Functionalized polyesters from organocatalyzed ROP of gluOCA, the O-carboxyanhydride derived from glutamic acid

Article abstract of DOI:10.1039/b800852c

Well-controlled poly(α-hydroxyacids) featuring pendant carboxylic acid groups were prepared under mild conditions via DMAP-catalyzed ROP of the O-carboxyanhydrides derived from glutamic and lactic acids. The Royal Society of Chemistry.

Full text of DOI:10.1039/b800852c

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Functionalized polyesters from organocatalyzed ROP of gluOCA, the
O-carboxyanhydride derived from glutamic acidw
Olivier Thillaye du Boullay, Colin Bonduelle, Blanca Martin-Vaca* and
Didier Bourissou*
Received (in Cambridge, UK) 16th January 2008, Accepted 19th February 2008
First published as an Advance Article on the web 17th March 2008
DOI: 10.1039/b800852c
Well-controlled poly(a-hydroxyacids) featuring pendant
carboxylic acid groups were prepared under mild conditions
via DMAP-catalyzed ROP of the O-carboxyanhydrides derived
from glutamic and lactic acids.
much faster than that of lactide (typically within a few minutes
at room temperature vs. a few days at 35 1C), and affords PLA
of controlled molecular weights and narrow polydispersities.13
These promising results prompted us to investigate further the
use of O-carboxyanhydrides as activated equivalents of
1,4-dioxane-2,5-diones, and we report here the synthesis,
characterization and polymerization of L-gluOCA, the O-
carboxyanhydride derived from glutamic acid. Well-controlled
homo- and co-polymers featuring pendant carboxylic acid
groups are shown to be accessible under mild conditions via
DMAP-catalyzed ROP.
Over the last three decades, biodegradable synthetic poly-
esters, and especially poly(lactic acid) (PLA), have received
increasing attention as resorbable biomaterials as well as
commodity thermoplastics derived from renewable resources.1
Concomitantly, various systems, including well-defined metal
complexes and organocatalysts, have been developed to pro-
mote the efficient ring-opening polymerization (ROP) of
lactide (the cyclic dimer of lactic acid) under mild conditions
and in a highly controlled fashion.2 Current efforts in this area
are also devoted to the introduction of various pendant groups
on the polymer backbone. Indeed, it is necessary to vary and
finely tune the physico-chemical properties of poly(a-hydro-
xyacids) in order to extend their application further. In this
regard, n-alkyl and phenyl substituents were shown to affect
strongly the glass transition temperature (Tg ranging from ꢀ40
to 90 1C vs. B45 1C for PLA) and degradation rate of poly-
(a-hydroxyacids).3 The introduction of pendant functional
groups is also highly desirable in order to impart hydrophili-
city and to allow post-polymerization derivatization with
biologically relevant compounds.4–11 However, such modula-
tions are so far complicated by the moderate accessibility12
and poor reactivity of the required 1,4-dioxane-2,5-diones.
Indeed, the homo- and co-polymerization of 1,4-dioxane-2,5-
diones 1–35–7 derived from aspartic and glutamic acids (Fig. 1)
do not systematically proceed to high monomer conversion
even under harsh conditions, and the density of pendant
carboxyl groups in the resulting polymers does not exceed
50% (so far, 2, but neither 1 nor 3, could be efficiently
homopolymerized).
The functionalized monomer L-gluOCA was prepared in
two steps from g-benzyl L-glutamic acid (Scheme 1). Diazoti-
zation with sodium nitrite in aqueous acetic acid14 first led to
the corresponding a-hydroxy acid, namely g-benzyl 2-hydro-
xyglutaric acid. Subsequent treatment with dicyclohexylamine
(DCHA) and diphosgene in the presence of polystyrene-sup-
ported diisopropylethylamine (PS-DIEA) afforded L-gluOCA
in 45% overall yield with an optical purity 495% (as deter-
mined by HPLC after derivatization with (+)-a-methylbenzyl
amine).15 L-gluOCA was characterized by elemental analysis,
mass spectrometry, NMR spectroscopy and X-ray diffraction
analysis.z Notably, its five-membered ring adopts a perfectly
planar conformation, whereas more or less flattened boat
arrangements were found for 1,4-dioxane-2,5-diones.7,16
The homopolymerization of L-gluOCA was then investi-
gated with the same organocatalytic system (ROH/DMAP)
than that used previously for the ROP of L-lacOCA.13 Poly-
(L-glu) with degree of polymerization (DP) up to 100 were
prepared under mild conditions (room temperature in dichloro-
methane) using n- or neo-pentanol as initiator (Scheme 2,
Table 1). The reaction times required to achieve complete
conversion of L-gluOCA are similar to those observed for L-
lacOCA,13 meaning that, in marked contrast with that re-
ported for dioxane-diones,5–7 the lateral functional group does
not significantly affect the reactivity of OCAs. Notably, the
molecular weights (Mn) of the poly(L-glu) samples increase
linearly with the monomer to initiator ratio, and their
In this context, we have recently reported that the ROP of
L-lacOCA (the O-carboxyanhydride derived from lactic acid)
catalyzed by DMAP (4-dimethylaminopyridine) proceeds
´ ´
´
Laboratoire Heterochimie Fondamentale et Appliquee du CNRS
`
(UMR 5069), Equipe )Ligands Bifonctionnels et Polymeres
Biode´gradables*, Universite´ Paul Sabatier, 118 route de Narbonne,
31062 Toulouse Cedex 09, France. E-mail: dbouriss@chimie.-
ups-tlse.fr; Fax: 33 (0)561558204; Tel: 33(0)561557737
w Electronic supplementary information (ESI) available: Experimental
details and characterization data, including crystallographic data for
L-gluOCA. CCDC 674939. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b800852c
Fig. 1 1,4-Dioxane-2,5-diones featuring pendant carboxyl groups
(P = protecting group).
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Scheme 1 Synthesis of L-gluOCA from g-benzyl L-glutamic acid.
Table 1 Polymerization of L-gluOCA with the ROH/DMAP systema
DPb
Mn
Mw/Mn
c
c
Initiator
M0/I0
t/min
Scheme 3 Block and random copolymerization of L-gluOCA and
L-lacOCA.
Neo-PentOH
Neo-PentOH
Neo-PentOH
Neo-PentOH
Neo-PentOH
n-PentOH
n-PentOH
n-PenOH
15
20
50
75
100
10
20
50
o5
o5
5
20
90
o5
o5
5
15
20
52
74
103
9
3000
3500
6300
14 900
18 300
2260
1.16
1.19
1.18
1.14
1.18
1.24
1.25
1.18
Table 2 Block and random copolymerization of L-gluOCA (M) and
L-lacOCA (M0) with the ROH/DMAP systema
21
50
3290
6290
b
c
c
Initiator
M0 : M00 : I0
M : M0
Mn
Mw/Mn
a
Polymerizations in CH2Cl2 at 25 1C with an initiator to catalyst ratio
of 1. In all experiments, conversions were higher than 96%. Calcu-
n-PentOHd
0 : 20 : 1
10 : 0 : 1
1 : 10 : 1
2 : 10 : 1
10 : 10 : 1
45 : 55 : 1
—
1140
2540
1130
1560
2800
11 600
1.24
1.23
1.38
1.33
1.38
1.30
b
1 : 1.9
1 : 10.9
1 : 5.1
1 : 1
lated by relative integration of the corresponding 1H NMR signals
c
(polymer and ester chain end). Obtained from Size Exclusion
Chromatography (in THF) using polystyrene standards.
n-PentOH
n-PentOH
n-PentOH
Neo-PentOH
a
1 : 1.1
Polymerizations in CH2Cl2 at 25 1C with an initiator to catalyst ratio
b
of 1 : 1. In all experiments, conversions were higher than 96%. Cal-
polydispersities are fairly low (Mw/Mn 1.14–1.25) up to high
culated by relative integration of the corresponding 1H NMR
monomer conversion. In addition, quantitative incorporation
1
of the initiator as an ester chain end was demonstrated by H
c
signals. Obtained from size exclusion chromatography (in THF)
d
using polystyrene standards. Block copolymerisation.
NMR spectroscopy and MALDI-MS spectrometry, and the
formation of perfectly isotactic polymers was indicated by 13
NMR spectroscopy.15
C
Given their similar reactivities toward homopolymerization,
the random copolymerization of L-gluOCA and L-lacOCA
was then considered as a promising route to PLA functiona-
lized with pendant carboxyl groups all along the polymer
backbone. Accordingly, various random copolymers were
synthesised with L-gluOCA : L-lacOCA ratios ranging from
1 : 10 to 1 : 1. In all cases, the monomer composition in the
copolymer was in close agreement with the initial feed
(Table 2). The random character of the polymer was sup-
ported by 13C NMR spectroscopy15 and the conditions used
for the deprotection of the pendant carboxyl groups of the
homopolymer also proved effective for the copolymers. In
After acetylation of the terminal hydroxyl group with acetic
anhydride, the pendant carboxyl groups of poly(L-glu) were
deprotected by hydrogenolysis. The complete removal of the
benzyl protecting groups was deduced from the disappearance
1
of all of the aromatic signals from the H NMR spectrum. In
addition, SEC analyses showed that neither the acetylation
reaction nor the deprotection step affected the polymer
backbone.15
The copolymerization of L-gluOCA and L-lacOCA was then
investigated (Scheme 3). The access to block copolymers was
first studied by successive ROP of both monomers. A PLA
macroinitiator with Mn = 1140 g molꢀ1 and Mw/Mn = 1.24
was prepared by the ROP of 20 equiv. of L-lacOCA initiated
with n-pentanol. Polymerization was then restarted by addi-
tion of 10 equiv. of L-gluOCA to afford a copolymer with
Mn = 2540 g molꢀ1 and Mw/Mn = 1.23 (Table 2). The
formation of the diblock copolymer upon addition of L-
gluOCA is accompanied by the disappearance of the quartet
signal at 4.34 ppm associated with the terminal PLA-CHOH
1
proton in the H NMR spectrum.15
Fig. 2 Conversion of L-gluOCA and L-lacOCA vs. time during
Scheme 2 ROP of L-gluOCA and deprotection of the pendant
carboxyl groups.
random copolymerization.
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addition, the co-polymerisation of L-gluOCA (45 equiv. rela-
tive to neo-pentanol used as initiator) and L-lacOCA (55
equiv.) was monitored in situ by 1H NMR in order to compare
the polymerization rate of both monomers (Fig. 2). Accord-
ingly, the functionalized monomer L-gluOCA proved slightly
more reactive than L-lacOCA (50% conversion being reached
in approximately 8 and 19 min, respectively). This behavior
markedly contrasts with the pronounced deactivation induced
by the introduction of pendant functional groups to the 1,4-
dioxane-2,5-dione core. Indeed, only moderate monomer con-
versions (o30%), resulting in low molecular weight polymers
(Mn o 3000 g molꢀ1), have been reported for the ROP of the
malic acid dimer 1.5 Similar limitations were encountered with
the unsymmetrical monomer 3 derived from glutamic acid:
homopolymerization proceeds with only 29% conversion, and
no more than 14% of the functional monomer is incorporated
upon copolymerization with lactide.7
Simmons and G. L. Baker, Biomacromolecules, 2001, 2, 658; (c) T.
Liu, T. L. Simmons, D. A. Bohnsack, M. E. Mackay, M. R. Smith
III and G. L. Baker, Macromolecules, 2007, 40, 6040; (d) F. Jing,
M. R. Smith III and G. L. Baker, Macromolecules, 2007, 40, 9304.
´
4 (a) X. Lou, C. Detrembleur and R. Jerome, Macromol. Rapid
Commun., 2003, 24, 161; (b) C. K. Williams, Chem. Soc. Rev., 2007,
36, 1573.
5 T. Ouchi and A. Fujino, Makromol. Chem., 1989, 190, 1523.
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molecules, 1988, 21, 3338; (b) Y. Kimura, K. Shirotani, H. Yamane
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K. Kobayashi and Y. Kimura, Int. J. Biol. Macromol., 1999, 25,
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7 W. W. Gerhardt, D. E. Noga, K. I. Hardcastle, A. J. Garcia, D. M.
Collard and M. Weck, Biomacromolecules, 2006, 7, 1735.
8 For hydroxyl-functionalized poly(a-hydroxyacids), see ref. 7 and
(a) J. Y. Yang, J. Yu, H. Z. Pan, Z. W. Gu, W. X. Cao and X. D.
Feng, Chin. J. Polym. Sci., 2001, 19, 509; (b) M. Leemhuis, J. H.
van Steenis, M. J. van Uxem, C. F. van Nostrum and W. E.
Hennink, Eur. J. Org. Chem., 2003, 3344; (c) M. Leemhuis, C. F.
van Nostrum, J. A. W. Kruijtzer, Z. Y. Zhong, M. R. ten Breteler,
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J. van Steenbergen, C. F. van Nostrum and W. E. Hennink,
Macromolecules, 2007, 40, 7208; (e) M. Leemhuis, J. A. W.
Kruijtzer, C. F. vanNostrum and W. E. Hennink, Biomacromole-
cules, 2007, 8, 2943.
9 For 1,4-dioxane-2,5-diones featuring pendant oligo(ethylene
oxide) groups, see: X. Jiang, M. R. Smith III and G. L. Baker,
Macromolecules, 2008, 41, 318.
10 For 1,4-dioxane-2,5-diones derived from D-gluconic acid, see: K.
Marcincinova-Benabdillah, M. Boustta, J. Coudane and M. Vert,
Biomacromolecules, 2001, 2, 1279.
11 Morpholine-diones have also been used to prepare functionalized
poly(ester-amides). For selected references, see: (a) P. J. A. in’t
Veld, P. J. Dijkstra and J. Feijen, Makromol. Chem., 1992, 193,
2713; (b) D. A. Barrera, E. Zylstra, P. T. Lansbury, Jr and R.
Langer, J. Am. Chem. Soc., 1993, 115, 11010; (c) P. J. Dijkstra and
J. Feijen, Macromol. Symp., 2000, 153, 67.
In conclusion, the functionalized O-carboxyanhydride
L-gluOCA exhibits remarkable reactivity compared with re-
lated 1,4-dioxane-2,5-diones. Its DMAP-catalyzed ROP pro-
ceeds under mild conditions and with a high level of control,
giving access to homopolymers as well as block and random
copolymers featuring pendant carboxyl groups.17
We are grateful for the financial support of this work by
Isochem, the CNRS and the Universite Paul Sabatier. C. B.
´
acknowledges the French Ministry of Higher Education and
Research for his PhD grant. We thank H. Gornitzka for his
assistance in the X-ray diffraction analysis of L-gluOCA.
Helpful discussions with J. P. Senet and Y. Robin have been
particularly appreciated.
12 Self-condensation of a-hydroxyacids is practically limited to sym-
metrical volatile dioxane-diones. The preparation of unsymmetri-
cally-substituted monomers by step-by-step condensation of an
a-hydroxy acid and an a-haloacyl halide usually requires carefully-
controlled conditions in order to avoid undesirable oligomeriza-
tion reactions during the final cyclization step.
13 (a) D. Bourissou, O. Thillaye du Boullay, E. Marchal and B.
Martin-Vaca, Int. Pat., WO2006037812, April 13, 2006; (b) O.
Thillaye du Boullay, E. Marchal, B. Martin-Vaca, F. Cossıo and
´
Notes and references
z Crystal data for L-gluOCA. C13H12O6, M = 264.23, orthorhombic,
space group P212121, a = 5.6733(14), b = 7.7930(19), c = 27.552(7)
A, V = 1218.1(5) A3, T = 173(2) K, Z = 4, 4778 reflections collected
(1466 independent, Rint = 0.1047), 172 parameters, R1 [I 4 2s(I)] =
0.0536, wR2 (all data) = 0.1012.
D. Bourissou, J. Am. Chem. Soc., 2006, 128, 16442.
14 S. Deechongkit, S.-L. You and J. W. Kelly, Org. Lett., 2004, 6,
497.
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Ed., 2004, 43, 1078.
2 For general reviews dealing with the preparation of PLA, see: (a)
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G. Lohmeijer and J. L. Hedrick, Chem. Rev., 2007, 107, 5813.
3 For alkyl- and aralkyl-substituted poly(a-hydroxyacids), see: (a)
M. Yin and G. L. Baker, Macromolecules, 1999, 32, 7711; (b) T. L.
15 See ESIw for details.
16 (a) G. J. Van Hummel, S. Harkema, F. E. Kohn and J. Feijen, Acta
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logr., Sect. E., 2005, 61, o898, o901 and o3480.
17 D. Bourissou, O. Thillaye du Boullay and B. Martin-Vaca, Int.
Pat., WO2007113304, October 11, 2007.
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1788 | Chem. Commun., 2008, 1786–1788