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High Molecular Weight Poly (L-lactic acid) s by
Polyesterification using Diisopropylcarbodiimide (DIPC) and
4-(Dimethylamino) pyridinium-p-toluene sulfonate (DPTS)
S. Shyamroy, B. Garnaik and S. Sivaram*
Polymer Science and Engineering Division
CSIR-National Chemical Laboratory,Pune-411008, India
Phone no- +9120-25902304
Fax no- +9120-25902615
Email: b.garnaik@ncl.res.in; s.sivaram@ncl.res.in
ABSTRACT
High molecular weight poly (L-Lactic acid) have been prepared from the corresponding
functionally terminated oligomers employing a polyesterification method at room
temperature using diisopropyl carbodiimide (DIPC) and 4-(dimethylamino) pyridinium-p-
toluene sulfonate (DPTS). Self-condensation of hydroxyl and carboxylic acid-terminated
poly (L-Lactic acid) oligomers (Mn: ~1000) resulted in polymers with high molecular
weights (Mn> 45,000) under mild conditions. End group analysis by MALDI-TOF
provided evidence for N- acylurea formation in the product under the reaction conditions
employed.
Introduction
Poly (L-lactic acid) (PLLA) is a synthetic and biodegradable aliphatic polyester.
Increasing concerns regarding sustainability of polymer materials have resulted in
greater focus on renewable and biodegradable polymers derived from biomass. PLLA is
a thermoplastic which has useful properties and are derived from sugars. PLLA is being
explored as a potential alternative to petroleum derived polymers, such as, poly (olefin)
s, poly (ester) s and poly (styrene) [1-4]. PLLA has good mechanical properties and can
be either rigid or elastic in nature. The polymer finds many applications, especially, as
fibers, films and transparent thermoplastics in packaging, consumer goods and many
articles of short life-cycle use.
Synthesis of high molecular weight PLLA can be accomplished by two methods, namely,
1) dehydrative melt polycondensation of L (+)-lactic acid (LA) [5] and 2) ring opening
polymerization (ROP) of a cyclic dimer (lactide) [6]. The method of choice is ROP of
cyclic lactide and is used for the large scale production of PLLA [7-8] . This method
involves the polymerization of LA to low molecular weight oligomers which is then
depolymerized to a cyclic dimer (lactide), purified by melt crystallization followed by
ROP to PLLA (Mw>50,000 ) using a suitable catalyst. Melt phase polycondensation of
LA has been widely studied [9-12]. Melt phase polycondensation methods have several
drawbacks, such as inability to achieve high molecular weights due to competitive
formation of cyclic oligomers at higher temperatures, undesirable side reactions leading
to broad polydispersity color, racemization and difficulties in removal of water
effectively from a high viscosity melt. Solid state polycondensation is another alternative
method for the synthesis of high molecular weight PLLA. However, the low melting point
of lactic acid oligomers and the slow reaction rate have limited the scope of this method
for the synthesis of PLLA [13-15].
Direct room temperature unactivated polymerization of a carboxylic acid with phenol
using diisopropyl carbodiimide (DIPC) and 4-(dimethylamino) pyridinum-p-toluene
sulfonate (DPTS) has been suggested as a mild method for the synthesis of high
molecular weight polyesters by Moore and Stupp [16]. They examined the self-
condensation of several hydroxyl acid monomers, wherein, both the hydroxyl and the
carboxyl group are attached to an aromatic ring. The reagent DPTS was found to be an
effective catalyst resulting in polymers with DP > 50 at room temperature. More
significantly, N-acyl urea could not be detected as a terminal group. Typically,
carbodiimide promoted esterification reactions are known to result in the formation of
unreactive N-acyl urea (Scheme 1) [16-17]. In a polymer analogous reaction, N-acyl
urea formation will limit the chain growth process. Use of DPTS is believed to depress
the formation of N-acyl urea. Hyperbranched poly(ε-caprolactone)s have been prepared
by condensation of AB2 polyesters at room temperature using 1,3-
dicyclohexylcarbodiimide (DCC) and DPTS[18]. Hyperbranched block polymers have
been prepared by the co-condensation of AB2 macromonomers in presence of DCC and
DPTS [19]. The AB2-type macromonomers have been condensed into long chain
branched poly(Lactide)s at room temperature using DCC and DPTS [20].
Surprisingly, little attention has been paid to polyesterification methods for the synthesis
of PLLA. Akutsu et al studied the effect of condensing agents, such as 1, 1-carbonyl-
diimidazole, N, N, N’, N’-tetramethylchloroformamidium chloride and N, N’-
dicyclohexylcarbodiimide / 4-dimethylaminopyridine in direct polyesterification of LA [21].
Aqueous solution of LA was first azeotropically distilled followed by polyesterification at
room temperature for 24 hours. PLLA with a maximum Mn of 15,000 was produced.
Neither the nature of starting oligomers nor the presence of terminal N-acyl urea groups
was reported.
A direct polyesterification method for synthesizing PLLA has certain advantages. Direct
polyesterification can be used to synthesize model polymers of LA or copolymers with
other naturally occurring α, ω- hydroxyl carboxylic acids. Such copolymerization
reactions are not possible with cyclic lactides. Furthermore, room temperature
polyesterification is free of complications, such as, trans-esterification, cyclization and
racemization normally observed in high temperature polymerization processes.
Moreover, this reaction is insensitive to traces of moisture.
In view of above, we undertook a careful study of polyesterification of well characterized
LA oligomers to high molecular weight PLLA using DIPC/DPTS system. A 1:1 adduct,
namely 4-(dimethylamino)-pyridinium-p-toluene sulfonate (DPTS) was prepared using a
mixture of a strongly basic, super-acylation catalyst, 4-(dimethylamino)-pyridine (DMAP)
and a strongly acidic (protonic) catalyst p-toluene sulfonic acid (PTSA). The diisopropyl
urea by-product derived from DIPC is claimed to be non-toxic and FDA approved [22].
The objective of the present study was to explore the scope of this reaction and to
assess the importance of N-acyl urea formation during this reaction.
Materials and Methods
Materials. L (+) -Lactic acid was obtained from Purac, USA as 88 % (w/w) aqueous
solution and was used without further purification. Tetraphenyltin and 4-
dimethylaminopyridine (DMAP) were obtained from Aldrich, USA and used as such. p-
Toluene sulfonic acid (PTSA) obtained from Aldrich, USA was dried azeotropically using
benzene and recrystallized from petroleum ether. Benzene, p-xylene, dichloromethane
(DCM), ethylene dichloride (EDC), chlorobenzene and toluene were obtained from
Aldrich, USA. EDC and chlorobenzene were dried over CaH2, whereas, toluene was
dried over metallic sodium. Diisopropyl carbodiimide (DIPC) was obtained from Aldrich,
USA and was used without further purification. DPTS was synthesized as per reported
procedure [16].
Synthesis of PLLA oligomer [13]
Using a reactor vessel equipped with a Dean and Stark type condenser, 40.2 g of 88 %
L-lactic acid was azeotropically dehydrated using 40 mL of p- xylene for 6 h at the reflux
temperature of the azeotrope. The reaction vessel was cooled to 50°C, tetraphenyltin
(0.0707g) was added followed by heating the reaction mixture slowly to the reflux
temperature (143oC) of the solvent under mild stirring for 15 h. The reaction mixture was
cooled to room temperature and 100 mL of chloroform was added. The resultant
solution was poured into 400 mL of n-hexane for precipitating the oligomer. The
oligomer was collected by filtration and further purified by repeated dissolution and
precipitation. The yield of the isolated oligomer was 97%. Mn, Mw and polydispersity of
the obtained oligomer was 900, 2100 and 2.3, respectively, as determined by SEC. The
Mn determined by VPO was 1200. In the 13C spectrum of PLA oligomer (Figure 1), the
peaks appearing at 169.4 to 169.9 ppm are due to ester carbonyl groups and at 173.0
to 173.4 ppm are due to carboxylic acid end functional group. The DPn was estimated
based on the relative integral ratio of these signals. Reproducibility was established
using two consecutive NMR experiments [23]. The value of Mn and degree of
polymerization (DPn) were calculated independently from 13C NMR and was found to be
1100 and 15 respectively (Figure 1). Carboxylic acid equivalent of PLLA was also
determined using quantitative 13C NMR and found to be 0.909 meq/g, which
corresponds to an average of one equivalent of carboxylic group per chain of the
oligomer. The rotation of PLLA oligomer (1g/dl in CHCl3) was measured at 20 oC and
was found to be -157o (98-100% optical purity). The Tg and Tm as determined by DSC
were 44 and 146°C, respectively.
General procedure for polyesterification of PLLA oligomer using DIPC - DPTS
To a glass reactor fitted with septum adaptor, PLLA oligomer, obtained as above and
DPTS were added. To this was added a dry solvent (DCM, EDC, toluene or
chlorobenzene as the case may be) in 10 mL / 100 mg PLLA proportion, followed by
addition of DIPC (1.2 mole equivalent of carboxylic acid present in the PLLA oligomer).
The reaction mixture was stirred for a defined period in the temperature range of 30-
80°C. After completion of the reaction, the viscous solution was diluted with
dichloromethane and the byproduct DIPC-urea filtered off. The organic layer was
washed with a 10 wt% solution of aqueous acetic acid followed by two washings with
distilled water, dried over MgSO4 and evaporated in vaccuo. The product (a white solid)
was further purified by dissolution in CH2Cl2, and precipitating from petroleum ether
[20]. The polymer was characterized by SEC and VPO for weight average and number
average molecular weights, respectively.
Analysis
Molecular weights (Mn and Mw) and polydispersity were determined with respect to
polystyrene standards by SEC on a Waters 150 C machine at 25°C by eluting PLLA
solutions (10 mg/ mL in CHCl3) with toluene as internal standard, through a series of μ-
Styragel columns (30 cm length) of pore sizes 105, 104, 103, 500, and 100 A°,
respectively. Chloroform was used as the mobile phase (flow rate 1 mL/ min) and a
refractive index detector was used for detection. Number average molecular weight was
determined using a Knauer K-7000 Vapor Pressure Osmometer. Samples for 1 H NMR
were prepared in chloroform-d in 5 mm dia NMR tubes at room temperature. The
sample concentration for 13C NMR measurements was 10 % by weight. Proton
decoupled 13C NMR spectra with NOE were recorded on a Bruker DRX 500 MHz NMR
spectrometer working at 125.577 MHz for Carbon-13. 13C-NMR spectroscopy was also
performed on the Bruker DRX 500 MHz NMR spectrometer in 10 mm o.d. sample tubes.
CDCl3 served as solvent and TMS as internal standard for all 13C-NMR measurements.
Relative peak areas were proportional to the number of carbon atoms. Peak areas were
calculated by deconvolution method using WIN-NMR software.
MALDI-TOF MS analysis was performed on a Kratos Kompact MALDI -IV spectrometer
equipped with 0.7 m linear and 1.4 m reflection flight tubes as well as 337 nm nitrogen
LASER of pulse width 3 ns. All experiments were carried out at an accelerating potential
of 20 kV. In general, mass spectra from 200 shots were accumulated to produce a final
spectrum. The samples were dissolved in tetrahydrofuran (1 mg/ mL) and mixed with the
matrix (15 mg/ mL of THF) before drying on the sample plate. 2, 4, 6-
trihydroxyacetophenone (THAP) was used as the matrix. The sample plate was inserted
into the apparatus under high vacuum (~ 10 –5 Pa).
Results and Discussion
Polyesterification reaction of PLLA oligomer using DIPC - DPTS
PLLA oligomer prepared by a procedure reported earlier [13] was subjected to
polyesterification using DIPC-DPTS in DCM solvent at 30°C to establish the initial
feasibility of the reaction. The results are shown in Table 1.
The carboxyl group equivalent: DPTS: DIPC for the PLLA oligomer was 1:1:1(entry no.
1) and 1:0.1:1.2 (entry nos. 2 to 26, Table 1). It was found that 1.2 equivalent of DIPC
with respect to the carboxyl-equivalent of the oligomer gave best results. This ratio was
used in all subsequent experiments. Chlorinated and aromatic solvents were used with
a view to achieve different reaction temperatures. Several catalyst concentrations were
also examined.
Reaction in DCM at room temperature and reduced DPTS concentration (0.1 equivalent)
resulted in high molecular weight PLLA (Mn = 45,600, entry no. 4, Table 1). The reaction
is favored by lowering of the solvation efficiency of the solvent. The weakly solvated
oligomer, either in, monomeric or dimeric form exhibits higher reactivity.
Reaction at 30 °C resulted in highest observed molecular weights (Mn = 45,600 entry
no.4, Table 1). Mn tends to decrease at higher reaction temperature. It was observed
that molecular weight leveled off after a certain period of time in all solvents and at all
temperatures. Polyesterification (activated acylation) involves a number of equilibria
between conjugate protonic acid-base pairs. Therefore, a non-polar aprotic solvent
should be most suitable since it will not interfere with these equilibria, either, by acting
as proton donor or acceptor [24]. Non-polarity and low dielectric constant are also
important to ensure that the ion-pairs are tightly caged. Reduction in DPTS
concentration from a stoichiometric equivalent to 0.1 equivalent resulted in higher
molecular weights of the resulting polymers. A similar observation was made by Moore
and Stupp who reported that DTPS is very effective in low concentrations [16].
Both DMAP and PTSA play a crucial role in this acylation mechanism as shown in
Scheme 1[16]. DMAP forms adducts with different protonated intermediate species,
thereby, accelerating the conversion of O-acyl urea to alkyl urea and the ester as well as
acylation by the anhydride once that is formed. On the other hand, PTSA causes a
depression of an important side reaction, namely, conversion of the O-acyl urea to an N-
acyl urea, which does not take part in the final acylation. This conversion is
thermodynamically facile, particularly, in a weakly acidic system. The conversion of O-
acyl urea to N-acyl urea needs migration of the lone pair of the imine nitrogen to the
carbonyl carbon. But the spatial disposition of the lone pair is away from the carbon; so
a rotational inversion of the already existing C-N double bond is necessary. A weak acid
causes a protonation-deprotonation equilibrium with the basic imine nitrogen, such that
sp3 character of the C-N double bond increases. This renders rotation around the C-N
bond more facile and the rearrangement easier.
However, in presence of a strong acid like p-toluene sulfonic acid (PTSA) the nitrogen of
the DMAP is cationated, whereas the nitrogen of the carbodiimide is protonated.
Therefore, the rearrangement is inhibited. A 1:1 molar ratio of DMAP and PTSA has
been found to be the best catalyst composition [16].
The effect of variation of DMAP and PTSA with respect to DPTS was studied and the
results are shown in Table 2. The results show that a small excess of DMAP along
with DPTS (entry no.1 to 4) caused a reduction in the molecular weights ( compare with
entry no.2 to 5 in Table 1). An excess of PTSA along with DPTS (entry no.5 to 8, Table
2) had little effect on the molecular weight (compare with entry no.2 to 5 in Table 1).
This implies that DMAP causes either degradation or some other side reaction that is
responsible for the reduction of molecular weight. An increase in the concentration of
DMAP relative to PTSA available in DPTS results in the generation of more conjugate
base of PTSA; therefore, less PTSA was available for trapping the O-acyl urea
intermediate by protonation. This, in turn, allows more O-acyl urea to be converted to N-
acyl urea, which did not take part in further reaction. This could be one possible reason
for reduced molecular weights. The reduction of molecular weight due to increase in the
DMAP concentration can be explained based on a degradation mechanism involving
traces of moisture in the system. The DMAP being a very strong base catalyzes
hydrolytic degradation of the PLLA chain. Such side reactions result in many different
types of chains as was evidenced by the emergence of shoulders towards lower
molecular weight regions in the SEC elugrams (Figure 2).
Mn increased up to 12 h after which it levels off (entry no.5, Table 1). This leads to
tailing of peaks and emergence of new peaks in the SEC eluegram, in the lower
molecular weight region, indicating occurrence of more side reactions or hydrolytic
degradation. Emergence of new peaks in the lower molecular weight side of the elugram
was very prominent when an increased amount of DPTS (1.0 equivalent) was used.
Under these conditions the molecular weight achieved was also lower.
MALDI-TOF MS Analysis
The occurrence of lower molecular weight shoulders in the SEC elugram was also
examined further by MALDI-TOF MS. The MALDI-TOF MS of the sample at entry no.1,
Table 1, is shown in Figure 3. The spectrum (Figure 3) is dominated by a series of
intense peaks in the region ranging from 1000 to 3000 Da corresponding to an empirical
formula of (CH3)2CH-NH-CO-N(CH(CH3)2)-(CO-CH(CH3)-O)n-H-----Na+, and formula
weight (72n + 143 +23), where n ranges from 15 to 41. A particular peak at 1318 Da
corresponds to an empirical formula of (CH3)2CH-NH-CO-N(CH(CH3)2)-(CO-CH(CH3)-
O)n-H-----Na+ and formula weight (72n+143+23),where n is 16. The most intense peaks
belonging to this series, corresponding to oligomers with n = 15 to 25 in the region from
1000 to 2000 Da are reported enlarged in Figure 3a. In this region, the MALDI spectrum
of corresponding potassium adducts were also seen (mass = 72n + 143 + 39). There
was another set of peaks in the region ranging from 2000 to 3600 Da are reported in
Figure 3b, which corresponded to an empirical formula (CH3)2N-C5H5N+-(CO-CH(CH3)-
O)-H-----Na+ and formula weight (72n + 122 + 23), where n ranged from 26 to 34.
It is, therefore, evident that in presence of large excess of DMAP, the carboxylic terminal
group of the PLLA chains were largely capped as either N-acylurea derivative or salt of
DMAP, both of which prevented the chain from further growth. Presence of significant
amount of N-acylurea derivative meant that under such conditions PTSA failed to trap
the O-acylurea derivative by protonation. The detrimental effect of DMAP on the
molecular weight is supported by MALDI-TOF spectral evidence. The shoulders in the
SEC elugram of the corresponding sample were also attributed to such end-capped,
low molecular weight PLLA chains.
Conclusions
PLLA with a Mn ~45,000 was obtained by polyesterification of a preformed hydroxyl-
carboxyl telechelic oligomer using diisopropylcarbodiimide as a condensing agent and
DPTS as the activator. It was observed that DPTS prepared from a 1:1 ratio of DMAP
and PTSA when used in low concentration (0.1 equivalents) was most effective. Use of
PTSA in slight excess had little effect on polyesterification; however, use of excess
DMAP caused a reduction in molecular weight. This was attributed to reduced
availability of protons from PTSA for trapping the O-acylurea by protonation and
inhibiting its conversion to N-acylurea. MALDI TOF provided support for this hypothesis.
The effect of solvent on the mechanism of the polyesterification reaction appears more
complicated and warrants further studies.
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Table 1. Polyesterification of Lactic acid oligomersa
Entry
No.
Solvent
DPTS:DIPC
(Mole ratio)
Temp
Time
Mn(SEC)
Mw(SEC)
(°C)
( h)
1
DCM
1:1
30
12
7,500
17,400
2
DCM
0.1:1.2
30
3
18,600
36,200
3
DCM
0.1:1.2
30
6
32,400
49,700
4
DCM
0.1:1.2
30
12
45,600
88,200
5
DCM
0.1:1.2
30
24
39,900
70,100
6
EDC
1:1.2
30
12
13,500
21,400
7
EDC
0.1:1.2
30
3
11,500
29,800
8
EDC
0.1:1.2
30
6
11,900
30,000
9
EDC
0.1:1.2
30
12
15,400
31,200
10
EDC
0.1:1.2
30
24
8,700
24,500
11
EDC
0.1:1.2
45
3
11,400
21,600
12
EDC
0.1:1.2
45
6
15,600
31,900
13
EDC
0.1:1.2
45
12
8,800
23,500
14
EDC
0.1:1.2
45
24
8,000
17,500
15
EDC
0.1:1.2
80
3
8,600
11,500
16
EDC
0.1:1.2
80
6
8,200
11,400
17
EDC
0.1:1.2
80
12
4,800
6,300
18
EDC
0.1:1.2
80
24
1,300
2,700
19
Toluene
0.1:1.2
30
3
9,500
19,600
20
Toluene
0.1:1.2
30
6
12,900
30,300
21
Toluene
0.1:1.2
30
12
13,200
33,100
22
Toluene
0.1:1.2
30
24
13,000
27,500
23
Chlorobenzene
0.1:1.2
30
3
6,500
19,300
24
Chlorobenzene
0.1:1.2
30
6
10,900
25,800
25
Chlorobenzene
0.1:1.2
30
12
11,400
25,600
26
Chlorobenzene
0.1:1.2
30
24
11,700
26,000
a PLLA oligomer carboxyl group equivalent: DPTS: DIPC was 1:1:1(entry no-1) and 1:0.1:1.2 (entry no-2
to 26)
Table 2. Effect of concentration of DMAP and PTSA on the Polyestrification of
Oligomers (DCM,30 °C)
Entry
No.
Mol.Equivalents
(DPTS:DMAP:PTSA)
(mol/mol of oligomer)
Time
(h)
Mn(SEC)
Mw(SEC)
1
0.1:0.05:0
3
4,100
6,600
2
0.1:0.05:0
6
6,400
11,200
3
0.1:0.05:0
12
10,300,
19,000
4
0.1:0.05:0
24
10,100
20,200
5
0.1:0:0.05
3
17,800
32,200
6
0.1:0:0.05
6
26,600
48,300
7
0.1:0:0.05
12
40,100
79,700
8
0.1:0:0.05
24
37,800
68,300
Figure Captions:
Figure 1. Quantitative 13C-NMR (500 MHz) spectrum around carbonyl (ester), carbonyl
(acid) and carbonyl (lactone) areas of PLLA oligomer.
Figure 2. SEC of PLLA from polyesterification reaction: (a) entry no.2 (b) entry no.3 (c)
entry no.4 (d) entry no.5 and (e) entry no.1, Table 1.
Figure 3. MALDI-TOF MS of PLLA sample entry no.1,Table 1 obtained after
polyesterification using DIPC and 1.0 equivalent DPTS, solvent DCM, 30 °C, 12 h. (
entry no.1, Table 1)
Scheme Captions:
Scheme 1. Polyesterification of oligomers of L(+)-lactic Acid
Scheme 1. Polyesterification of oligomers of L(+)-lactic Acid
Figure 1. Quantitative 13C-NMR (500 MHz) spectrum around carbonyl (ester), carbonyl
(acid) and carbonyl (lactone) areas of PLLA oligomer samples
Figure 2. SEC of PLLA from polyesterification reaction: (a) entry no.2 (b) entry no.3 (c)
entry no.4 (d) entry no.5 and (e) entry no.1, Table 1.
Figure 3. MALDI-TOF MS of PLLA sample entry no.1,Table 1 obtained after
polyesterification using DIPC and 1.0 equivalent DPTS, solvent DCM, 30 °C, 12 h. (
entry no.1, Table 1),a: expanded region (1000-2000Da) and b: expanded region (2000-
3500Da)
