Synthesis and organocatalytic ring-opening polymerization of cyclic esters derived from l-malic acid

Article abstract of DOI:10.1021/bm1004355

The synthesis of 3-(S)-[(benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-dione (BMD) and 3,6-(S)-[di(benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-dione (malide) from commercially available l-malic acid is reported. Ring-opening polymerization (ROP) studies of BMD are reported showing that the controlled ROP of this monomer is possible in the absence of transesterification side reactions, despite the presence of side-chain esters, using 1-(3,5- bis(trifluoromethyl)phenyl)-3-cyclohexylthiourea and (-)-sparteine to catalyze the polymerization. The ROP of malide with this system was ineffective. Investigation of the effect of initiating species revealed that the electronic nature of the alcohol had a greater effect on the ultimate molecular weight and hence initiator efficiency than steric considerations. Deprotection of the resultant poly(BMD) using H₂ and Pd/C resulted in hydrophilic poly(glycolic-co-malic acid)s (PGMAs) that were able to undergo autocatalytic degradation in dilute H₂O solution such that complete degradation was observed within 6 days.

Full text of DOI:10.1021/bm1004355

1930
Biomacromolecules 2010, 11, 1930–1939
Synthesis and Organocatalytic Ring-Opening Polymerization of
Cyclic Esters Derived from L-Malic Acid
Ryan J. Pounder and Andrew P. Dove*
Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K.
Received April 21, 2010; Revised Manuscript Received June 29, 2010
The synthesis of 3-(S)-[(benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-dione (BMD) and 3,6-(S)-[di(benzyloxycar-
bonyl)methyl]-1,4-dioxane-2,5-dione (malide) from commercially available L-malic acid is reported. Ring-opening
polymerization (ROP) studies of BMD are reported showing that the controlled ROP of this monomer is possible
in the absence of transesterification side reactions, despite the presence of side-chain esters, using 1-(3,5-
bis(trifluoromethyl)phenyl)-3-cyclohexylthiourea and (-)-sparteine to catalyze the polymerization. The ROP of
malide with this system was ineffective. Investigation of the effect of initiating species revealed that the electronic
nature of the alcohol had a greater effect on the ultimate molecular weight and hence initiator efficiency than
steric considerations. Deprotection of the resultant poly(BMD) using H2 and Pd/C resulted in hydrophilic
poly(glycolic-co-malic acid)s (PGMAs) that were able to undergo autocatalytic degradation in dilute H2O solution
such that complete degradation was observed within 6 days.
is the ROP of functional cyclic ester monomers. ROP of these
monomers can be complicated by reduced polymerization
activity resulting from steric crowding of the esters and
consequently reduced ring strain of the monomers. Furthermore,
protection of pendant functional groups is also generally required
to prevent side reactions during the polymerization. It is
noteworthy that several studies have also focused on the
synthesis and application in ROP of functional ε-caprolac-
tones,21-23 δ-valerolactones,24-28 and ꢀ-propiolactones.29-33
Introduction
Aliphatic poly(ester)s have received great interest over the
past three decades primarily as a consequence of their biocom-
patibility and biodegradability.1-3 Poly(lactide), PLA, has been
an exemplar in this field and, in addition to being derived from
renewable resources, has been utilized in a range of biomedical
applications including controlled drug and gene delivery and
degradable scaffolds for tissue growth.1-7 For many applica-
tions, the ability to tune the physical properties of the PLAs is
highly desirable. PLAs are commonly accessed by either
polycondensation methods or by the ring-opening polymeriza-
tion (ROP) of lactide. While polycondensation allows more
ready access to a wider range of functional polymers, ROP
enables greater levels of control over the molecular character-
istics of the polymers to be attained and the ability to control
molecular weight (including access to high molecular weight
PLAs under milder conditions), tacticity, polydispersity (PDI),
access to block copolymers, and end group fidelity.5,8-10
Consequently, manipulation of the stereochemistry, crystallinity,
and polymer architecture or copolymerization with glycolide,11-15
ε-caprolactone,16-20 or other monomers allows for tailoring of
the polymer degradation rates, cross-linking, and physical
properties. However, PLA and other aliphatic poly(ester)s
including poly(glycolide) (PGA), poly(ε-caprolactone) (PCL),
poly(δ-valerolactone) (PVL), and poly(ꢀ-propiolactone) (PPL)
have limitations resulting from their hydrophobicity. The
potential impact of functionality along the polymer backbone
would enable careful tuning of the polymer properties including
decreased hydrophobicity and the ability to covalently attach
therapeutic molecules.
In order to investigate the potential for the synthesis of a
versatile poly(ester) by ROP, we chose to examine the use of
malic acid (MA, 1). MA is a relatively inexpensive, com-
mercially available R-hydroxy acid equivalent to aspartic acid,
thus possessing a pendant carboxylic acid moiety that would
potentially support a range of functional groups providing a high
level of control over degradation times and physical properties
of the resultant polymers. Previous studies to utilize MA in ROP
include the synthesis of a range of ꢀ-lactones from ring closure
between the hydroxyl group and ꢀ-carboxylic acid. These studies
have resulted in a range of functional ꢀ-malolactones that
through ROP result in a range of functional poly(hydroxyal-
kanoates)s including the highly desirable poly(ꢀ-malic acid)
(PMA).34,35 ROP of six-membered rings derived from MA has
received relatively little attention despite being previously
reported. Kimura et al. reported the synthesis and ROP of 3-(S)-
[(benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-dione (BMD, Fig-
ure 1). ROP of BMD mediated by stannous(II) octanoate
(Sn(Oct)2) resulted in relatively poorly defined poly(ester)s (e.g.,
[M]/[I] ) 100; Mn ) 10 500 g ·mol-1; PDI ) 2.0). Despite this
poor control, BMD and its statistical copolymers with lactide
have received some study, including micelle formation through
self-assembly of an amphiphilic block copolymer with poly-
(ethylene oxide) (PEO).36-39 Ouchi and co-workers also
reported the synthesis of the cyclic diester of MA, 3,6-(S)-
[di(benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-dione (malide,
Figure 1). ROP of malide with different organotin catalysts
between 130 and 220 °C led to polymers with low reactivities
for ROP and unpredictable molecular parameters.40 In both
cases, the relatively poor control compared to that of less
Several synthetic strategies have been considered for the
introduction of functionality in poly(ester)s. Postpolymerization
functionalization provides an attractive possibility, requiring a
single prepolymer to provide many different characteristics;
however, to date, the harsh conditions often applied result in
some polymer degradation. The more commonly reported route
* To whom correspondence should be addressed: Phone: +44 (0)24 7652
4107. Fax: +44 (0)24 7652 4112. E-mail: a.p.dove@warwick.ac.uk.
10.1021/bm1004355
 2010 American Chemical Society
Published on Web 07/22/2010

Ring-Opening Polymerization of Cyclic Esters
Biomacromolecules, Vol. 11, No. 8, 2010 1931
Laboratories PLGel 5 µM, 50 × 7.5 mm) and two mixed D columns
(Varian Polymer Laboratories PLGel 5 µM, 300 × 7.5 mm). The mobile
phase was tetrahydrofuran with 5% triethylamine eluent at a flow rate
of 1.0 mL min-1, and samples were calibrated against Varian Polymer
Laboratories Easi-Vials linear poly(styrene) standards (162-2.4 × 105
g mol-1) using Cirrus v3.3. GPC in aqueous media was conducted on
a system composed of a Varian 390-LC-Multi detector suite fitted with
differential refractive index (DRI), viscometer (VIS), and ultraviolet
(UV) detectors equipped with a guard column (Varian Polymer
Laboratories PL-aquagel-OH Guard 8 µM, 50 × 7.5 mm), two Varian
Polymer Laboratories PL-aquagel-OH 30 8 µM, 300 × 7.5 mm columns
and one Varian Polymer Laboratories PL-aquagel-OH 40 8 µM, 300
× 7.5 mm column. The mobile phase was an aqueous solution
containing 2 L of H2O, 34 g of sodium nitrate, and 3.12 g of sodium
phosphate monobasic dehydrate that was adjusted to pH 8.2 with a 1
M NaOH(aq) solution. The eluent flow rate was 1.0 mL min-1, and
samples were calibrated against Varian Polymer Laboratories Easi-
Figure 1. Cyclic diester monomers 3-(S)-[(benzyloxycarbonyl)methyl]-
1,4-dioxane-2,5-dione BMD (6) and 3,6-(S)-[di(benzyloxycarbonyl)-
methyl]-1,4-dioxane-2,5-dione malide (7) synthesized from malic acid
and 1-(3,5-bis(trifluoromethyl)phenyl)-3-cyclohexylthiourea (8)/(-)-
sparteine organic catalysts.
Vials linear poly(ethylene glycol) standards (106-9.1 × 105 g mol-1
)
using Cirrus v3.3. 1H and 13C NMR spectra were recorded on a Bruker
DPX-300, DPX-400, AC400, or DRX-500 spectrometer at 293 K unless
stated otherwise. Chemical shifts are reported as δ in parts per million
(ppm) and referenced to the chemical shift of the residual solvent
hindered cyclic esters is thought to be a result of transesterifi-
cation reactions. In all cases reported to date, ROP has been
catalyzed by Sn(Oct)2, while that being extensively applied in
ROP is known to readily mediate transesterification reactions
that may therefore limit control over the polymerization.
Several recent advances in ROP catalysis have resulted in
greatly enhanced levels of selectivity for both ring opening of
cyclic esters in preference to transesterification side reactions
and selectivity for preferential ring opening based on the
stereochemistry of the adjacent chiral center.5,41 One of the most
notable examples is the dual component thiourea/amine catalysts
(Figure 1).41,42 These organic molecules exhibit exceptional
selectivity toward ring opening of lactide compared to trans-
esterification of the polymer chain such that, even at very high
monomer conversions and extended reaction times, polydisper-
sities remain e1.07.42,43 We hypothesized that selective and
controlled ROP of malic-acid-based monomers would be
possible using these highly selective catalysts to provide a
potentially versatile platform for the synthesis of poly(ester)s
with pendant ester functionality. Herein we report the improved
synthesis of 3-(S)-[(benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-
dione (BMD) and 3,6-(S)-[di(benzyloxycarbonyl)methyl]-1,4-
dioxane-2,5-dione (malide) from commercially available L-malic
acid and describe the application of organic catalysts to mediate
the controlled ROP of BMD to yield copolymers consisting of
glycolic acid and benzyl R-L-malate units (PBMD).
1
resonances (CDCl3: H δ ) 7.26 ppm; 13C δ ) 77.16 ppm). Mass
spectra were acquired by MALDI-TOF (matrix-assisted laser desorption
and ionization time-of-flight) mass spectrometry using a Bruker
Daltonics Ultraflex II MALDI-TOF mass spectrometer, equipped with
a nitrogen laser delivering 2 ns laser pulses at 337 nm with positive
ion TOF detection performed using an accelerating voltage of 25 kV.
Solutions of trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propyliden-
e]malonitrile (DCTB) as matrix (0.3 µL of a 10 g L-1 acetone solution),
sodium trifluoroacetate as cationization agent (0.3 µL of a 10 g L-1
acetone solution), and analyte (0.3 µL of a 1 g L-1 DCM solution)
were applied sequentially to the target followed by solvent evaporation
to prepare a thin matrix/analyte film. The samples were measured in
reflectron ion mode and calibrated by comparison to 2 × 103 and 5 ×
103 g mol-1 poly(ethylene glycol) standards. Elemental analyses were
performed by Warwick Analytical Services. Phenolphthalein was used
as the pH indicator to monitor the degradation of PBMA in H2O.
Synthesis of 2-[2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic Acid
(2).44 To a mixture of L-malic acid (20 g, 0.15 mol) and 2,2-
dimethoxypropane (74 mL, 0.60 mol) in a Schlenk tube under nitrogen
was added p-toluenesulfonic acid monohydrate (0.29 g, 1.5 mmol), and
the solution was stirred at room temperature for 3.5 h. H2O (100 mL)
containing NaHCO3 (0.13 g, 1.5 mmol) was added to the solution before
the aqueous layer was separated and extracted with DCM (5 × 100
mL). The combined organic layers were dried with NaSO4 and filtered,
and the solvent was removed under reduced pressure. The resulting
solid was recrystallized from Et2O, yielding a white solid (16.89 g, 97
mmol, 65%). Data were in accordance with that previously reported.
1H NMR (CDCl3, 400.0 MHz): δ ) 11.02 (1H, s, -COOH), 4.71 (1H,
Experimental Section
Materials. L-Lactide was purified by recrystallization from dry
dichloromethane and sublimation (×2). Chloroform and (-)-sparteine
were dried over CaH2, distilled, degassed, and stored under a nitrogen
atmosphere. All alcohol and amine initiators were dried over suitable
dry agents and were distilled, degassed, and/or sublimed as required.
Triethylamine, acetone, and benzylamine were dried and stored over 4
Å molecular sieves. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-cyclohexy-
lthiourea (8) was prepared as previously reported.42 Compounds 2-7
and 9-16 were prepared using modified literature procedures.43-51 All
other chemicals and solvents were obtained from Aldrich and used as
received.
General Considerations. All manipulations were performed under
moisture- and oxygen-free conditions either in a nitrogen-filled glovebox
or by standard Schlenk techniques. Gel-permeation chromatography
(GPC) was used to determine the molecular weights and polydispersities
of the synthesized polymers. GPC in THF was conducted on a system
composed of a Varian 390-LC-Multi detector suite fitted with dif-
ferential refractive index (DRI), light scattering (LS), and ultraviolet
(UV) detectors equipped with a guard column (Varian Polymer
3
3
dd, JH-H ) 6.53 Hz, JH-H ) 3.76 Hz, -CHCO-), 3.00 (1H, dd,
2JH-H ) 17.32 Hz, 3JH-H ) 3.76 Hz, -CH2COOH), 2.86 (1H, dd, 2JH-H
3
) 17.31 Hz, JH-H ) 6.53 Hz, -CH2COOH), 1.62 (3H, s, -CH3),
1.57 (3H, s, -CH3). 13C NMR (CDCl3, 100.0 MHz): δ ) 175.1
(-COOH), 171.9 (-COO-), 111.4 (-C(CH3)2), 70.4 (-CHCOO-),
36.0 (-CH2COOH), 26.8 (-CH3), 25.8 (-CH3).
Synthesis of 2-[2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic Acid
Benzyl Ester (3).45 To a solution of 2 (10 g, 61 mmol) in dry acetone
under nitrogen was added dry NEt3 (10.2 mL, 73 mmol) followed by
benzyl bromide (8.9 mL, 75 mmol). The solution was refluxed for 60 h
at 50 °C before being cooled to room temperature. The solids were
removed by filtration and washed with acetone before the volatile
organic solvents were removed under reduced pressure. The resulting
residue was dissolved in EtOAc (300 mL) and H2O (150 mL). The
aqueous layer was further extracted with EtOAc (2 × 100 mL) before
the combined organic layers were dried with MgSO4, filtered, and
reduced in vacuo. The resultant solid was recrystallized from Et2O to

1932 Biomacromolecules, Vol. 11, No. 8, 2010
Pounder and Dove
yield white crystals (12.14 g, 46 mmol, 80%). Data were in accordance
to reflux for 50 h, with the resulting water formed continuously removed
via Dean-Stark apparatus. The solution was then concentrated in vacuo
and the resulting crude solid purified by column chromatography (3:1
hexane/EtOAc) followed by washing with diethyl ether to yield a white
solid (1.57 g, 3.8 mmol, 30%). Data were in accordance with that
previously reported. 1H NMR (CDCl3, 400.0 MHz): δ ) 7.37 (5H, m,
with that previously reported. 1H NMR (CDCl3, 400.0 MHz): δ ) 7.36
3
(5H, m, -CHaromatic), 5.18 (2H, d, JH-H ) 2.01 Hz, -CH2Ar), 4.74
3
3
(1H, dd, JH-H ) 6.53 Hz, JH-H ) 3.77 Hz, -CHCOO-), 2.98 (1H,
dd, 2JH-H ) 16.94 Hz, 3JH-H ) 3.77 Hz, -CH2COOCH2Ar), 2.84 (1H,
dd, 2JH-H ) 16.81 Hz, 3JH-H ) 6.52 Hz, -CH2COOCH2Ar), 1.58 (3H,
s, -CH3), 1.56 (3H, s, -CH3). 13C{1H} NMR (CDCl3, 100.0 MHz): δ
) 169.1 (-COO-), 135.3 (-Cipso-aromatic), 128.6 (-CHmeta-aromatic), 128.5
(-CHpara-aromatic), 128.4 (-CHortho-aromatic), 111.2 (-C(CH3)2), 70.7
(-CHCOO-), 67.0 (-CH2Ar), 36.3 (-CH2COOCH2Ar), 26.7 (-CH3),
25.9 (-CH3).
3
3
-CHaromatic), 5.45 (1H, dd, JH-H ) 4.86 Hz, JH-H ) 3.27 Hz,
-CHCOO-), 5.19 (2H, d, 3JH-H ) 2.00 Hz, -CH2Ar), 3.23 (1H, dd,
3
2JH-H ) 17.48 Hz, JH-H ) 4.86 Hz, -CH2COOCH2Ar), 3.07 (1H,
dd, 2JH-H ) 17.57 Hz, 3JH-H ) 6.73 Hz, -CH2COOCH2Ar). 13C{1H}
NMR (CDCl3, 100.0 MHz): δ ) 168.5 (-CHCOOCH-), 164.9
(-CH2COOCH2Ar), 135.0 (-Cipso-aromatic), 128.7 (-CHmeta-aromatic), 128.6
(-CHpara-aromatic), 128.4 (-CHortho-aromatic), 72.6 (-CHCOO-), 67.5
(-CH2Ar), 35.7 (-CH2COOCH2Ar).
Synthesis of 2-Hydroxysuccinic Acid 4-Benzyl Ester (4).46
A
solution of 3 (20.47 g, 77 mmol) was dissolved in AcOH/THF/H2O
(1:1:1) (300 mL) and heated for 24 h at 40 °C. The solvent was removed
under reduced pressure, and the resulting colorless oil was freeze-dried
to yield a white solid (16.02 g, 72 mmol, 92%). Data were in accordance
with that previously reported. 1H NMR (CDCl3, 400.0 MHz): δ ) 7.35
General Procedure for Polymerization of 6 ([M]/[I] ) 20). A
solution of 8 (0.01 g, 0.027 mmol, 25 mol %), (-)-sparteine (0.99 µL,
0.004 mmol, 5 mol %), and initiator (0.0044 mmol, 1 equiv) was added
to 6 (23 mg, 0.087 mmol, 20 equiv) in CHCl3 (0.3 mL). The solution
was left to stir at room temperature for the allotted time period before
being diluted with DCM (4 mL), washed with cold 2 M HCl(aq) (2 ×
5 mL), and brine (5 mL). The organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The excess thiourea was then
removed by washing with Et2O, and the PBMD was precipitated into
ice-cold petroleum ether (b.p. 40-60 °C) to yield pure PBMD as a
3
(5H, m, -CHaromatic), 5.18 (2H, d, JH-H ) 2.01 Hz, -CH2Ar), 4.58
3
3
(1H, dd, JH-H ) 4.52 Hz, JH-H ) 3.14 Hz, -CHCOO-), 2.99 (1H,
dd, 2JH-H ) 16.94 Hz, 3JH-H ) 4.52 Hz, -CH2COOCH2Ar), 2.90 (1H,
dd, 2JH-H ) 16.69 Hz, 3JH-H ) 6.27 Hz, -CH2COOCH2Ar). 13C{1H}
NMR (CDCl3, 100.0 MHz): δ ) 176.8 (-COOH), 171.0 (-COO-),
135.1 (-Cipso-aromatic), 128.7 (-CHmeta-aromatic), 128.5 (-CHpara-aromatic),
128.4 (-CHortho-aromatic), 67.2 (-CH2Ar), 67.0 (-CHCOO-), 38.2
(-CH2COOCH2Ar).
1
white solid (0.022 g, 0.0042 mmol, 96%). H NMR (CDCl3, 400.0
MHz): δ ) 7.40-7.25 (100H, m, -CHaromatic), 5.65-5.54 (20H, m,
-CHCOO-), 5.15-5.11 (40H, m, -CH2Ar), 4.82-4.49 (40H, m,
-COCH2OCOCH-), 3.83-3.80 (2H, m, -CH2(CH3)3), 3.08-2.85
(40H, m, -CH2COOCH2Ar), 0.92 and 0.89 (9H, s, -CH2(CH3)3). GPC
(THF, RI): Mn (PDI) ) 6750 g mol-1 (1.17) (initiation from 2,2-
dimethyl-1-propanol).
Synthesis of 2-(2-Bromoacetoxy)succinic Acid 4-Benzyl Ester
(5).47 A solution of R-hydroxy acid, 4 (6.6 g, 0.029 mol), and NEt3
(4.1 mL, 29 mmol) in CH2Cl2 (200 mL) was added to a solution of
bromoacetyl bromide (2.56 mL, 29 mmol) and DMAP (0.36 g, 29
mmol) in CH2Cl2 (125 mL) at 0 °C. The resulting solution was stirred
at room temperature for 16 h under a nitrogen atmosphere. The reaction
was then concentrated in vacuo, and the salts were precipitated out
with the addition of Et2O (150 mL). After filtration, the solvent was
evaporated, yielding the product as an orange oil that was used as
obtained without further purification (9.87 g, 29 mmol, 97%). Data
General Procedure for the Deprotection of PBMD ([M]/[I] )
20). A balloon of H2 was bubbled through a suspension of PBMD (0.05
g, 0.0095 mmol) and Pd/C (0.01 g, 10 wt % loading) in THF (20 mL).
The solution was maintained under a H2 atmosphere at 30 °C for 4 h
before being filtered to remove Pd/C and concentrated in vacuo. The
PGMA was extracted into MeOH and concentrated in vacuo to yield
the desired product as a colorless oil (0.024 g, 0.006 mmol, 73%). 1H
NMR (THF-d8, 400.0 MHz): δ ) 5.60 -5.55 (20H, m, -CHCOO-),
4.44 (20H, br s, -COOH), 4.86-4.64 (40H, m, -COCH2OCOCH-),
3.03-2.70 (40H, m, -CH2COOCH2Ar), 0.9 (9H, s, -CH2(CH3)3).
13C{1H} NMR (THF-d8, 100.0 MHz): δ ) 170.6 (-COOCH2C(CH3)3),
1
were in accordance with that previously reported. H NMR (CDCl3,
400.0 MHz): δ ) 7.30-7.19 (5H, m, -CHaromatic), 5.48 (1H, dd, 3JH-H
) 6.53 Hz, 3JH-H ) 3.77 Hz, -HOOCCHOCO-), 5.05 (2H, d, 3JH-H
) 2.01 Hz, -CH2Ar), 3.75 (2H, m, -COCH2Br), 2.94 (2H, dd, 2JH-H
3
) 16.54 Hz, JH-H ) 4.52 Hz, -CH2COOCH2Ar). 13C{1H} NMR
(CDCl3, 100.0 MHz): δ ) 173.3 (-COOH), 168.5 (-CH2COOCH2Ar),
166.2 (-COOCH2Br), 135.0 (-Cipso-aromatic), 128.6 (-CHmeta-aromatic),
128.5 (-CHpara-aromatic), 128.4 (-CHortho-aromatic), 69.0 (-CHCOO-), 66.9
(-CH2Ar), 35.5 (-CH2COOCH2Ar), 24.8 (-COOCH2Br).
168.7
(-CHCOOCH2-),
61.5
167.2
(-CH2COOH),
70.3
36.2
(-CH2COOCHCOO-),
(-CH2COOCHCOO-),
(-CH2COOCH2Ar). GPC (H2O, RI): Mn (PDI) ) 2410 g mol-1 (1.08).
Synthesis of 3-(S)-[(Benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-
dione (6).48 To a vigorously stirred solution of NaHCO3 (0.73 g, 8.7
mmol) in DMF (200 mL) at room temperature was added 5 (2.0 g, 5.8
mmol) in DMF (40 mL) via a syringe pump over 28 h. The solution
was then filtered and the DMF removed in vacuo. The residual salts
were precipitated by addition of EtOAc and filtered before the solution
was concentrated in vacuo. The resulting brown solid was washed with
hexane (200 mL) followed by MeOH (100 mL) before being recrystal-
lized from 2-propanol to yield white needles that were dried over 4 Å
molecular sieves in CH2Cl2 solution (0.84 g, 3.2 mmol, 55%). Data
General Procedure for the Degradation of PGMA ([M]/[I] )
20). PGMA (14.5 mg, 0.0042 mmol) was dissolved in H2O (7.5 mL)
and monitored via acid-base titration of a sample (0.2 mL) with an
aqueous NaOH solution (18.36 mg L-1) using phenolphthalein as a
1
pH indicator, H NMR spectroscopy in D2O, and GPC analysis.
Synthesis of Isopropyl 2-hydroxyacetate (9).50 Glycolic acid (12.5
g, 164 mmol) was dissolved in 2-propanol (50 mL) containing
p-toluenesulfonic acid (0.125 g, 0.657 mmol). The solution was refluxed
overnight in a Soxhlet extractor containing 4 Å molecular sieves. After
cooling, the reaction was poured into 10% Na2CO3 and extracted into
CH2Cl2. The organic layer was washed with brine and dried over
MgSO4. The solution was concentrated in vacuo to yield the desired
product as a colorless oil which was further purified by distillation (60
°C, 0.025 mmHg) (11.3 g, 95.2 mmol, 58%). 1H NMR (CDCl3, 400.0
1
were in accordance with that previously reported. H NMR (CDCl3,
3
400.0 MHz): δ ) 7.32-7.19 (5H, m, -CHaromatic), 5.22 (1H, t, JH-H
) 4.68 Hz, -CHCH2COOCH2Ar), 5.11 (2H, s, -CH2Ar), 5.02-4.88
2
2
(2H, dd, JH-H ) 16.83 Hz, JH-H ) 29.92 Hz, -COOCH2COO-),
3.12 (2H, d, JH-H ) 4.68 Hz, -CHCH2COOCH2Ar). 13C{1H} NMR
3
3
(CDCl3, 100.0 MHz):
δ ) 169.0 (-CHCOOCH2-), 164.7
MHz): δ ) 5.12 (1H, sept, JH-H ) 6.27 Hz, -COOCH(CH3)2), 4.10
3
(-CH2COOCH2Ar), 162.8 (-CH2COOCH-), 134.6 (-Cipso-aromatic),
128.8 (-CHmeta-aromatic), 128.7 (-CHpara-aromatic), 128.4 (-CHortho-aromatic),
72.0 (-CHCOO-), 67.6 (-CH2Ar), 65.5 (-COOCH2COO-), 36.4
(-CH2COOCH2Ar).
(2H, s, -COOCH2OH), 1.27 (6H, d, JH-H
) 6.27 Hz,
-COOCH(CH3)2). 13C{1H} NMR (CDCl3, 100.0 MHz): δ ) 172.9
(-COOCH(CH3)2), 69.5 (-COOCH(CH3)2), 60.8 (-COOCH2OH),
21.8 (-COOCH(CH3)2). ESI-MS: obs, 119.09 m/z; calcd for C5H11O3,
119.14 m/z. Anal. Calcd (Found): C 50.8 (50.85); H 8.5 (8.65).
Synthesis of Neopentyl 2-Hydroxyacetate (11).50 A solution of
glycolic acid (12.5 g, 164 mmol), 2,2-dimethyl-1-propanol (15.9 g, 180
Synthesis of 3,6-(S)-[Di(benzyloxycarbonyl)methyl]-1,4-dioxane-
2,5-dione (7).49 A solution of 4 (5.6 g, 25 mmol) and p-toluenesulfonic
acid monohydrate (0.48 g, 2.5 mmol) in toluene (500 mL) was heated

Ring-Opening Polymerization of Cyclic Esters
Biomacromolecules, Vol. 11, No. 8, 2010 1933
mmol), and p-toluenesulfonic acid (0.125 g, 0.657 mmol) in THF (50
mL) was refluxed overnight in a Soxhlet extractor containing 4 Å
molecular sieves. After cooling, the reaction was poured into 10%
Na2CO3 and extracted into CH2Cl2. The organic layer was washed with
brine and dried over MgSO4. The solution was concentrated in vacuo
to yield the desired product as a colorless oil, which was further purified
(-CHmeta-aromatic), 128.5 (-CHpara-aromatic), 128.4 (-CHortho-aromatic), 69.8
(-COOCH(CH3)2), 68.5 (-CHCOO-), 66.9 (-CH2Ar), 36.2
(-CH2COOCH2Ar), 21.6 (-COOCH(CH3)2), 20.2 (-CHOCOCH3).
ESI-MS: obs, 309.10 m/z ([MH]+); calcd for C16H21O6, 309.13 m/z.
Anal. Calcd (Found): C 62.3 (62.0); H 6.5 (6.7).
Synthesis of 2-Acetoxy-4-(benzyloxy)-4-oxobutanoic Acid (12).51
This compound was synthesized using the same procedure as
described for 13 from 4 (0.61 g, 2.72 mmol) and acetyl chloride (3.0
1
by distillation (60 °C, 0.027 mmHg) (10.2 g, 69.8 mmol, 42%). H
NMR (CDCl3, 400.0 MHz): δ ) 4.18 (2H, s, -COOCH2OH), 3.90
1
(2H, s, -COOCH2C(CH3)3), 0.94 (9H, s, -COOCH2C(CH3)3). 13C{1H}
mL, 42.2 mmol) (0.54 g, 2.03 mmol, 75%). H NMR (CDCl3, 400.0
3
MHz): δ ) 7.36 (5H, m, -CHaromatic), 5.53 (1H, t, JH-H ) 6.01 Hz,
NMR (CDCl3, 100.0 MHz):
δ ) 173.6 (-COOCH2C(CH3)3),
3
-CHCOO-), 5.17 (2H, d, JH-H ) 7.45 Hz, -CH2Ar), 2.95 (2H, d,
74.7 (-COOCH2OH), 60.5 (-COOCH2C(CH3)3), 31.4 (-COOCH2-
C(CH3)3), 26.3 (-COOCH2C(CH3)3). ESI-MS: obs, 147.01 m/z
([MH]+); calcd for C7H15O3, 147.10 m/z. Anal. Calcd (Found): C 57.5
(57.0); H 9.65 (9.8).
3JH-H ) 6.01 Hz, -CH2COOCH2Ar), 2.09 (3H, s, -CHOCOCH3).
13C{1H} NMR (CDCl3, 100.0 MHz): δ ) 175.7 (-COOH), 170.0
(-CH2COOCH2Ar), 169.0 (-CHOCOCH3), 135.3 (-Cipso-aromatic), 128.6
(-CHmeta-aromatic), 128.5 (-CHpara-aromatic), 128.4 (-CHortho-aromatic), 67.8
(-CHCOO-), 67.1 (-CH2Ar), 36.0 (-CH2COOCH2Ar), 20.5 (-CHO-
COCH3). ESI-MS: obs, 289.1 m/z ([MNa]+); calcd for C13H14O6Na,
289.07 m/z. Anal. [M + 1/2H2O] Calcd (Found): C 56.7 (56.4); H 5.5
(5.3).
Synthesis of Isopropyl 2-acetoxyacetate (13).51 A mixture of 9
(0.61 g, 5.16 mmol) and acetyl chloride (1.0 mL, 14.1 mmol) was stirred
at room temperature for 2 h. The resulting solution was reduced under
vacuum before the oily residue was extracted with CH2Cl2 (100 mL).
The combined organic extracts were dried over MgSO4 and concentrated
1
Synthesis of 4-Benzyl 1-neopentyl 2-acetoxysuccinate (16).52 To
a solution of 12 (0.57 g, 2.12 mmol), DMAP (0.026 g, 0.21 mmol),
and 2,2-dimethyl-1-propanol (0.17 g, 1.88 mmol) in CH2Cl2 (25 mL)
was added dropwise a solution of DCC (0.44 g, 2.12 mmol) in CH2Cl2
(25 mL). The resulting solution was stirred at room temperature
overnight. DCU was removed by filtration, and the solution was
concentrated in vacuo. The product was extracted into EtOAc (3 ×
100 mL), filtered, and reduced under vacuum to yield the desired
in vacuo to yield 13 as a colorless oil (0.52 g, 3.25 mmol, 64%). H
3
NMR (CDCl3, 400.0 MHz): δ ) 5.08 (1H, sept, JH-H ) 6.27 Hz,
-COOCH(CH3)2), 4.55 (2H, s, -COOCH2OCOCH3), 2.15 (3H, s,
-COOCH2OCOCH3), 1.26 (6H, d, 3JH-H ) 6.27 Hz, -COOCH(CH3)2).
13C{1H} NMR (CDCl3, 100.0 MHz): δ ) 170.4 (-COOCH2OCOCH3),
167.4 (-COOCH2OCOCH3), 69.3 (-COOCH(CH3)2), 61.0
(-COOCH2OCOCH3),
21.7
(-COOCH(CH3)2),
18.4
(-COOCH2OCOCH3). ESI-MS: obs, 161.21 m/z ([MH]+); calcd for
C7H13O4, 161.08 m/z. Anal. Calcd (Found): C 52.5 (52.2); H 7.55 (7.5).
Synthesis of Neopentyl 2-acetoxyacetate (15).51 This compound
was synthesized using the same procedure as described for 13 using
11 (3.46 g, 23.7 mmol) and acetyl chloride (3.5 mL, 49.2 mmol) (1.87
g, 9.94 mmol, 41%). 1H NMR (CDCl3, 400.0 MHz): δ ) 4.63 (2H, s,
-COOCH2OCOCH3), 3.86 (2H, s, -COOCH2C(CH3)3), 2.16
(3H, s, -COOCH2OCOCH3), 0.93 (9H, s, -COOCH2C(CH3)3).
13C{1H} NMR (CDCl3, 100.0 MHz): δ ) 170.4 (-COOCH2C(CH3)3),
1
product as a brown oil (0.35 g, 1.04 mmol, 49%). H NMR (CDCl3,
400.0 MHz): δ ) 7.33 (5H, m, -CHaromatic), 5.53 (1H, t, 3JH-H ) 6.05
Hz, -CHCOO-), 5.13 (2H, d, 3JH-H ) 7.37 Hz, -CH2Ar), 3.81 (2H,
q, 3JH-H ) 10.38 Hz, -COOCH2C(CH3)3), 2.87 (2H, d, 3JH-H ) 6.05
Hz, -CH2COOCH2Ar), 2.02 (3H, s, -CHOCOCH3), 0.90 (9H, s,
-COOCH2C(CH3)3). 13C{1H} NMR (CDCl3, 100.0 MHz): δ ) 171.4
(-COOCH2C(CH3)3), 169.2 (-CH2COOCH2Ar), 168.9 (-CHOC-
OCH3), 135.4 (-Cipso-aromatic), 128.6 (-CHmeta-aromatic), 128.5
(-CHpara-aromatic), 128.4 (-CHortho-aromatic), 68.3 (-CHCOO-), 66.8
(-CH2Ar), 60.4 (-COOCH2C(CH3)3), 36.5 (-CH2COOCH2Ar), 31.9
(-COOCH2C(CH3)3), 26.3 (-COOCH2C(CH3)3), 20.6 (-CHOC-
OCH3). ESI-MS: obs, 359.1 m/z ([MNa]+); calcd for C18H24O6Na,
359.15 m/z. Anal. Calcd (Found): C 64.3 (64.4); H 7.2 (7.3).
168.0
(-COOCH2OCOCH3),
74.5
(-COOCH2OCOCH3),
60.7 (-COOCH2C(CH3)3), 31.4 (-COOCH2C(CH3)3), 26.3
(-COOCH2C(CH3)3), 20.5 (-COOCH2OCOCH3). ESI-MS: obs, 188.94
m/z ([MH]+); calcd for C9H17O4, 189.11 m/z. Anal. Calcd (Found): C
57.4 (57.3); H 8.6 (8.7).
Synthesis of 4-Benzyl 1-isopropyl 2-hydroxysuccinate (10).50 This
compound was synthesized using the same procedure as described for
9 from 4 (2.5 g, 11.2 mmol), p-toluenesulfonic acid (0.02 g, 0.105
Results and Discussion
Monomer Synthesis. The synthesis of 3-(S)-[(benzyloxy-
carbonyl)methyl]- and 3,6-(S)-[di(benzyloxycarbonyl)methyl]-
1,4-dioxane-2,5-diones (BMD, 6, and malide, 7, respectively)
was achieved via an improved synthesis of ꢀ-benzyl malate from
L-malic acid in three steps (Scheme 1). First, the reaction of
L-malic acid, 1, with 2,2-dimethoxypropane in the presence of
catalytic p-toluenesulfonic acid (pTsOH) resulted in the selective
acetonide protection of the R-hydroxy acid. Subsequent ben-
zylation of the remaining ꢀ-carboxylic acid was achieved by
reaction with benzyl bromide followed by deprotection of the
acetonide group carried out at 40 °C in an AcOH/THF/H2O
(1:1:1) solvent mixture for 24 h to give a 48% yield over three
steps. Coupling of the resultant R-hydroxy acid with bro-
moacetyl bromide and subsequent intramolecular cyclization in
the presence of NaHCO3 through slow addition into DMF
resulted in the isolation of BMD, 6, in a 55% yield (Scheme
1). A pseudo-high dilution cyclization technique was utilized
to reduce the amount of byproduct formed such that significant
predilution of 5 (0.14 M) in DMF before slow injection (0.707
mL h-1) into a NaHCO3/DMF suspension provided a substantial
improvement in yield compared to previous syntheses of this
monomer.36
1
mmol), and 2-propanol (50 mL) (1.51 g, 5.67 mmol, 51%). H NMR
(CDCl3, 400.0 MHz): δ ) 7.35 (5H, m, -CHaromatic), 5.15 (2H, s,
3
-CH2Ar), 5.09 (1H, sept, JH-H ) 6.27 Hz, -COOCH(CH3)2), 4.46
3
3
(1H, dd, JH-H ) 6.03 Hz, JH-H ) 4.51 Hz, -CHCOO-), 2.89 (1H,
dd, 2JH-H ) 16.57 Hz, 3JH-H ) 4.51 Hz, -CH2COOCH2Ar), 2.82 (1H,
dd, 2JH-H ) 16.31 Hz, 3JH-H ) 5.98 Hz, -CH2COOCH2Ar), 1.23 (6H,
2
3
dd, JH-H ) 18.41, Hz, JH-H ) 6.27 Hz, -COOCH(CH3)2). 13C{1H}
NMR (CDCl3, 100.0 MHz): δ ) 172.9 (-COOCH(CH3)2), 170.3
(-CH2COOCH2Ar), 135.5 (-Cipso-aromatic), 128.6 (-CHmeta-aromatic), 128.4
(-CHpara-aromatic), 128.3 (-CHortho-aromatic), 70.1 (-COOCH(CH3)2), 67.3
(-CHCOO-), 66.8 (-CH2Ar), 38.8 (-CH2COOCH2Ar), 21.7
(-COOCH(CH3)2). ESI-MS: obs, 267.04 m/z ([MH]+); calcd for
C14H19O5, 267.12 m/z. Anal. Calcd (Found): C 63.15 (62); H 6.8 (6.8).
Synthesis of 4-Benzyl 1-isopropyl 2-acetoxysuccinate (14).51 This
compound was synthesized using the same procedure as described for
13 from 10 (0.60 g, 2.25 mmol) and acetyl chloride (1.0 mL, 14.1
mmol) (0.53 g, 1.72 mmol, 76%). 1H NMR (CDCl3, 400.0 MHz): δ )
7.35 (5H, m, -CHaromatic), 5.43 (1H, t, 3JH-H ) 6.27 Hz, -CHCOO-),
5.16 (2H, d, 3JH-H ) 5.81 Hz, -CH2Ar), 5.04 (1H, sept, 3JH-H ) 6.27
3
Hz, -COOCH(CH3)2), 2.91 (2H, d, JH-H
)
6.27 Hz,
2
-CH2COOCH2Ar), 2.08 (3H, s, -CHOCOCH3), 1.22 (6H, dd, JH-H
) 15.54, Hz, JH-H ) 6.27 Hz, -COOCH(CH3)2). 13C{1H} NMR
3
The R-hydroxy acid was additionally dimerized in refluxing
toluene with catalytic pTsOH to yield malide, 7 (30%, Scheme
(CDCl3, 100.0 MHz):
(-CH2COOCH2Ar), 168.3 (-CHOCOCH3), 135.4 (-Cipso-aromatic), 128.6
δ ) 170.0 (-COOCH(CH3)2), 169.0

1934 Biomacromolecules, Vol. 11, No. 8, 2010
Pounder and Dove
Scheme 1. Synthesis of 3-(S)-[(Benzyloxycarbonyl)methyl]-1,4-
dioxane-2,5-dione, 6, and 3,6-(S)-[Di(benzyloxycarbonyl)methyl]-
1,4-dioxane-2,5-dione, 7, from L-Malic Acid, 1a
a Conditions: (i) Me2C(OMe)2, pTsOH; (ii) PhCH2Br, NEt3, acetone; (iii)
AcOH, THF/H2O; (iv) BrC(O)CH2Br, NEt3, DMAP, CH2Cl2; (v) NaHCO3,
DMF; (vi) ∆, pTsOH, toluene.
Figure 2. Plot of Mn versus monomer conversion (measured by 1H
NMR spectroscopy) for the ROP of 6 ([M]/[I] ) 50, [6]0 ) 0.32 M)
using 25 mol % of 8 and 5 mol % of (-)-sparteine as cocatalysts and
neopentanol as initiator.
Scheme 2. Ring-Opening Polymerization of 3-(S)-[(Benzyloxycar-
bonyl)methyl]-1,4-dioxane-2,5-dione, 6, Using 1-(3,5-Bis(trifluorom-
ethyl)phenyl)-3-cyclohexylthiourea, 8, and (-)-Sparteine
reaction times led to a decrease in molecular weight and a
broadening of the PDI consistent with the occurrence of
transesterification side reactions. In an attempt to achieve higher
conversions, we first investigated the effect of polymerization
temperature. Raising the temperature to 60 °C resulted in
retardation of the polymerization with only 15% monomer
conversion being observed after 180 min. This observation is
consistent with decreased ring strain of the monomer, resulting
from the increased bulk of the ring substituents, limiting the
exothermicity of the ring-opening process thus leading to ring
opening being preferred at lower temperatures.53,54 Maintaining
the polymerization temperature at 25 °C, we decided to increase
the loading of 8 in an attempt to increase the selectivity for
ROP over transesterification. To this end, employing a 15 mol
% loading of 8 resulted in increased monomer conversions such
that, for a [M]/[I] ) 50, 96% monomer conversion was observed
after 120 min. Furthermore, high levels of control over the
polymerization resulted in a polymer exhibiting Mn ) 9900 g
mol-1 and PDI ) 1.16. A further increase in loading of 8 to 25
mol % resulted in a further decrease in the time required for
high monomer conversions to be achieved such that after only
30 min PBMD with Mn ) 9500 g mol-1 and PDI ) 1.15 was
obtained. Higher loadings of 8 (35+ mol %) increased the rate
of polymerization further but resulted in a small loss of control
with a broadening of PDI attributed to transesterification.
Interestingly, the ROP of 6 is complete approximately 4 times
faster (t ) 30 min, monomer conversion ) 92%) than the ROP
of lactide (t ) 120 min) under identical conditions, possibly a
consequence of the reduced steric demands of the glycolic acid
unit.
1). Again, as with the synthesis of 6, the yield of this final
cyclization step was severely hindered by the formation of
undesired oligomer byproducts and transesterification. Dilute
conditions (0.05 M) were employed in an attempt to increase
the yield; however, this provided no considerable improvement.
Despite the poor yield of the final cyclization step, the overall
synthesis of 7 provides an improvement on previously reported
yields.40
Ring-Opening Polymerization Studies. Attempts to poly-
merize malide, 7, with the thiourea 8/(-)-sparteine system did
not result in the isolation of any polymeric materials, most likely
a consequence of the high steric hindrance and low ring strain
of the monomer.53,54 As such, our efforts were concentrated on
the polymerization of BMD, 6, as the less hindered glycolic
acid unit was postulated to lead to a more facile polymerization.
ROP of 6 catalyzed by 8 and (-)-sparteine using a range of
initiators was initially investigated at 25 °C in CHCl3 solution
(Scheme 2). 1H NMR spectroscopy provided a convenient
method for monitoring the progress of the polymerization by
observation of the reduction of the methylene resonance of the
malate unit of the monomer at δ ) 3.12 ppm and the appearance
of the corresponding broad multiplet at δ ) 3.08-2.85 ppm in
PBMD. Upon completion of the allotted time, polymerizations
were quenched by the removal of (-)-sparteine via a 1 M HCl
wash with removal of 8 by its extraction into Et2O. The
polymers were precipitated into ice-cold petroleum ether (b.p.
40-60 °C).
Investigation of the polymerization control resulted in the
observation of a linear correlation between Mn and monomer
conversion (Figure 2) and between Mn and initial monomer-
to-initiator ratio (Figure 3). However, notably both charts do
not display a zero intercept, which indicates that the rate of
propagation is greater than the rate of initiation. The isolation
of oligomers in attempted single turnover experiments, even in
the presence of a large excess of initiator, further confirms this
hypothesis. Nonetheless, following standard workup, analysis
of a low DP PBMD ([M]/[I] ) 20) with Mn ) 6750 g mol-1
Initial studies investigated the ROP of 6 under conditions
previously reported for lactide ROP, initiating from neopentanol
in the presence of 10 mol % of 8 and 5 mol % of (-)-sparteine
as cocatalysts. At a monomer-to-initiator ratio of 50 ([M]/[I] )
50), the ROP of 6 achieved 79% monomer conversion after
180 min. While analysis of the resultant polymer indicated that
the polymerization was well controlled (Mn ) 7420 g mol-1
;
1
PDI ) 1.17), prolonged reaction times did not lead to increased
and PDI ) 1.17 by H NMR spectroscopy confirmed a DP )
levels of monomer conversion. Indeed exposure to increased
24 polymer based on the integration of the tert-butyl neopentanyl

Ring-Opening Polymerization of Cyclic Esters
Biomacromolecules, Vol. 11, No. 8, 2010 1935
a single distribution centered around m/z ) 5394.0, which
corresponds to a sodium-charged DP20 polymer chain with a
neopentanol end group; a regular spacing equal to the molecular
weight of the repeat unit of 6 (m/z ) 264) demonstrates the
lack of significant transesterification of the polymer chains
(Figure 5).
In an attempt to characterize the two different R-chain groups
and thus enable estimation of the preference for ring opening
at either ester, model compounds 15 and 16 were synthesized
via condensation reaction of glycolic acid or ꢀ-benzyl malate,
4, with neopentanol and subsequent acetylation of the remaining
alcohol group by treatment with acetyl chloride (Scheme 3).
Examination of the 1H NMR spectra of 15 and 16 reveal singlet
resonances at δ ) 0.93 and 0.90 ppm, respectively, providing
a good correlation to those observed on the polymer chain ends
(Figure 6). Integration of the polymer chain end resonances from
three polymer samples reveals approximately a 2:1 ratio
(glycolate/malate opening), which corresponds to a 67 ( 1%
selectivity toward ring opening at the least hindered glycolate
ester of the ring.
Figure 3. Plot of [M]/[I] versus Mn and PDI for ROP of 6 ([6]0 )0.32
M) using 25 mol % of 8 and 5 mol % of (-)-sparteine as cocatalysts
and neopentanol as initiator.
Initiator Versatility. In order to further study the initiator
efficiency, ROP of 6 was initiated from a more sterically
hindered secondary alcohol, specifically 2-propanol. A range
of PBMD with varying [M]/[I] were prepared in a comparable
manner to that previously described, and again, correlation of
the [M]/[I] and monomer conversion with Mn resulted in a linear
relationship with a nonzero intercept. Analysis of the polymers
resonances against those of the main-chain methine protons.
Interestingly, the R-chain end was assigned to two distinctive
singlets at δ ) 0.92 and 0.89 ppm (Figure 4), arising from the
nonselective ring opening of the asymmetric 6 by neopentanol
during the initiation step, clearly demonstrating a notable
electronic difference between the two resultant chain ends.
Further analysis of the polymer by MALDI-TOF MS revealed
1
using H NMR spectroscopy and MALDI-TOF MS analysis
1
Figure 4. H NMR spectrum of PBMD ([M]/[I] ) 20) initiated from neopentanol (400 MHz; CDCl3).
Figure 5. MALDI-TOF MS analysis of a PBMD ([M]/[I] ) 20) initiated from neopentanol.

1936 Biomacromolecules, Vol. 11, No. 8, 2010
Pounder and Dove
Scheme 3. Synthesis of Glycolate and ꢀ-Benzylmalate End
Group Models
distorting the measurement of DP with respect to GPC analysis
of the polymers.
Close analysis of the 1H NMR spectrum of the polymer again
revealed two R-chain end methyl resonances (from the isopropyl
group), a doublet at δ ) 1.24 ppm, and an overlapping doublet
of doublets centered at δ ) 1.21 ppm. Comparison to model
compounds suggested that, as expected, the doublet at δ ) 1.24
ppm results from initial ring opening of a glycolate ester of 6,
whereas the overlapping doublet of doublets arises from ring
opening of the monomer to generate a malate ester with an
adjacent chiral center leading to the inequivalence of the methyl
resonances. Integration of these resonances suggests that initia-
tion from 2-propanol also results in approximately a 69 ( 1%
selectivity toward ring opening at the less hindered carbonyl of
the monomer. While indeed this suggests that the initiator
efficiency relates to the molecular weight of the resultant
polymer, the unchanged distribution of glycolate ester to malate
ester end groups indicates that steric effects may not be the
primary factor determining initiator efficiency. To this end, we
broadened our investigations with respect to initiating alcohol.
Initiation of the ROP of 6 changing only the alcoholic initiator
(Table 2) resulted in a significant spread of polymer molecular
weights. Initiation from benzyl alcohol, ethanol, 1-phenyletha-
nol, and 2-butanol ([M]/[I] ) 20) resulted in PBMD with
confirmed end group fidelity of a PBMD ([M]/[I] ) 20) with
Mn ) 11 020 g mol-1 and PDI ) 1.12, with the major peak at
5366.0 m/z again corresponding to a sodium-charged DP20
polymer chain with an isopropyl R-chain end. Interestingly,
molecular weights of 5920, 8800, 6600, and 13 300 g mol-1
,
1
despite DP (measured by H NMR) again roughly correlating
respectively, and narrow PDIs (Table 2). End group fidelity and
DP of the polymers were confirmed by both MALDI-TOF MS
and 1H NMR spectroscopy. Again, we note that DP (measured
by 1H NMR) remains largely invariant, whereas Mn (measured
by GPC) changes dramatically with different initiators. Notably,
however, these results show that steric hindrance is not the major
contributing factor to correlation of polymer molecular weight
to that predicted from the monomer-to-initiator ratio. Compari-
son of a PBMD initiated from 1-phenylethanol to those initiated
from ethanol and 2-propanol reveals that, despite being the most
sterically hindered, initiation from 1-phenylethanol results in
the polymer with the lowest molecular weight (Mn ) 6600 g
mol-1), presumably a consequence of more efficient initiation
resulting from the electron-deficient nature of the initiator.
to the [M]/[I] ratio, the Mn of each polymer, as determined by
GPC analysis, was higher than that obtained when ROP was
initiated from neopentanol (Table 1). We tentatively postulate
that this discrepancy arises as a consequence of the formation
of low molecular weight impurities, such as cyclic oligomers
occurring within the initiation period, consuming initiating
alcohol but producing low molecular weight species that are
indistinguishable from the polymer by NMR spectroscopy, thus
Further attempts to optimize the initiator efficiency of the
polymerization focused on the synthesis and application of
initiators that were good models for the putative propagating
species. To this end, isopropyl-2-hydroxyacetate, 9, and 4-ben-
zyl-1-isopropyl 2-hydroxysuccinate, 10, were applied to initiate
ROP. Analysis of the resultant polymers by GPC revealed the
lowest molecular weights, correlating most closely to the DP
1
measured by H NMR end group analysis, while maintaining
low polydispersities throughout the polymerization. Poor initia-
tion commonly also leads to a broadening of the PDI of the
resultant polymers arising from the rapid propagation of initiated
chains with new chains being initiated. To further investigate
the observed effects, a competition experiment between neo-
pentanol and 2-propanol initiators was performed. ROP of 6
using a 1:1 molar ratio of alcohols and a target overall
[M]/[alcohol] ) 10 ([M]/[I] ) 20 with respect to each initiating
alcohol) resulted in a polymer with a monomodal distribution
with Mn ) 6780 g mol-1 and PDI ) 1.18 by GPC analysis,
comparable to polymers obtained by initiation from neopentanol
1
with a [M]/[I] ) 20. Analysis of the polymer by H NMR
spectroscopy revealed both neopentanol and 2-propanol end
groups in a 2:1 ratio. These data suggest that the increased
initiator efficiency of neopentanol compared to 2-propanol
results in the majority of the initial ring opening of 6 to occur
through neopentanol; however, the increased rate of initiation
Figure 6. Expansion of δ ) 0.80 to 1.00 ppm region of 1H NMR
spectra (400 MHz; CDCl3) showing the neopentyl methyl reso-
nances of (a) 15, (b) 16, and (c) PBMD prepared by the
ring-opening polymerization of 6 initiated from neopentanol using
8/(-)-sparteine.

Ring-Opening Polymerization of Cyclic Esters
Biomacromolecules, Vol. 11, No. 8, 2010 1937
Table 1. Effect of [M]/[I] for Neopentanol versus 2-Propanol Initiation of the Ring-Opening Polymerization of 6a
initiating
alcohol
time
(min)
monomer
conversion (%)
Mn (NMR)b
Mn (GPC)c
[M]/[I]
DPb
(g mol-1
)
(g mol-1
)
PDIc
neopentanol
neopentanol
neopentanol
neopentanol
2-propanol
2-propanol
2-propanol
2-propanol
10
20
50
100
10
20
5d
10d
20d
40d
6e
98
98
92
96
98
97
99
97
13
24
43
3520
6430
11440
4700
6750
9490
18070
9530
11020
18200
26050
1.19
1.17
1.15
1.12
1.17
1.12
1.14
1.11
12
24
41
3230
6400
10880
12e
25e
50e
50
100
a [6]0 ) 0.32 M; 5 mol % of (-)-sparteine; CHCl3. b Determined by 1H NMR spectroscopy. c Determined by GPC analysis. d With 25 mol % of 8. e With
35 mol % of 8.
Table 2. Effect of Alcohol Initiator in the Ring-Opening
Polymerization of 6a
c
initiating Alcohol [M]/[I] time (min) DPb Mn (g mol-1
)
PDIc
9
20
20
20
20
20
20
20
20
20
20
6d
18
19
4700
5650
5920
6600
6750
1.14
1.12
1.17
1.17
1.17
1.12
1.12
1.10
1.19
1.14
10
6e
benzyl alcohol
1-phenylethanol
neopentanol
ethanol
2-propanol
2-butanol
benzyl amine
1,3-propanediol
8d
8e
16
24
23
24
28
10d
12d
12e
20e
8d
8800
11020
13300
7390
8d
20f
11380
b
a [6]0 ) 0.32 M; 5 mol % of (-)-sparteine; CHCl3. Determined by 1H
NMR spectroscopy. c Determined by GPC analysis. d With 25 mol % of
8. e With 35 mol % of 8. f DP per alcohol.
Figure 7. GPC traces of PLLA20-OH (Mn ) 8360 g mol-1, PDI ) 1.11)
and PLLA20-b-PBMD20 (Mn ) 19 080 g mol-1, PDI ) 1.18) prepared by
ring-opening polymerization of 6 from a PLLA macroinitiator.
of neopentanol with respect to 2-propanol and relative propaga-
tion rates of the more activated growing polymer chains result
in very few new polymer chains being initiated after the primary
initiation event, despite the presence of excess 2-propanol.
Further initiator versatility was investigated to prepare a
telechelic PBMD ([M]/[I] ) 40) ([M]/[I] ) 20 per alcohol
group) by initiation from 1,3-propanediol with the polymeri-
zation achieving 99% monomer conversion within 8 min and
the resultant polymer displaying Mn ) 11 380 g mol-1 and PDI
) 1.14 as determined by GPC analysis. The initiator tolerance
was also tested using benzyl amine. PBMD ([M]/[I] ) 20) was
successfully prepared showing no significant difference in rate
or control compared to alcohols reaching 99% monomer
conversion in 8 min with Mn ) 7390 g mol-1 and PDI ) 1.19.
Block Copolymers. Further extension of this methodology
was investigated to enable the synthesis of block copolymers.
Primarily, the synthesis of amphiphilic poly(ethylene oxide)-
b-PBMD block copolymers by initiation from commercially
Scheme 4. Deprotection of
Poly(3-(S)-[(benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-dione),
PBMD, Using Hydrogenolysis
achieved after 30 and 75 min, respectively. Chain growth of 6
1
([M]/[I] ) 20) from PLLA20-OH was confirmed by H NMR
spectroscopy, showing the presence of both the lactide methyl
and malate resonances at δ ) 1.58 and 3.08-2.85 ppm,
respectively. Additionally, GPC analysis revealed an increase
in molecular weight from 8360 g mol-1 (PLLA20-OH) to
19 080 g mol-1 (PLLA20-b-PBMD20), with a narrow PDI being
maintained (Figure 7). Chain growth from PLLA50-OH (Mn
) 14 020 g mol-1, PDI ) 1.09) was also achieved, resulting in
the successful synthesis of PLLA50-b-PBMD20 (Mn ) 24 160 g
mol-1, PDI ) 1.07).
available PEO2K and PEO5K (Mn ∼ 2000 and 5000 g mol-1
,
respectively) macroinitiators was investigated. ROP of 6 (target
[M]/[I] ) 20) with PEO2K-monomethylether (Mn ) 3400 g
mol-1, PDI ) 1.05) as the initiator resulted in >99% monomer
conversion after 30 min. GPC analysis of the copolymer
confirmed PBMD chain growth (PEO2K-b-PBMD20; Mn
)
9260 g mol-1, PDI ) 1.13). Successful block copolymer
preparation was also achieved with initiation from PEO5K (Mn
) 8200 g mol-1, PDI ) 1.04), realizing the desired block
copolymer PEO5K-b-PBMD20 (Mn ) 12 340 g mol-1, PDI )
1.15).
Deprotection of PBMD. Deprotection of the pendant car-
boxylic acid groups of PBMD (DP20; Mn ) 5950 g mol-1; PDI
) 1.16) was accomplished by hydrogenolysis using H2 over
Pd/C and resulted in hydrophilic poly(glycolic-co-malic acid)s
(PGMA) (Scheme 4). Clean and complete removal of the benzyl
protecting groups was deduced from the disappearance of all
Block copolymers were also demonstrated to be accessible
with poly(L-lactide), PLLA, prepared from poly(L-lactide) as a
macroinitiator for the polymerization of 6 ([M]/[I] ) 20). PLLAs
([M]/[I] ) 20 and 50) were synthesized by ROP of L-lactide
using identical conditions as described above with 35 mol %
of 8 and 5 mol % of (-)-sparteine, initiated from neopentanol.
Complete monomer conversion for [M]/[I] ) 20 and 50 was
1
the aromatic and benzylic signals from both the H (Figure 8)
and 13C NMR spectra. Further confirmation was obtained from
the change in solubility of the resulting polymer from the PBMD
(soluble in CHCl3, insoluble in MeOH) to the PGMA (soluble
in MeOH, insoluble in CHCl3). This process did not result in
degradation of the poly(ester) backbone, as shown by the lack

1938 Biomacromolecules, Vol. 11, No. 8, 2010
Pounder and Dove
Conclusions
In conclusion, we have successfully demonstrated an im-
proved synthesis of both BMD, 6, and malide, 7, monomers
from L-malic acid. Homopolymerization of 6 using the orga-
nocatalytic 8/(-)-sparteine system enabled the synthesis of
functional poly(ester)s with pendant benzyl protected carboxylic
acid groups to high monomer conversions in the absence of
transesterification side reactions. The choice of initiator was
demonstrated to be important, such that initiating species that
more closely resembled the propagating species led to lower
molecular weight polymers. Nonetheless, the versatility of the
polymerization system was shown with successful initiation from
a range of alcohols and amines including the use of PEO and
PLLA as macroinitiators in the preparation of block copolymers.
Removal of the benzyl protecting groups was successful without
any polymer backbone scission to yield hydrophilic poly(ester)s,
and studies of the resultant PGMAs in H2O showed that
degradation occurred within 6 days as determined by titration,
1
aqueous GPC analysis, H NMR, and mass spectrometry. The
derivation of this versatile functional poly(ester) from a biore-
newable resource thus provides a potential route to a range of
functional poly(ester)s via this platform.
Acknowledgment. The Research Councils UK (RCUK) are
acknowledged for funding a fellowship to A.P.D. We gratefully
acknowledge financial support from EPSRC (EP/C007999/1)
for the purchase of the Bruker Ultraflex MALDI-TOF MS
instrument, and Dr Lijiang Song for assistance with mass
spectrometry measurements. The GPC equipment used in this
research was obtained through Birmingham Science City:
Innovative Uses for Advanced Materials in the Modern World
(West Midlands Centre for Advanced Materials Project 2), with
support from Advantage West Midlands (AWM) and part
funded by the European Regional Development Fund (ERDF).
Figure 8. 1H NMR spectra of (i) PBMD20 and (ii) PGMA20 (THF-d8,
400 MHz; / indicates residual solvent signal).
of resonances associated with changes to the electronic environ-
ment of the methine protons associated with a neighboring
hydroxy proton in the 1H NMR spectrum that would be apparent
upon cleavage of the backbone. Furthermore, analysis of the
polymer by aqueous GPC showed a single narrow distribution
with a Mn ) 2410 g mol-1 and PDI ) 1.12 (compared to PEG
standards). We postulate that the hydrophobic nature of the
poly(ester) backbone results in tightly coiled polymers thus
leading to low molecular weight values by aqueous GPC
analysis.
Supporting Information Available. Additional charts and
MALDI-TOF/NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
References and Notes
Degradation of PGMA. Degradations were performed in
H2O on PGMA ([M]/[I] ) 20) at a concentration of 0.55 mmol
L-1. The degradations were monitored via acid-base titration
using a 0.50 mmol L-1 aqueous NaOH solution with four drops
of a phenolphthalein in methanol solution as the pH indicator.
Phenolphthalein produces a strong pink color when the pH of
the solution reaches 8.2, thus providing a simple method with
which to determine the extent of the degradation. Degradation
was complete after 6 days, determined when 3 equiv of the
NaOH solution was required to neutralize the reaction. Aqueous
GPC analysis provided a simple method to monitor the
molecular weight loss during the degradation. The Mn gradually
decreased over time along with a broadening of the PDI that
plateaued after 6 days, in agreement with the titration experi-
ment. Examination of 1H NMR spectra during the degradation
in D2O demonstrates a gradual reduction of resonances attributed
to PGMA at δ ) 5.93-5.85 and 3.32-3.22 ppm with a
corresponding increase of new resonances at δ ) 4.54-4.48
and 3.19-3.01 ppm resulting from the degradation products.
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confirmed the presence of a range of degradation products
including malic acid ([M + Na]+ ) 157.01), glycolic acid dimer
([M + Na]+ ) 157.01), malic/glycolic acid dimer ([M + Na]+
) 215.02), and malic acid dimer ([M + Na]+ ) 273.02).
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