Organo-catalyzed ring opening polymerization of a 1,4-dioxane-2,5-dione deriving from glutamic acid

Article abstract of DOI:10.1021/bm100433c

The (3S)-[(benzyloxycarbonyl)ethyl]-1,4-dioxan-2,5-dione (BED) was prepared in four steps starting from glutamic acid and bromoacetyl bromide. According to X-ray diffraction analysis, the pendant functional group is located in equatorial position and points away from the six-membered ring. The organo-catalyzed ring-opening polymerization of BED was promoted with 4-dimethylaminopyridine (DMAP) and the combination of thiourea TU^Cy and (-)-sparteine. PolyBED samples of number-average molar mass M_n up to 36000 and narrow polydispersity (M_w/M_n < 1.25) were thereby prepared in a controlled manner under mild conditions (dichloromethane solution, 30 °C), as substantiated by size-exclusion chromatography, matrix-assisted laser desorption ionization time-of-flight-mass spectrometry (MALDI-TOF-MS) and nuclear magnetic resonance (NMR) spectroscopy. The pendant functional group does not interfere with the polymerization and BED was even found to be slightly more reactive than lactide. Despite the strongly dissymmetric substitution pattern of the 1,4-dioxan-2,5-dione core, the ensuing polyBED polymers present a random distribution of glycolic-[(benzyloxycarbonyl) ethyl]glycolic (gly glu) units, as supported by a ¹H-¹³C HMBC 2D NMR experiment. The preparation of 1:1 adducts with n-pentanol confirmed that ring-opening of BED occurs almost indifferently on either of the endocyclic ester groups. Poly(α-hydroxyacids) featuring pendant carboxylic acids were finally obtained by acetylation of the terminal OH groups followed by hydrogenolysis.

Full text of DOI:10.1021/bm100433c

Biomacromolecules 2010, 11, 1921–1929
1921
Organo-Catalyzed Ring Opening Polymerization of a
1,4-Dioxane-2,5-dione Deriving from Glutamic Acid
Olivier Thillaye du Boullay,† Nathalie Saffon,‡ Jean-Pierre Diehl,§ Blanca Martin-Vaca,*,†
and Didier Bourissou*,†
UPS, LHFA, Universite´ de Toulouse, 118 route de Narbonne, F-31062 Toulouse, France, LHFA UMR
5069, F-31062 Toulouse, France, Structure Fe´de´rative Toulousaine en Chimie Mole´culaire, Universite´ Paul
Sabatier, FR2599, 118 Route de Narbonne, F-31062 Toulouse, France, and Minasolve, 145 Chemin des
Lilas, F-59310 Beuvry-La-Foreˆt, France
Received April 21, 2010; Revised Manuscript Received June 8, 2010
The (3S)-[(benzyloxycarbonyl)ethyl]-1,4-dioxan-2,5-dione (BED) was prepared in four steps starting from glutamic
acid and bromoacetyl bromide. According to X-ray diffraction analysis, the pendant functional group is located
in equatorial position and points away from the six-membered ring. The organo-catalyzed ring-opening
polymerization of BED was promoted with 4-dimethylaminopyridine (DMAP) and the combination of thiourea
TUCy and (-)-sparteine. PolyBED samples of number-average molar mass Mn up to 36000 and narrow polydispersity
(Mw/Mn < 1.25) were thereby prepared in a controlled manner under mild conditions (dichloromethane solution,
30 °C), as substantiated by size-exclusion chromatography, matrix-assisted laser desorption ionization time-of-
flight-mass spectrometry (MALDI-TOF-MS) and nuclear magnetic resonance (NMR) spectroscopy. The pendant
functional group does not interfere with the polymerization and BED was even found to be slightly more reactive
than lactide. Despite the strongly dissymmetric substitution pattern of the 1,4-dioxan-2,5-dione core, the ensuing
polyBED polymers present a random distribution of glycolic-[(benzyloxycarbonyl)ethyl]glycolic (gly glu) units,
as supported by a 1H-13C HMBC 2D NMR experiment. The preparation of 1:1 adducts with n-pentanol confirmed
that ring-opening of BED occurs almost indifferently on either of the endocyclic ester groups. Poly(R-hydroxyacids)
featuring pendant carboxylic acids were finally obtained by acetylation of the terminal OH groups followed by
hydrogenolysis.
to confer hydrophilicity, to increase degradation rate, and to
graft biologically active compounds to the poly(R-hydroxyac-
ids).12 Although the preparation of such functionalized poly(R-
hydroxyacids) is still in its infancy, significant progress has been
achieved over the past few years, especially with monomers
featuring pendant-protected hydroxyl groups. Vert et al. reported
in the early 2000s the ROP of monomers Ia,b (Figure 1)
deriving from gluconic acid with tin octanoate SnOct2.5,6 Around
the same time, metal-catalyzed ROP of the serine-based 1,4-
dioxan-2,5-diones IIa,b was investigated with success by Feng,
Hennink, Collard, and Weck.7 Comparatively, the preparation
of poly(R-hydroxyacids) featuring pendant carboxyl groups has
proved more challenging. Although Kimura demonstrated the
feasibility of polymerizing monomer IIIb with SnOct2 as early
as in 1988,8-10 only modest control and broad molar mass
distributions (Mw/Mn from 1.4 to 3.5) were obtained. Recently,
the metal-catalyzed ROP of functionalized 1,4-dioxan-2,5-diones
has been extended to monomers IVa,b and Va derived from
glutamic acid and lysine, respectively.7d,10 But again rather
drastic conditions were employed (SnOct2, 140 °C in bulk), and
the polymerization efficiency and control are not optimal
(30-60% yield, Mw/Mn ∼ 1.4).
Introduction
Polyhydroxyacids such as polylactic acid (PLA), polyglycolic
acid (PGA), and their copolymers (PLGA) have attracted
considerable interest in recent years as resorbable biomaterials
as well as commodity thermoplastics derived from renewable
resources.1 A number of catalytic systems have been found to
perform the ring-opening polymerization (ROP) of lactide under
mild conditions and with high level of control in terms of molar
mass, polydispersity, end-group fidelity as well as tacticity. In
addition to well-defined, single-site metal complexes,2a-e which
are the most widely used systems for the ROP of cyclic esters,
several organo-catalysts have been shown recently to promote
efficient ROP of lactide.2d-h
However, the lack of structural diversity of the polyesters
derived from lactide and glycolide appears as an important
limitation, and increasing efforts are currently devoted to the
introduction of pendant groups along the polymer chain to
modulate further the physicochemical properties of poly(R-
hydroxyacids).3-12 Accordingly, Baker et al. recently reported
the ROP of several alkyl- and aryl-substituted 1,4-dioxan-2,5-
diones, and the glass transition temperature for the ensuing
polymers were found to vary in a broad range (from -40 °C to
more than 100 °C, as to compared with ∼45 °C for PLA).3a,4
The incorporation of pendant functional groups,2e,f,3b and
especially proteinogenic side chains, is also of utmost interest
The spectacular progress achieved over the past few years in
metal-free ROP raises the question as to whether organo-
catalysts are applicable to the controlled preparation of func-
tionalized poly(R-hydroxyacids). One common advantage im-
parted to organocatalysis is high functional group tolerance.
Indeed, this has been exploited in the context of polymer
synthesis to prepare well-defined complex architectures from
polyfunctional initiators.13 However, to the best of our knowl-
* To whom correspondence should be addressed. Fax: (+33)(0)561558204.
E-mail: dbouriss@chimie.upstlse.fr.
† Laboratoire He´te´rochimie Fondamentale et Applique´e.
‡ Structure Fe´de´rative Toulousaine en Chimie Mole´culaire.
§ Minasolve.
10.1021/bm100433c
 2010 American Chemical Society
Published on Web 07/15/2010

1922 Biomacromolecules, Vol. 11, No. 8, 2010
Boullay et al.
just prior to use. 4-Dimethylaminopyridine (DMAP; 99%, Aldrich) was
purified by recrystallization from toluene and stored under argon.
L-lactide (Purac) was purified by two recrystallizations from toluene
and stored under argon at -20 °C. n-Pentanol (99+%) was dried over
sodium and distilled before use. γ-Benzyl glutamic acid (Acros, 99%),
sodium nitrite (Aldrich, 99,5%), dicyclohexylamine (Aldrich, 99%),
bromoacetyl bromide (Acros, 98%), tetrabutylammonium iodide (Al-
drich, 99%), triethylamine (Et3N; Aldrich, 99.5%), and diisopropyl-
ethylamine (Aldrich, 99%) were used as received.
Characterizations. NMR Spectra were recorded in chloroform-d
or acetone-d6 on BRUKER Avance 300, 400, and 500 MHz spectrom-
eters at room temperature. Chemical shifts are reported in ppm relative
1
to Me4Si as an external standard. H NMR measurements were used
to determine the monomer conversion and the chain end groups. The
degree of polymerization DP was determined from the relative
integration of the signals for the glycolate units and chain ends. HMBC
spectra were recorded on BRUKER Avance 500 MHz spectrometer
equipped with a cryo-probe TCI 5 mm indirect detection with 1/(2JXH
)
) 50 ms. The number-average and weight-average molar masses (Mn
and Mw, respectively, in g/mol) and polydispersity indexes (Mw/Mn) of
the polyester samples were determined by size exclusion chromatog-
raphy (SEC) at 40 °C with a Waters 600 liquid chromatograph equipped
with a Waters 2410 Refractive Index Detector. Tetrahydrofuran (THF)
was used as the eluent and the flow rate was set up at 1.0 mL/min. A
Waters pre-column and a Waters STYRAGEL column (HR 4E,
50-100000 g/mol) were used. Calibrations were performed using
polystyrene standards (400-100000 g/mol).
The exact number-average molar masses were determined by size
exclusion chromatography (SEC) at 40 °C with a Waters 510 liquid
chromatograph equipped with a minDAWN Light Scattering Detector
instrument (3 angles). Tetrahydrofuran was used as the eluent and the
flow rate was set up at 1.0 mL/min. The refractive index increment
(dn/dc ) 0.1137 ( 0.00098 mL/g) of dilute solutions of polymer was
measured in THF at 30 °C with a differential refractometer (PSS-2010)
working at 620 nm.
Matrix-assisted laser desorption ionization time-of-flight-mass
spectrometry (MALDI-TOF-MS) analysis was performed on a Voyager
System DE-STR from Applied Biosystems equipped with a 337 nm
nitrogen laser. An accelerating voltage of 20 kV was applied. Mass
spectra of 1000 shots were accumulated. The polymer sample was
dissolved in dichloromethane at a concentration of 1 mg/mL. The
cationization agent used was NaI dissolved in methanol at a concentra-
tion of 10 mg/mL. The matrix used was dithranol and was dissolved
in dichloromethane at a concentration of 10 mg/mL. Solutions of matrix,
salt, and polymer were mixed in a volume ratio of 3:1:1, respectively.
The mixed solution was hand-spotted on a stainless steel MALDI target
and left to dry. The spectrum was recorded in the reflectron mode.
Baseline corrections and data analyses were performed using Data
Explorer version 4.0 from Applied Biosystems.
Figure 1. Main monomers investigated for the preparation of func-
tionalized poly(R-hydroxyacids).
edge, the ability of organo-catalysts to promote the ROP of
functionalized 1,4-dioxan-2,5-diones has not been substantiated
thus far. Only the O-carboxyanhydride VI, an activated mono-
mer derived from glutamic acid, has been polymerized under
mild conditions using 4-dimethylaminopyridine (DMAP) as the
catalyst.14 As far as substituted 1,4-dioxan-2,5-diones are
concerned, the only precedent of organo-catalyzed ROP is the
recent work by Hillmyer and co-workers on monomer VII.15
Taking advantage of the high activity of 1,5,7-triazabicy-
clododecene (TBD, a bicylic guanidine) as catalyst, the trisub-
stituted 1,4-dioxan-2,5-dione VII was readily polymerized under
mild conditions and PLA composites with enhanced toughness
were obtained by sequential ROP/ring-opening metathesis
polymerization (ROMP). In order to evaluate if organo-catalyzed
ROP is a viable route to functionalized poly(R-hydroxyacids)
of controlled structure, we have investigated the metal-free
polymerization of monomer IVb (referred to as BED), and
report here the results of this study. Special attention has been
devoted to the influence of the pendant functional group on the
polymerizability of the 1,4-dioxan-2,5-dione moiety, as well as
on the selectivity of ring-opening.
The optical purity (>99.9%) of BED and compound 3 was checked
by Chiral HPLC (Alliance system from Waters equipped with a
photodiode array detector Waters 996). Separations were performed
with Chiracel OD-H column using hexane +0.05% trifluoroacetic acid
(80%) and isopropanol (20%) as eluents at the flow rate of 1 mL/min.
Melting points were measured with an Electrothermal digital melting
point apparatus and are uncorrected.
Experimental Section
Preparation of 2-Amino-pentanedioic Acid 5-Benzyl Ester (2).
Methane sulfonic acid (0.82 mol, 53 mL) was added dropwise to a
warmed (45 °C) suspension of benzyl alcohol (1.02 mol, 106 mL) and
glutamic acid (1; 0.68 mol, 100 g) in toluene (100 mL). After 2 h at
45 °C, the homogeneous reaction mixture was stirred at 30 °C for
additional 3 h. Water was added (200 mL) and the organic layer was
eliminated. The aqueous layer was diluted with ethanol (100 mL).
Compound 3 precipitated when pH was adjusted to 6 by the slow
addition of ammoniac (20% aqueous solution, 110 mL). The white solid
was washed twice with cold ethanol (150 mL), twice with water (150
mL), and dried under vacuum at 50 °C (105.2 g, 67%). Analytical data
Materials. All reactions were performed under inert atmosphere of
argon, using standard Schlenk techniques. Solvents were dried and
distilled prior to use: toluene (>99.9%), tetrahydrofurane (THF; >99.9%)
and diethyl ether (>99.9%) over sodium, pentane (>99%) over calcium
dihydride, and dichloromethane (CH2Cl2; >99.95%) over phosphorus
pentoxide. Thiourea catalysts (TUCy, TUNMe ) were prepared according
2
to literature procedures16 and purified by three recrystallizations from
chloroform. (-)-Sparteine (Aldrich, 99%) was distilled twice over
calcium dihydride and stored under argon. 1,8-Diazabicyclo[5.4.0]undec-
7-ene (DBU; Aldrich, 98%) was distilled twice over calcium dihydride

Polymerization of a 1,4-Dioxane-2,5-dione
Biomacromolecules, Vol. 11, No. 8, 2010 1923
are in agreement with reported literature data.17 Mp: 175-177 °C (lit.:
172-180 °C). HPLC-MS: 100%, [M + H]+: 238.18.
C14H15O6: C, 60.43; H, 5.07. Found: C, 60.52; H, 4.93. Optical purity
> 99.9% (chiral HPLC).
Crystal Structure Determination of BED. Data were collected at
173(2) K using an oil-coated shock-cooled crystal on a Bruker-AXS
APEX II diffractometer with Mo KR radiation (λ ) 0.7103 Å; see
Supporting Information). Semi-empirical absorption corrections were
employed.19 The structures were solved by direct methods (SHELXS-
97)20 and refined using the least-squares method on F2.21
Preparation of 5-Benzyloxycarbonyl-2-hydroxy-pentanedioic
Acid (3). A 2 mol/L aqueous solution of a NaNO2 (210.0 mmol, 105
mL) was added dropwise in 30 min, at 30 °C, to a suspension of
L-BnOGlu (2; 105.0 mmol, 25.0 g) in a mixture of H2O and acetic
acid (400 mL, ratio 8/2). The reaction mixture was then stirred at this
temperature for 4 h, after which it became homogeneous. Water (200
mL) was then added and the title compound was extracted by ethyl
acetate (3 × 150 mL). The organic layers were combined, washed with
water and brine, and dried over sodium sulfate. The solvent was
removed by evaporation to give 20.5 g of viscous oil (1H and 13C NMR
data in agreement to literature data).18
Typical Procedure for the Polymerization of BED Catalyzed
by TUCy/(-)-Sparteine. Prior to polymerization, BED was passed on
a short plug of silica (petroleum ether/ethyl acetate 70/30 v/v),
recrystallized twice in toluene, and dried overnight under high vacuum.
In a dried Schlenk, a solution of n-pentanol in dichloromethane (40
µmol, 100 µL from stock solution, [M]0/[I]0 ) 25) was added to a
solution of monomer (1.0 mmol, 280 mg) in dichloromethane (700
µL). The reaction mixture was heated at 30 °C and catalysts (40 µmol
TUCy + 40 µmol (-)-sparteine, 200 µL from a stock 0.2 mol/L
dichloromethane solution) was added under argon. Aliquots of the
reaction mixture were quenched with benzoic acid and the conversion
was determined by 1H NMR spectroscopy. At the end of the reaction,
the reaction medium was diluted with 5 mL of dichloromethane, washed
with cold HCl (2 mol/L), dried over sodium sulfate and concentrated.
The polymer was precipitated by addition of the dichloromethane
solution into cold methanol and dried under vacuum. The number-
average molar mass was determined by SEC (Mn ) 7890, Mw/Mn )
Dicyclohexyamine (86.0 mmol, 17.3 mL) was added to a cold
solution of the crude hydroxyacid in methyl-t-butylether (150 mL). The
mixture was stirred for 30 min at this temperature. The salt was filtered,
washed with cold methyl-t-butylether, and dried under vacuum to yield
1
a white powder (24.85 g, 56% overall). H NMR (CDCl3, 300 MHz):
δ
ppm 7.33 (m, 5H, Ph), 5.11 (s, 2H, CH2Ph), 3.90 (dd, 1H, J ) 7.6 and
3.9 Hz, CHOH), 2.96 (m, 2H, NCH(cyclohexyl)), 2.60 (m, 2H,
CH2CH2CO2), 2.18 (m, 1H, CHHCH2CO2), 2.00-1.10 (m, 22H,
CHHCH2CO2, CH2cyclohexyl, OH). Mp: 125-126 °C; optical purity
> 99.9% (chiral HPLC).
Preparation of 5-Benzyloxycarbonyl-2-(2-bromo-acetyloxy)-
pentandioic Acid (4). A solution of the dicyclohexylamine salt (3;
58.4 mmol, 24.5 g) in dichloromethane (100 mL) was mixed with Et3N
(58.4 mmol, 8.14 mL) and was added dropwise (30 min) to a chilled
solution of bromoacetyl bromide (75.9 mmol, 6.60 mL) in dichlo-
romethane (300 mL). The heterogeneous mixture was stirred for 4 h
and was then diluted with dichloromethane (200 mL), washed twice
with cold HCl (1 mol/L), twice with water and then brine. The organic
layer was dried over sodium sulfate and the solvent was eliminated
under reduced pressure to give a viscous oil (22.5 g). This oil was
dissolved in dichloromethane (20 mL) and the solution was slowly
poured over pentane (600 mL). The solvent was discarded and the
residual oil was washed twice with pentane. The oil was dried under
vacuum to yield light brown oil (19.65 g, 94%), and was engaged
directly in the next step without further purification. 1H NMR (CDCl3,
300 MHz): δppm 7.36 (m, 5H, Ph), 5.14 (s, 2H, CH2Ph), 5.17 (dd, 1H,
J ) 7.6 and 3.9 Hz, CHOH), 3.86 (m, 2H, CH2Br), 2.51 (m, 2H,
CH2CH2CO2), 2.18 (m, 1H, CHHCH2CO2), 2.28 (m, 1H,
CHHCH2CO2). 13C NMR (CDCl3, 75 MHz): δppm 173.4 (CHCOOH),
172.2 (COOCH2Ph), 166.6 (COCH2Br), 135.3 (Cipso, Ph), 128.5-128.2
(CH, Ph), 72.0 (CHOCO), 66.6 (OCH2Ph), 29.4 (CH2CH2CHO), 25.7
(CH2CH2CHO), 24.9 (CH2Br). MS (DCI, NH3) m/z: 376.3 (M + NH4+),
378.3 (M + NH4+), 298.4, 210.4, 165.3, 148.3.
1
1.22) and the degree of polymerization was determined by H NMR
spectroscopy (DP ) 28).
1H NMR (CDCl3, 300 MHz): δppm 7.34 (m, ∼145H, Ph), 5.22 (m,
∼28H, CHO), 5.10 (s br, ∼55H, CH2Ph), 4.86-4.52 (m, ∼56H,
CH2gly), 4.37 (m, CHOH), 4.19 (m, CH2OH), 4.11 (m, 2H,
CH2CH2CH2O), 2.54-2.37 (m, ∼114H, CH2CH2CO2Bn), 1.41 (m, 2H,
CH3CH2CH2CH2CH2O), 1.15 (m, 4H, CH3CH2CH2CH2CH2O), 0.89 (t,
3H, J ) 6.3 Hz, CH3CH2CH2CH2CH2O). 13C NMR (CDCl3, 75 MHz):
δ ppm 171.9 (COBn), 168.2 (COgly), 166.3 (COglu), 135.8 (Cipso, Ph),
128.6-128.3 (CH, Ph), 71.6 (CHOCO), 66.5 (PhCH2O), 60.8
(COCH2OCO), 29.2 (CH2CH2COOBn), 26.0 (CH2CH2COOBn).
Typical Procedure for the Polymerization of BED Catalyzed
by DMAP. In a dried Schlenk, a solution of n-pentanol in dichlo-
romethane (40 µmol, 100 µL from stock solution, [M]0/[I]0 ) 25) was
added to a solution of monomer (1.0 mmol, 280 mg) in dichloromethane
(700 µL). The reaction mixture was heated at 30 °C and DMAP (100
µmol, 200 µL from a stock 0.5 mol/L dichloromethane solution) was
added under argon. Aliquots of the reaction mixture were quenched
with benzoic acid and the conversion was monitored by 1H NMR
spectroscopy. At the end of the reaction, the reaction medium was
diluted with 5 mL of dichloromethane, washed with cold HCl (2 mol/
L), dried over sodium sulfate, and concentrated. The polymer was
precipitated by the addition of the dichloromethane solution into cold
methanol and dried under vacuum. The number-average molar masses
were determined by SEC and the degrees of polymerization were
Preparation of L-3-(2-Benzyloxycarbonyl)ethyl-1,4-dioxane-2,5-
dione (BED). Tetrabutylammonium iodide (0.26 mol, 92.0 g) was
added to a solution of iPr2EtN (3.56 mol, 615 mL) in methylisobu-
tylketone (23.0 L), and the mixture was heated at 60 °C under inert
atmosphere. A solution of the bromoacetyl compound (4; 1.78 mol,
639.0 g) in methylisobutylketone (5.0 L) was added dropwise (over
6 h, pump). The reaction mixture was heated for 1 h and left overnight
at room temperature under stirring. The reaction mixture was then
washed with cold HCl (2 mol/L, 2 × 5.0 L) and water and dried over
sodium sulfate. The solvent was eliminated under reduced pressure to
give a light-yellow solid, which was triturated in a mixture of
methylisobutylketone and methyltbutylether (1/10, v/v) to yield an off-
white powder (265.3 g, 54%). 1H NMR (CDCl3, 300 MHz): δppm 7.36
(m, 5H, Ph), 5.14 (s, 2H, CH2Ph), 5.17 (dd, 1H, J ) 9.3 and 5.3 Hz,
CHOH), 4.90 (s, 2H, CH2gly), 2.64 (t, 2H, J ) 7.2 Hz, CH2CH2CO2),
2.44 (m, 1H, CHHCH2CO2), 2.26 (m, 1H, CHHCH2CO2).13C NMR
(CDCl3, 75 MHz): δppm 171.9 (COOCH2Ph), 165.7 (CHCOOCH2),
164.4 (COCH2OCO), 135.4 (Cipso, Ph), 128.4-128.0 (CH, Ph), 73.8
(CHOCO), 66.4 (PhCH2O), 65.3 (COCH2OCO), 28.3 (CH2CH2CHO),
25.4 (CH2CH2CHO). Mp: 78-80 °C. HRMS (DCI CH4) m/z: Calcd
for [C14H15O6 + H]+, 279.0869; found, 279.0864. Anal. Calcd. for
1
determined by H NMR spectroscopy.
Preparation of Adducts 5 and 6. In a round-bottom flask, catalyst
(0.1 mmol) was added to a solution of BED (1.0 mmol, 280 mg) in
dichloromethane (10.0 mL) and n-pentanol (10.0 mmol, 1.0 mL). The
reaction mixture was stirred at room temperature for 1 h and completion
1
was controlled by H NMR spectroscopy. The two compounds were
separated by flash chromatography (CH2Cl2/MeOH, 99/1).
1
Compound 5. H NMR (CDCl3, 300 MHz): δppm 7.34 (m, 5H, Ph),
5.11 (s, 2H, CH2Bn), 4.74 and 4.62 (AB system, 2H, J ) 15.9 Hz,
CH2), 4.37 (m, 1H, CHOH), 4.11 (t, 2H, J ) 6.9 Hz, OCH2CH2CH2),
3.21 (d, 1H, J ) 5.7 Hz, OH), 2.59 (m, 2H, CH2CH2), 2.28 (m, 1H,
CHHCH2), 2.06 (m, 1H, CHHCH2), 1.63 (m, 2H, CH2), 1.32 (m, 4H,
CH2CH2), 0.89 (t, 3H, J ) 6.4 Hz,CH3). 13C NMR (CDCl3, 75 MHz):
δ
ppm 173.8 (COOCH2Ph), 173.0 (CHCOOCH2), 167.2 (COCH2OCO),
135.8 (Cipso, Ph), 128.1-128.5 (CH, Ph), 69.4 (CH2CHOHCO), 66.3
(PhCH2O), 65.7 (COCH2OCO), 61.2 (CH3CH2CH2CH2CH2O), 29.4
(COCH2CH2CHOH),
29.1
(COCH2CH2CHOH),
28.0

1924 Biomacromolecules, Vol. 11, No. 8, 2010
Boullay et al.
Scheme 1. Improved Procedure for the Preparation of BEDa
a Reagents and conditions: (a) BnOH, MeSO3H; (b) NaNO2, AcOH/H2O; (c) Cy2NH, t-BuOCH3; (d) BrCH2COBr, Et3N, 0 °C, CH2Cl2; (e) n-Bu4NI,
i-Pr2NEt, i-BuCOCH3.
(CH3CH2CH2CH2CH2O), 27.8 (CH3CH2CH2CH2CH2O), 22.1
(CH3CH2CH2CH2CH2O), 13.8 (CH3CH2CH2CH2CH2O). MS (EI): 91,
108, 189, 259, 349, 367 (M + H+).
(3) Acetylation. Anhydride acetic (1.0 mL) and DMAP (30 mg) were
added to the precedent solution and the reaction mixture was stirred
for 2 h at room temperature. The complete protection of the terminal
1
1
Compound 6. H NMR (CDCl3, 300 MHz): δppm 7.35 (m, 5H, Ph),
alcohols was confirmed by H NMR spectroscopy and the number-
5.17 (dd, 1H, J ) 8.1, 4.8 Hz, CH), 5.12 (s, 2H, CH2Bn), 4.22 (d, 2H,
J ) 5.4 Hz, CH2OH), 4.11 (t, 2H, J ) 6.6 Hz, CH2O), 2.57 (m, 2H,
CH2CH2), 2.24 (m, 2H, CHHCH2), 1.63 (m, 2H, CH2), 1.31 (m, 4H,
CH2CH2), 0.90 (t, 3H, J ) 6.9 Hz, CH3). 13C NMR (CDCl3, 75 MHz):
δppm 172.5 (C(O)OCH2Ph), 171.9 (CHC(O)OCH2), 169.1
(C(O)CH2OC(O)), 135.6 (Cipso, Ph), 128.1-128.5 (CH, Ph), 71.8
(CHOC(O)), 66.5 (C(O)CH2OH), 65.9 (PhCH2O), 60.3
(CH3CH2CH2CH2CH2O), 29.6 (C(O)CH2CH2CHOC(O)), 28.0
(C(O)CH2CH2CHOC(O)), 27.8 (CH3CH2CH2CH2CH2O), 26.1
(CH3CH2CH2CH2CH2O), 22.1 (CH3CH2CH2CH2CH2O), 13.8
(CH3CH2CH2CH2CH2O). MS (EI): 91, 131, 189, 146, 201, 290, 338,
367 (M + H+).
Typical Procedure for Kinetic Studies (DP100). In a dried Schlenk,
a solution of n-pentanol in dichloromethane (50 µmol, 500 µL from
stock solution) was added to a solution of BED (5.0 mmol, 1.40 g) in
dichloromethane (3.5 mL). The reaction mixture was heated at 30 °C
and catalyst (0.1 mmol TUCy + 0.1 mmol (-)-sparteine, 500 µL from
a stock 0.2 mol/L dichloromethane solution) was added under argon.
At determinate times, aliquots of the reaction mixture were quenched
with benzoic acid and the conversion was monitored by 1H NMR
spectroscopy and average molar masses determined by SEC chroma-
tography. After complete conversion, the polymer was precipitated by
addition of the dichloromethane solution into cold methanol and dried
under vacuum. The number-average molar masses were determined
by SEC and the degrees of polymerization were determined by 1H NMR
spectroscopy.
average molar mass was checked by SEC (Mn ) 12240, Mw/Mn ) 1.12).
DMAP and excess of anhydride acetic were removed by acidic aqueous
work-up (2 mL of cold 2 mol/L HCl). The solvent was removed under
reduced pressure to yield the acetylated polymer as a white sticky
material. 1H NMR (CDCl3, 300 MHz): δppm 7.33 (m, ∼260H, Ph), 5.22
(m, ∼50H, CHO), 5.10 (s br, ∼100H, CH2Ph), 4.86-4.52 (m, ∼102H,
CH2gly), 4.11 (m, 2H, CH2CH2CH2O), 2.54-2.37 (m, ∼209H,
CH2CH2CO2Bn), 2.06 (s, 3H, CHOCOCH3, CH2OCOCH3), 1.60 (m,
2H, CH3CH2CH2CH2CH2O), 1.31 (m, 4H, CH3CH2CH2CH2CH2O), 0.89
(t, 3H, J ) 6.3 Hz, CH3CH2CH2CH2CH2O).
(4) Deprotection. Palladium on charcoal (10%, 100 mg) was added
to the acetylated polymer dissolved in propanone (5 mL). The mixture
was stirred under a hydrogen atmosphere (1 atm) for 2 h at room
temperature. The catalyst was removed by filtration over Celite and
the solvent was eliminated under reduced pressure to yield a white
solid. The polymer was washed three times with chloroform (1.0 mL)
and dried under vacuum to yield white foam. The complete deprotection
1
was confirmed by H NMR spectroscopy. The number-average molar
mass of the fully deprotected polymer was determined by SEC (Mn )
1
10 250, Mw/Mn ) 1.13). H NMR (acetone-d6, 300 MHz): δppm 5.44
(m, ∼50H, CHO), 5.05-4.85 (m, ∼100H, CH2gly), 4.25 (m,
CH2CH2CH2O), 2.66-2.19 (m, ∼200H, CH2CH2CO2H), 1.75 (m, 2H,
CH3CH2CH2CH2CH2O), 1.44 (m, 4H, CH3CH2CH2CH2CH2O), 0.99 (t,
3H, J ) 6.3 Hz, CH3CH2CH2CH2CH2O). 13C NMR (acetone-d6, 75
MHz): δ ppm 175.2 (COOH), 170.3 (COgly), 168.6 (COglu), 73.4
(CHOCO), 62.6 (COCH2OCO), 30.3 (CH2CH2COOH), 28.0
(CH2CH2COOH).
Preparation of a Poly(r-hydroxyacid) Featuring Pendant Car-
boxyl Groups. (1) Polymerization. In a dried Schlenk, a solution of
n-pentanol in dichloromethane (20 µmol, 100 µL from a stock 0.2
mol·L-1 solution, [M]0/[I]0 ) 50) was added to a solution of BED
(1.0 mmol, 280 mg) in dichloromethane (700 µL). The reaction mixture
Results and Discussion
Monomer Preparation. The functionalized 1,4-dioxan-2,5-
dione BED had been previously prepared in four steps (∼10%
overall yield) starting from glutamic acid and bromoacetyl
bromide.10 The initial procedure was slightly modified (Scheme
1), which increased the overall yield (19% on >250 g scale)
and avoided chromatographic purification. γ-Benzylation fol-
lowed by diazotation of glutamic acid led to the corresponding
R-hydroxyacid, whose dicyclohexylammonium salt 3 was
readily isolated by crystallization. Subsequent reaction with
bromoacetyl bromide in the presence of triethylamine afforded
compound 4. The key cyclization step was then performed under
conditions inspired from those reported by Collard and Weck
for the synthesis of IIa, IVa, and Va (bromine to iodine
exchange prior to cyclization).7d Compound 4 was slowly added
(∼5 mmol/min) at 60 °C to a solution of diisopropylethylamine
(1 equiv) containing a catalytic amount of tetrabutylammonium
iodide (15 mol %). Methylisobutylketone was preferred as
solvent over the commonly used dimethylformamide and
was heated at 30 °C, TUNMe catalyst and (-)-sparteine in dichlo-
2
romethane (40 µmol of each one, 200 µL from stock solution) was
added under argon. After 3 h, the reaction completion was confirmed
by 1H NMR spectroscopy and number-average molar masses were
1
determined by SEC (Mn ) 11370, Mw/Mn ) 1.16). H and 13C NMR
spectra are in agreement with those reported for the polymer prepared
with TUCy as catalyst.
(2) Purification. The reaction mixture was diluted with 2 mL of
dichloromethane and the catalytic system trapped overnight with
Amberlyst15 (150 mg). The complete removal of both TUNMe and (-)-
2
sparteine was checked by 1H and 19F NMR spectroscopy. SEC
chromatography confirmed the absence of side reactions (Mn ) 11250,
1
Mw/Mn ) 1.14). H NMR (CDCl3, 300 MHz): δppm 7.34 (m, ∼260H,
Ph), 5.22 (m, ∼50H, CHO), 5.10 (s br, ∼100H, CH2Ph), 4.86-4.52
(m, ∼102H, CH2 Gly), 4.37 (m, CHOH), 4.19 (m, CH2OH), 4.11 (m,
2H, CH2CH2CH2O), 2.54-2.37 (m, ∼209H, CH2CH2CO2Bn), 1.41 (m,
2H, CH3CH2CH2CH2CH2O), 1.15 (m, 4H, CH3CH2CH2CH2CH2O), 0.89
(t, 3H, J ) 6.3 Hz, CH3CH2CH2CH2CH2O).

Polymerization of a 1,4-Dioxane-2,5-dione
Biomacromolecules, Vol. 11, No. 8, 2010 1925
functional groups to the 1,4-dioxane-2,5-dione core. The unique
reactivity of BED most likely results from the less sterically
demanding glycolic unit and a slight inductive activation of the
1,4-dioxane-2,5-dione by the pendant (benzyloxycarbonyl)ethyl
group.
The structure of the obtained polyBED was assessed by mass
spectrometry and NMR spectroscopy. Figure 4 depicts the
matrix-assisted laser desorption ionization time-of-flight (MALDI-
TOF) mass spectrum of a polymer sample prepared from 25
equiv of BED with TUCy/(-)-sparteine as catalyst (entry 5; see
Supporting Information for a MALDI-TOF mass spectrum
associated to a polymer prepared with DMAP as catalyst). A
single population is observed with mass increment of 278.3
g/mol (that is the molar mass of BED), and m/z values
corresponding to polymers of formula n-PentO(BED)nH·Na+.
This indicates the exclusive initiation with n-pentanol, the
integrity of the pendant functional groups and the absence of
Figure 2. Molecular view of BED in the solid state (thermal ellipsoids
at 50% probability).
1
transesterification reactions. H NMR spectroscopy (Figure 5)
corroborated the incorporation of the initiator as an ester chain
end, the characteristic CH2 ester signal (e) appearing at 4.10
ppm. The spectrum also showed signals corresponding to the
glycolic (k) and (benzyloxycarbonyl)ethylglycolic (f,g,h) units.
The degree of polymerization, as estimated from the relative
integrations (g,h/e) and (k/e) (DPNMR ) 28), is close to the initial
monomer to initiator ratio ([BED]0/[n-pentOH]0 ) 25). Signals
(i) and (j) associated with the aromatic and benzylic protons,
respectively, are found at the expected chemical shifts (7.34
and 5.10 ppm) and their integrations relative to (e) are also
consistent with a degree of polymerization of about 28.
According to these mass and NMR data, the polymerization of
BED proceeds selectively by ring-opening of the 1,4-dioxane-
2,5-dione core, without affecting the pendant ester groups. Such
functional group tolerance had been previously observed during
the DMAP-catalyzed ROP of the O-carboxyanhydride derived
from glutamic acid.14c The fact that undesirable transesterifi-
cation reactions with the pendant groups are also absent with a
less reactive monomer, such as BED, and a more active catalyst,
such as the TUCy/(-)-sparteine system, opens new opportunities
for the preparation of functionalized polymers.
Interestingly, the 1H NMR spectrum of the polyBED sample
also showed two small multiplet signals at 4.37 and 4.19 ppm
(f′ and k′) associated with two types of hydroxyl chain ends,
namely a (benzyloxycarbonyl)ethylglycolic COCH(CH2CH2-
CO2Bn)OH moiety and a glycolic COCH2OH unit. This
indicates that ring-opening of BED had occurred on either of
the ester groups of the 1,4-dioxane-2,5-dione core with low
differentiation, despite their dissymmetric substitution pattern.
Accordingly, the organo-catalyzed ROP of BED leads to
polymers presenting a random rather than alternated distribution
of glycolic (gly) and [(benzyloxycarbonyl)ethyl]glycolic (glu)
units. The random character of the polyBED was further
corroborated by a 1H-13C HMBC 2D NMR experiment (Figure
6). In addition to the CH2gly-COglu and CHglu-COgly
correlation marks expected for an alternated distribution,
CH2gly-COgly and CHglu-COglu correlations marks were
observed. Thus, the polymers derived from ROP of BED consist
in the random enchainment of (gly glu) units, and the absence
of transesterification reactions, as apparent from mass spec-
trometry, implies that no more than two consecutive units are
of the same nature, so that the pendant functional groups are
regularly distributed all along the polymer backbone.
Figure 3. Structure of the organo-catalysts used for the ROP of BED.
acetone. The structure of BED was unambiguously established
by 1H and 13C NMR spectroscopy, and its optical purity
(>99.9%) was assessed by chiral HPLC performed on two
samples deriving from L- and rac-glutamic acids (see Supporting
Information).
Crystals of BED suitable for X-ray diffraction analysis were
obtained upon cooling a hot methylt-butylketone solution to
room temperature (Figure 2). As typically observed for
1,4-dioxane-2,5-diones,7c,d,22 BED adopts a twisted boat con-
formation in the solid state. The pendant (benzyloxycarbonyl-
)ethyl group is located in equatorial position and points away
from the six-membered ring. This arrangement contrasts with
that observed by Hennink et al. for (3S)-3-(benzyloxymethyl)-
1,4-dioxane-2,5-dione (IIa), the lateral group being located here
in axial position, folded toward the six-membered ring.7c
Polymerization of BED. The organo-catalyzed ring-opening
polymerization of BED was investigated with 4-dimethylami-
nopyridine (DMAP) and the combination of thiourea TUCy and
(-)-sparteine, that both proved active toward lactide under mild
conditions (Figure 3).16,23,24 Reactions were carried out at 30
°C in dichloromethane solution ([BED]0 ) 1 mol/L) with
n-pentanol as initiator, monomer to initiator ratios from 10 to
200, and 1 to 5 mol % catalyst (Table 1). Both catalytic systems
were found to efficiently promote the ROP of BED, complete
monomer conversions being achieved in a few minutes to a few
hours. According to SEC analyses, polymers with number-
average molar mass Mn increasing from ∼3000 (for M0/I0 )
10) to ∼36000 (for M0/I0 ) 200) and narrow distributions (Mw/
Mn < 1.27) were obtained. The TUCy/(-)-sparteine system is
significantly more active than DMAP (see for example entries
2 vs 5), comparable to that observed with lactide.16,23 In
addition, the functionalized monomer BED was found to be
slightly more reactive than lactide under similar conditions: the
TUCy/(-)-sparteine system required only 15 min to achieve
complete conversion of 100 equivalents of BED vs 90 min for
lactide (entries 9 and 10). This behavior contrasts with the
deactivation usually induced by the introduction of pendant
To get more insight into the selectivity of the ring-opening,
BED was reacted with an excess of n-pentanol in the presence
of the organo-catalyst. With both DMAP and TUCy/(-)-

1926 Biomacromolecules, Vol. 11, No. 8, 2010
Boullay et al.
Table 1. Polymerization of BED Initiated by n-Pentanol and Catalyzed with 4-Dimethylaminopyridine (DMAP) or Thiourea TUCy
(-)-Sparteinea
/
b
c
entry
catalyst
M0/I0
cat/I0
time (min)
DPNMR
Mn (g/mol)c
Mw/Mn
1
2
3
4
5
6
7
8
DMAP
DMAP
DMAP
DMAP
10
25
50
100
25
50
100
200
100
100
1
2.5
5
420
1080
1080
1440
20
30
60
60
15
90
10
26
2870
8950
14200
18690
7890
13840
20660
36200
24640
21150
1.27
1.16
1.19
1.23
1.22
1.13
1.16
1.12
1.17
1.06
58
5
80d
28
TUCy/(-)ssparteine
TUCy/(-)-sparteine
TUCy/(-)-sparteine
TUCy/(-)-sparteine
TUCy/(-)-sparteine
TUCy/(-)-sparteine
1/1
2/2
2/2
4/4
5/2.5
5/2.5
48
92
nd
110
104
9
10e
a Polymerizations of BED in CH2Cl2 solution (initial concentration ) 1 mol/L) at 30 °C, monomer conversion >98% according to 1H NMR spectroscopy.
b Obtained from 1H NMR spectroscopy. c Number-average molar mass (Mn) and polydispersity index (Mw/Mn) obtained from size exclusion chromatography
(in tetrahydrofuran, THF) using polystyrene standards. d Monomer conversion ) 80%. e Polymerization of L-lactide.
diastereotopic hydrogens of the CH2 glycolic unit, and a doublet
of doublets at 4.37 ppm (J ) 4.2 and 7.5 Hz) for the terminal
CHOH group. For the minor compound 6, the terminal
methylene group CH2OH appears at 4.22 ppm (d, J ) 5.1 Hz),
while the methine moiety of the glu unit resonates as a doublet
of doublets at 5.17 ppm (J ) 4.8 and 7.8 Hz). This result
confirms that the ring-opening of BED occurs almost indiffer-
ently at the two ester groups of the 1,4-dioxane-2,5-dione core,
in agreement with the random character of the polyBED. The
conformation of the monomer as observed in the solid-state
might explain why the pendant functional group does not
significantly influence the regioselectivity of the ring-opening
in this case, as the steric hindrance is possibly compensated by
some inductive effects.
Figure 4. MALDI-TOF MS (region m/z 1000-12800) of a polyBED
prepared by polymerization of BED with n-pentanol (CH2Cl2, 25 °C,
[BED]0/[n-pentOH]0/[TUCy]/[(-)-sparteine] 25/1/1/1, [BED]0 ) 1 mol/
L); m/z ) 88.1 (Mn-pentOH) + n × 278.3 (MBED) + 23.0 (Na+).
Controlled Character of the Polymerization. As mentioned
before, increasing the monomer to initiator ratio (from 10 to
200) led to polyBED of increasing molar mass (Mn from 3000
to 36000, see Table 1). With both catalytic systems, the number-
average molar mass (Mn) of the polyBED samples increases
linearly with the monomer to initiator ratio (Figure 8a) and
monomer conversion (Figure 8b), and the polydispersity index
Mw/Mn remains fairly low (1.16-1.27 for DMAP and 1.12-1.22
for TUCy) up to high monomer conversions (see Supporting
sparteine, ring-opening took place rapidly and irreversibly to
give a 1/0.75 mixture of adducts 5 and 6 (Figure 7). Both
compounds were fully characterized after separation by column
chromatography. The 1H NMR spectrum of the major derivative
5 displays an AB system at 4.74 and 4.62 ppm for the
Figure 5. 1H NMR spectrum (CDCl3, 300 MHz) of a polyBED sample obtained by polymerization of BED with n-pentanol as initiator (CH2Cl2, 30
°C, [BED]0/[n-pentOH]0/[TUCy]/[(-)-sparteine] 25/1/1/1, [BED]0 ) 1 M). *Residual TUCy
.

Polymerization of a 1,4-Dioxane-2,5-dione
Biomacromolecules, Vol. 11, No. 8, 2010 1927
Figure 6. CH-CH2/CO region of 1H-13C HMBC NMR spectrum of a polyBED sample obtained by polymerization of BED with n-pentanol as
initiator (CH2Cl2, 30 °C, [BED]0/[n-pentOH]0/[TUCy]/[(-)-sparteine] 100/1/2/2, [BED]0 ) 1 M).
Figure 7. Ring-opening of BED with an excess of n-pentanol and
TUCy/(-)-sparteine as catalyst ([BED]0/[n-pentOH]0/[TUCy]/[(-)-
sparteine] 1/10/1/1): 1H NMR spectrum of the crude reaction mixture
(4.0-5.5 ppm region).
Information for related plots associated with DMAP-catalyzed
ROP of BED). These observations indicate that transesterifi-
cation reactions do not occur to a significant extent, in agreement
with that observed by MALDI-TOF mass spectrometry. The
absence of undesirable side-reactions was further supported by
Figure 8. (a) Plot of number-average molar mass Mn ([) and
polydispersity index Mw/Mn (]; estimated by size exclusion chroma-
tography SEC) vs monomer to initiator ratio (CH2Cl2, 30 °C, [n-pen-
tOH]0/[TUCy]/[(-)-sparteine] ) 1/1/1 to 1/4/4, [BED]0 ) 1 mol/L). (b)
Plot of Mn ([) and Mw/Mn (]; estimated by SEC) vs monomer
conversion (estimated by 1H NMR spectroscopy) (CH2Cl2, 30 °C,
[BED]0/[n-pentOH]0/[TUCy]/[(-)-sparteine] ) 100/1/2/2, [BED]0 ) 1
mol/L).
1
first-order kinetic rate of polymerization, as deduced from H
NMR monitoring of monomer consumption (see Supporting
Information). To estimate the exact molar mass of polyBED,
two samples (prepared with monomer to initiator ratios of 25
and 100) were analyzed with a SEC apparatus equipped with a
three-angle light scattering detector (using dn/dc ) 0.1137
mL/g, as determined at 620 nm). In line with that expected from
the presence of pendant lateral groups, the hydrodynamic
volumes of polyBED are significantly higher than those of
polylactide and, in fact, the RI response of polyBED only
slightly deviates from that of the polystyrene standards in the
range Mn 8000-30000 (correction factor ) 0.95 for polyBED
vs 0.58 for polylactide25).
of 1 equiv of TUCy/(-)-sparteine. Polymerization was then
restarted by addition of 25 equiv of monomer to yield a
polyBED of about twice the number-average molar mass (Mn
) 13130) and still low polydispersity index (Mw/Mn ) 1.17).
Purification and Deprotection of PolyBED. DMAP and
(-)-sparteine are easily removed from polyBED by acidic
treatment, but trace amount of TUCy remained even after several
precipitations in methanol. To facilitate the removal of the
thiourea compound, TUNMe tagged with a tertiary amine
2
In addition, the living character of the ROP of BED was
supported by a second feed experiment (Figure 9). A polyBED
with Mn ) 7530 and Mw/Mn ) 1.21 was first prepared by ROP
of 25 equiv. of BED initiated with n-pentanol in the presence
group14b was used as the catalyst. TUNMe requires the presence
2
of (-)-sparteine to promote efficiently the ROP of BED and
notwithstanding, shows slightly lower activity than TUCy.

1928 Biomacromolecules, Vol. 11, No. 8, 2010
Boullay et al.
namely, (3S)-[(benzyloxycarbonyl)ethyl]-1,4-dioxan-2,5-di-
one BED. The polymerization takes place under mild
conditions with a high level of control. The pendant
functional group does not interfere with the polymerization
and BED was even found to be slightly more reactive than
lactide. Despite the strongly dissymmetric substitution pattern
of the 1,4-dioxan-2,5-dione core, the ring-opening of BED
occurs almost indifferently on either of the endocyclic ester
groups so that the ensuing polyBED polymers present a
random distribution of glycolic-[(benzyloxycarbonyl)ethyl]g-
lycolic (gly-glu) units. The absence of undesirable transes-
terification reactions insures that the functional groups are
distributed over the polymer backbone. After acetylation of
the terminal OH groups and deprotection by hydrogenolysis,
well-controlled poly(R-hydroxyacids) featuring pendant car-
boxylic acid groups are obtained.
Figure 9. SEC traces of (a) polyBED DPth ) 25 (full line) and (b)
polyBED DPth ) 50 (dashed line).
Table 2. Polymerization of BED Initiated by n-Pentanol and
a
Catalyzed with TUNMe /(-)-Sparteine
2
b
Mn (g/mol)b
Mw/Mn
polymerization
purification
acetylation
11370
11250
12240
10250
1.16
1.14
1.12
1.13
The organo-catalyzed ROP of functionalized 1,4-dioxan-2,5-
diones, thus, appear as an attractive route to poly(R-hydroxy-
acids) with pendant functional groups.26 According to prelimi-
nary investigations, this approach is not limited to the two
organo-catalytic systems reported here, and can be extrapolated
to more active catalysts. The bicyclic guanidine DBU (1,8-
diazabicyclo[5.4.0]-undec-7-ene)27 was indeed found to poly-
merize 100 equivalents of BED within only 10 min at room
temperature (with a catalyst loading of 0.2 mol % with respect
to the alcohol initiator), leading to a polyBED of controlled
molar mass (Mn ) 22810 g/mol) and narrow distribution (Mw/
Mn ) 1.13).
hydrogenolysis
a Polymerizations of BED in CH2Cl2 solution at 30 °C with [BED]/[n-
pentOH]0 ) 50, [n-pentOH]0/[TUNMe ]/[(-)-sparteine] ) 1/2/2, [BED]0 ) 1
2
mol/L). According to 1H NMR spectroscopy, monomer conversion >98%
after 180 min and DP ) 48. b Number-average molar mass (Mn) and
polydispersity index (Mw/Mn) obtained from size exclusion chromatography
(in tetrahydrofuran, THF) using polystyrene standards.
Accordingly, a polymer sample of DP ∼50 was prepared in
180 min (Table 2). The two catalyst components TUNMe and
2
(-)-sparteine were completely removed from the polymer
sample by acidic treatment with Amberlyst 15, as apparent from
1
the 19F and H NMR spectra. Deprotection of the pendant
Acknowledgment. We are grateful to Minakem, the ANR
(ANR-08-CP2D-01-BIOPOLYCAT), the CNRS and the UPS
for financial support of this work. We also thank Chantal Zedde
for assistance in Chiral-HPLC.
functional groups was then achieved following the same protocol
used for the polymer derived from gluOCA.14c The terminal
hydroxyl groups were first acetylated with acetic anhydride to
prevent competitive reactions (especially lactonization). The
pendant carboxyl groups were then deprotected by hydrogenoly-
sis using Pd/C as catalyst. The complete removal of the benzyl
protecting groups was deduced from the disappearance of all
of the aromatic signals from the 1H NMR spectrum (Figure 10).
In addition, SEC analyses showed that none of these three steps
(purification by acidic treatment, acetylation, and hydrogenoly-
sis) affected the polymer backbone both Mn and Mw/Mn
remaining fairly constant.
Supporting Information Available. (1) Chiral HPLC chro-
matograms of (rac-3) and (3), (rac-BED) and (BED); (2)
Crystallographic data for BED; (3) MALDI-TOFF MS of a
polyBED prepared by DMAP-catalyzed ROP of BED; (4)
Plot of the number-average molar mass and molecular
distribution versus monomer to initiator ratio and plot of the
degree of polymerization versus monomer conversion for
DMAP-catalyzed ROP of BED; (5) Semilogarithmic plot of
BED conversion versus time; (6) 1H NMR spectra for
polyBED deprotection sequence; and (7) crystallographic
information file for BED (CIF; CCDC 773604). This material
is available free of charge via the Internet at http://
pubs.acs.org.
Conclusion
The organo-catalysts DMAP or TUCy/(-)-sparteine com-
bination were found to promote the efficient ring-opening
polymerization of a functionalized 1,4-dioxan-2,5-dione,
Figure 10. Reaction sequence for polyBED purification and deprotection; related SEC traces.

Polymerization of a 1,4-Dioxane-2,5-dione
Biomacromolecules, Vol. 11, No. 8, 2010 1929
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