Stereoselective polymerization of rac- and meso-lactide catalyzed by sterically encumbered N-heterocyclic carbenes

Article abstract of DOI:10.1039/b601393g

New sterically encumbered N-heterocyclic carbene catalysts were synthesized and used to polymerize rac-lactide to give highly isotactic polylactide or meso-lactide to give heterotactic polylactide. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b601393g

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Stereoselective polymerization of rac- and meso-lactide catalyzed by
sterically encumbered N-heterocyclic carbenes{
Andrew P. Dove,a Hongbo Li,a Russell C. Pratt,a Bas G. G. Lohmeijer,a Darcy A. Culkin,b
Robert M. Waymouth*b and James L. Hedrick*a
Received (in Berkeley, CA, USA) 31st January 2006, Accepted 10th May 2006
First published as an Advance Article on the web 6th June 2006
DOI: 10.1039/b601393g
New sterically encumbered N-heterocyclic carbene catalysts
were synthesized and used to polymerize rac-lactide to give
highly isotactic polylactide or meso-lactide to give heterotactic
polylactide.
Polylactide (PLA) has emerged as a relatively new commodity
polymer derived from renewable feedstocks for packaging, fiber
and biomedical applications.1 The mechanical properties of PLA
are critically linked to its microstructure, and hence, the
stereoselective polymerization of lactide (LA) has become a subject
of considerable attention.2 Metal alkoxides,3 which control the
stereochemistry of the resultant polymers by two distinct
mechanisms: chain end control, in which the stereochemistry of
the last inserted monomer defines the stereochemistry of the
subsequent ring-opening step; and enantiomorphic site control
polymerization, in which the chirality of the catalyst defines the
stereochemistry of the monomer insertions.4 Various achiral
organometallic catalysts for stereoselective lactide polymerization
have been reported, and chain end control was proposed for such
selectivity,5 whereas chiral metal complexes have achieved stereo-
specific polymerization by a proposed enantiomorphic site
control.6–9 Furthermore, polymer microstructure has been found
to be highly dependent upon the ancillary ligand substituents5 and
solvent.10 Recently, it was reported that a N-heterocyclic carbene
(NHC) and the Zn complex of the same carbene give strikingly
different stereoselectivity patterns.11 Herein we report our
investigations into organocatalytic stereoselective ring-opening
polymerization (ROP) by employing new sterically encumbered
NHCs that catalyze the formation of highly isotactic polylactide
from rac-LA monomer at low temperature with high activity, and
the formation of heterotactic PLA using meso-LA monomer under
similar conditions.
Fig. 1 NHCs 1 and 2.
Our initial investigations focused on the synthesis and testing of
carbene 2 (Fig. 1), a sterically hindered saturated chiral carbene
previously reported by Grubbs.13 Treatment of this species with
one equivalent of initiating alcohol (either methanol or isopropa-
nol) and rac-LA resulted in no observable polymerization activity
even at elevated temperatures. Given the propensity of saturated
NHCs to form alcohol adducts,14 we postulated that the adduct
formed with this carbene was unusually thermally stable and thus
inhibited polymerization activity.
The formation of alcohol adducts is generally prohibited with
the unsaturated NHC analogues however, access to sterically
encumbered NHCs is synthetically challenging. The synthesis of
NHCs 3 and 4 was achieved and is outlined in Scheme 1. The steric
bulk from the phenyl rings in the carbene backbone resulted in the
failure of traditional synthetic methods for cyclization.15 A new
methodology developed by Glorius et al.16 that generates the
alkylating reagent in situ was successfully adopted to cyclize these
sterically demanding structures. After ion exchange and deproto-
nation, 3 was isolated in an overall yield of 52%. NHCs (R,R)-4
and (S,S)-4 were obtained in similarly high yields providing access
to highly sterically hindered unsaturated chiral and achiral
NHCs.17
The conditions and stereoselectivity for rac-LA polymerization
were surveyed by varying catalyst. The use of 3 as catalyst provides
polymers with low polydispersities and molecular weights that
closely track the monomer-to-initiator ratio (Table 1). Catalyst
activities are remarkably high, with turnover frequencies of
The results of our and others’ studies have shown 1,3-
dimesitylimidazol-2-ylidene, 1 (Fig. 1), to produce mainly atactic
PLA.11,12 In order to gain a greater degree of control over the
stereochemistry of the PLA produced in these organocatalytic
polymerizations, we targeted the synthesis of more sterically
hindered NHCs.
aIBM Almaden Research Center, 650 Harry Road, San Jose, CA 95120,
USA. E-mail: hedrick@almaden.ibm.com; Fax: 01-408-927-3310;
Tel: 1-408-927-1632
bDepartment of Chemistry, Stanford University, Stanford, CA 94305,
USA. E-mail: waymouth@stanford.edu; Fax: 01-650-736-2262;
Tel: 1-650-723-4515
{ Electronic supplementary information (ESI) available: experimental
details and polymer tacticity data. See DOI: 10.1039/b601393g
Scheme 1 Synthesis of 3 and 4.
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Chem. Commun., 2006, 2881–2883 | 2881

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Table 1 Polymerization of rac-, meso-lactide using NHCs at different temperaturesa
Conversion (%)b
DPb
Mw/Mn
Pi18
c
Entry
Catalyst
Monomer
T (uC)
Time (min)
1
2
3
4
5
6
7
8
3
3
3
3
rac-LA
rac-LA
rac-LA
rac-LA
rac-LA
rac-LA
rac-LA
rac-LA
rac-LA
meso-LA
meso-LA
meso-LA
meso-LA
meso-LA
25
215
240
270
25
270
25
270
270
25
1
50
90
120
1
120
1
120
120
2
240
2
240
240
c
95
89
88
91
96
92
95
96
96
95
90
93
91
95
97
96
95
95
96
94
94
95
95
97
95
94
93
96
1.24
1.18
1.21
1.20
1.18
1.19
1.28
1.26
1.48
1.22
1.25
1.27
1.24
1.46
0.59
0.72
0.80
0.90
0.57
0.83
0.59
0.88
0.88
0.62
0.83
0.55
0.67
0.58
1
1
(R,R)-4
(R,R)-4
(R,R)-4 + (S,S)-4
3
3
9
10
11
12
13
14
a
240
25
240
240
1
1
(R,R)-4
Monomer : initiator: 100 : 1. Determined by 1H NMR spectroscopy. Determined by GPC (relative to polystyrene in THF).
b
site control or merely a reflection of the sterically hindered active
site. In the case of enantiomorphic site control, an initial preference
for ROP of one enantiomer of lactide, corresponding to the
chirality of the catalyst, would be expected. However, as the chiral
purity of the monomer pool is changed towards the enantiomer of
lactide opposite to that of the catalyst, the polymer would be
expected to slowly reach high conversions resulting in a tapered
stereoblock copolymer comparable to that observed by Spassky
for the chiral-(SalBINAP)AlOCH3.7
Radano, Smith and Baker8 have previously demonstrated
that employment of an enantiomeric mixture of chiral-
(SalBINAP)AlOCH3 complexes resulted in the generation of
stereoblock PLA with each enantiomer of catalyst preferentially
polymerizing one enantiomer of lactide.19 We used rac-4 to initiate
the polymerization of rac-LA but observed no significant
enhancement of the Pi of the polymer obtained under these
conditions over that obtained when the single enantiomer, (R,R)-4
is employed. These data suggest that the dominating factor
determining stereocontrol is the steric congestion of the active site,
despite the chirality of the catalyst.
Fig. 3 Methine region of homonuclear decoupled 1H-NMR spectra of
poly(meso-LA) obtained at different polymerization temperatures using 3
as catalyst (Table 1, entries 10 and 11).3a
95 min21 at room temperature (Table 1, entry 1). The high
catalytic activity enables the polymerization at low temperatures to
generate a highly isotactic polylactide. The Pi increases from 0.59
at room temperature to 0.90 at 270 uC, as shown in Fig. 1
To further investigate the mechanism of stereo-control by
carbene catalysts, the polymerization of meso-LA was investigated
using NHCs 3 and (R,R)-4. Stereochemical control of meso-LA
polymerization would be expected to yield markedly different
results depending on the mechanism of stereocontrol. For
example, syndiotactic PLA is most likely obtained by a site
controlled mechanism,16 whereas heterotactic PLA is expected
when a chain end controlled mechanism is in operation.
1
(Table 1, entries 1–4 and Fig. 3).18 Homonuclear decoupled H-
NMR spectroscopy (Fig. 2) reveals the isotactic iii tetrad, the
defect iis, sii, isi tetrads in a 1 : 1 : 1.3 ratio, and a much smaller sis
tetrad, consistent with isotactic PLA with blocks of (R,R)-LA and
(S,S)-LA in the main chain.3a The polymer produced from entry 4
showed a melting point by differential scanning calorimetry of
153.3 uC (DHfus 5 12.8 J/g).6 Under the same polymerization
conditions, 3 is more stereoselective than 1, particularly at lower
temperatures (entry 4 vs. entry 6). The bulky phenyl groups at the
back of 3 can presumably influence the steric hindrance around the
catalytic site, and thus enhance the stereoselectivity.
The polymerization activities of meso-LA are lower than those
of rac-LA and the meso isomer is also less soluble at low
temperature than the racemic mixture. Compared with 1, 3 exhibits
a pronounced higher stereoselectivity for the polymerization of
meso-LA, particularly at lower temperatures (240 uC, Pi 5 0.83 vs.
0.67, Table
1
entries 11 and 13 respectively).19 Notably,
Polymerization of rac-LA using the chiral NHCs also resulted in
high levels of isotacticity. At 25 uC, these catalysts remain highly
active for polymerization however, only a mild preference for
stereospecific ROP is observed. Upon lowering the temperature of
the polymerization to 270 uC, ROP catalyzed by (R,R)-4
polymerization of meso-LA catalysed by the chiral NHC, (R,R)-
4, also produces heterotactic polymer (240 uC, Pi 5 0.58, Table 1
entry 14).
We have previously proposed a monomer-activated mechanism
for the NHC-catalyzed polymerization of lactide.12 The observa-
tion of highly isotactic polymer from rac-LA and heterotactic
polymer with meso-LA are consistent with a chain end control
mechanism for both achiral and chiral NHCs suggesting that even
demonstrated a marked increase in isotacticity (270 uC,
Pi 5 0.59 vs. 0.88, Table 1 entries 7 and 8 respectively). This
could be a result of the chiral carbene enforcing an enantiomorphic
2882 | Chem. Commun., 2006, 2881–2883
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In summary, new sterically encumbered, unsaturated chiral and
achiral N-heterocyclic carbene catalysts polymerize rac-LA to form
highly isotactic PLA at low temperature, while meso-LA yields
heterotactic PLA. A proposed mechanism involving chain end
control explains these examples of stereoselective polymerization.
We gratefully acknowledge support from the NSF Center on
Polymeric Interfaces and Macromolecular Assemblies (CPIMA)
(NSF-DMR-0213618), and an NSF-GOALI Grant (NSF-CHE-
0313993).
Notes and references
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Fig. 2 Methine region of homonuclear decoupled 1H-NMR spectra of
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catalyst (Table 1, entries 1 and 4).3a
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chain leading to isotactic enchainment (Scheme 2). The formation
of heterotactic-enriched PLA from meso-LA is also consistent with
a chain end control mechanism. In this case, the oxygen adjacent
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Scheme 2 Proposed chain end control mechanisms for (top) rac-lactide
and (bottom) meso-lactide polymerizations.
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Chem. Commun., 2006, 2881–2883 | 2883