Controlled ring-opening polymerization of lactide by bis-sulfonamide/ amine associations: Cooperative hydrogen bonding catalysis

Article abstract of DOI:10.1002/pola.23852

The bis-sulfonamide m-C₆H₄(SO₂NHPh) ₂ efficiently promotes the ring-opening polymerization of lactide when combined with tertiary amines, such as N,N-dimethylamino-pyridine. Polylactides of controlled molecular weights (M_n up to 17,700 g moT^-1) and very narrow molecular weight distributions (M _w/M_n < 1.11) are obtained under mild conditions and in a living fashion. The reaction takes place through a bifunctional mechanism involving activation of both the alcohol and the monomer. Modulation of the sulfonamide component supports cooperative dual hydrogen-bonding of lactide involving the two (SO₂NHAr) moieties.

Full text of DOI:10.1002/pola.23852

Controlled Ring-Opening Polymerization of Lactide by Bis-Sulfonamide/
Amine Associations: Cooperative Hydrogen-Bonding Catalysis
1,2
1,2
AURELIE ALBA, AURELIA SCHOPP, ANNE-PAULA DE SOUSA DELGADO,3 ROLAND CHERIF-CHEIKH,3
´
´
1,2
BLANCA MARTIN-VACA, DIDIER BOURISSOU1,2
´
1Universite´ de Toulouse, UPS, LHFA, 118 route de Narbonne, F-31062 Toulouse, France
2CNRS, LHFA UMR 5069, F-31062 Toulouse, France
3Ipsen Pharma, Ctra. Laurea` Miro´ 395, E-08980 Sant Feliu de Llobregat, Spain
Received 13 October 2009; accepted 24 November 2009
DOI: 10.1002/pola.23852
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: The bis-sulfonamide m-C6H4(SO2NHPh)2 efficiently
promotes the ring-opening polymerization of lactide when
combined with tertiary amines, such as N,N-dimethylamino-
pyridine. Polylactides of controlled molecular weights (Mn up
to 17,700 g molꢀ1) and very narrow molecular weight distri-
butions (Mw/Mn < 1.11) are obtained under mild conditions
and in a living fashion. The reaction takes place through a
bifunctional mechanism involving activation of both the alco-
hol and the monomer. Modulation of the sulfonamide com-
ponent supports cooperative dual hydrogen-bonding of
C
V
lactide involving the two (SO2NHAr) moieties.
2010 Wiley
Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 959–
965, 2010
KEYWORDS: biodegradable polymers; hydrogen bonds; organo-
catalysis; ring-opening polymerization; polyester; sulfonamides
INTRODUCTION Over the last decade organo-catalysis has
been an area of very intense investigations, and spectacular
advances have been achieved in terms of scope, activity, and
selectivity.1,2 Among the different approaches, hydrogen-
bonding catalysis occupies a forefront position,2 and in line
with enzymatic catalysis, multi-center systems leading to
several synergistic interactions with the reaction substrates
have proved extremely efficient.1(a,b),2(d–g) This strategy is
nicely illustrated by the combination of hydrogen bond do-
nor and acceptor moieties that allows the cooperative activa-
tion of electrophilic and nucleophilic partners.
activation was proposed for the ROP of lactide promoted by
this bifunctional system. Hydrogen-bonding to the thiourea
group would activate the carbonyl group of the monomer,
while the basic amine group of the catalyst would facilitate
the nucleophilic attack of the initiating/propagating alcohol
(Fig. 1). Thanks to these cooperative weak interactions, the
thiourea/amine combination shows high selectivity for poly-
merization over undesirable transesterification, and because
of high functional group tolerance, it is well-suited to the
preparation of complex architectures.5(d,f)
Recently, we have demonstrated the ability of (trifluoro)-
methane sulfonic acids to catalyze the controlled polymeriza-
tion of lactide and e-caprolactone under mild conditions via
monomer activation.6 Here, we wondered if sulfonamides
could be used as hydrogen-bond donors in organo-catalyzed
ROP of lactones, the trivalent nature of the nitrogen atom
providing in addition room for structural modulation. Sulfo-
namides have only been scarcely explored as organo-cata-
lysts. Most of the contributions reported in this area concern
bifunctional systems combining sulfonamide and amine moi-
eties.7–10 A few examples also involve bis-sulfonamides in
their own for the activation of carbonyl derivatives (Chart
1).11–13
Over the last few years, the scope of organo-catalyzed reac-
tions has been further extended to the ring-opening poly-
merization (ROP) of lactones. The ensuing polyesters, and
especially those derived from lactide, are attracting increas-
ing attention due to their biodegradable and biocompatible
properties.3,4 Taken into account the application fields of
these polymers (medical devices, microelectronics, etc.),
metal-free ROP is highly desirable. This approach was pio-
neered in 2001 using N,N-dimethylaminopyridine (DMAP),
and various organo-catalysts were then shown to efficiently
promote and control the ROP of lactide.4(d,e) Among them,
the combination of a thiourea and a tertiary amine provides
an excellent compromise between activity and selectivity, as
reported in 2005 by Hedrick and coworkers.5 On the basis
of experimental5(a–c) and theoretical5(e) studies, a multicenter
The combination of a bis-sulfonamide and a tertiary amine
was evaluated here for the hydrogen-bonding catalysis of the
ROP of lactide. The polymerization has been found to
Additional Supporting Information may be found in the online version of this article.
Correspondence to: D. Bourissou (E-mail: dbouriss@chimie.ups-tlse.fr) or B. Martı´n-Vaca (E-mail: bmv@chimie.ups-tlse.fr)
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Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 48, 959–965 (2010) 2010 Wiley Periodicals, Inc.
ROP OF LACTIDE, ALBA ET AL.
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JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
molꢀ1) were used. Calibrations were performed using poly-
styrene standards (400–100,000 g molꢀ1).
Electrospray-ionization mass spectra (ESI-MS) were per-
formed on an Applied Biosystem API-365 spectrometer or
Applied Biosystem Qtrap spectrometer operating in positive
ion mode, HRMS were performed on a Micromass Waters
LCT apparatus. Samples were dissolved in acetonitrile, doped
with traces of ammonium hydroxide, and infused with a sy-
ringe pump at 5 mL minꢀ1
.
General Procedure for the Synthesis of the
Bis-Sulfonamides
FIGURE 1 Hydrogen-bonding catalysis proposed for the ring-
opening of lactide with a tertiary amine and a thiourea (ROH
refers to the initiating/propagating alcohol).
To a mixture of 2 equiv amine RNH2 and 2 equiv pyridine in
THF (1 mol Lꢀ1) was added 1 equiv bis-sulfonyl chloride
R0(SO2Cl)2. The mixture was stirred at room temperature
until total conversion of the starting materials according to
1H NMR spectroscopy. The solvent was removed under vac-
uum and the reaction mixture was purified by column chro-
matography (eluent gradient CH2Cl2/MeOH).
proceed under mild conditions in a controlled and living
manner. Particular attention has been devoted to support the
cooperative dual hydrogen-bonding activation of the mono-
mer by the bis-sulfonamide. During the preparation of this
manuscript, Dubois and coworkers reported the use of fluo-
rinated bis-alcohols (as dual hydrogen bond donors) in com-
bination with sparteine for the ROP of lactide, b-butyrolac-
tone and a functionalized trimethylene carbonate.14
Catalyst 1
Yield: 80%. The obtained analytical data were in agreement
with published data.15
Catalyst 2
Yield: 60%. 1H NMR (CD3OD, 300 MHz): d 8.21 (t, 3J ¼ 7.7
4
3
EXPERIMENTAL
Hz, 1H, CH), 8.03 (dd, J ¼ 1.7 Hz, J ¼ 7.7 Hz, 2H, CH), 7.74
(t, 3J ¼ 1.7 Hz, 1H, CH), 7.60 (s, 2H, CH), 7.58 (s, 4H, CH)
ppm. 13C (CD3OD, 75 MHz): d 142.2 (C), 140.6 (C), 133.9 (q,
2JCAF ¼ 33.7 Hz, C), 132.5 (CH), 132.1 (CH), 126.6 (C), 124.2
Materials
Solvents and reagents were used as received, unless speci-
fied. All polymerizations were performed under an inert
atmosphere of argon, using standard Schlenk techniques.
When necessary, solvents were dried and distilled before
use: dichloromethane (DCM) (>99.95%) over phosphorus
pentoxide, toluene over sodium or with a Mbraun solvent
purification system (MB-SPS-800), diethyl ether over sodium,
and pentane over CaH2. D,L-Lactide (LA; 99.5%) (PURAC)
was purified by azeotropic distillation, recrystallised in tolu-
ene and stored under argon. n-Pentan-1-ol (99þ%) was
dried over sodium and distilled before use.
1
3
(q, JCAF ¼ 271.6 Hz, CF3), 120.9 (q, JCAF ¼ 3.5 Hz, CH),
3
118.7 (q, JCAF ¼ 3.9 Hz, CH) ppm. 19F (CD3OD, 282 MHz): d
– 63.2 ppm. MS (CI, NH3): 678 [MþNH4]þ. ELEM. ANAL.: Calcu-
lated for C22H12F12N2O4S2 C 40.01%, H 1.83%, N 4.24%.
ꢁ
Found C 40.38%, H 1.26%, N 4.19%. Mp ¼ 159.0–159.6 C.
Catalyst 3
Yield: 70%. 1H NMR (CDCl3, 300 MHz): d 8.58 (t, 4J ¼ 1.7
4
3
Hz, 1H, CH), 7.83–7.80 (q, J ¼ 1.7 Hz, J ¼ 7.8 Hz, 2H, CH),
Characterizations
Spectra were recorded in CDCl3 on Bruker Advance 300 MHz
at room temperature. 1H and 13C chemical shifts are
reported in ppm relative to Me4Si as an external standard.
19F chemical shifts are reported in ppm relative to CF3COOH
as an external standard. 1H NMR measurements were used
to determine the monomer conversion and the chain end
groups. Monomer conversion was determined from the rela-
tive intensities of the methyl signals for the monomer (dou-
blet at d 1.61 ppm) and polymer (multiplet at d 1.58 ppm).
The number-average and weight-average molar masses (Mn
and Mw, respectively) and polydispersity indexes (Mw/Mn) of
the Polylactide (PLA) samples were ꢁ determined by size
exclusion chromatography (SEC) at 35 C with a Waters 600
high-speed liquid chromatograph equipped with a R410 re-
fractometer detector. Tetrahydrofuran (THF) was used as the
eluent, and the flow rate was set up at 1.0 mL minꢀ1 A Styr-
agel guard column (WAT054405) and two STYRAGEL col-
umns (HR1, 100–5000 g molꢀ1, and HR4E, 50–100,000 g
CHART 1 Representative sulfonamides used as organo-
catalysts.
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7.51 (t, 3J ¼ 7.8 Hz, 1H, CH), 6.84 (s, 4H, CH), 6.71 (s, 2H,
NH), 2.25 (s, 6H, CH3), 2.00 (s, 12H, CH3) ppm. 13C (CDCl3,
75 MHz): d 142.6 (C), 138.1 (C), 137.5 (C), 131.1 (CH),
130.0 (CH), 129.7 (CH), 129.3 (C), 125.9 (CH), 20.9 (CH3),
18.7 (CH3) ppm. MS (EI): 233 [M]þ. ELEM. ANAL.: Calculated
for C24H28N2O4S2 C 60.99%, H 5.97%, N 5.93%. Found C
chromatography (eluent CH2Cl2/MeOH 95/5) to yield 7 as a
white powder with 50% yield. H NMR (CDCl3, 300 MHz): d
1
8.09 (t, 1H, CH), 7.94–7.91 (m, 1H, CH), 7.60–7.56 (m, 1H,
CH), 7.49 (m, 1H, CH), 7.29–7.26 (m, 6H, CH), 7.09 (m, 1H,
CH), 7.06 (m, 1H, CH), 6.98–6.94 (m, 2H, CH), 6.84 (br s, 1H,
NH), 3.09 (s, 3H, CH3) ppm. 13C (CDCl3, 75.5 MHz): d 140.7
(C), 140.2 (C), 138.0 (C), 135.7 (C), 131.9 (CH), 131.2 (CH),
129.7 (CH), 129.6 (CH), 129.2 (CH), 127.9 (CH), 126.6 (CH),
126.4 (CH), 126.2 (CH), 122.1 (CH), 38.4 (CH3) ppm. HRMS
DCI (CH4): found 403.0769 (MþHþ- C19H19N2O4S2), calc.
ꢁ
60.90%, H 5.91%, N 5.85%. Mp ¼ 197.9–199.5 C.
Catalyst 4
Yield: 75%. 1H NMR (CDCl3, 300 MHz): d 7.35 (m, 4H, CH),
7.27 (m, 2H, CH), 7.23–7.18 (m, 4H, CH), 7.04 (s, 2H, NH),
3.32–3.27 (t, 3J ¼ 7.2 Hz, 4H, CH2), 2.41–2.36 (qt, 3J ¼ 7.2
Hz, 2H, CH2) ppm. 13C (CDCl3, 75 MHz): d 136.4 (C), 129.8
(CH), 125.7 (CH), 121.2 (CH), 48.8 (CH2), 18.1 (CH2) ppm.
MS (EI): 354 [M]þ. ELEM. ANAL.: Calculated for C15H18N2O4S2
C 50.83%, H 5.12%, N 7.90%. Found C 51.01%, H 4.74%, N
ꢁ
403.0786 (ꢀ1.7; ꢀ4.2). Mp ¼ 162.0–162.6 C.
Synthesis of Monomethylated Bis-Sulfonamide 8
Under an inert atmosphere of argon, 1.1 equiv NaH (206 mg,
8.6 mmol, oil removed by three dry pentane washes) was
added to a solution of 1 equiv bis-sulfonamide 4 (2.75 g, 7.8
mmol) in dry diethyl ether (110 mL). After 30 min at room
temperature, 1 equiv methyl triflate (880 lL, 7.8 mmol) was
added and the mixture was stirred overnight at room tem-
perature. The solvent was evaporated. The crude was redis-
solved in CH2Cl2, washed two times with HCl 1N, then brine,
dried over sodium sulfate, filtrated and reevaporated. The
solid obtained (mixture 0.4/0.2/0.4 nonmethylated/mono-
methylated/dimethylated) was purified by column chroma-
tography (eluent CH2Cl2/MeOH 95/5) to yield 8 as a white
powder (12%). 1H (CDCl3, 300 MHz): d 7.34 (br s, 1H, NH),
7.27 (m, 4H, CH), 7.24–7.19 (m, 3H, CH), 7.16–7.13 (m, 2H,
CH), 7.08 (m, 1H, CH), 3.21 (s, 3H, CH3), 3.13 (m, 4H, CH2),
2.23 (m, 2H, CH2) ppm. 13C (CDCl3, 75.5 MHz): d 140.9 (C),
136.6 (C), 129.7 (CH), 129.5 (CH), 127.7 (CH), 126.7 (CH),
125.3 (CH), 120.8(CH), 49.4 (CH2), 47.1 (CH2), 38.6 (CH3),
18.0 (CH2). HRMS DCI (CH4): found 369.0957 (MþHþ-
ꢁ
7.85%. Mp ¼ 129.8–131.6 C.
General Procedure for Synthesis of the
Mono-Sulfonamides
To a mixture of 1 equiv amine RNH2 and 1 equiv pyridine in
THF (1.8 mol Lꢀ1) was added 1 equiv sulfonyl chloride
R0SO2Cl. The mixture was stirred at room temperature until
total conversion of the starting materials according to 1H
NMR spectroscopy. The solvent was removed under vacuum
and the reaction mixture was purified by column chromatog-
raphy (eluent gradient CH2Cl2/MeOH).
Catalyst 5
Yield: 90%. 1H NMR (CDCl3, 300 MHz): d 7.96 (d, 3J ¼ 7.7
Hz, 2H, CH), 7.73–7.68 (m, 1H, CH), 7.63–7.58 (m, 2H, CH),
7.43–7.39 (m, 2H, CH), 7.31–7.23 (m, 3H, CH), 7.03 (s, 1H,
NH) ppm. 13C (CDCl3, 75 MHz): d 138.96 (C), 136.4 (C),
133.1 (CH), 129.4 (CH), 129.1 (CH), 127.3 (CH), 125.5 (CH),
121.7 (CH) ppm. MS (EI): 233 [M]þ. ELEM. ANAL.: Calculated
for C12H11NO2S C 61.78%, H 4.75%, N 6.00%. Found C
C
16H21N2O4S2), calc. 369.0943 (1.4;ꢀ3.8). Mp
¼
93.6–
ꢁ
94.2 C.
ꢁ
61.86%, H 4.50%, N 5.97%. Mp ¼ 110.5–112.0 C.
General Polymerization Procedure
Catalyst 6
Yield: 95%. 1H NMR (CDCl3, 300 MHz): d 7.38–7.32 (m, 2H,
CH), 7.21–7.15 (m, 3H, CH), 6.31 (s, 1H, NH), 3.12–3.06 (m,
2H, CH2), 1.86–1.75 (m, 2H, CH2), 1.48–1.36 (m, 2H, CH2),
0.90 (t, 3J ¼ 7.2 Hz, 3H, CH3) ppm. 13C (CDCl3, 75 MHz): d
137.1 (C), 129.5 (CH), 124.8 (CH), 120.3 (CH), 51.1 (CH2),
25.2 (CH2), 21.3 (CH2), 13.4 (CH3) ppm. MS (EI): 213 [M]þ.
ELEM. ANAL.: Calculated for C10H15NO2S C 56.31%, H 7.09%, N
6.57%. Found C 55.72%, H 7.27%, N 6.42%.
LA (500 mg, 3.47 mmol, 10 equiv) and the catalysts (1 equiv
sulfonamide and 1 equiv tertiary amine), were dissolved in
DCM (3.5 mL, [LA]0 ¼ 1 mol Lꢀ1). The initiator, n-pentan-1-
ol (38 lL, 0.35 mmol, 1 equiv) was then added. The reaction
ꢁ
mixture was stirred at 25 C until the complete consumption
of lactide, monitored by 1H NMR spectroscopy. 1H NMR
(CDCl3, 300 MHz): d 5.19–5.13 (m, 18H, OCHCH3), 4.36 (q,
J ¼ 6.8 Hz, 1H, HOCHCH3), 4.13 (m, 2H, OCH2(CH2)3CH3),
1.67–1.47 (m, 63H, OCHCH3), 1.34–1.25 (m, 4H,
OCH2(CH2)3CH3), 0.90 (s, 3H, CH3). DPNMR ¼ 9.6. SEC (THF):
Mn ¼ 2021, Mw/Mn ¼ 1.11.
Synthesis of the Monomethylated Bis-Sulfonamide 7
To a mixture of 1 equiv pyridine (1.47 mL, 18 mmol) and 1
equiv N-methyl aniline (1.97 mL, 18 mmol) in THF (50 mL)
was added 1 equiv 1,3 benzene disulfonyl chloride (5g, 18
mmol). After 2 h at room temperature, 1 equiv aniline (1.66
mL, 18 mmol) and 1 equiv pyridine (1.47 mL, 18 mmol)
were added. The mixture was stirred overnight at room tem-
perature. The solvent was removed under vacuum and the
crude was dissolved in CH2Cl2, washed with HCl 0.1N then
water, dried with sodium sulfate, filtrated, and reevaporated.
The solid obtained (mixture 0.33/1/0.33 nonmethylated/
monomethylated/dimethylated) was purified by column
Procedure for Kinetic Studies
Polymerization was carried out at 25 ꢁC in CH2Cl2 solution
with a lactide concentration of 1 mol Lꢀ1, and a lactide/n-
pentan-1-ol/bis-sulfonamide/DMAP molar ratio of 10/1/1/1.
Aliquots were taken at different times during the polymer-
ization, evaporated and redissolved in the analysis solvent.
1
Lactide conversion was determined by H NMR spectroscopy
and molecular mass by SEC.
ROP OF LACTIDE, ALBA ET AL.
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JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
RESULTS AND DISCUSSION
TABLE 1 ROP of Lactide Catalyzed by the Combination of
Bis-Sulfonamides 1–3 and DMAPa
To the best of our knowledge, the use of bis-sulfonamides as
dual hydrogen-bond donors was pioneered by Crabtree and
coworkers in the late 90s. Compound 1 was used for anion
recognition15 as well as catalysis of aldehyde imination.12
With this system, the rigid meta-phenylene linker can be
anticipated to favor two point hydrogen-bonding and the
variation of the aryl groups on the nitrogen atoms offers the
opportunity to modulate the acidity of the sulfonamide moi-
eties. To investigate their catalytic activity in the ROP of
lactide, the bis-sulfonamides 1–3 were prepared from 1,3-
benzenedisulfonyl chloride and the corresponding anilines
(Scheme 1). Compared with the experimental conditions
used previously,15 we found advantageous to perform the
reaction in THF in the presence of 2 equiv pyridine. Accord-
ingly, the presence of trace amounts of DMF (that may inter-
fere with the hydrogen-bonding catalysis) was avoided, and
the bis-sulfonamides 1–3 were isolated in 60–80% yields af-
ter column chromatography.
Monomer Conversion (%)
Catalytic System
After 5 hb
1/DMAP
2/DMAP
3/DMAP
DMAP
a
97
76
68
37
LA/n-PentOH/bis-sulfonamide/DMAP ¼ 5/1/1/1 and [LA]0 ¼ 1 mol Lꢀ1
.
b
As determined by 1H NMR spectroscopy.
tyl groups (compound 3) also resulted in slower
polymerization.
The catalytic activity of the bis-sulfonamides 1–3 towards
the ROP of lactide was evaluated in DCM solution at 25 ꢁC
using n-pentan-1-ol as the initiator. Under these conditions,
none of the bis-sulfonamide 1–3 was able to promote the
polymerization (no monomer conversion after 24 h accord-
ing to 1H NMR monitoring). In contrast, polymerization
occurred when the bis-sulfonamides 1–3 were combined
with a tertiary amine, such as DMAP. A control experiment
carried out with DMAP alone led to a significantly lower
monomer conversion (37% vs. 68–97% after 5 h, Table 1),
indicating that the two components of the bifunctional sys-
tem act synergistically. The higher activity was found for the
‘‘parent’’ bis-sulfonamide 1. The more acidic bis-sulfonamide
2 featuring strong electron-withdrawing CF3 groups was
found slightly less efficient, probably due to some acid/base
deactivation. The introduction of sterically demanding mesi-
The influence of the amine component of the bifunctional
system was then evaluated for the bis-sulfonamide 1. In
addition to DMAP, 1 was combined with collidine (2,4,6-tri-
methylpyridine), (NMe2)2Cy, NMe2Cy, 1,4-diazabicyclo[2.2.2]-
octane (DABCO), diisopropylethylamine and (ꢀ)-sparteine.
Similarly to that observed by Hedrick and coworkers for the
thiourea/amine association,5(b) the structure of the amine
significantly influences the activity. Here, the aliphatic amines
induced slower polymerization rates (Table 2), and DMAP is
the optimal base to combine with the bis-sulfonamide 1.
This contrasts with the situation reported for the cyclohexyl-
3,5-(CF3)2-phenyl-thiourea, where sparteine led to the best
results.5(b) The differences in activity observed between the
various amines likely result from the combination of the
steric and electronic effects and from acid/base association
equilibria that may deactivate the bifunctional system.
TABLE 2 ROP of Lactide Catalyzed by the Combination of the
Bis-Sulfonamide 1 and Different Aminesa
Monomer Conversion
Catalytic System
(%) After 5 hb
1/collidinec
1/DMAP
1/(NMe2)2Cyd
1/NMe2Cye
1/DABCOf
1/DIEAg
11
97
73
77
23
45
73
1/(ꢀ)-sparteine
a
LA/n-PentOH/bis-sulfonamide/DMAP ¼ 5/1/1/1 and [LA]0 ¼ 1 mol Lꢀ1
As determined by 1H NMR spectroscopy.
Collidine ¼ 2,4,6-Trimethylpyridine.
.
b
c
d
e
f
(NMe2)2Cy ¼ 1,2-Bis(dimethylamino)cyclohexane.
NMe2Cy ¼ N,N-Dimethylcyclohexylamine.
DABCO ¼ 1,4-Diazabicyclo[2.2.2]-octane.
DIEA ¼ Diisopropylethylamine.
g
SCHEME 1 Preparation of the bis-sulfonamides 1–3.
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TABLE 3 Polymerization of D,L-Lactide Initiated by n-Pentan-1-ol
and Catalyzed by the Combination 1/DMAPa
Time Conversion
(%)b
DPNMR Mn(SEC)
Mw/Mn
c
c
LA/n-PentOH (h)
10
13
98
95
95
95
96
10
35
51
70
85
2020
6200
1.11
1.07
1.07
1.06
1.07
30d
50d
75d
100d
a
23
39
9620
72
14070
17680
156
Reactions carried out in CH2Cl2 at 25 ꢁC with n-PentOH/1/amine ¼ 1/1/
1 and [LA]0 ¼ 1 mol Lꢀ1
.
b
As determined by 1H NMR spectroscopy.
As determined by SEC in THF.
n-PentOH/1/amine ¼ 1/10/10.
c
d
The optimal catalytic system 1/DMAP was then investigated
in more detail. PLAs with molecular weights up to Mn
¼
17,700 g molꢀ1 and very narrow molecular weight distribu-
tions (Mw/Mn < 1.11) were prepared under mild conditions
by increasing the monomer to initiator ratio (Table 3). The
protic initiator (n-pentan-1-ol) was quantitatively incorpo-
rated in the resulting PLA as a n-pentyl ester chain-end, as
1
demonstrated by H NMR spectroscopy and ESI-MS (see Sup-
porting Information). ESI-MS revealed also the absence of
transesterification reactions as only oligomers with even
numbers of lactate units were detected (the polymer chain
grows by two lactate units per monomer). The absence of
transesterification reactions even at high monomer conver-
sions substantiates the strong preference of the catalyst to
activate the monomer rather than the polymer chain, result-
ing in very narrow molecular weight distributions.
FIGURE 2 a) Mn(SEC) (n) and Mw/Mn (~) versus [LA]0/[n-
PentOH]0 ratio (CH2Cl2, 25 ꢁC, [n-PentOH]0/[1]0/[DMAP]0 ¼ 1/1/1 for
[LA]0/[n-PentOH]0 ¼ 10 and [n-PentOH]0/[1]0/[DMAP]0 ¼ 1/10/10 for
[LA]0/[n-PentOH]0 ¼ 30, 50, 75 and 100, [LA]0 ¼ 1.0 mol L–1). b)
Mn(SEC) (^) and Mw/Mn (~) versus D,L-lactide conversion (meas-
ured by 1H NMR) (CH2Cl2, 25 ꢁC, [LA]0/[n-PentOH]0/[1]0/[DMAP]0
30/1/10/10, [LA]0 ¼ 1.0 mol L–1).
¼
The linear relationship observed between the experimental
Mn(SEC) values and the initial monomer to initiator ratios
[Fig. 2(a)], together with the narrow molecular weight distri-
butions support the controlled character of the polymeriza-
tion.16 This is further confirmed by the linear variation of
the Mn(SEC) values with the monomer conversion [Fig. 2(b)]
and the first-order dependence of the polymerization rate on
the monomer concentration (see Supporting Information).
sulfonamide moieties act independently [Fig. 4(b)]. Notably,
in the study of the complexation of fluoride with the bis-sul-
fonamide 1, Crabtree and coworkers found both 1:1 and 1:2
adducts.15 A third possibility involves enhancement of the
Bro¨nsted acidity of one sulfonamide group by intramolecular
Furthermore, the living character of the polymerization was
supported by a second feed experiment. Accordingly, a PLA
with Mn ¼ 6200 g molꢀ1 and Mw/Mn ¼ 1.07 was first pre-
pared by complete polymerization of 30 equiv lactide with
n-pentan-1-ol/1/DMAP 1/10/10 [Fig. 3(a)]. Subsequent
addition of 30 equiv lactide allowed the polymerization to
restart, affording a PLA of Mn ¼ 11,900 g molꢀ1 and Mw/Mn
¼ 1.07 [Fig. 3(b)].
The results discussed above are in agreement with a bifunc-
tional mechanism in which the bis-sulfonamide 1 activates
the monomer while DMAP activates the alcohol.17 By analogy
with that encountered with thioureas,5 the two (SO2NHAr)
groups of the bis-sulfonamide can be envisaged to act coop-
eratively via two point hydrogen-bonding [Fig. 4(a)].18 But
taking into account the greater flexibility of bis-sulfonamide
1 compared to thioureas, it cannot be excluded that the two
FIGURE 3 Superposed size exclusion chromatography (SEC)
traces for the polylactide samples: (a) obtained after the first
feed of D,L-lactide (LA) (CH2Cl2, 25 ꢁC, [LA]0/[n-PentOH]0/[1]0/
[DMAP]0 30/1/10/10, [LA]0 ¼ 1.0 mol Lꢀ1) and (b) after a second
feed of 30 equiv D,L-lactide.
ROP OF LACTIDE, ALBA ET AL.
963

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
FIGURE 4 Possible modes of action of the bis-sulfonamides for
the activation of lactide.
FIGURE 5 Comparison of the different kobs values obtained
when combining the mono- and bis-sulfonamides 1, 4–8 with
DMAP (CH2Cl2, 25 ꢁC, [LA]0/[n-PentOH]0/[bis-sulfonamide]0/
hydrogen-bonding [Fig. 4(c)], so-called Bro¨nsted acid
assisted Bro¨nsted acid (BBA) catalysis.19
[DMAP]0
¼
10/1/1/1 and [LA]0/[n-PentOH]0/[mono-sulfona-
mide]0/[DMAP]0 ¼ 10/1/2/1, [LA]0 ¼ 1.0 mol L–1).
To gain more insight into the mode of action of the bis-sul-
fonamide 1, the related mono- and bis-sulfonamides 4–8
(Chart 2) were prepared and evaluated in combination with
DMAP for the ROP of 10 equiv lactide (Fig. 5). The initiator/
sulfonamide/DMAP ratio was set to 1/1/1 for the bis-sulfo-
namides and 1/2/1 for the mono-sulfonamides, to keep con-
stant the ratio between the hydrogen-bond donor moieties
and the other partners.
10–3 min–1) and N-methylated bis-sulfonamide 8 (kobs(8)
¼
2.07 10–3 min–1). Notably, the activity of the bis-sulfonamide
1 is substantially higher than that of 4. The higher rigidity of
the meta-phenylene linker, when compared with the tri-
methylene spacer, most likely favors the dual hydrogen-
bonding by the two sulfonamide groups.
The bis-sulfonamide 1 was first compared with the related
mono-sulfonamide, namely 5. The activity of 1 was found
significantly higher than that of 5 (kobs(1) ¼ 3.35 10–3 min–1
vs kobs(5) ¼ 2.12 10–3 min–1), in agreement with cooperative
dual hydrogen-bond activation of lactide by the bis-sulfona-
mide. This hypothesis was further corroborated by the mod-
erate activity displayed by 7, a monomethylated bis-sulfona-
mide with only one (SO2NHPh) moiety available for
hydrogen bonding (kobs(7) ¼ 2.49 10–3 min–1). The higher ac-
tivity of 7 compared to 5 does not support the hypothesis of
BBA activation (intramolecular hydrogen-bonding would
deactivate 7), and can probably be attributed to the elec-
tron-withdrawing character of the (SO2NMePh) group pres-
ent in 7. Similar trends were observed when comparing the
activity of the bis-sulfonamide 4 (kobs(4) ¼ 2.77 10–3 min–1)
with those of the related mono-sulfonamide 6 (kobs(6) ¼ 1.95
CONCLUSIONS
Due to their ability to engage in two point hydrogen-bonding
towards carbonyl groups, bis-sulfonamides have been found
to efficiently promote the ROP of lactide under mild condi-
tions. The combination of bis-sulfonamide 1 and DMAP gives
access to PLAs of controlled molecular weights and very
narrow molecular weight distributions. The polymerization
most probably proceeds via a bifunctional mechanism: the
bis-sulfonamide activates the monomer through cooperative
dual hydrogen-bonding while the amine activates the alcohol.
These results further emphasize the interest of multi-center
hydrogen-bonding in ROP catalysis.
The authors thank the CNRS, the ANR (ANR-08-CP2D-01-BIO-
POLYCAT), the University Paul Sabatier (France), and the Ipsen
Pharma for financial support of this work.
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