Organocatalytic ring-opening polymerization of cyclic esters mediated by highly active bifunctional iminophosphorane catalysts

Article abstract of DOI:10.1021/ma402258y

Highly active bifunctional iminophosphorane catalysts have been applied to the organocatalytic ring-opening polymerization (ROP) of l-lactide (LA), δ-valerolactone (VL), and ε-caprolactone (CL). LA polymerization using catalyst 2 at 1 mol % loading rapidl

Full text of DOI:10.1021/ma402258y

Article
pubs.acs.org/Macromolecules
Organocatalytic Ring-Opening Polymerization of Cyclic Esters
Mediated by Highly Active Bifunctional Iminophosphorane Catalysts
Anna M. Goldys and Darren J. Dixon*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: Highly active bifunctional iminophosphorane catalysts have been applied to the organocatalytic ring-opening
polymerization (ROP) of L-lactide (LA), δ-valerolactone (VL), and ε-caprolactone (CL). LA polymerization using catalyst 2 at 1
mol % loading rapidly gave poly(LA) in full conversion and with excellent control over the molecular weight distribution. VL and
CL were polymerized under the control of catalyst 3 at 5 mol % loading. Poly(VL) was obtained in high conversion and with
very good control over the molecular weight distribution. The catalyst system was suitable for the formation of short lengths of
poly(CL), with good control over the molecular weight distribution. The formation of block copolymers by sequential monomer
addition and the use of macroinitiators such as monomethoxy-terminated poly(ethylene glycol) (mPEG) were also demonstrated
using the catalyst system. Control experiments using nonbifunctional N-alkyl iminophosphorane 5 demonstrated the roles of
both components of the bifunctional catalyst in the ROP reaction. Notably, the bifunctional iminophosphorane catalysts are
moisture-stable and nonhygroscopic, enabling the assembly of ROP reactions on the open bench.
in the organocatalytic ROP of cyclic esters.5 These catalysts
have the advantage of being highly active (in the case of TBD in
particular), commercially available and competent in facilitating
INTRODUCTION
■
The ability to prepare a variety of structurally well-defined
polymers underlies the design and application of advanced
very well-controlled polymerizations. However, the more active
polymeric materials, for example the development of polymer-
somes for use as nanoreactors1 or for the encapsulation and
catalytic systems (such as TBD) exert decreased levels of
controlled release of drugs and medical imaging agents.2 Of the
control over the polymerization of more reactive monomers
such as LA, while the more finely controlled catalytic systems
existing polymerization techniques, organocatalytic ring-open-
ing polymerization, pioneered by Hedrick and co-workers,3−5 is
(DBU/thiourea) require prolonged reaction times and, in some
cases, result in incomplete monomer conversion. Furthermore,
characterized by its ability to produce polymers with excep-
amidines and guanidines are highly hygroscopic, making their
tionally low polydispersity and excellent end-group fidelity. In
recent years, the development of highly reactive guanidine,
amidine and N-heterocyclic carbene catalysts, as well as the
extension of organocatalytic techniques to a variety of
handling difficult in the absence of a glovebox. Indeed, ROP
reactions using these catalysts are performed in a glovebox5 and
in our hands, attempts to utilize them on the open bench were
met with limited success. Accordingly, a catalytic system that is
functionalized monomers have made organocatalysis an
both highly active, exerts exquisite control over ring-opening
attractive and practical alternative to traditional, metal-catalyzed
ROP.6 Furthermore, organocatalytic ROP provides unique
polymerization and is easy to handle is desirable.
Our group has recently disclosed the invention of a novel
advantages such as the production of polymers which are
class of potent bifunctional iminophosphorane organocatalysts
entirely free from metal residues and comparative ease of
and their application in the asymmetric nitro-Mannich
operation compared to metal-catalyzed polymerization.
The bases 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-
methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), in combination with a
simple thiourea cocatalyst, represent the current state-of-the-art
Received: November 1, 2013
Revised: January 22, 2014
© XXXX American Chemical Society
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reaction.7 These consist of a triaryl iminophosphorane linked to
a hydrogen bond donor, such as a thiourea (Figure 1). The
NMR spectra were recorded using a Bruker Avance 250, 400, or 500
MHz spectrometer and chemical shifts (δ) are quoted in parts per
million (ppm) referenced to the residual solvent peak. Conversion was
measured by the ratio of the integrations of the NMR signals of the α-
methylene or methine protons of the monomer compared to those of
the polymers. The tacticity of synthesized poly(LA) was determined
1
from the integration of the methine region of the homodecoupled H
NMR spectrum. Pi, the probability of forming an isotactic dyad, was
calculated using literature methods.9
MALDI-ToF MS analysis was performed on a Waters MALDI
micro equipped with a 337 nm nitrogen laser and an accelerating
voltage of 25 kV. The polymer samples were dissolved in THF at a
concentration of 1.0 mg mL−1. The cationization agent used was
potassium trifluoroacetate (Sigma-Aldrich, >99%) dissolved in THF at
a concentration of 5.0 mg mL−1. The matrix used was trans-2-[3-(4-
tert-butylphenyl)-2-methyl-2-propenylidene]malononitrile (DCTB)
(Sigma-Aldrich) and was dissolved in THF at a concentration of 40
mg mL−1. Solutions of matrix, salt and polymer were mixed in a
volume ratio of 2: 1: 2, respectively. The mixed solution was hand
spotted on a stainless steel MALDI target and left to air-dry. The
spectra were recorded in the reflectron mode.
Polymer molecular weights (Mw, Mn, and PDI) were determined by
GPC using a Polymer Laboratories PL-GPC50 Plus instrument
equipped with a Polymer Laboratories PLgel MixedD column (300
mm length, 7.5 mm diameter) and refractive index (RI) detector.
Samples were dissolved in THF (Fisher, HPLC grade, stabilized with
BHT, 2.5 ppm) at a concentration of 2.0 mg mL−1 and filtered prior to
injection. THF (Fisher, HPLC grade, stabilized with BHT, 2.5 ppm)
was used as the eluent at 30 °C and the flow rate was set to 1.0 mL
min−1. Linear polystyrenes (Polymer Laboratories) were used as the
primary calibration standards and the appropriate Mark−Houwink
corrections for poly(LA) and poly(CL) in THF at 30 °C were used to
calculate the experimental molecular weights.
Figure 1. General structure of bifunctional iminophosphorane
catalysts. R = aryl group; EWG = electron-withdrawing group.
strong basicity of these organocatalysts, comparable to that of
guanidines, enables their application in transformations where
the low reactivity of traditional tertiary amine organocatalysts is
a limiting factor. Conveniently, when combined with a thiourea
moiety, triaryl iminophosphoranes were found to be air- and
moisture-stable. The catalysts can be isolated and handled in air
and have been stored for several months in screw-cap vials at 4
°C with minimal decomposition. In light of the successful
application of guanidine and amidine bases in organocatalytic
ROP, we undertook to test our bifunctional iminophosphorane
catalysts in the ROP of cyclic esters (Figure 2).
GENERAL EXPERIMENTAL DETAILS
■
EXPERIMENTAL SECTION
■
L-Lactide was purchased from Alfa Aesar, D,L-lactide was purchased
from Sigma-Aldrich. Both were recrystallized three times from toluene
under anhydrous conditions then dried in vacuo before use. VL was
purchased from Acros Organics and CL was purchased from Alfa
Aesar. Both were distilled twice from calcium hydride before use. 1-
Pyrenebutanol and monomethoxy-terminated poly(ethylene glycol)
(MW ∼ 2000) were purchased from Sigma-Aldrich and dried before
use by dissolving in THF and stirring over calcium hydride overnight,
followed by filtration and recovery by removal of solvent under
nitrogen flow. Anhydrous toluene and dichloromethane were obtained
by filtration through activated alumina (powder ∼150 mesh, pore size
58 Å, basic, Sigma-Aldrich) columns, followed by standing over
activated 4 Å molecular sieves for 24 h. Chlorobenzene was distilled
from calcium hydride. 1H-Imidazole-1-sulfonyl azide hydrochloride
was prepared according to literature procedures.8 All other reagents
purchased from commercial sources were used as supplied. Solvents
were stored in sealed Schlenk flasks over activated 4 Å molecular
sieves, VL and CL were stored in sealed Schlenk flasks. LA was stored
in a desiccator under vacuum over phosphorus pentoxide. Reaction
assembly was performed on an open bench under a blanket of
nitrogen.
Catalyst Precursor 1. To a solution of bromoethylamine
hydrobromide (1.00 g, 4.88 mmol) in water (5 mL) at room
temperature was added sodium azide (0.952 g, 14.6 mmol) and the
reaction mixture was heated at 80 °C overnight. The reaction mixture
was allowed to cool to room temperature then basified with potassium
hydroxide (1.60 g, 28.5 mmol). The reaction mixture was then
extracted with diethyl ether (3 × 50 mL) and the combined organic
extracts washed with brine, dried over anhydrous sodium sulfate and
the solvent removed under a flow of nitrogen. The crude aminoazide
was dissolved in anhydrous THF (25 mL), treated with 3,5-
bis(trifluoromethyl)phenyl isothiocyanate (0.664 mL, 3.64 mmol)
and the reaction mixture stirred under argon atmosphere for 3 h. The
solvent was removed in vacuo and the crude reaction mixture purified
by flash column chromatography over silica (petroleum ether, followed
by 10% ethyl acetate in petroleum ether, then 20% ethyl acetate in
petroleum ether) to give the product as a colorless solid (1.03 g, 2.89
1
mmol, 59% over 2 steps). H NMR (500 MHz, CDCl3), δ (ppm):
8.54 (1 H, br s), 7.81 (2 H, s), 7.74 (1 H, s), 6.54 (1 H, br s), 3.94−
3.74 (2 H, m), 3.72−3.54 (2 H, m). 13C NMR (125 MHz, CDCl3), δ
(ppm): 181.1, 138.6, 133.4 (q, JFC = 34.3 Hz), 124.3 (d, JFC = 3.8 Hz),
Figure 2. Representation of dual activation of a monomer and growing polymer chain by a bifunctional iminophosphorane organocatalyst. R = aryl
group; EWG = electron-withdrawing group.
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122.8 (q, JFC = 272.8 Hz), 120.1 (t, JFC = 3.8 Hz), 50.4, 44.4. 19F NMR
(470 MHz, CDCl3), δ (ppm): −63.1. Mp: 84−85 °C. IR (νmax/cm−1):
3238, 2116, 1537, 1469, 1379, 1336, 1270, 1166, 1127, 971, 894, 847,
713, 680, 649. HRMS (ES+): calcd for C11H9F6N5NaS [M + Na]+,
380.0375; found, 380.0366.
(COOCH2 PCL backbone), 34.2 (CH2COO PCL backbone), 28.5
(CH2CH2CH2 PCL backbone), 25.6 (one of CH2CH2CH2 PCL backbone),
24.7 (one of CH2CH2CH2 PCL backbone). GPC (RI): Mn (PDI) = 4900
g mol−1 (1.23).
Block Copolymerization of VL and CL. To a stirred solution of
catalyst 3 (26.3 mg, 0.0347 mmol, 5 equiv) and 1-pyrenebutanol (1.9
mg, 0.0069 mmol, 1 equiv) in chlorobenzene (0.34 mL) under argon
atmosphere was added δ-valerolactone (32 μL, 0.35 mmol, 50 equiv)
and the reaction mixture stirred for 4 h at room temperature. After
removal of a 50 μL aliquot of the reaction mixture for analysis of the
conversion, molecular weight and polydispersity of the first polymer-
ization, ε-caprolactone (38 μL, 0.35 mmol, 50 equiv) was added and
the reaction mixture stirred at room temperature for 48 h, then
quenched by the addition of acetic acid (0.1 mL, 1 M in CH2Cl2). The
solvent was removed in vacuo and the crude reaction mixture analyzed
by 1H NMR to determine conversion and GPC to determine the
Catalyst 2. Catalyst precursor 1 (0.945 g, 2.64 mmol) and tris(4-
methoxy)phenylphosphine (0.932 g, 2.64 mmol) were dissolved in
anhydrous diethyl ether (8 mL) and stirred at room temperature
under argon atmosphere overnight. The resulting colorless precipitate
was collected by filtration, washed with pentane (10 mL) and dried
under vacuum overnight, yielding 2 (1.59 g, 2.33 mmol, 88%) as a
1
colorless solid. H NMR (500 MHz, CDCl3), δ (ppm): 7.57−7.45 (8
H, m), 7.28 (1 H, br s), 6.98−6.95 (6 H, m), 3.84 (9 H, s), 3.68−3.61
(2 H, m), 3.10−3.07 (2 H, m). 13C NMR (125 MHz, CDCl3), δ
(ppm): 182.1, 163.9, 134.9 (d, JPC = 11.4 Hz), 130.7 (q, JFC = 32.4
Hz), 125.1, 124.3 (br s), 123.8 (q, JFC = 272.8 Hz), 116.0 (br s), 115.2
(d, JPC = 13.4 Hz), 115.0−114.7 (m), 77.4 (br s), 55.6, 47.1 (br s),
46.5. 19F NMR (470 MHz, CDCl3), δ (ppm): −62.1. 31P NMR (202
MHz, CDCl3), δ (ppm): 27.9 (br s). Mp 96−98 °C. IR (νmax/cm−1):
1595, 1502, 1466, 1416, 1374, 1299, 1273, 1179, 1114, 1013, 867, 836,
804, 699, 678. HRMS (ES+): calcd for C32H31F6N3O3PS [M + H]+,
682.1722; found, 682.1772.
1
molecular weight and polydispersity. H NMR (500 MHz, CDCl3), δ
(ppm): (selected peaks) 8.27−7.85 (9 H, m, ArH), 4.09−4.03 (144 H,
m, COOCH2 PCL/PVL backbone), 2.35−2.29 (157 H, m, CH2COO
PCL/PVL backbone), 1.73−1.61 (309 H, m, CH2CH2CH2 PCL backbone and
CH2CH2 PVL backbone), 1.43−1.35 (67 H, m, CH2CH2CH2 PCL backbone).
13C NMR (100 MHz, CDCl3), δ (ppm): (selected peaks) 173.8 (CO
PCL sequence), 173.3 (CO PVL sequence), 64.2 (COOCH2 PCL backbone), 64.0
(COOCH2 PVL backbone), 34.2 (CH2COO PCL backbone), 33.7 (CH2COO
Typical Procedure for LA Polymerization. To a stirred solution
of L-lactide (100 mg, 0.694 mmol, 100 equiv) in CH2Cl2 (0.1 mL)
under argon atmosphere was added a solution of catalyst 2 (4.7 mg, 0.
0069 mmol, 1 equiv) and 1-pyrenebutanol (1.9 mg, 0.0069 mmol, 1
equiv) in CH2Cl2 (0.2 mL). The reaction mixture was stirred for 10
min at room temperature, then quenched by the addition of acetic acid
(0.05 mL, 1 M in CH2Cl2). Solvent was removed in vacuo and the
crude reaction mixture analyzed by 1H NMR to determine conversion.
The crude polymer was dissolved in a minimum amount of CH2Cl2,
then precipitated from methanol and isolated by filtration. The
purified polymer was analyzed by GPC to determine its molecular
b a c k b o n e ) , 2 8 . 4 ( C H 2 C H2 C H2
b a c k b o n e ) , 2 8 . 1
P V L
P C L
(COOCH2CH2 PVL backbone), 25.6 (one of CH2CH2CH2 PCL backbone),
24.6 (one of CH2CH2CH2 PCL backbone), 21.5 (CH2CH2COO
PVL back-
bone). GPC (RI): Mn (PDI) VL sequence = 4050 g mol−1 (1.10); final
polymer = 5920 g mol−1 (1.19).
Block Copolymerization of VL and LA. To a stirred solution of
catalyst 3 (26.3 mg, 0.0347 mmol, 5 equiv) and 1-pyrenebutanol (1.9
mg, 0.0069 mmol, 1 equiv) in chlorobenzene (0.34 mL) under argon
atmosphere was added δ-valerolactone (32 μL, 0.35 mmol, 50 equiv)
and the reaction mixture stirred for 5 h at room temperature. After
removal of a 50 μL aliquot of the reaction mixture for analysis of the
conversion, molecular weight, and polydispersity of the first polymer-
ization, a solution of L-lactide (50.0 mg, 0.347 mmol, 50 equiv) in
CH2Cl2 (0.5 mL) was added in one portion and the reaction mixture
stirred for 10 min and then quenched by the addition of acetic acid
(0.1 mL, 1 M in CH2Cl2). The solvent was removed in vacuo and the
crude reaction mixture analyzed by 1H NMR to determine conversion
1
weight and polydispersity. H NMR (400 MHz, CDCl3), δ (ppm):
(selected peaks) 8.25−7.83 (9 H, m, ArH), 5.15 (196 H, q, J = 7.2 Hz,
CH PLA backbone), 4.35 (1 H, q, J = 6.9 Hz, CH−OH), 4.20 (2 H, td, J =
6.4, 1.6 Hz, 1-pyrenebutanol CH2), 1.57 (608 H, d, J = 7.3 Hz,
CH3 PLA backbone). 13C NMR (100 MHz, CDCl3), δ (ppm): (selected
peaks) 169.7 (CO), 69.1 (CH PLA backbone), 16.8 (CH3 PLA backbone).
GPC (RI): Mn (PDI) = 27 500 g mol−1 (1.04).
Typical Procedure for VL Polymerization. To a stirred solution
of catalyst 3 (75.8 mg, 0.100 mmol, 5 equiv) and 1-pyrenebutanol
(5.50 mg, 0.0200 mmol, 1 equiv) in chlorobenzene (1 mL) under
argon atmosphere was added δ-valerolactone (186 μL, 2.00 mmol, 100
equiv) and the reaction mixture stirred for 9 h at room temperature
and then quenched by the addition of acetic acid (0.1 mL, 1 M in
CH2Cl2). The solvent was removed in vacuo and the crude reaction
1
and GPC to determine the molecular weight and polydispersity. H
NMR (500 MHz, CDCl3), δ (ppm): (selected peaks) 8.27−7.85 (9 H,
ArH), 5.16 (88 H, q, J = 7.1 Hz, CHPLA backbone), 4.09−4.05 (89 H, m,
COOCH2 PVL backbone), 2.36−2.29 (87 H, m, CH2COOPVL backbone),
1.68−1.67 (180 H, m, CH2CH2 PVL backbone), 1.58 (260 H, d, J = 7.2
Hz, CH3 PLA backbone). 13C NMR (125 MHz, CDCl3), δ (ppm):
1
mixture analyzed by H NMR to determine conversion and GPC to
1
(selected peaks) 173.3 (CO PVL), 169.6 (CO PLA), 69.0 (CH
determine the molecular weight and polydispersity. H NMR (500
PLA back-
bone), 64.0 (COOCH2 PVL backbone), 33.7 (CH2COO PVL backbone), 28.1
MHz, CDCl3), δ (ppm): (selected peaks) 8.27−7.84 (9 H, ArH),
4.12−4.01 (170 H, m, COOCH2 PVL backbone), 2.39−2.25 (169 H, m,
CH2COO PVL backbone), 1.73−1.54 (347 H, m, CH2CH2 PVL backbone).
13C NMR (125 MHz, CDCl3), δ (ppm): (selected peaks) 173.4 (CO),
64.0 (COOCH2 PVL backbone), 33.8 (CH2COO PVL backbone), 28.2
(COOCH2CH2 PVL backbone), 21.5 (CH2CH2COO PVL backbone). GPC
(RI): Mn (PDI) = 10 100 g mol−1 (1.13).
(one of COOCH2CH2 PVL backbone), 21.5 (one of CH2CH2COO
PVL
backbone), 16.7 (CH3 PLA backbone). GPC (RI): Mn (PDI) VL sequence =
3930 g mol−1 (1.12); final polymer = 7530 g mol−1 (1.13).
Block Copolymerization of CL and LA. To a stirred solution of
catalyst 3 (26.3 mg, 0.0347 mmol, 5 equiv) and 1-pyrenebutanol (1.9
mg, 0.0069 mmol, 1 equiv) in chlorobenzene (0.34 mL) under argon
atmosphere was added ε-caprolactone (38 μL, 0.35 mmol, 50 equiv)
and the reaction mixture stirred for 48 h at room temperature. After
removal of a 50 μL aliquot of the reaction mixture for analysis of the
conversion, molecular weight and polydispersity of the first polymer-
ization, a solution of L-lactide (50.0 mg, 0.347 mmol, 50 equiv) in
CH2Cl2 (0.5 mL) was added in one portion and the reaction mixture
stirred for 10 min and then quenched by the addition of acetic acid
(0.1 mL, 1 M in CH2Cl2). The solvent was removed in vacuo and the
crude reaction mixture analyzed by 1H NMR to determine conversion
Typical Procedure for CL Polymerization. To a stirred solution
of catalyst 3 (75.8 mg, 0.100 mmol, 5 equiv) and 1-pyrenebutanol
(5.50 mg, 0.0200 mmol, 1 equiv) in toluene (1 mL) under argon
atmosphere was added ε-caprolactone (222 μL, 2.00 mmol, 100 equiv)
and the reaction mixture stirred for 100 h at room temperature, then
quenched by the addition of acetic acid (0.1 mL, 1 M in CH2Cl2). The
solvent was removed in vacuo and the crude reaction mixture analyzed
1
by H NMR to determine conversion and GPC to determine the
1
molecular weight and polydispersity. H NMR (500 MHz, CDCl3), δ
1
(ppm): (selected peaks) 8.30−7.81 (9 H, m, ArH), 4.05 (162 H, t, J =
6.8 Hz, COOCH2 PCL backbone), 2.23−2.35 (177 H, m, CH2COO
PCL backbone), 1.56−1.70 (349 H, m, CH2CH2CH2 PCL backbone), 1.32−
1.44 (175 H, m, CH2CH2CH2 PCL backbone). 13C NMR (125 MHz,
and GPC to determine the molecular weight and polydispersity. H
NMR (500 MHz, CDCl3), δ (ppm): (selected peaks) 8.33−7.88 (9 H,
ArH), 5.32−5.21 (124 H, m, CHPLA backbone), 4.11 (89 H, t, J = 6.7 Hz,
COOCH2 PCL backbone), 2.37−2.35 (82 H, m, CH2COO PCL backbone),
1.74−1.68 (171 H, m, CH2CH2CH2 PCL backbone), 1.66−1.61 (396 H,
CDCl3),
δ (ppm): (selected peaks) 173.7 (CO), 64.3
C
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Scheme 1. Synthesis of Bifunctional Iminophosphorane Catalyst 2
m, CH3 PLA backbone), 1.47−1.39 (92 H, m, CH2CH2CH2 PCL backbone).
13C NMR (100 MHz, CDCl3), δ (ppm): (selected peaks) 173.4 (CO
P C L ), 169.8 (CO P L A ), 69.1 (CH P L A b a c k b o n e ), 64.3
(COOCH2 PCL backbone), 34.3 (CH2COO PCL backbone), 28.5
(CH2CH2CH2 PCL backbone), 25.7 (one of CH2CH2CH2 PCL backbone),
24.7 (one of CH2CH2CH2 PCL backbone), 16.8 (CH3 PLA backbone). GPC
(RI): Mn (PDI) CL sequence = 3480 g mol−1 (1.12); final polymer =
5670 g mol−1 (1.16).
temperature, then quenched by the addition of acetic acid (0.1 mL, 1
M in CH2Cl2). The solvent was removed in vacuo and the crude
1
reaction mixture analyzed by H NMR to determine conversion and
1
GPC to determine the molecular weight and polydispersity. H NMR
(400 MHz, CDCl3), δ (ppm): (selected peaks) 4.06−4.03 (64 H, t, J =
6.6 Hz, COOCH2 PCL backbone), 3.63 (186 H, CH2 mPEG), 3.37 (3 H, s,
CH3 mPEG‑OMe), 2.33−2.25 (67 H, m, CH2COO PCL backbone), 1.68−
1.54 (140 H, m, CH2CH2CH2 PCL backbone), 1.41−1.32 (74 H, m,
CH2CH2CH2 PCL backbone). 13C NMR (100 MHz, CDCl3), δ (ppm):
(selected peaks) 173.6 (CO), 70.5 (CH2 mPEG), 64.1
(COOCH2 PCL backbone), 34.1 (CH2COO PCL backbone), 28.3
(CH2CH2CH2 PCL backbone), 25.5 (one of CH2CH2CH2 PCL backbone),
24.6 (one of CH2CH2CH2 PCL backbone). GPC (RI): Mn (PDI) = 4910
g mol−1 (1.18).
Polymerization of LA Using mPEG50 Macroinitiator. To a
stirred solution of L-lactide (100 mg, 0.694 mmol, 100 equiv) in
CH2Cl2 (0.8 mL) under argon atmosphere was added a solution of
catalyst 2 (23.6 mg, 0.0347 mmol, 5 equiv) and mPEG50 (13.9 mg,
0.00694 mmol, 1 equiv) in CH2Cl2 (0.2 mL). The reaction mixture
was stirred for 10 min at room temperature, then quenched by the
addition of acetic acid (0.1 mL, 1 M in CH2Cl2). Solvent was removed
Azide 4. Phenethylamine (100 mg, 0.825 mmol), copper(II) sulfate
pentahydrate (2.1 mg, 0.0083 mmol) and potassium carbonate (193
mg, 1.40 mmol) were taken up in methanol (4.1 mL) at room
temperature. 1H-imidazole-1-sulfonyl azide hydrochloride (205 mg,
0.990 mmol) was added portionwise with stirring and the reaction was
stirred overnight at room temperature. The solvent was removed
under a flow of nitrogen and the residue was partitioned between
water and diethyl ether. The organic layer was washed with brine,
dried over anhydrous sodium sulfate and the solvent removed under a
flow of nitrogen. The residue was purified by flash column
chromatography over silica (petroleum ether, then 10% diethyl ether
in petroleum ether) to give the product as a colorless oil (79 mg, 0.54
mmol, 65%). 1H NMR (250 MHz, CDCl3), δ (ppm): 7.43−7.27 (5 H,
m), 3.57 (2 H, d, J = 7.3 Hz), 2.96 (2 H, d, J = 7.3 Hz). 13C NMR
(100 MHz, CDCl3), δ (ppm): 138.2, 128.9, 128.8, 126.9, 52.6, 35.5.
Polymerization Catalyzed by Iminophosphorane 5. Azide 4
(5.1 mg, 0.035 mmol) and tris(4-methoxy)phenylphosphine (12.2 mg,
0.0347 mmol) were dissolved in THF and stirred at room temperature
under argon atmosphere overnight, after which TLC analysis indicated
complete consumption of the starting materials and mass spectrometry
indicated the presence of iminophosphorane 5. Maintaining the flask
under inert atmosphere, THF was removed under a flow of nitrogen
and the residue was dissolved in CH2Cl2 (0.2 mL). The CH2Cl2
solution of 5 was then added to a solution of L-lactide (100 mg, 0.694
mmol) and 1-pyrenebutanol (1.9 mg, 0.0069 mmol) in CH2Cl2 (0.8
mL) under argon atmosphere and the reaction stirred at room
temperature for 1 h. The reaction was quenched by addition of acetic
acid (0.1 mL, 1 M in CH2Cl2), the solvent removed in vacuo and the
1
in vacuo and the crude reaction mixture analyzed by H NMR to
determine conversion and GPC to determine the molecular weight
and polydispersity. H NMR (400 MHz, CDCl3), δ (ppm): (selected
1
peaks) 5.16 (193 H, q, J = 7.1 Hz, CHPLA backbone), 3.64 (169 H, br s
CH2 mPEG), 3.38 (3 H, s, CH3 mPEG‑OMe), 1.58 (618 H, d, J = 7.1 Hz,
CH3 PLA backbone). 13C NMR (100 MHz, CDCl3), δ (ppm): (selected
peaks) 169.7 (CO), 70.7 (CH2 mPEG), 69.1 (CH PLA backbone), 55.8
(CH3 mPEG‑OMe), 16.7 (CH3 PLA backbone). GPC (RI): Mn (PDI) = 16
800 g mol−1 (1.07).
Polymerization of VL Using mPEG50 Macroinitiator. To a
stirred solution of catalyst 3 (13.1 mg, 0.0173 mmol, 5 equiv) and
mPEG50 (13.9 mg, 0.00694 mmol, 1 equiv) in chlorobenzene (0.34
mL) under argon atmosphere was added δ-valerolactone (32 μL, 0.35
mmol, 50 equiv) and the reaction mixture stirred for 5 h at room
temperature, then quenched by the addition of acetic acid (0.1 mL, 1
M in CH2Cl2). The solvent was removed in vacuo and the crude
1
reaction mixture analyzed by H NMR to determine conversion and
1
GPC to determine the molecular weight and polydispersity. H NMR
(500 MHz, CDCl3), δ (ppm): (selected peaks) 4.06−4.03 (64 H, m,
COOCH2 PVL backbone), 3.61 (127 H, CH2 mPEG), 3.35 (3 H, s,
CH3 mPEG‑OMe), 2.36−2.29 (67 H, m, CH2COO PVL backbone), 1.67−
1.64 (146 H, m, CH2CH2 PVL backbone). 13C NMR (100 MHz, CDCl3),
δ (ppm): (selected peaks) 173.3 (CO), 70.6 (CH2 mPEG), 64.0
(COOCH2 PVL backbone), 33.7 (CH2COO PVL backbone), 28.1
(COOCH2CH2 PVL backbone), 21.5 (CH2CH2COO PVL backbone). GPC
(RI): Mn (PDI) = 4600 g mol−1 (1.04).
Polymerization of CL Using mPEG50 Macroinitiator. To a
stirred solution of catalyst 3 (13.1 mg, 0.0173 mmol, 5 equiv) and
mPEG50 (13.9 mg, 0.00694 mmol, 1 equiv) in toluene (0.34 mL)
under argon atmosphere was added ε-caprolactone (38 μL, 0.35 mmol,
50 equiv) and the reaction mixture stirred for 72 h at room
1
residue analyzed by H NMR to determine conversion and GPC to
determine the molecular weight and polydispersity.
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A linear relationship between the conversion and molecular
weight and uniform polydispersity with respect to conversion
indicated a well-controlled polymerization (Figure 4). Fur-
thermore, the conversion vs time data could be well-fitted by
first-order kinetics (see Supporting Information).
RESULTS AND DISCUSSION
■
A unique feature of the bifunctional iminophosphorane
organocatalysts is the tunability of the modular basic
functionality. From mechanistic and pKa studies within our
group,7 it was known that tris(4-methoxy)phenyl substituted
iminophosphoranes were the most strongly basic and the most
active of those investigated to date, therefore this iminophos-
phorane was chosen for use in this work. An achiral variant of
the bifunctional iminophosphorane catalyst, featuring an
unsubstituted two carbon scaffold, was prepared in a simple,
three-step procedure requiring only one purification by flash
column chromatography. Bromoethylamine hydrobromide was
heated overnight with sodium azide to give crude 2-azidoethyl-
amine, which was treated with 3,5-bis(trifluoromethyl)phenyl
isothiocyanate to give the thiourea 1. This was then reacted
with tris(4-methoxy)phenylphosphine to give the catalyst 2,
which was isolated by simple filtration and used without further
purification (Scheme 1). A racemic phenyl-substituted catalyst,
3 (Figure 3), was prepared from ( )-phenylglycine, following
literature procedures.7
Figure 4. Ring-opening polymerization of LA with [M0]/[I0] of 100
■
catalyzed by 2. Plot of Mn, (×) and PDI ( ), as determined by GPC,
1
vs monomer conversion determined by H NMR.
Polymerization of rac-lactide at room temperature gave a Pi
value of 0.64, indicating a slight isotactic enhancement.
Conducting the polymerization at −78 °C increased the Pi
slightly to 0.74, but a conversion of only 36% was achieved in 4
h. Changing the catalyst to the more bulky phenyl-substituted
catalyst 3 did not significantly affect the tacticity.
The bifunctional iminophosphorane was also found to be a
capable catalyst for the polymerization of VL and CL, though
reaction rates were slower than for LA, consistent with previous
work on the organocatalytic ROP of cyclic esters.5 Because of
the poor solubility of catalyst 2 in the reaction solvents, toluene
and chlorobenzene, the phenyl substituted catalyst 3 was used
for the polymerization of these monomers. At 5 mol % catalyst
loading in chlorobenzene and with a monomer to initiator (1-
pyrenebutanol) ratio of 100:1, 94% conversion to poly(VL)
with a molecular weight of 10 100 g mol−1 and a PDI of 1.13, as
determined by GPC using polystyrene standards, was achieved
within 9 h. MALDI-ToF spectra confirmed that the 1-
pyrenebutanol initiator was incorporated into the polymer
(see Supporting Information). Poly(VL) with molecular weight
up to 37 400 g mol−1 was synthesized with high conversion and
good control over the molecular weight distribution (Table 2).
Similarly, 91% conversion of CL to poly(CL) with a
molecular weight of 4860 g mol−1 and PDI of 1.23 was
achieved in toluene 100 h. In the polymerization of CL, a less
reactive monomer, an increasing discrepancy between the
target molecular weight and Mn as measured by GPC was
observed as the monomer to initiator ratio increased, however
Figure 3. Racemic phenyl-substituted catalyst 3.
Catalyst 2 was found to be highly effective for the ROP of
LA, catalyzing the formation of poly(LA) in short reaction
times, high conversion and with excellent control over the
molecular weight distribution. At 1 mol % catalyst loading in
CH2Cl2 and with a monomer to initiator (1-pyrenebutanol)
ratio of 100:1, quantitative conversion to poly(LA) with a
molecular weight of 27 500 g mol−1 and a PDI of 1.04, as
determined by GPC using polystyrene standards, was achieved
within 10 min. As the catalyst is nonhygroscopic and air-stable,
it could be weighed out in air, then transferred to the reaction
1
flask under a blanket of nitrogen. H NMR analysis revealed a
degree of polymerization of 98 and comparison with literature
spectra5 indicated that the initiator had been entirely
incorporated into the polymer chain. MALDI-ToF spectra
further confirmed the end-group fidelity (see Supporting
1
Information). Homodecoupled H NMR showed that, within
the limits of detection, no epimerization had taken place during
the polymerization. Poly(LA) with a monomer to initiator ratio
of up to 500 was prepared in quantitative conversion (Table 1).
a
a
Table 1. Polymerization of LA Catalyzed by 2
Table 2. Polymerization of VL Catalyzed by 3
b
c
c
b
b
c
c
Mn (g mol−1
)
PDI
[M]0/[I]0 time (min) convn (%)
Mn (g mol−1
)
PDI
DP
29
[M]0/[I]0
time (h)
convn (%)
25
50
3
5
99
99
99
99
99
6380
11 200
27 500
32 922
d
1.06
1.05
1.04
1.04
d
50
100
200
500
4
9
94
94
92
92
7 260
10 100
22 400
37 400
1.10
1.13
1.11
1.08
54
98
100
200
500
10
20
50
16
24
206
491
a
Reaction was performed in PhCl with 5 mol % catalyst loading
relative to monomer and [VL] = 2.0 M. Measured by H NMR.
Measured by GPC in THF using Mark−Houwink parameters for
a
b
1
Reaction was performed in CH2Cl2 at room temperature with 1 mol
% catalyst loading relative to monomer and [LA] = 2.3 M. Measured
by H NMR. Measured by GPC in THF. Not soluble in THF.
b
c
c
d
1
polystyrene.
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the PDI and conversion remained consistently good. We
postulate that in the extended reaction times required for CL,
initiation from the catalyst itself (vide infra) competes with
extension of the 1-pyrenebutanol-initiated chains, leading to
consumption of the monomer and the formation of lower
molecular weight oligomers. However poly(CL) with catalyst-
derived end-groups was not observed directly; only 1-
pyrenebutanol initiated chains are seen in MALDI-ToF spectra
of poly(CL) (see Supporting Information). Thus, poly(CL)
with molecular weight of only up to 9310 g mol−1 could be
synthesized using this catalytic system (Table 3).
Table 5. Synthesis of Polymers from mPEG50 Macroinitiator
b
a
a
monomer [M0]/[I0]
time
convn (%) Mn (g mol−1
)
PDI
LA
VL
CL
100
50
10 min
5 h
99
99
86
16800
4600
4910
1.07
1.04
1.18
50
27 h
a
Measured by GPC in THF using Mark−Houwink parameters for
b
polystyrene. Measured by 1H NMR. For mPEG50: Mn = 2830 g mol−1
and PDI = 1.05 (measured by GPC in THF using Mark−Houwink
parameters for polystyrene).
LA, VL, and CL were all polymerized (Table 6), albeit
requiring longer reaction times to reach full conversion than in
a
Table 3. Polymerization of CL Catalyzed by 3
b
c
c
Table 6. Polymerization of Monomers in the Presence of 5
mol % of Catalyst 2
[M]0/[I]0
time (h)
convn (%)
Mn (g mol−1
)
PDI
50
100
200
500
48
100
120
240
79
91
91
94
3000
4860
5370
9310
1.16
1.23
1.25
1.24
a
monomer
time
convn (%)
LA
VL
CL
10 min
24 h
75
70
20
a
Reaction was performed in PhMe with 5 mol % catalyst loading
relative to monomer and [CL] = 2.0 M. Measured by H NMR.
24 h
b
1
a
1
Measured by H NMR.
c
Measured by GPC in THF.
Block copolymers of LA, VL, and CL were successfully
synthesized by the sequential addition of monomers. In a
typical example, VL was polymerized in chlorobenzene using 10
mol % catalyst 3 and 1-pyrenebutanol initiator with an [M]0/
[I]0 of 50 for 5 h, at which point an aliquot was removed for
the presence of an alcohol initiator. On the basis of the known
reactivity between esters and iminophosphoranes to form
amides in the Staudinger ligation,12 it is likely that the nitrogen
of the iminophosphorane acts as a nucleophile to open the
monomer and form an initiating species. This is supported in
part by the demonstrated reaction between an iminophosphor-
ane and VL (see Supporting Information), which leads to the
opening of the cyclic ester and formation of the corresponding
amide upon hydrolysis. In spite of this, we cannot
unequivocally rule out the possibility of initiation by
adventitious moisture.13
Next the role of the thiourea moiety was investigated by
studying the ROP of LA catalyzed by iminophosphorane 5,
which features an N-alkyl substituent rather than a linked H-
bond donor. Iminophosphorane 5, formed in situ from azide 4
and tris(4-methoxy)phenylphosphine (Scheme 2), is able to
catalyze the polymerization of LA initiated by 1-pyrenebutanol,
with a monomer to initiator ratio of 100:1 (Table 7). However,
the reaction rate is slower than that achieved with bifunctional
catalyst 2, requiring 1 h to reach 92% conversion and the
polydispersity of the resulting polymer is greater than that
obtained using the bifunctional catalyst (1.14 vs ≤1.05). This is
consistent with the findings of Hedrick and co-workers who
show that the association constants of VL and CL and 1-(3,5-
bis(trifluoromethyl)phenyl)-3-cyclohexylthiourea are much
greater than that of the thiourea and ethyl acetate.5,14 From
this data it is inferred that the preferential activation of cyclic
ester monomers over the polymer backbone suppresses
transesterification. Thus, the thiourea moiety increases the
1
NMR and GPC analysis. H NMR indicated 87% conversion,
while GPC showed a peak with Mn of 4 050 g mol−1 and PDI of
1.10. 50 equiv of CL (relative to the initiator) were then added
and the reaction continued until 82% conversion was reached,
1
as indicated by H NMR, then quenched by addition of acetic
acid. GPC analysis of the resulting polymer showed a single,
unimodal peak with Mn of 5 920 g mol−1 and a PDI of 1.19,
indicating that a diblock copolymer had been formed. The final
Mn compares favorably with the calculated molecular weight of
9 000 g mol−1, given that this value was calculated directly from
the polystyrene calibration curve of the GPC. Poly(VL)-block-
poly(LA) and poly(CL)-block-poly(LA) were also prepared in
this fashion (Table 4). In agreement with previous work,5 the
order of monomer addition was an important factor when LA
was used.10 Polymerization could also be initiated from
macroinitiators such as mPEG (Table 5).
Although phosphazene bases are established ROP catalysts,11
to the best of our knowledge, they have not been previously
combined with thiourea additives. Consequently, several
control experiments were carried out in order to investigate
the roles of both the iminophosphorane and thiourea moieties.
First the ability of the bifunctional iminophosphoranes to
initiate polymerization was tested. In the presence of 5 mol %
catalyst 2, but with no additional initiating nucleophilic species,
Table 4. Synthesis of Diblock Copolymers
Mn (g mol−1
)
Mn (g mol−1
)
a
a
a
a
b
monomer 1
convnb (%)
GPC
NMR
PDI
monomer 2
convn (%)
GPC
NMR
PDI
VL
VL
CL
87
92
93
4050
3930
3480
4200
4500
5130
1.10
1.12
1.12
CL
LA
LA
82
99
99
5920
7530
5670
8000
11 000
14 100
1.19
1.13
1.16
a
Measured by GPC in THF using Mark−Houwink parameters for polystyrene. [M]0/[I]0 for monomer 1 relative to 1-pyrenebutanol = 50; then 50
equiv of monomer 2 relative to 1-pyrenebutanol are added.
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Scheme 2. Preparation of Iminophosphorane 5
rapid and well-controlled polymerization. We anticipate that
the ease of handling of these catalysts, combined with their high
reactivity and ability to impart exquisite control on ring-
opening polymerization will make them useful to the synthetic
community.
Table 7. Polymerization of LA in the Presence of 5 mol % 5
(Relative to Monomer)
time
(h)
convn
a
Mn
b
b
c
[M]0/[I]0 initiator
(%)
(g mol−1
)
PDI
Pi
100
1-PB
1
1
92
74
8190
8160
1.14
1.25
0.68
0.66
−
−
ASSOCIATED CONTENT
a
b
c
1
■
Measured by H NMR. Measured by GPC in THF. Measured by
homodecoupled H NMR.
1
S
* Supporting Information
NMR spectra of catalysts and polymers, first-order linear fit of
LA polymerization kinetic data, MALDI−ToF spectra, GPC
traces of polymers and copolymers, and the reaction of
iminophosphorane with VL. This material is available free of
charge via the Internet at http://pubs.acs.org.
rate of polymerization through monomer activation while also
suppressing undesirable transesterification reactions.
However, it is also possible that iminophosphorane 5 is more
basic and/or more nucleophilic than catalyst 2. Initiation from
the more nucleophilic iminophosphorane 5 may successfully
compete with initiation from the alcohol, leading to the
formation of lower molecular weight oligomers as well as
consumption of the catalyst, which would lead to lower
monomer conversion. This is consistent with the low value of
Mn when using iminophosphorane 5 (8190 g mol−1 vs 27 500 g
mol−1 for [M]0/[I]0 = 100 using catalyst 2). The increased
basicity may also result in increased transesterification.
Iminophosphorane 5 also catalyzes the polymerization of LA
in the absence of an initiating alcoholwith 5 mol % catalyst
loading LA is polymerized in 74% conversion after 1 h. This is
slower than polymerization in the absence of an alcohol
initiator using bifunctional catalyst 2, in agreement with the
proposed activation of the monomer by thiourea.
AUTHOR INFORMATION
■
Corresponding Author
*(D.J.D.) E-mail: darren.dixon@chem.ox.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the EPSRC (Leadership
Fellowship to D.J.D.) and the Clarendon Fund in conjunction
with Magdalen College, University of Oxford (graduate
scholarship to A.M.G.). The authors gratefully acknowledge
the Mountford research group (University of Oxford) for
assistance with gel phase chromatography.
Interestingly, significant epimerization occurs when using
iminophosphorane 5 and the resulting polymer has a Pi of
0.66−0.68. Stirring a sample of poly(LA) (previously prepared
using catalyst 2) with iminophosphorane 5 in CH2Cl2 for 1 h at
room temperature does not result in any observable
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Poly(CL) could also be synthesized, however the utility of the
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incomplete consumption (<30%) of the second monomer (VL or
G
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1
CL) was noted by H-NMR. This reflects the poor propensity of the
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spectra of the catalyst.
H
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