Thermally stable and photoreactive polylactides by the terminal conjugation of bio-based caffeic acid

Article abstract of DOI:10.1039/b803615b

Caffeic acid terminally conjugated with polylactide showed high thermal stability and photoreactivity, and may be useful as a functional polylactide in the environmental and medical fields. The Royal Society of Chemistry.

Full text of DOI:10.1039/b803615b

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Thermally stable and photoreactive polylactides by the terminal
conjugation of bio-based caffeic acidw
Tran Hang Thi,ab Michiya Matsusakia and Mitsuru Akashi*a
Received (in Cambridge, UK) 4th March 2008, Accepted 23rd May 2008
First published as an Advance Article on the web 2nd July 2008
DOI: 10.1039/b803615b
Caffeic acid terminally conjugated with polylactide showed high
thermal stability and photoreactivity, and may be useful as a
functional polylactide in the environmental and medical fields.
calculated by the integral of the peak area ratio of the vinylene
proton in DACA, and the C-H proton in PLLA (Table 1). The
1
calculated LLA units from the H-NMR spectra agreed well
with the results from gel permeation chromatography (GPC)
measurements. DACA-PLLAs dissolved in tetrahydrofuran
(THF), chloroform, dichloromethane (DCM) and aprotic
amidic solvents, and their solubilities were identical to that
of a PLLA of the same molecular weight (see ESIw).
Poly-L-lactide (PLLA) has received much interest in recent
years because it is synthesized from renewable resources, is
resorbable in the human body and is nontoxic after biodegra-
dation.1 Therefore, it is expected to have various applications
not only as a biomedical material, but also as a biodegradable
plastic material. Many researchers have reported synthesis of
polylactides by ring-opening polymerization of lactides with
various initiators or catalysts.2 Recently, the copolymerization
of PLLAs with other monomers or polymers such as photo-
reactive cinnamic acid, 4-hydroxycinnamic acid (4HCA) or
PEG has been reported to improve the thermal and mechan-
ical properties, but less the functionalities of PLLA.3 In
previous studies, we reported that coumaric acid derivative
homopolymers and copolymers showed liquid crystal phases,
photoreactivities, degradabilities and cell compatibilities.4 The
bio-based coumaric acid derivative 3,4-dihydroxycinnamic
acid: caffeic acid (DHCA) has photoreactive, biometaboliz-
able and nontoxic properties. We reported that the copoly-
merization of 4HCA with DHCA enhanced its mechanical and
thermal properties.4c Therefore, the modification of PLLA
with DHCA can produce high performance PLLAs applicable
to the environmental and biomedical fields.
The thermal properties of the DACA-PLLAs were analyzed
by DSC and TGA measurements. The melting points (Tm) of
the DACA-PLLAs ranged from 137 1C to 169 1C depending
on the molecular weight, and these values were about 10 1C
higher than for PLLA of the same molecular weight (Table 1
and see ESIw). The crystallization temperatures (Tc) of the
samples were 15 1C higher than for PLLA of the same
molecular weight. Surprisingly, the 10% weight-loss tempera-
tures (T10) of the DACA-PLLAs ranged from 330 1C to
340 1C, which was over 100 1C higher than for PLLA of the
same molecular weight (Fig. 1a). Although this increase in the
Tm and T10 of PLLA via copolymerization with hydrophobic
monomers has been reported,3f,5 to the best of our knowledge,
an extreme increase of over 100 1C to the thermal stability of
PLLA by only terminal conjugation has never been reported.
The detailed mechanism and reason for this phenomenon have
not been clarified yet, but we speculate that one of the reasons
might be the intermolecular stacking interaction of the term-
inal DACA units in DACA-PLLAs.6
In this paper, we report for the first time a novel thermally
stable and photoreactive 3,4-diacetoxycinnamic acid (DACA)-
terminally conjugated PLLA (DACA-PLLA).
The DACA-PLLAs were synthesized according to Scheme
1, and Table 1 shows their synthetic conditions and properties.
3,4-Diacetoxycinnamoyl chloride (DACC) was conjugated to
the terminal hydroxyl group of the PLLAs, and DACA-
PLLAs were obtained. The FT-IR and 1H-NMR spectra
suggested a successful conjugation of DACC to the PLLAs
(see ESIw), and DACA-PLLAs of various molecular weights
were obtained in high yield (Table 1). The composition ratio of
L-lactic acid (LLA) and DACA in the modified PLLAs was
a Department of Applied Chemistry, Graduate School of Engineering,
Osaka University, 2-1 Yamada-oka, Suita 565-0871, Japan. E-mail:
akashi@chem.eng.osaka-u.ac.jp; Fax: +81-6-6879-7359; Tel: +81-
6-6879-7356
b Faculty of Technology of Organic Chemistry, College of Chemistry,
Ministry of Industry, Tien Kien, Lam Thao, Phu Tho, Vietnam
w Electronic supplementary information (ESI) available: Detailed
synthesis and evaluation, by DSC measurements, XRD analyses,
and fluorescent dye conjugation, of PLLAs and DACA-PLLAs.
See DOI: 10.1039/b803615b
Scheme 1 Synthesis of DACA-PLLA.
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Table 1 Synthetic conditions and properties of DACA-PLLAsa
c
c
Mn
Mw/Mn
LLA/
DACAd
(unit)
Yielde
(wt%)
Before
UV
Before
UV
Sampleb
Tmf/1C
137
157
147, 158
168
Tc /1C
T10g/1C
f
After UV
After UV
DACA-PLLA16
DACA-PLLA38
DACA-PLLA49
DACA-PLLA79
DACA-PLLA120
a
1440
2090
3690
6010
8250
3070
3950
5450
11 310
13 200
2.1
2.1
2.8
2.8
1.4
1.6
2.1
2.5
1.9
1.5
16/1
38/1
49/1
79/1
96
92
93
92
93
117
103
107
106
106
b
333
329
333
336
343
120/1
169
The conjugation of DACA into the PLLA end chains was carried out at 0 1C for 2 h, and at room temperature for 24 h. The numbers in the
c
sample names are the unit numbers of LLA. The molecular weights were estimated by GPC in THF with polystyrene standards (UV irradiation
time: 90 min, l 4280 nm, intensity: 56 mW cmꢁ2). The composition ratio of LLA and DACA (LLA/DACA) was estimated by 1H-NMR
d
spectroscopy. The yields present results after the purification. The Tm and Tc were measured by DSC upon a second heating (10 1C minꢁ1), and
e
f
the ‘‘Tc’’ means the crystallization temperature. The 10% weight-loss temperatures, T10, were measured by TGA under nitrogen (20 1C minꢁ1).
g
The crystallinity of the DACA-PLLAs was analyzed by
wide-angle X-ray diffraction (WAXD) (see ESIw). The results
from DACA-PLLAs without annealing showed amorphous
phases. When they were annealed at 100 1C for 1 h, some
peaks were observed at 2y = 15, 16.7, 19.1 and 22.51 (y =
diffraction angle) corresponding to spacings of 5.9, 5.3, 4.6
and 3.9 A, respectively. This is consistent with the peaks at 15,
16, 18.5 and 22.51 reported by Ikada et al.7 Furthermore, DSC
results indicated that DACA-PLLA49 formed a0 + a-phases
and the others formed a-phase with 103 helical chain con-
formation (see ESIw).8 In addition, their crystallization degrees
were above 80%, the same as for PLLAs (see ESIw). Crossed-
polarizing microscopic observations showed that the crystal
domains of the DACA-PLLAs were similar to those of the
PLLAs. These results suggested that the crystallinity of the
PLLAs was maintained after the conjugation of DACA to the
terminal PLLAs.
DACA-PLLAs are expected to be photoreactive because of
the photoreactive terminally-conjugated DACA. The time
dependent UV absorption changes of DACA-PLLA38 dis-
solved in DMF are shown in Fig. 1b. The maximal absorption
peak at lmax = 286 nm decreased with increasing UV irradia-
tion time, and the other DACA-PLLAs and DACA monomer
also showed the same behavior (Fig. 1c). All DACA-PLLAs
showed an approximately 80% conversion after UV irradia-
tion at l 4280 nm for 100 min, the same as the photoreactiv-
ities of DACA, indicating that the terminally conjugated
DACA maintained their photoreactivity. The photoreaction
of DACA at l 4280 nm is known to be a [2+2]
cycloaddition,4c and thus we confirmed the photoreaction of
Fig. 1 (a) TG curves of all PLLAs and DACA-PLLAs at 20 1C minꢁ1; (b) UV absorption change of DACA-PLLA38 in DMF at 0.25 mg mlꢁ1
during UV irradiation at l 4280 nm; (c) maximal absorption (lmax = 286 nm) change of DACA-PLLAs and DACA during UV irradiation at l
4280 nm; and (d) photoreaction scheme of DACA-PLLA by UV irradiation at l 4280 nm.
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dye could be reacted with DACA-PLLA38 to form cyclo-
butane by UV irradiation. These results demonstrated that
DACA-PLLAs are useful as photo-conjugative PLLAs which
can conjugate target molecules containing photoreactive
coumarin groups like DHCA-conjugated Alexa fluor555.
In conclusion, DACA-terminally conjugated PLLAs were
successfully synthesized, and their thermal properties were
significantly improved, especially the T10. However, the crystal-
linities of the PLLAs were well-maintained after the conjuga-
tion of DACA. All DACA-PLLAs showed photoreactivities
related to the terminal DACA, and DHCA-conjugated fluor-
escent dyes were clearly attached onto a DACA-PLLA film by
UV irradiation. DACA-PLLA may be useful as a photoreac-
tive PLLA with high thermal stability for biomedical and
environmental applications. These DACA-PLLAs easily
formed branched copolymers by melt-polycondensation, and
may be interesting as functional biodegradable polymers. The
synthesis and evaluation of branched DACA-PLLA copoly-
mers are now in progress.
This research was supported by an Osaka University 21st
Century COE Program ‘‘Center for Integrated Cell and Tissue
Regulation’’. We acknowledge Prof. H. Uyama of the Depart-
ment of Applied Chemistry, Graduate School of Engineering,
Osaka University for the TGA measurements.
Fig. 2 (a) Schematic illustration of the UV conjugation of a fluor-
escent dye onto a DACA-PLLA38 film; photograph of PLLA36 and
DACA-PLLA38 films in (b, d) phase contrast and (c, e) fluorescence
images after UV irradiation at l 4280 nm for 100 min, respectively.
The UV irradiation was performed with the fluorescent dye and the
films were washed with pure water. The insert in (e) is fluorescence
intensity of the conjugated dye on DACA-PLLA38 film by line
scanning. All scale bars are 100 mm.
Notes and references
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1
DACA-PLLAs by H-NMR measurements before and after
UV irradiation (see ESIw). After the UV irradiation, a new
peak appeared at 4.0–4.2 ppm, suggestive of cyclobutane
formation by intermolecular [2+2] cycloaddition, as shown
in Fig. 1d. The conversion of cyclobutane formation was
calculated at about 77% from the 1H-NMR. The solubility
of all the DACA-PLLAs was not changed after versus before
UV irradiation. When the molecular weight of the DACA-
PLLAs after UV irradiation at l 4280 nm was measured by
GPC, the elution times were earlier (see ESIw) and the
calculated molecular weights were about two-fold higher than
those before UV irradiation (Table 1). In other words, a
dimerization of the PLLA molecules had occurred via the
photoreaction of terminally conjugated DACA.
These photoreactive DACA-PLLAs are expected to have
biomedical applications as photoreactive PLLAs. We per-
formed the photo-conjugation of a fluorescent dye as a model
molecule onto a DACA-PLLA38 film. DHCA-conjugated
Alexa fluor555 (see ESIw) was dissolved in PBS and dropped
onto a DACA-PLLA38 film, and the subsequent UV irradia-
tion was performed at l 4280 nm for 100 min. After the
photoreaction, the film was washed with pure water and
observed by confocal fluorescence scanning microscopy
(Fig. 2). The DACA-PLLA38 film showed a clear fluorescence
image assigned to Alexa fluor555, although the PLLA36 film
itself did not show any fluorescence. The DHCA conjugated
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