP via AMM, creates a chain with an amino group
at one end and a carboxyl group at the other resulting from
the attack of H2O to the N-acyl-NCA end group.26
To investigate the mechanism, ALA NCA was polymerized by
Y(BH4)3(THF)3 at room temperature for 3 days with the
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FIGURE 4 ESI-MS spectrum (negative ionization) of the reaction mixture of ALA NCA and equivalent Y(BH4)3(THF)3.
FIGURE 5 FT-IR spectra of ALA NCA (A), Y(BH4)3(THF)3 (B), and the reaction mixture (C) of ALA NCA with equivalent
Y(BH4)3(THF)3.
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FIGURE 6 Partial 13C NMR spectrum of the product of ALA NCA with equivalent Y(BH4)3(THF)3 using CF3COOD as the solvent.
FIGURE 7 1H NMR spectrum of PBLG initiated by the product of ALA NCA reacting with equivalent Y(BH4)3(THF)3. Reaction condi-
tions: [BLG NCA] ¼ 1.0 mol/L, m(BLG NCA)/m(equivalent reaction product) ¼ 800/11.6 mg, THF, 25 ꢁC, 3 days.
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FIGURE 8 MALDI-TOF mass spectrum (Kþ doping) of PALA catalyzed by Y(BH4)3(THF)3 at 25 ꢁC.
FIGURE 9 1H NMR spectra of PALA catalyzed by Y(BH4)3(THF)3 (A) and PALA by H2O (B and C) for comparison. CF3COOD is used
as the solvent.
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nucleophilic carbamate group. Further, chain growth can
proceed either via RP-1 at the rare earth carbamate end or
via nucleophilic attack at the 5-CO group of the N-acyl NCA
end of IX by another N-rare earth metallated NCA (VIII) or
rare earth carbamate end. PALA with a N-acyl NCA end
group and a rare earth carbamate end group is formed after
complete consumption of NCA monomers. The carboxylic
end group is generated by the addition of H2O which
attacks at the 5-CO of N-acyl NCA end group followed by
decarboxylation. The amino end group results from the hy-
drolysis of the rare earth carbamate end group. It is worth
mentioning that growing chains can switch back and forth
between the RP-1 and RP-2 processes during the polymer-
ization. The active rare earth carbamate chain end of RP-1
can attack at the active N-acyl NCA end group of RP-2 or a
N-rare earth metallated NCA, whereas the active rare earth
carbamate chain end of RP-2 can also proceed a polymer-
ization through a normal chain propagation of RP-1. Thus,
GPC traces exhibit a mono-modal peak though two different
RPs take place at the same time and the obtained Mns are
higher than theoretical ones (Table 1).
FIGURE 10 13C NMR spectrum of PALA catalyzed by
Y(BH4)3(THF)3. CF3COOD is used as the solvent.
amino end group are partially overlapped with the main
chain signals in 1H and 13C spectra and can be resolved by
means of 1H–1H COSY (Supporting Information Fig. S2) and
1H–13C HMQC (Supporting Information Fig. S3) spectra.46
Synthesis of a-Hydroxyl-x-Aminotelechelic Polypeptide
Compared with conventional a-carboxylic-x-amino-protein,
a-hydroxyl-x-aminotelechelic polypeptide may have different
self-assembly behaviors and salting-out effects. Furthermore,
the hydroxyl end group provides a potential site for drug
conjugation, facilitating its use as drug/gene carrier or in
other biomedical applications. However, its preparation by
reduction from the corresponding a-carboxylic-x-aminotele-
chelic polypeptide is prone to either over-reduction or
incomplete reduction by the common reducing agents,
namely LiAlH4 or H2/Pd-C and NaBH4 (data not shown).
Therefore, the synthesis of a pure a-hydroxyl-x-aminotele-
chelic polypeptide is of great interest. It is well known that
nucleophilic attack at 5-CO is a fast initiation step while
deprotonation at 3-NH is a much slower process requiring a
higher activation energy.9 Hence, when the polymerization
was performed at 0 ꢁC to suppress RP-2, we demonstrated
that only RP-1 took place. The MALDI-TOF MS of the product
is shown in Figure 11. Only one population corresponding to
From the results above, two different RPs take place concur-
rently during the ROP of NCA catalyzed by Ln(BH4)3(THF)3
as summarized in Scheme 2. RP-1 and RP-2 are proposed to
explain the formation of the a-hydroxyl-x-aminotelechelic
PALA chain and the a-carboxylic-x-aminotelechelic PALA
chain, respectively. In RP-1 (Scheme 2), after attacking at 5-
CO by Ln(BH4)3(THF)3, the NCA ring opens and inserts into
the LnAHBH3 bond resulting an intermediate [ALn{OC(O)
NHCH(CH3)C(O)HBH3}] (Product VII) in which the HBH3
group immediately reacts with the a-carbonyl group to form
the corresponding rare earth ALA carbamate derivative
ALn{OC(O)NHCH(CH3)CH2(OBH2)} (V). Similar reductive
ability of the borohydride ligand in Ln(BH4)3(THF)3 has been
well studied in lactone polymerization by Guillaume and co-
workers.29,31 Polymerization of ALA NCA by V then pro-
ceeds through the rare earth carbamate attacking at the 5-
CO of the monomer resulting in the C5AO1 acyl-oxygen
bond cleavage followed by the release of a CO2 molecule.
The reaction is quenched by H2O resulting in the hydrolysis
of the active LnAOCONH bond and release of CO2, generat-
ing the amino chain end. Meanwhile, the other end of the
polymer chain capped with a hydroxyl group results from
the hydrolysis of the ANHCH(CH3)CH2(OBH2) chain end. As
there are no termination steps, a living polymerization is
expected in the case of RP-1. The competing RP-2 process,
however, is a combination of chain propagation and step-
1
the structure A is resolved. In H NMR (Supporting Informa-
tion Fig. S4), the proton of the methine linked to carboxylic
group disappears while the set of the hydroxyl group is still
resolved. The results indicate that a lowering reaction tem-
perature can effectively avoid the deprotonation step, pro-
ducing pure telechelic polypeptides with amino and hydroxyl
end groups.
CONCLUSIONS
Rare earth borohydride complexes Ln(BH4)3(THF)3 (Ln ¼ Sc,
Y, La, and Dy) have been applied to catalyze the ROP of BLG
NCA for the first time. The catalysts exhibit high activities
producing polypeptides in quantitative yields. The MWs of
the PBLG can be controlled by the molar ratios of monomer
to catalyst, and the MWDs are relatively narrow (1.16ꢃ1.65)
depending on the rare earth metals and reaction tempera-
tures. Block copolypeptides have been facilely synthesized by
growth processes.
A deprotonation step at 3-NH by
Ln(BH4)3(THF)3 happens forming a N-rare earth metallated
NCA (Product VIII) accompanied with the BH3ꢄTHF adduct
and a molecule of hydrogen gas. Attack at the 5-CO of ALA
NCA by complex VIII leads to a dimer (Product IX) contain-
ing a highly electrophilic N-acyl NCA end group and a
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SCHEME 2 Mechanism for the ROP of ALA NCA catalyzed by Ln(BH4)3(THF)3.
sequential addition of two monomers. Random copolypep-
tide with MWD as narrow as 1.07 has been produced. In
mechanic studies, we have found two active species, that is,
an yttrium ALA carbamate derivative (V) and a N-yttrium-
lated ALA NCA (VIII) which are derived from the reactions
of 5-CO and 3-NH of ALA NCA with Y(BH4)3(THF)3, respec-
tively, initiate the polymerizations simultaneously, leading to
the a-hydroxyl-x-aminotelechelic polypeptides and a-carbox-
ylic-x-aminotelechelic ones. Lowering the reaction tempera-
ture to 0 C can effectively suppress the deprotonation of 3-
ꢁ
NH, producing a pure a-hydroxyl-x-aminotelechelic polypep-
tide. This study highlights that it provides an insight into the
mechanism of NCA polymerization catalyzed by organometal-
lic catalysts. The improved versatility of such rare earth tris(-
borohydride) compounds, relative to other catalysts, lies in
their ability to generate an unprecedented a-hydroxyl-x-
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FIGURE 11 MALDI-TOF mass spectrum (Kþ doping) of PALA catalyzed by Y(BH4)3(THF)3 at 0 ꢁC.
10 Deming, T. J. J. Am. Chem. Soc. 1997, 119, 2759–2760.
11 Lu, H.; Cheng, J. J. Am. Chem. Soc. 2008, 130, 12562–12563.
12 Deming, T. J. Nature 1997, 390, 386–389.
aminotelechelic polypeptide which may be used as an
improved biomaterial or an effective macroinitiator to afford
a polyester/polypeptide conjugate.
13 Deming, T. J. J. Am. Chem. Soc. 1998, 120, 4240–4241.
14 Lu, H.; Cheng, J. J. Am. Chem. Soc. 2007, 129, 14114–14115.
ACKNOWLEDGMENTS
H. R. Kricheldorf is warmly acknowledged for his helpful dis-
cussions. The authors are grateful to the National Natural Sci-
ence Foundation of China (21174122), the Special Funds for
Major Basic Research Projects (G2011CB606001), the Zhejiang
Provincial Natural Science Foundation of China (Y4110115),
and the Fundamental Research Funds for the Central Univer-
sities (2011QNA4025).
15 Lu, H.; Wang, J.; Lin, Y.; Cheng, J. J. Am. Chem. Soc. 2009,
131, 13582–13583.
16 Aliferis, T.; Latrou, H.; Hadjichristidis, N. Biomacromolecules
2004, 5, 1653–1656.
17 Karatzas, A.; Latrou, H.; Hadjichristidis, N.; Inoue, K.;
Sugiyama, K.; Hirao, A. Biomacromolecules 2008, 9, 2072–2080.
18 Aliferis, T.; Latrou, H.; Hadjichristidis, N. J. Polym. Sci. Part
A: Polym. Chem. 2005, 43, 4670–4673.
19 Cottet, H.; Vayaboury, W.; Kirby, D.; Giani, O.; Taillades, J.;
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