Synthesis and characterization of new malolactonate polymers and copolymers for biomedical applications

Article abstract of DOI:10.1021/ma0111257

A new class of malolactonate polymers and copolymers were synthesized, starting from the corresponding lactones, and then characterized. Different lateral groups were selected for these polyesters to achieve a wide range of materials characteristics and possible biological recognition. The monomers were prepared according to two established procedures, which gave rather good overall yields. The polymers were obtained by the anionic ring-opening polymerization of the corresponding four-member ring monomers in the presence of a quaternary ammonium salt as the initiator. Final macromolecular and thermal characteristics were in agreement with the designed monomer structures. Molecular weights in the range 4-20 kDa were obtained, as a result of chain transfer reactions. The prepared polyesters displayed stability up to 200°C, and, when tested in preliminary cell culture experiments, provided indications for future applications in the biomedical field.

Full text of DOI:10.1021/ma0111257

Macromolecules 2002, 35, 1215-1223
1215
Synthesis and Characterization of New Malolactonate Polymers and
Copolymers for Biomedical Applications
Ra n ier i Bizza r r i,† F ed er ica Ch iellin i,† Rober to Sola r o,† Em o Ch iellin i,*,†
Sa n d r in e Ca m m a s-Ma r ion ,‡ a n d P h ilip p e Gu er in ‡
Department of Chemistry and Industrial Chemistry, University of Pisa, via Risorgimento 35,
56126 Pisa, Italy; and Laboratoire de Recherche sur les Polymeres, UMR C7581 CNRS,
Universite´ Paris Val de Marne, 2 a` 4 rue Henry Dunant, 94320 Thiais, France
Received J uly 4, 2001; Revised Manuscript Received October 16, 2001
ABSTRACT: A new class of malolactonate polymers and copolymers were synthesized, starting from
the corresponding lactones, and then characterized. Different lateral groups were selected for these
polyesters to achieve a wide range of materials characteristics and possible biological recognition. The
monomers were prepared according to two established procedures, which gave rather good overall yields.
The polymers were obtained by the anionic ring-opening polymerization of the corresponding four-member
ring monomers in the presence of a quaternary ammonium salt as the initiator. Final macromolecular
and thermal characteristics were in agreement with the designed monomer structures. Molecular weights
in the range 4-20 kDa were obtained, as a result of chain transfer reactions. The prepared polyesters
displayed stability up to 200 °C, and, when tested in preliminary cell culture experiments, provided
indications for future applications in the biomedical field.
In tr od u ction
functionalized to obtain a large set of polymers and
copolymers with different hydrophobic/hydrophilic bal-
ances,14,15 which proved useful for realizing biocompat-
ible devices.16-20 The stereogenic center in the poly-
(malolactonate) chains may be further exploited to tune
the polymer characteristics and bioactivity. Convenient
procedures for the preparation of both malolactone
monomers and the corresponding polymers have been
developed over the last 20 years starting from com-
mercially available natural products.21-23
Following our continued interest in the production of
bioerodible and biodegradable functional polymers for
biomedical applications,24-32 we synthesized and char-
acterized a series of polyesters and copolyesters from
new malolactonate monomers. Functionalization of the
lateral chain of the malic residues was performed
through esterification with readily available alcohols.
Lateral groups were chosen either to make the material
strongly hydrophobic, to target specific biological in vivo
recognition of natural terpene structures, or to provide
a reactive site for further functionalization. Indeed, our
target was the realization of degradable polymers of
high bioactivity which could be used as minor compo-
nents of poly(2-hydroxyethyl methacrylate)-based semi-
interpenetrating networks for tissue engineering appli-
cations. The biological responses of these new materials
will be the subject of a forthcoming paper.33
Bioerodible and biodegradable polymers are recog-
nized as useful materials for many important biomedical
applications. In the drug delivery field, for instance, they
facilitate the excretion of the releasing device after
overall drug depletion, thus also allowing for a prede-
termined release rate, which is frequently controlled by
the polymer degradation pathway.1 In tissue engineer-
ing, a quickly developing branch of biomedicine that
attempts to solve the dramatic problem of tissue loss
or organ failure,2 degradable materials provide polymer
scaffolds where the transplanted cells can remodel their
intrinsic tissue superstructural organization and hence
ultimately lead to the desirable 3D structure and
physiological functionality of a regenerated organ.3,4
However, the use of biodegradable polymers requires
careful investigation into their interaction and compat-
ibility with the human organism, to avoid tissue damage
and immunogenic phenomena due to both the whole
polymeric matrix and its low molecular weight degrada-
tion products.5 To date, natural or artificial polyesters
constitute the most developed class of biomaterials
because of their excellent mechanical properties and
good biocompatibility.6-9 Nevertheless, the strongly
hydrophobic nature and lack of available reactive sites
of most polyesters [poly(lactic acid), poly(glycolic acid),
poly(lactic acid-co-glycolic acid), and poly(ꢀ-caprolac-
tone)] used for bioapplications require special synthetic
methods to realize true biologically activated materi-
als.10,11
Exp er im en ta l Section
Ma ter ia ls. All chemicals were purchased from Aldrich
Chemical Co. THF was dried by distillation over sodium. (R,S)-
Benzyl malolactonate (4i) and malolactone (5) were prepared
according to the original procedure developed by Guerin et
al.21,35
Meth od s. TLC was performed on silica gel 60 F254 (Merck)
with detection by UV light at 254 nm, and either iodine or
hydroxamic acid staining. Flash chromatography: Merck Silica
Gel 60 (230-400 mesh). Liquid chromatography: Merck Silica
Gel 60 (70-230 mesh). FT-IR spectra were recorded on films
or KBr pellets by a Perkin-Elmer 1600 spectrophotometer. 1H/
13C NMR spectra were recorded by either a Varian Gemini
Poly(malic acid) represents an interesting material for
biomedical applications, since it is biocompatible12 and
degrades to nontoxic malic acid under physiological
conditions.13 The side-chain carboxylic groups can be
* Corresponding author. Telephone: international code + 050-
918299. Fax: international code + 050-28438. E-mail: chlmeo@
dcci.unipi.it.
† University of Pisa.
‡ Universite´ Paris Val de Marne.
10.1021/ma0111257 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/18/2002

1216 Bizzarri et al.
Macromolecules, Vol. 35, No. 4, 2002
200 or a Bruker AF 300 spectrometer at room temperature
on sample solution in perdeuterated solvents. Chemical shifts
are referred to tetramethylsilane and expressed in ppm. Peak
multiplicity was denoted by the following: s (singlet), bs (broad
singlet), d (doublet), dd (double doublet), t (triplet), q (quartet),
m (multiplet). SEC analyses were carried out at 25 °C using
a HPLC Perkin-Elmer 10 equipped with a J asco RI detector
and two PL mixed C5 columns connected in series, usingwith
chloroform as the eluent at a flow rate of 1 mL/min. Mono-
dispersed poly(styrene) samples were used as standards.
Differential scanning calorimetry (DSC) analyses were carried
out between -50 and +50 °C at 10 °C/min on 5-10 mg samples
using a Mettler DSC-30 TA4000 system. Glass transition
temperatures were measured from the inflection points in the
thermograms relevant to the second heating cycles. Thermal
gravimetric analyses (TGA) were recorded under dry nitrogen
atmosphere in the 25-590 °C range at 10 °C/min by a Mettler
TG 50 instrument; in every case, only the degradation onsets
are reported.
(R,S)-4-((R,S)-2-Meth yl-4-(p h en ylm eth yl)oxybu tyl)oxy-
ca r bon yl-2-oxeta n on e (4a ). Trifluoroacetic anhydride (3.8
mL, 26 mmol) was added dropwise to a solution of 2-bromo-
1,4-butanedioic acid (4 g, 20 mmol) in anhydrous THF (10 mL)
at 0-5 °C, and the reaction mixture was stirred for 2 h at room
temperature. Volatile compounds were removed under vacuum
and the oily residue was stirred with 1a for 14 h at 45 °C.
The mixture was diluted in ether (60 mL), washed with water
(20 mL) and brine (20 mL), and dried over Na2SO4 for 12 h.
The residue was dissolved in ether (5 mL), water (25 mL) was
added, and the pH was then adjusted to 7.2-7.3 with 2 N
NaOH, while keeping the temperature below 30 °C. CH2Cl2
(60 mL) was added, and the heterogeneous mixture was stirred
at 42 °C for 4 h. The organic phase was washed with water
(100 mL) and brine (100 mL) and dried over Na2SO4 for 12 h.
Solvent evaporation afforded an oily mixture, which was
purified by flash chromatography on silica gel (eluent: hexane/
ethyl acetate 26/10), to give 4a as a transparent oil (1.57 g,
28% on 1a ). FT-IR (liquid film): 1846 (ν(CdO lactone)) and
1746 (ν(CdO ester)) cm-1 1H NMR (CDCl3): 0.95-0.99 (m,
.
2-Meth yl-4-p h en ylm eth yloxy-1-bu ten e. Benzyl chloride
(65.8 g, 520 mmol) was added dropwise to a mixture of
3-methyl-3-buten-1-ol (40 g, 464 mmol), NaOH 50% (200 g,
2500 mmol) and tetrabutylammonium bisulfate (8 g, 23 mmol),
at 40 °C under vigorous stirring. After 4 h, the organic layer
was separated and the acqueous phase was diluted to 700 mL
with pure water and extracted with diethyl ether (3 × 200
mL). The organic phases were collected together, washed with
brine (100 mL), and dried on Na2SO4 overnight. Solvent
evaporation afforded a crude product, which was purified by
distillation (bp 62-64 °C/0.2 mbar), to give pure 2-methyl-4-
phenylmethyloxy-1-butene as a transparent oil (72.8 g, 90%).
FT-IR (liquid film): 1650 (νCdC) and 1104 (νCOC) cm-1. 1H NMR
(CDCl3): 1.76 (s, 3H; CH3), 2.32-2.39 (t, 2H; CH2Cd), 3.56-
3.63 (t, 2H; CH2CH2O), 4.53 (s, 2H; CH2Ph), 4.75 (m, 1H; dCH
cis), 4.79 (m, 1H; dCH trans), and 7.32-7.36 ppm (m, 5H; Ph-
H). 13C NMR (CDCl3): δ ) 22.87 (CH3), 38.05 (CH2Cd), 68.97
(CH2CH2O), 73.10 (CH2-Ph), 111.66 (CH2d), 127.71 (Ph: C4),
127.84 (Ph: C2, C6), 128.53 (Ph: C3, C5), 138.74 (Ph: C1),
and 143.63 ppm (CH3Cd).
3H; CH3), 1.41-1.60 (m, 1H; CHCH2CH2), 1.65-1.82 (m, 1H;
CHCH2CH2), 1.99-2.16 (m, 1H; CHCH3), 3.46-3.62 (dd + m,
3H; CH2CHO + CH2CH2O), 3.70-3.82 (2 dd, 1H; CH2CHO),
4.07-4.15 (m, 2H; CH2OCO), 4.49 (s, 2H; OCH2Ph), 4.80-4.86
(dd, 1H; CHO), and 7.25-7.35 ppm (m, 5 H; Ph-H). 13C NMR
(CDCl3): 16.88 (CH3), 30.10 (CHCH3), 33.30 (CHCH2CH2),
43.60 (CH2CdO), 65.47 (CHO), 67.95 (CH2CH2O), 71.08 (CH2-
OCdO), 73.19 (OCH2Ph), 127.82 (Ph: C2, C4, C6), 128.58
(Ph: C3, C5), 138.52 (Ph: C1), 165.85 (CH2Cd), and 168.29
ppm (CHCdO).
(R,S)-4-(3-Meth yl-2-bu ten -1-yl)oxyca r bon yl-2-oxeta n -
on e (4b). The same procedure used for the 4a synthesis was
adopted for the preparation of 4b. Reagents: 2-bromo-1,4-
butanedioic acid (4 g, 20 mmol), 1b (1.748 g, 20 mmol), and
trifluoroacetic anhydride (3.8 mL, 26.4 mmol). Solvents: THF
(10 mL) and CH2Cl2 (30 mL). Workup after lactonization: the
organic phase was separated, washed with water (2 × 12 mL)
and brine (2 × 12 mL), and dried over Na2SO4 for 12 h. Solvent
evaporation afforded an oily mixture, which was purified by
flash chromatography on silica gel (eluent: hexane/ethyl
acetate 35/10), to give 4b as a transparent oil (1.05 g, 28% on
1b). FT-IR (liquid film): 1846 (ν(CdO lactone)), 1744 (ν(CdO
ester)), and 1676 (ν(CdC)) cm-1. 1H NMR (CDCl3): 1.70-1.75
(2 s, 6 H; CH3), 3.51-3.61 (dd, 1H; CH2CdO), 3.71-3.82 (dd,
1H; CH2CdO), 4.69-4.72 (d, 2H; CH2O), 4.80-4.85 (dd, 1H;
CHO), and 5.37-5.29 (m, 1H, CHd) ppm. 13C NMR (CDCl3):
18.19 (cis-CH3), 25.87 (trans-CH3), 43.56 (CH2CdO), 63.22
(CH2O), 65.47 (CHO), 117.45 (CHd), 141.07 (Cd), 165.92
(CH2CdO), and 168.22 (CHCdO) ppm.
(R,S)-2-Meth yl-4-(p h en ylm eth yloxy)bu ta n -1-ol (1a ). A
1M solution of BH3 in THF (33 mL, 33 mmol) was added
dropwise (30 min) to 2-methyl-4-(phenylmethyloxy)-1-butene
(12.2 g, 69.5 mmol) at 0-10 °C, and the solution was stirred
at room temperature for 2 h. The excess hydride was decom-
posed by adding water (1 mL) at 0-10 °C. After hydrogen
evolution, 3 M NaOH was added (11 mL, 33 mmol) followed
by a dropwise (15 min) addition of 30% H2O2 (10.4 mL, 91
mmol), at a temperature below 10 °C. Stirring was maintained
for further 1.5 h at room temperature. Then, 5% NaHCO3 (100
mL) was added, the organic layer was separated, and the water
phase was extracted with diethyl ether (3 × 100 mL). The
organic phases were collected together, washed with brine (50
mL), and dried on Na2SO2 overnight. Solvent evaporation
afforded a crude product which was purified by distillation (bp
95 °C/0.04 mbar), to give pure 1a as a transparent oil (11.5 g,
84%). FT-IR (liquid film ) 3406 (νOH): 1096 (νCOC(ether)), and
1044 (νCCO(alcohol)) cm-1. 1H NMR (CDCl3): 0.90-0.94 (s, 3H;
CH3), 1.47-1.89 (2m, 3H; CH2CH2CH), 2.75 (bs, 1H; OH),
3.37-3.65 (2 m, 4H; CH2CH2O + CH2OH), 4.52 (s, 2H; CH2-
Ph), and 7.28-7.53 (m, 5H; Ph-H) ppm. 13C NMR (CDCl3):
17.27 (CH3), 34.08 (CH), 34.14 (CHCH2), 68.15 (CH2CH2O),
68.82 (CH2OH), 77.26 (CH2-Ph), 127.82 (Ph: C4), 127.87
(Ph: C2, C6), 128.57 (Ph: C3, C5), and 138.23 (Ph: C1) ppm.
(R,S)-4-(3-Meth yl-3-bu ten -1-yl)oxyca r bon yl-2-oxeta n -
on e (4c). The same procedure used for the 4a synthesis was
adopted for the preparation of 4c. Reagents: 2-bromo-1,4-
butanedioic acid (4 g, 20 mmol), 1c (1.749 g, 20 mmol), and
trifluoroacetic anhydride (3.8 mL, 26.4 mmol). Solvents: THF
(10 mL) and CH2Cl2 (30 mL). Yield: 0.93 g (26%) of 4c as
transparent oil. FT-IR (liquid film): 1848 (ν(CdO lactone)),
1746 (ν(CdO ester)), and 1650 (ν(CdC)) cm-1 1H NMR
.
(CDCl3): 1.75 (s, 3H; CH3), 2.36-2.42 (t, 2H; CH2Cd), 3.51-
3.62 (dd, 1H; CH2CdO), 3.72-3.83 (dd, 1H; CH2CdO), 4.32-
4.39 (t, 2H; CH2O), 4.73 (s, 1H; CHd), and 4.80-4.86 (2H;
CHO + CHd) ppm. 13C NMR (CDCl3): 22.45 (CH3), 36.72
(CH2CCH3), 43.74 (CH2CdO), 64.35 (CH2O), 65.44 (CHO),
113.08 (CH2d), 141.10 (CCH3), 165.85 (CH2CdO), and 168.22
(CHCdO) ppm.
r-Hyd r oxy-ω-m eth yloligo(la ctic a cid ) (1e). Trimethyl-
silyl diazomethane (2.0 M in hexanes, 6 mL, 12 mmol) was
added under vigorous stirring to a solution of oligo(lactic acid)
[MW ) 470] (3.125 g, 6.65 mmol) in methanol (9.2 mL) and
toluene (32.5 mL). The reaction mixture was stirred for 3h at
room temperature. Solvent evaporation afforded a crude
product that was purified by precipitation into cyclohexane,
then dried under reduced pressure. Pure 1e (2.1 g, 62%) was
recovered as a pale yellow oil. 1H NMR (CDCl3): 1.3-1.6 (3H;
CH2CH), 3.7 (s, 3H; CH3O), 4.2-4.4 (1H; CHOH), and 5.0-
5.2 ppm (1H; CHOCdO).
(R,S)-4-(3,7-Dim eth yl-(E)-2,6-octadien -1-yl)oxycar bon yl-
2-oxeta n on e (4d ). The same procedure used for the 4a
synthesis was adopted for the preparation of 4d . Reagents:
2-bromo-1,4-butanedioic acid (2 g, 10 mmol), 1d (1.54 g, 10
mmol), and trifluoroacetic anhydride (1.9 mL, 13.2 mmol).
Solvents: THF (5 mL) and CH2Cl2 (40 mL). Workup after
lactonization: the organic phase was separated, ether (200 mL)
was added, the solution was washed with brine (2 × 100 mL),
and dried over Na2SO4 for 12 h. Solvent evaporation afforded
an oily mixture, which was purified by flash chromatography

Macromolecules, Vol. 35, No. 4, 2002
New Malolactonate Polymers and Copolymers 1217
Ta ble 1. An ion ic P olym er iza tion of â-Ma lola cton a te
on silica gel (eluent: hexane/ethyl acetate 35/10), to give 4b
as a transparent oil (0.318 g, 12% on 1d ). FT-IR (liquid film):
1850 (ν(CdO lactone)), 1746 (ν(CdO ester)), and 1668 (ν(Cd
Mon om er s
a
feed 4i time yield polymer
Tg
C)) cm-1 1H NMR (CDCl3): 1.52-1.72 (3 s, 9 H; CH3), 2.06
.
sample (mol %) (days) (%) 4i (mol %) Mw Mw/Mn (°C)
(m, 4H; CH2Cd), 3.52-3.62 (dd, 1H; CH2CdO), 3.72-3.83 (dd,
1H; CH2CdO), 4.72-4.76 (d, 2H; CH2O), 4.81-4.86 (dd, 1H;
CHO), 5.01-5.06 (m, 1H; OCH2CHd), and 5.30-5.37 (t, 1H;
(CH2)2CHd) ppm. 13C NMR (CDCl3): 16.67 (CH3CCH2), 17.83
(cisCH3CCH3), 25.80 (CH2CH2CH), 26.35 (transCH3CCH3),
39.63 (CH2CH2CH3), 43.60 (CH2CdO), 63.25 (CH2O), 65.47
(CHO), 117.16 (OCH2CH), 123.67 (CH2CH2CH), 132.12 (CH3-
CCH3), 144.34 (CH3CCH2), 165.89 (CH2CdO), and 168.22
(CHCdO) ppm.
p (4b)
p (4c)
p (4d )
p (4e)
p (4f)
0
0
0
0
0
31b
24b
16b
21b
4c
37
28
33
31
91
91
41
71
74
85
62
68
71
73
0
0
0
0
0
11200 1.19
9900 1.15
12800 1.23
6650 1.25
24800 1.70
20900 1.23
3100 1.15
10600 1.43
8800 1.47
6500 1.73
12150 1.80d
16700 1.69d
5350 1.30
5500 1.26
2.1
-13.6
-33.7
36.3
p (4i)
0
8b
0
33.7
1.2
13.6
8.8
42.2
28.3
14.1
27.6
28.0
c(4a )
c(4b)
c(4c)
c(4f)
c(4g)1
c(4g)2
c(4h )1
c(4h )2
55
39
49
79
83
39
94
91
24b
24b
24b
4c
60
42
53
76
85
43
96
94
(R,S)-4-r-(ω-Met h yloxyca r b on yloligo(la ct yl))oxyca r -
bon yl-2-oxeta n on e (4e). Dicyclohexylcarbodiimide (1.1 g,
5.46 mmol) was added to a solution of 1e (2.1 g, 4.2 mmol)
and 5 (0.48 g, 4.2 mmol) in THF (10 mL) at 0 °C, and the
mixture was allowed to warm at room temperature and stirred
for 2 days. The precipitated dicyclohexylurea was filtered off
on Celite. Solvent evaporation afforded a crude mixture that
was dissolved in a minimum of dichloromethane, cooled to 0
°C, and filtered again. Pure 4e (1.6 g, 30%) was recovered as
a clear oil after precipitation in cyclohexane. FT-IR (liquid
4c
4c
8b
8b
a
b
d
On second heating cycle. In bulk. c In THF. Bimodal dis-
tribution.
Ta ble 2. Th er m ogr a vim etr ic An a lysis of th e P r ep a r ed
P olyester s
film): 1850 (ν(CdO lactone)) and 1746 (ν(CdO ester)) cm-1
.
sample
Td (°C)a
∆w1 (%)b
Td (°C)a
∆w2 (%)b
1H NMR (CDCl3): 1.3-1.6 (3H; CH3CH), 3.7-3.8 (5H; CH3O
+ CH2CdO), 4.8 (1H; CH2CHO), and 5.0-5.2 (1H; CH3CHO)
ppm.
1
2
p (4d )
p (4e)
p (4f)
p (4i)
c(4b)
c(4g)2
187
195
225
237
194
258
48 (53)
57
7.5
217
280
250
50
40
80
(R,S)-4-Ch olester yloxyca r bon yl-2-oxeta n on e (4f). The
same procedure used for the 4e synthesis was adopted for the
preparation of 4f. Reagents: dicyclohexylcarbodiimide (2.7 g,
13.1 mmol), 1f (5 g, 12.9 mmol), and 5 (1.5 g, 12.9 mmol).
Reaction time: 2 days. Workup: filtration on Celite afforded
a crude mixture which was purified by liquidi chromatography
(eluent: dichloromethane), to give 4f as a white solid (2.8 g,
45. FT-IR (cast film): 1834 (ν(CdO lactone)) and 1736 (ν(Cd
99
18 (20)
100
238
81
a
b
Degradation onset. Weight loss.
OOCH2), 4.86-4.89 (dd, 1H; CHO), 5.60 (s, 1H; CH2d trans),
and 6.11 (s, 1H; CH2d cis) ppm. 13C NMR (CDCl3): 18.40
(CH3), 43.73 (CH2CdO), 61.96 (CH2OCdOCH), 64.10 (CH2-
OCdOCd), 65.26 (CHO), 126.59 (CH2d), 135.88 (CH3Cd),
165.67 (CH2CdO), 167.21 (dCCdO), and 168.12 (CHCdO)
ppm.
O ester)) cm-1 1H NMR (CDCl3): 0.68 (s, 3H; Chol-CH3-
.
CCHCHCH3), 0.85-2.04 (38 H; Chol-H), 2.33-2.39 (m, 2H;
Chol-CHCH2Cd), 3.55-3.62 (dd, 1H; CH2CdO), 3.74-3.82
(dd, 1H; CH2CdO), 4.70-4.80 (m, 1H; Chol-CHO), 4.81-4.84
(dd, 1H; OdCCH2CHO), and 5.39-5.41 (m, 1H; Chol-CHd)
ppm. 13C NMR (CDCl3): 12.08, 18.93, 19.48, 21.25, 22.78,
23.03, 24.05, 24.50, 27.77, 28.24, 28.43, 32.04, 32.10, 36.00,
36.39, 36.76, 37.05, 38.02, 39.74, 39.91, 42.52, 43.65 (CH2Cd
O), 50.20, 56.35, 56.88, 65.62 (CHCdO), 76.66 (CHO Chol),
118.82, 123.59, 139.12, 165.97 (CH2CdO), and 167.73 (CHCd
O) ppm.
Syn t h esis of P olyest er s. The monomers or comonomer
mixtures were placed in a Schlenk flask, the bottom of which
was previously coated with tetraethylammonium benzoate by
evaporation under vacuum from an ethanol solution (0.14-
0.16 M) of the quaternary ammonium salt. The monomer/
initiator ratio was set to 1000/1. The mixture was stirred under
a nitrogen atmosphere for 4-31 days at 38-42 °C (see Table
2). The prepared polymers were purified by double precipita-
tion in absolute ethanol from concentrated dichloromethane
solutions (1/10 dichloromethane/ethanol volume ratio), and
dried under high vacuum for 12 h prior characterization. FT-
IR and 1H NMR spectral data of the polymers are reported
below.
(R,S)-4-(2-Meth oxyeth yl)oxycar bon yl-2-oxetan on e (4g).
The same procedure used for the 4e synthesis was adopted
for the preparation of 4g. Reagents: dicyclohexylcarbodiimide
(1.92 g, 9.3 mmol), 1g (0.59 g, 7.76 mmol), and 5 (0.9 g, 7.76
mmol). Reaction time: 1 day. Workup: filtration on Celite
afforded a crude mixture which was purified by two consecu-
tive flash chromatography cycles (eluent 1, chloroform/acetone
12/1; eluent 2, acetone/hexane 12/10), to give 4g as a white
wax (0.609 g, 45%). FT-IR (liquid film): 1848 (ν(CdO lactone)),
P oly((R,S)-3-m eth yl-2-bu ten -1-yl m a lola cton a te) [p 4b].
FT-IR (cast film): 1768, 1736, 1675, 1194, 1150, 1068, and
1045 cm-1. 1H NMR (CDCl): 1.67-1.73 (2 s, 6 H; CH3), 2.84-
3.06 (2H; CH2CdO), 4.60-4.63 (d, 2H; CH2O), 5.25-5.32 (t,
1H, CHd), and 5.47 (1H; CHO) ppm.
1
and 1750 (ν(CdO ester)) cm-1. H NMR (CDCl3): δ ) 3.35 (s,
3H; CH3), 3.53-3.63 (dd + m, 3H; CH2CdO + CH3OCH2),
3.73-3.84 (dd, 1H; CH2CdO), 4.33-4.38 (m, 2H; CH2OCdO),
and 4.85-4.90 (dd, 1H; CHO) ppm. 13C NMR (CDCl3): 43.69
(CH2CdO), 59.07 (CH3), 64.16 (CH2OCdO), 65.27 (CHO),
70.00 (CH3OCH2), 165.87 (CH2CdO), and 168.29 (CHCdO)
ppm.
P oly((R,S)-3-m eth yl-3-bu ten -1-yl m a lola cton a te) [p 4c].
FT-IR (cast film): 1763, 1746, 1650, 1197, 1159, 1079, and
1054 cm-1. H NMR (CDCl3): 1.72 (s, 3H; CH3), 2.30-2.36 (t,
1
2H; CH2Cd), 2.97 (1H; CH2CdO), 4.20-4.31 (2H; CH2O),
4.71-4.79 (2 s, 2H; CHd), and 5.47 (1H; CHO) ppm.
(R,S)-4-(2-Meth yleth en oyloxyeth yl)oxyca r bon yl-2-ox-
eta n on e (4h ). The same procedure used for the 4a synthesis
was adopted for the preparation of 4h . Reagents: dicyclohexyl-
carbodiimide (4 g, 19.4 mmol), 1h (2.10 g, 16.2 mmol), and 5
(1.87 g, 16.2 mmol). Reaction time: 5 h. Workup: filtration
on Celite afforded a crude mixture which was purified by
chromatography (eluent: chloroform), followed by flash chro-
matography (eluent: acetone/hexane 10/4), to give 4g as a pale
yellow oil (0.328 g, 17%). FT-IR (liquid film): 1848 (ν(CdO
lactone)), 1750 (ν(CdO ester)), 1720 (ν(CdO methacryl ester)),
and 1638 (ν(CdC)) cm-1. 1H NMR (CDCl3): 1.93 (s, 3H; CH3),
3.60-3.67 (dd, 1H; CH2CdO), 3.76-3.84 (dd, 1H; CH2CdO),
4.39-4.42 (m, 2H; CHCdOOCH2), 4.48-4.51 (m, 2H; CCd
P oly((R,S)-3,7-d im eth yl-(E)-2,6-octa d ien -1-yl m a lola c-
ton a te) [p 4d ]. FT-IR (cast film): 1768, 1752, 1669, 1195,
1164, 1103, and 1054 cm-1. 1H NMR (CDCl3): 1.59-1.67 (3 s,
9 H; CH3), 2.04 (4H; CH2Cd), 2.98 (2H; CH2CdO), 4.63-4.66
(d, 2H; CH2O), 5.05 (1H; OCH2CHd), 5.26-5.33 (t, 1H;
(CH2)2CHd), and 5.46 (1H; CHO) ppm.
P oly((R,S)-r-(ω-m eth yloxyca r bon yloligo(la ctyl)) m a l-
ola cton a te) [p 4e]. FT-IR (cast film): 1754, 1192, 1131, 1092,
and 1054 cm-1 1H NMR (CDCl3): 1.47-1.56 (3H; CH3CH),
.
3.03 (2H; CH2CdO), 3.73 (s, 3H; CH3O), 5.14 (1H; CH3CHO),
and 5.55 (1H; CH2CHO) ppm.

1218 Bizzarri et al.
Macromolecules, Vol. 35, No. 4, 2002
Sch em e 1. Syn th esis of â-Ma lola cton a te Mon om er s
P oly((R,S)-ch olester yl m a lola cton a te) [p 4f]. FT-IR (cast
film): 1749, 1197, 1161, 1076, and 1055 cm-1 1H NMR
(CDCl3): 0.67 (s, 3H; Chol-CH3CCHCHCH3), 0.84-2.03 (38
H; Chol-H), 2.31 (2H; Chol-CHCH2Cd), 3.00 (2H; CH2Cd
O), 4.61 (1H; Chol-CHO), 5.35 (m, 1H; Chol-CHd), and 5.47
(1H; OdCCH2CHO) ppm.
1748, 1163, and 1054 cm-1 1H NMR (CDCl3): (Chol-CH3-
.
.
CCHCHCH3), 0.85-2.09 (Chol-H), 2.30 (Chol-CHCH2Cd),
2.92 (CH2CdO), 4.63 (Chol-CHO), 5.14 (CH2-Ph), 5.34
(Chol-CHd), 5.50 (OdCCH2CHO), and 7.27 (Ph-H) ppm.
P oly((R,S)-(ben zyl m a lola cton a te-co-(R,S)-2-m eth oxy-
eth yl m a lola cton a te) 80:20 a n d 40:60 [c4g1, c4g2]. FT-IR
(cast film): 1751, 1164, and 1054 cm-1. 1H NMR (CDCl3): 3.00
(CH2CdO), 3.31-3.35 (CH3), 3.50-3.55 (CH3OCH2), 4.28 (CH2-
OCdO), 5.13 (CH2-Ph), 5.51 (CHO), and 7.30 (Ph-H) ppm.
P oly((R,S)-b en zyl m a lola ct on a t e-co-(R,S)-2-m et h yl-
eten oyloxyeth yl m a lola cton a te)) 5:95 a n d 10:90 [c4h 1,
P oly((R,S)-p h en ylm eth yl m a lola cton a te) [p 4i]. FT-IR
1
(cast film): 1747, 1211, 1164, 1081, and 1054 cm-1. H NMR
(CDCl3): 2.91 (2H; CH2CdO), 5.10 (s, 2H; OCH2), 5.51-5.53
(1H; CHO), and 7.28 (5H; Ph-H) ppm. 13C NMR (CDCl3):
35.56 (CH2CdO), 67.69 (CH2O), 68.79 (CHO), 128.40 (Ph: C2,
C6), 128.69 (Ph: C3, C5), 128.80 (Ph: C4), 135.21 (Ph: C1),
168.11 (CH2CdO), and 168.29 (CHCdO) ppm.
P oly((R,S)-ben zyl m a lola cton a te-co-(R,S)-2-m eth yl-4-
(p h en ylm eth yl)oxybu tyl m a lola cton a te) 60:40 [c4a ]. FT-
IR (cast film): 1752, 1197, 1164, 1098, and 1054 cm-1. 1H NMR
(CDCl3): 0.91 (CH 3), 1.44 (CHCH 2CH2), 1.65 (CHCH 2CH2),
1.99 (CHCH3), 2.95 (CH2CdO), 3.47 (CH2CH2O), 4.00 (CHCH2-
O), 4.46 (CH2OCH2-Ph), 5.11 (Ph-CH2OCdO), 5.52 (CHO),
and 7.25-7.35 (Ph-H) ppm.
c4h 2]. FT-IR (cast film): 1750, 1640, 1162, and 1052 cm-1
.
1H NMR (CDCl3): 1.89 (CH3), 2.91 (CH2CdO), 4.28 (OCH2CH2),
5.09 (CH2-Ph), 5.51 (CHO + CHd trans, 6.11 (CHd cis), and
7.27 (Ph-H) ppm.
Resu lts a n d Discu ssion s
Syn th esis of Mon om er s. The preparation of the
â-malolactonates was carried out using two different
synthetic methodologies (Scheme 1). The first class of
compounds, 4a -d , and benzyl malolactonate were
synthesized in three steps, according to a well-estab-
lished procedure (aspartic acid route) beginning with
racemic aspartic acid.23,35 In the first step, the R-amino
group of the amino acid was replaced with a bromine
atom. The linear monoterpene side chains were intro-
duced in the second step by reaction of the correspond-
ing monoterpenols 1a -d with activated bromosuccinic
anhydride, which was previously formed through de-
hydration of bromosuccinic acid by trifluoroacetic an-
hydride. The preferential formation (71-74%) of lac-
P oly((R,S)-(ben zyl m a lola cton a te-co-(R,S)-3-m eth yl-2-
bu ten -1-yl m a lola cton a te) 40:60 [c4b]. FT-IR (cast film):
1749, 1675, 1208, 1164, 1103, and 1054 cm-1 1H NMR
.
(CDCl3): 1.67-1.72 (2 s; CH3), 2.95 (CH2CdO), 4.60 (CH2Cd),
5.14 (CH2-Ph), 5.27 (CHd), 5.47 (CHO), and 7.30 (Ph-H)
ppm.
P oly((R,S)-(ben zyl m a lola cton a te-co-(R,S)-3-m eth yl-3-
bu ten -1-yl m a lola cton a te) 50:50 [c4c]. FT-IR (cast film):
1752, 1650, 1198, 1164, 1087, and 1056 cm-1 1H NMR
.
(CDCl3): 1.7 (CH3), 2.2-2.4 (CH2Cd), 2.8-3.1 (CH2CdO),
4.1-4.3 (OCH2CH2), 4.6 (CHd), 4.8 (CHd), 5.0-5.2 (CH2-
Ph), 5.4-5.6 (CHO) and 7.2-7.3 (Ph-H) ppm.
P oly((R,S)-ben zyl m a lola cton a te-co-(R,S)-ch olester yl
m a lola cton a te) 80:20 [c4f]. FT-IR (cast film: 2950, 2867,
1
tonizable alkyl monoesters 2a -d was confirmed by H

Macromolecules, Vol. 35, No. 4, 2002
New Malolactonate Polymers and Copolymers 1219
Sch em e 2. Syn th esis of â-Ma lola cton a te P olym er s
NMR analysis of the product mixtures, in agreement
with reported results.35 Finally, intramolecular dis-
placement reactions of the â-halocarboxylic acids led to
the formation of lactones 4a -d . Linear terpene alcohols
1b-d were commercially available, whereas 1a was
synthesized from 3-methyl-3-buten-1-ol using a two-step
procedure involving benzylation of the hydroxyl group
followed by hydroboration/oxidation of the alkene link-
age.
the reaction mixtures, by recording the intensity of the
lactone band at 1848 cm-1 at timed intervals. Upon
complete disappearance of this band, the polymerization
experiments were interrupted by the addition of a small
amount of acid and the polymers were recovered by
precipitation in alcoholic solvents. Reaction times ranged
from 4 to 30 days (Table 1). Faster polymerization rates
were recorded in THF rather than in the more viscous
bulk phase, indicating a marked dependence of the
reaction kinetics upon the molecular mobility of the
growing polymeric chains. The higher isolation yields
of p 4f and p 4i as compared with the other homopoly-
mers (Table 1), were attributed to their more compact
hydrophobic side groups, which favored polymer coagu-
lation in protic nonsolvents such as ethanol. Indeed, the
copolyesters of 4i were obtained in almost constant
yields, regardless of the comonomer structure.
The polymer samples, obtained as white amorphous
materials, were soluble at room temperature in polar
aprotic solvent such as DMSO, DMF, acetone, and
chloroform. FT-IR analysis of the polymers showed the
characteristic absorption bands of the two different ester
groups in the 1750-1740, 1190-1160, and 1100-1050
cm-1 spectral regions. Peaks due to the presence of
functional side chains were also observed (Figure 1).
NMR a n d SEC Ch a r a cter iza tion s. The NMR spec-
tra of the polyesters were consistent with their expected
structural features (Figure 2). Neither the rearrangment
of the p 4b-d vinyl bonds, nor thermal oligomerization
of the c4h 1-c4h 2 acrylic side chains were detected,
thus indicating the stability of these groups under the
polymerization conditions and during the workup pro-
cedures.
The second series of monomers 4e-h was synthesized
by direct esterification of malolactone, previously pre-
pared by hydrogenolysis of benzyl malolactonate 4i,
obtained from aspartic acid. This procedure was pre-
ferred over the previous one since the bulkier or less
hydrophobic alkyl groups introduced gave worse results
in the esterification step and in the following workup.
Indeed, this method has been successfully applied to a
number of complex molecules.18,37 It must be noted that
1e was obtained from an oligo(lactic acid) chain by
capping its carboxyl terminus with a methyl group to
avoid competition with the malolactone 5 in the subse-
quent esterification. Spectroscopic characterization of
the synthesized compounds was in agreement with the
proposed structures of the lactone monomers. Overall
yields (referred to the precursor alcohol) ranged from
12 to 45%. The yield was not significantly dependent
on the nature of the side groups, except for 4c, whose
surfactant properties negatively influenced the reaction
work up, and 4h , which contains an acrylic group that
is very reactive toward free-radical polymerization.
Syn th esis of P olym er s. The anionic ring-opening
polymerization and copolymerization of the monomers
(Scheme 2; Table 1) was carried out either in bulk or in
anhydrous THF using tetraethylammonium benzoate
(1‰ in mol) as the initiator. The polymerization tem-
perature was kept in the 38-42 °C range. Lactones
4b-f were homopolymerized, to obtain strongly hydro-
phobic materials. In the copolymerization of 4a -c and
4f-h with 4i, the comonomer ratios were selected to
produce materials with varying degrees of hydrophobic-
ity or, as in the case of 4h , to introduce functionalizable
moieties in the poly(benzyl malolactonate). Monomer 4i
was also homopolymerizated as a reference. The polym-
erization kinetics were monitored by FT-IR analyses of
The presence of a small peak at 6.9 ppm was at-
tributed to terminal fumaric vinyl protons formed by
the main chain-transfer mechanism which affects the
anionic ring opening polymerization of R-unsubstituted
â-lactones.38 Indeed, although the monomer/initiator
ratio was set to obtain final molecular weights of about
105, SEC values were observed to be 1 order of magni-
tude lower (Table 1). It has been reported that high
molecular weights for poly(benzyl malolactonate) can
only be achieved only after three sequential vacuum
distillations of the monomer.35 Therefore, it seems very

1220 Bizzarri et al.
Macromolecules, Vol. 35, No. 4, 2002
F igu r e 1. FT-IR spectra of p 4d .
F igu r e 2. 1H NMR spectra of c4b.
likely that the incidence of chain transfer reactions is
connected with monomer impurities. Unfortunately, the
limited thermal stability of the lactones investigated did
not allow for purification by vacuum distillation. How-
ever, the obtained molecular weights appeared to be
high enough for future medical applications, since the
polymer bioactivity was shown to be only slightly
influenced on the macromolecular length.33 In addition,
from a general viewpoint, lower molecular weights may
allow for faster degradation rates, which for typical poly-
(alkyl malolactonate)s such as poly(benzyl malolacto-
nate) are fairly slow.34 In this regard, it is worth noting
that selective deprotection of the benzyl side groups in
the prepared copolymers should provide materials with
higher hydrophilic characteristics and increased deg-
radation rate under physiological conditions.34
copolymers prepared in THF, where chain-transfer
mechanisms are likely to be more active.
In most cases, the polyesters had a monomodal
molecular weight distribution which, in the case of the
copolymers, suggested a statistical distribution of the
two residues along the chain (Figure 3). This was also
supported by the copolymer composition determined by
1H NMR, which was very close to that of the feed
mixtures (Table 1). Only c4g1 and c4g2 samples
exhibited a bimodal distribution, more marked at the
largest 4g content, thus indicating the preferential
tendency of this monomer to homopropagate (Figure 3).
The presence of one sharp and one broad peak in the
3.28-3.36 ppm range of the copolyester1H NMR spectra
was attributed to the side chain methyl group of
monomeric units in sequence and flanked by 4i units,
respectively (Figure 4).
The polymer molecular weights were not significantly
dependent on the nature of side ester groups, as
determined by SEC analysis (Table 1). Polydispersity
indexes were between 1 and 2, in agreement with a
poorly controlled living anionic polymerization. Higher
polydispersity values were recorded for both homo and
Th er m a l Ch a r a cter iza tion . DSC analysis of the
investigated polymers did not show the presence of
endothermal transitions, thus ruling out the presence
of a crystalline phase. This result must be attributed
to their atactic structures, due to the lack of stereoelec-

Macromolecules, Vol. 35, No. 4, 2002
New Malolactonate Polymers and Copolymers 1221
F igu r e 3. SEC analysis of c4g2 and c4b.
F igu r e 4. 1H NMR of c4g2: enlargement of the 2.5-4.75 ppm region.
tivity in the polymerization process of the racemic
monomers. Indeed, it has been reported that many
isotactic poly(alkyl malolactonate)s obtained from enan-
tiopure monomers are semicrystalline.39-41 All polyes-
ters except p 4f showed well-defined glass transition
temperatures (Table 1). The recorded Tg values spanned
about 80 °C, depending upon the length as well as the
nature of the side groups. For instance, significant
differences were found between the Tg values of p 4d
(-34 °C) and p 4e (36.3 °C), both polyesters containing
long side chains but with different structures. Tg values
computed for c4b (15.4 °C) and c4c (10.2 °C) by the
Couchman-Fox equation42 agreed well with experimen-
tal data, thus substantiating the random character of
these copolymers. Only one Tg was detected for c4g1-
c4g2, indicating that the two different components that
constitute the copolyesters gave rise to a homogeneous
phase in the solid state.
Thermogravimetric analyses of representative poly-
esters and copolyesters were carried out under a nitro-
gen atmosphere in order to verify if the side group
structure affected the stability of the materials (Table

1222 Bizzarri et al.
Macromolecules, Vol. 35, No. 4, 2002
2). The homopolymers with linear lateral chains showed
slightly lower onset degradation temperatures. Samples
p 4d and p 4e showed two degradation steps of compa-
rable size, whereas the bulky p 4f degraded essentially
only above 250 °C. Weight loss values suggested that
the first and second degradation steps of p 4d and p 4e
corresponded to the disruption of the lateral and back-
bone chain, respectively. On the other hand, the first
degradative step of p 4f may tentatively be attributed
to the loss of two methane and one hydrogen molecules
(weight loss ≈ 7.4%). In the last case, a stable conju-
gated structure would be generated in the cholesterol
side group, thus providing the thermodynamic driving
force for the reaction. Copolyesters c4b and c4g1
displayed different thermal behaviors compared to that
of their common parent homopolyester p 4i. The intro-
duction of a second lateral chain of hydrophobic nature
(c4b) led to a decreased thermal stability of the final
material (-30 °C at degradation onset), and a two-step
degradation mechanism, with initial loss of the terpene
group, was evidenced. On the contrary, complete dis-
ruption of more hydrophilic c4g1 occurred in a single
step and at a higher temperature. This suggests that
the chain stability is related to the polarity of mono-
meric units and their ability to form effective inter and
intrachain interactions.
chain structural characteristics. Thermogravimetric
analysis indicated the materials were stable up to 180-
200 °C; degradation pathways usually involved the
preliminary loss of the pendant chain followed by the
backbone disruption.
Our investigation focused essentially on the prepara-
tion of functional poly(alkyl malolactonate)s in an
effective and reproducible way starting from very simple
compounds. Some characteristics of the polymerization
mechanism, such as the tendency of monomer 4g to
homopropagate or the statistical nature of the obtained
polymers, do need further elucidation and experiments
in this perspective are currently underway. It is also
worth noting that the characteristics of the prepared
polymers appear promising for future biomedical ap-
plications, as indicated by preliminary cell culture
tests.33
Ack n ow led gm en t. The partial financial support by
MURST through PRIN 2000 is gratefully acknowl-
edged.Part of the work herewith reported has been
developed within the framework of the E.C. funded
project TATLYS G5RD-CT-2000-0294.
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