The role of neutral donor ligands in the isoselective ring-opening polymerization of: Rac -β-butyrolactone

Article abstract of DOI:10.1039/d0sc03507f

Isoenriched poly-3-hydroxybutyrate (P3HB) is a biodegradable material with properties similar to isotactic polypropylene, yet efficient routes to this material are lacking after 50+ years of extensive efforts in catalyst design. In this contribution, a novel lanthanum aminobisphenolate catalyst (1-La) can access isoenriched P3HB through the stereospecific ring-opening polymerization (ROP) of rac-β-butyrolactone (rac-BBL). Replacing the tethered donor group of a privileged supporting ligand with a non-coordinating benzyl substituent generates a catalyst whose reactivity and selectivity can be tuned with inexpensive achiral neutral donor ligands (e.g. phosphine oxides, OPR3). The 1-La/OPR3 (R = n-octyl, Ph) systems display high activity and are the most isoselective homogeneous catalysts for the ROP of rac-BBL to date (0 °C: Pm = 0.8, TOF ～190 h-1). Combined reactivity and spectroscopic studies provide insight into the active catalyst structure and ROP mechanism. Both 1-La(TPPO)2 and a structurally related catalyst with a tethered donor group (2-Y) operate under chain-end stereocontrol; however, 2-RE favors formation of P3HB with opposite tacticity (syndioenriched) and its ROP activity and selectivity are totally unaffected by added neutral donor ligands. Our studies uncover new roles for neutral donor ligands in stereospecific ROP, including suppression of chain-scission events, and point to new opportunities for catalyst design. This journal is

Full text of DOI:10.1039/d0sc03507f

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The role of neutral donor ligands in the isoselective
ring-opening polymerization of rac-b-
butyrolactone†
Cite this: DOI: 10.1039/d0sc03507f
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
Xiang Dong
and Jerome R. Robinson
Isoenriched poly-3-hydroxybutyrate (P3HB) is a biodegradable material with properties similar to isotactic
polypropylene, yet efficient routes to this material are lacking after 50+ years of extensive efforts in catalyst
design. In this contribution, a novel lanthanum aminobisphenolate catalyst (1-La) can access isoenriched
P3HB through the stereospecific ring-opening polymerization (ROP) of rac-b-butyrolactone (rac-BBL).
Replacing the tethered donor group of a privileged supporting ligand with a non-coordinating benzyl
substituent generates a catalyst whose reactivity and selectivity can be tuned with inexpensive achiral
neutral donor ligands (e.g. phosphine oxides, OPR3). The 1-La/OPR3 (R ¼ n-octyl, Ph) systems display
high activity and are the most isoselective homogeneous catalysts for the ROP of rac-BBL to date (0 ꢀC:
Pm ¼ 0.8, TOF ꢁ190 hꢂ1). Combined reactivity and spectroscopic studies provide insight into the active
catalyst structure and ROP mechanism. Both 1-La(TPPO)2 and a structurally related catalyst with
a tethered donor group (2-Y) operate under chain-end stereocontrol; however, 2-RE favors formation of
P3HB with opposite tacticity (syndioenriched) and its ROP activity and selectivity are totally unaffected by
added neutral donor ligands. Our studies uncover new roles for neutral donor ligands in stereospecific
ROP, including suppression of chain-scission events, and point to new opportunities for catalyst design.
Received 25th June 2020
Accepted 15th July 2020
DOI: 10.1039/d0sc03507f
rsc.li/chemical-science
degree of crystallinity and Tm of highly-enriched isotactic or
syndiotactic P3HB leads to brittle materials with processing
Introduction
challenges due to the proximity of the material's Tm and
decomposition temperature. Alternatively, isoenriched P3HB
with Pm (percentage of meso diads) ranging from 0.65–0.8 can
suitably balance mechanical and thermal properties, making
the development of efficient and economically viable methods
to access this material highly desirable.3c–f
The stereospecic ring-opening polymerization (ROP) of rac-
b-butyrolactone (rac-BBL) represents one such approach. This
racemic monomer can be readily derived from abundant and
Polyolens enable numerous applications and benets to
society; however, there is growing concern over the immense
amount of polymer waste entering landlls and waterways and
their unfavorable environmental persistence.1 Poly-3-
hydroxybutyrate (P3HB, Fig. 1), the most common member of
naturally occurring polyhydroxyalkanoates, is a biodegradable
aliphatic polyester which can have properties similar to
isotactic polypropylene and applications ranging from pack-
aging to bio-medical applications.2 Central to these applications
is the polymer's relative stereochemistry (tacticity), which plays
a critical role in its observed thermal,3 mechanical,3d–g,4 and
degradation3d,5 properties. For example, atactic P3HB is an
amorphous material with a glass transition temperature (Tg) of
ꢁ5 ꢀC with limited applications, while highly-enriched isotactic
and syndiotactic P3HB are crystalline with melting tempera-
tures (Tm) up to 183 ꢀC. (R)-P3HB is synthesized naturally by
many organisms through microbial fermentation; however,
industrial production costs with this method remain high and
only perfectly isotactic P3HB can be accessed.2a,6 The high
Department of Chemistry, Brown University, 324 Brook St., Providence, RI 02912, USA.
E-mail: jerome_robinson@brown.edu
† Electronic supplementary information (ESI) available. CCDC 1980000–1980002.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/d0sc03507f
Fig. 1 Key advances in catalyst development for the ROP of rac-BBL
to access iso-enriched P3HB with I, II, III, and the current work.
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inexpensive feedstocks (e.g. propylene oxide and carbon noted,13a,19 connections between catalyst structure and function
monoxide),7 displays favorable thermodynamics towards ROP have been limited.
thanks to its signicant ring-strain (DGp ¼ ꢂ59.2 kJ molꢂ1),8
Herein, we report the synthesis, characterization, and cata-
and highly efficient catalysts have been developed for the lytic activity of REIII benzyl-substituted amino-bisphenolate
stereospecic ROP of a variety of other lactone monomers.2a,9 complexes for the isoselective ROP of rac-BBL. Replacing the
Despite these desirable attributes and a diverse array of cata- tethered donor fragment of a tetradentate aminobisphenolate
lysts being explored over 50+ years,10 the development of effi- ligand with a non-coordinating benzyl substituent leads to a La
cient catalysts with high levels of stereocontrol has proven catalyst whose reactivity and selectivity are amplied by the
challenging.9,10n,11 Many catalysts which are stereoselective for addition of inexpensive neutral achiral donor ligands (e.g.
other lactone monomers (e.g. rac-lactide) display much lower phosphine oxides, OPR3). The LaIII/OPR3/iPrOH (R: Ph, n-octyl)
(or no) reactivity and/or stereoselectivity towards rac-BBL,10f,j,s,12 species display high activity and are the most isoselective
and both monomer and polymer are prone to side-reactions homogeneous catalysts for the ROP of rac-BBL to date (Pm ¼ 0.8
(e.g. transesterication, chain scission, deprotonation, at 0 ꢀC, TOF ¼ ꢁ190 hꢂ1). Despite the prevalence of such
elimination).
ligands in the coordination chemistry of RE's20 and other metal-
Extensive efforts in catalyst design have led to systems which ions,21 this is the rst report of added phosphine oxides
can access syndioenriched P3HB;3l,10n,o,13 however, few systems enhancing catalyst reactivity or selectivity in ROP. Evidence that
have led to isoenriched P3HB.3i–k,9a,10q,11,14 Early work by Tani, strong neutral donors can suppress unwanted side-reactions
Agostini, Lenz, and others identied that partial hydrolysis of such as chain-scission through base-promoted elimination are
alkyl aluminum species leads to catalysts which can produce also presented for the rst time. Statistical analysis of P3HB
a minor fraction of crystalline P3HB with properties similar to microstructure conrms that 1-La(TPPO)2 is the rst catalyst to
natural P3HB, albeit over prolonged reaction times ($7 d) and access isoenriched P3HB through chain-end stereocontrol.
with broad molecular weight distributions (Đ, Mw/Mn).3i,10c,14h–k While a structurally related catalyst with a tethered donor (2-Y)
Rieger and coworkers discovered that Cr salophen catalysts also operates under chain-end stereocontrol, 2-RE favor the
(Fig. 1, I) are capable of producing isoenriched P3HB with high opposite polymer tacticity (syndioenriched P3HB) and their
Mn and broad Đ through a complex dual-site mechanism.3j,14e,f performance in ROP are unaffected by added neutral donor
Thomas and coworkers developed the most isoselective ligands. Our studies uncover the effects of neutral donors on
heterogeneous catalyst to date (Pm
¼
0.85) by graing catalyst structure and function, and provide new opportunities
Nd(BH4)3(THF)2 to nonporous SiO2 dehydroxylated at 700 ꢀC for the design of catalysts for stereospecic ROP.
(Fig. 1, II), but the system displays modest reactivity.10q Most
recently, Yao and coworkers reported a series of REIII salan
catalysts whose stereospecic ROP is highly sensitive to N-
substitution.14g The Yb N-Ph derivative (Fig. 1, III) displays
Results and discussion
Catalyst synthesis
modest reactivity and limited control over Mn, but is the most
1
The white crystalline benzyl-amino-bisphenol ligand (H2 L) was
synthesized in one step by a Mannich condensation of benzyl
amine, 2,4-ditertbutylphenol and paraformaldehyde in 47%
yield (Scheme 1). H21L was then treated with one equivalent of
REIII amide (REIII: La, Y), REIII[N(SiHMe2)2]3(THF)2, to afford the
corresponding REIII complexes, LaIII(1L)[N(SiHMe2)2](THF)2 (1-
La) and {YIII(1L)[N(SiHMe2)2]}2 (1-Y2), in nearly quantitative
yields (Scheme 1). 1-La is a monomer in both the solid- and
solution-state as determined by single-crystal X-ray diffraction
(Fig. 2) and Diffusion Ordered NMR Spectroscopy (DOSY,
Fig. S10†). While X-ray quality crystals could not be grown of the
ꢀ
isoselective homogeneous catalyst to date (Pm ¼ 0.77 at 0 C).
Notably, Chen and coworkers reported the ROP of a designer 8-
membered diolide as an elegant alternative to circumvent
selectivity challenges associated with rac-BBL; however, opti-
mized catalysts produce perfectly isotactic P3HB.3k
Of all the catalyst platforms, trivalent rare-earth (REIII) sup-
ported by tetradentate tripodal amino-bisphenolate ligands
developed by Carpentier and coworkers (Fig. 1, 2-Y) stand out as
“privileged” structures due to their exceptional activity and
syndioselectivity.3l,10n,o Though numerous covalent modica-
tions to the ligand scaffold have been explored (e.g. aryloxide
substitution, donor identity, tether/linker, initiator, and REIII),
none have provided access to isoenriched P3HB – even though
such modications have led to syndio- and iso-enriched poly-
mers of other b-lactones.15 Amongst these modications, the
role of the tethered donor ligand remains obscure,16 and more
broadly speaking, our understanding of how neutral achiral
donor ligands inuence the reactivity and stereoselectivity of
ROP catalysts remains underdeveloped. In the eld of asym-
metric catalysis, introduction of achiral and meso neutral donor
ligands can augment stereocontrol for a variety of metal-based
catalysts,17 including rare-earths,18 in a facile and cost-effective
manner. While donor-related effects in ROP have been
Scheme 1 Synthesis of 1L and REIII complexes (1-La and 1-Y2).
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ligands could improve catalyst reactivity and selectivity
through enhanced steric pressure.
We initially tested this hypothesis by screening 1-La with two
equiv. of neutral monodentate ligands. Representative classes
included ethers (tetrahydrofuran, THF), tertiary amines (1,4-
diazabicyclo-[2.2.2]octane, DABCO), pyridines (4-dimethylami-
nopyridine, DMAP), phosphines, (PPh3), and phosphine oxides
(OPPh3, TPPO). Unlike some literature reports for group 13, 14,
and REIII-based systems,13a,19a–i weaker neutral ligands had
a minor impact on ROP reactivity and stereoselectivity (Table 1,
entries 2–5). In contrast, the harder phosphine oxide ligand,
TPPO (entry 6), led to nearly quantitative conversion in 1 h
(97%) and improved isoselectivity (Pm ¼ 0.71). Notably [1-
La] : [TPPO] ratios of at least 1 : 2 were needed to achieve
maximum reactivity and selectivity, where a 1 : 1 ratio only led
to 71% conversion and a Pm of 0.67 aer 6 h (Table S1,† entries
6–9). While simple monodentate phosphine oxides have been
reported as additives in asymmetric catalysis with hard metal-
ions,18a–d,26 this is the rst time they have been used to enhance
reactivity and/or selectivity in ROP.
Given the unprecedented and dramatic enhancement in
catalyst performance, we evaluated representative classes of
phosphine oxides (aromatic, aliphatic, phosphoramide, and
phosphate; Table 1, entries 6–9). Electron-rich donors, such as
hexamethylphosphoramide (HMPA, entry 7) and tri-
octylphosphine oxide (TOPO, entry 8) increased reactivity and
isoselectivity (Pm ¼ 0.73 and 0.75 respectively). In contrast, tri-
phenylphosphate (OP(OPh)3, entry 9), a weaker donor, didn't
increase reactivity and showed small improvements in selec-
tivity (Pm ¼ 0.63). Our results suggest both electronic and steric
contributions to catalyst reactivity and selectivity, and a more
comprehensive evaluation is warranted in future studies. This is
affirmed by reports of stereospecic ROP of (rac)-lactide by REIII
and group 13 complexes supported by chelating alkoxides,27
amides,28 and pyrazolyl scorpionates29 with tethered phosphine-
Fig. 2 Thermal ellipsoid plot of 1-La (THF, Et2O adduct) displayed at
50% probability.
THF adduct, slow evaporation of Et2O solutions enabled the
structural determination of the mixed THF/Et2O adduct (Fig. 2).
The geometry of the six-coordinate LaIII center in the solid-state
is best described as a distorted trigonal prism comprised of
1
tridentate L, –N(SiHMe2)2, and two coordinated solvent mole-
cules (THF and Et2O). 1L adopts a propeller-like conformation at
nitrogen and enforces fac-coordination. Agostic b-H–Si inter-
actions (La(H–Si) were observed in the solid-state as sup-
ported by the smaller angle :La(1)–N(2)–Si(1) compared to
:La(1)–N(2)–Si(2) (ꢁ15ꢀ), close La(1)–Si(1)–H contact
˚
(3.3497(13) A), and lower energy Si–H stretch in the IR spectrum
(non-agostic: 2075 cmꢂ1, agostic: 2011 cmꢂ1, Fig. S3d†).22
Unlike 1-La, the yttrium derivative (1-Y2) exists as a dimer in
1
solution as determined by H-DOSY NMR (Fig. S11†).
Reaction optimization and neutral donor ligand effects
1-La and 1-Y2 were evaluated as catalysts for the ROP of rac-BBL oxides, which display varied catalyst response depending on
(Tables 1 and S1†). Amide initiators displayed low efficiency ligand substituents. Given the diverse array of phosphine oxides
for the ROP of rac-BBL, where 1-Y2 was completely inactive and that can be derived from commercially available phosphines,
1-La formed 35% P3HB in 48 h at RT (Table S1,† entries 1 and this represents an exciting untapped opportunity to optimize
5). While 1-La was sluggish compared to Carpentier's 2-Y,3l,10o catalyst performance in stereoselective ROP.
formation of P3HB was encouraging as the related SmIII
Key polymer attributes could be tuned by adjusting reaction
borohydride complex supported by the propyl-amino- temperature, catalyst loading, and chain-transfer agent.
bisphenolate ligand reported by Mountford and coworkers Lowering the reaction temperature from RT to 0 and ꢂ30 ꢀC
was inactive for ROP of an arguably easier substrate, rac-lac- with TPPO and TOPO (entries 10–15) increased catalyst iso-
tide.16a Similar to other REIII catalysts,3l,10o,23 in situ generation selectivity to a maximum (Pm ¼ 0.80). This represents the
of alkoxide initiators by adding one equiv. iPrOH with respect highest values achieved for the ROP of rac-BBL by a homoge-
to REIII (Table 1, entries 1 and 2 vs. Table S1,† entries 1 and 5) neous catalyst to date.14g Furthermore, increased [rac-BBL]/[RE]
increased reactivity and furnished polymers with narrow Mw/ ratios (400) lead to higher molecular weight P3HB with
Mn (Đ). Microstructural analysis of P3HB determined by reasonable rates, identical selectivities, and narrow Đ (Table 1,
integration of polymer C]O resonances by inverse-gated 13C- entries 11 and 14). Overall, 1-La/OPR3/iPrOH systems display
NMR revealed a slight isotactic preference (Pm ¼ 0.57) using 1- excellent reactivity (TOF up to 200 hꢂ1) and selectivity (Pm up to
La. While modest, the polymer tacticity was opposite that 0.80) with respect to the state-of-the-art for isoselective ROP of
generated by 2-Y and other amino-bisphenolate catalysts with rac-BBL (Pm up to 0.77 (ref. 14g) and 0.85,10q TOF ꢁ5–6 hꢂ1
;
tethered donors.10n,o,24 Given the increased degree of coordi- Fig. 1).
native unsaturation of 1-RE compared to 2-RE and the attrib-
Alcohols can serve as chain-transfer agents in living poly-
uted importance of steric congestion to selectivity for other merizations to access “immortal” polymerization conditions,30
stereospecic ROP,3l,14g,25 we posited that added neutral donor offering further opportunities to control polymer molecular
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Table 1 Influence of neutral donor ligand in the ROP of (rac)-BBL catalyzed by 1-REa
g
Entry
Cat.
[BBL]/[RE]
Ligand
Temp (ꢀC)
Timeb (h)
Conv.c (%)
Mn,calcd (kg molꢂ1
)
Mn,expe (kg molꢂ1
)
Đe,f
Pm
1
2
3
4
5
6
7
8
1-Y2
1-La
1-La
1-La
1-La
1-La
1-La
1-La
1-La
1-La
1-La
1-La
1-La
1-La
1-La
200
200
200
200
200
200
200
200
200
200
400
200
200
400
200
—
—
DMAP
DABCO
PPh3
TPPO
HMPA
TOPO
OP(OPh)3
TPPO
TPPO
TPPO
TOPO
TOPO
TOPO
25
25
25
25
25
25
25
25
25
0
1
1
1
1
1
1
1
1
1
1
4
24
1
4
5
21
22
7
0.9
3.6
3.8
1.2
4.3
16.7
17.0
17.0
4.3
16.5
26.5
17.0
17.0
33.1
17.0
n.d.
2.9
3.6
n.d.
1.7
9.6
9.4
9.5
1.6
11.2
15.3
11.5
12.9
19.2
13.0
n.d.
1.04
1.07
n.d.
1.38
1.18
1.29
1.23
1.35
1.15
1.20
1.12
1.20
1.09
1.09
n.d.
0.57
0.59
n.d.
n.d.h
0.71
0.73
0.75
0.63
0.76
0.75
0.80
0.80
0.80
0.80
25
97
99
99
25
96
77
99
99
96
99
9
10
11
12
13
14
15
0
ꢂ30
0
0
ꢂ30
6
a
[BBL] ¼ 2.4 M. b Reaction times not optimized. c Determined by 1H-NMR integration of BBL and PHB methine resonances in the crude reaction
mixture. d [BBL]/[RE]/[iPrOH] ꢃ Conv. ꢃ 0.08609 + 0.0601 kg molꢂ1
.
Determined by gel permeation chromatography (GPC) at 30 ꢀC in THF using
e
polystyrene standards and corrected by Mark–Houwink factor of 0.54.51 Mw/Mn. g Probability of meso-linkages between repeat units. Determined by
integration of P3HB C]O resonances using inverse gated (IG) 13C-NMR. h 0.52 at 6 h (36% conversion).
f
weight.10g,23,31 A La catalyst was isolated from a toluene solution of attempts to crystallize the mono-TPPO adduct, 1-La(TPPO),
1-La and TPPO in a 1 : 2 molar ratio (vide infra), which displays have only led to isolation of crystalline 1-La(TPPO)2.
similar reactivity in the ROP of rac-BBL as the in situ generated
The solid-state structures of 1-RE(TPPO)2 were determined
catalyst from adding 2 equivalents of TPPO to 1-La (Table S2,† unambiguously by single crystal X-ray diffraction experiments
entry 2 and Table 1, entry 6). The ROP of rac-BBL (200 equiv.) (Fig. 4b, S25, and S26†). In the solid-state, 1L coordinates in
i
catalyzed by 1-La(TPPO)2 (1 equiv.) with PrOH (1 equiv.) dis- a mer-arrangement for 1-RE(TPPO)2 rather than the fac-
played characteristics of a living polymerization, such as narrow Đ arrangement for 1-La. The isostructural compounds contain six-
throughout the reaction and reasonable agreement between coordinate REIII centers in a distorted octahedron with equa-
experimental and calculated Mn (Table S4 and Fig. S24†). Adding torial sites occupied by 1L and –N(SiHMe2)2 and axial sites
iPrOH (0–4 equiv.) to 1-La(TPPO)2 maintained high catalyst occupied by TPPO. Comparison of 1-RE(TPPO)2 and tethered
activity and Pm, while producing P3HB with the expected changes
in molecular weight (Table S2,† entries 1–4).
Mechanistic studies
Binding studies and catalyst characterization. We set out to
isolate discrete REIII–TPPO species to better understand the
isoselectivity for 1-La/OPR3. Adding one and two equiv. of
TPPO to 1-La led to distinct mono- and bis-TPPO adducts
(Fig. 3 and S7;† 31P-NMR: mono: 37.5 ppm, bis: 33.3 ppm).
Addition of TPPO also resulted in a downeld shi of the Si–H
resonances, consistent with weakening and displacement of
the b-H–Si interactions (La(H–Si) and TPPO coordination
(Fig. 3, le).22d The bis-TPPO adduct displays a single signi-
cantly broadened 31P signal, indicative of exchange on the
NMR timescale. Isolation of crystalline bis-TPPO adducts,
REIII(1L)(N(SiHMe2)2)(TPPO)2 (1-RE(TPPO)2; REIII: Y, La), was
accomplished in high yields by adding two equiv. TPPO per
1
Fig. 3 Selected spectral regions of (left) H- and (right) 31P{1H}-NMR
REIII (1-La or 1-Y2) in toluene followed by layering with
studies in C6D6 at RT of: (a) 1-La(TPPO)2 (27 mM) (b) + 1 TPPO (c) + 2
hexanes (Fig. 4a). Although under active investigation, TPPO (d) + 3 TPPO. Full spectra are displayed in Fig. S7.†
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Fig. 4 (a) Synthesis of 1-RE(TPPO)2. (b) Partial space-filling diagrams comparing 1-La(TPPO)2 and 2-Y. Fragment color coding: phenolate (red),
amine (blue), labile neutral donors (gold). N(SiHMe2)2 shown as ellipsoids (50% probability).
i
donor system, 2-Y,32 revealed largely conserved equatorial sites temperature (Fig. 5a). Adding one equiv. PrOH to 1-La(TPPO)2
and signicantly perturbed axial sites (Fig. 4b). In 2-Y, the led to generation of HN(SiHMe2)2 and a La isopropoxide species
2
1
geometrically constrained tethered donor leads to a small NL
–
as determined by H-NMR (Fig. S16†). Bound TPPO exchanges
Y–OMe angle (68ꢀ) and a large OOMe–Y–OTHF angle (203ꢀ) much faster as evidenced by the nearly coalesced 31P resonances
compared to 1-La(TPPO)2 (Fig. 4b, :NL1–La–OTPPO
:
86ꢀ, at ꢂ30 ꢀC (Fig. 5b), while a small amount of free TPPO was
:OTPPO–La–OTPPO: 169ꢀ). The differences in bond angles reect generated alongside another minor species (tentatively
increasing steric pressure from the axial donors, and suggest assigned as a mono-phosphine oxide species, La(TPPO)).
a plausible structural origin for the selectivity in 1-La/OPR3.
Addition of rac-BBL (100 equiv.) increases the signal for free
Insight into the catalyst resting state and active specie(s). TPPO signicantly, while resonances associated with La(TPPO)n
With 1-La(TPPO)2 in hand, we pursued further spectroscopic (n ¼ 1, 2) were dramatically broadened (Fig. 5c and S16†).
studies to determine relevant catalyst speciation and resting Warming the reaction mixture from ꢂ30 ꢀC to ꢂ15 ꢀC and 0 ꢀC
states. Variable temperature NMR experiments performed in (Fig. S17†) increased exchange of free and bound TPPO as evi-
ꢀ
toluene-d8 over the range of ꢂ30 to +30 C allowed for an esti- denced by the increasing line-width of free TPPO (half-width at
mation of TPPO exchange at the two axial sites (DG‡ half-maximum, HWHM; 25, 80, and 150 Hz respectively), and
ꢁ58 kJ molꢂ1; Fig. S6†),33 which is consistent with other REIII– RT experiments produced similar species (Fig. S15b†). Reac-
TPPO exchange processes reported in the literature.34 At ꢂ30 ꢀC, tions performed at RT with one equiv. TPPO formed similar
1-La(TPPO)2 displays two well-resolved 31P resonances indi- species without generation of free TPPO (Fig. S15a†); however,
cating slow-exchange of the two-bound TPPO at this optimal catalyst reactivity and selectivity required at least two
equiv. of TPPO (vide supra, Table S1,† entries 6–9). Taken
together, our reaction optimization and in situ spectroscopic
studies support dissociation of one equiv. TPPO from the pre-
catalyst, 1-La(TPPO)2, and dynamic phosphine oxide exchange
during catalysis. While La(TPPO) was identied as a catalyst
resting state, the observed TPPO-dependent reactivity and
observed speciation implicates both La(TPPO)n (n ¼ 1, 2) as
catalytically relevant species.
Stereocontrol and polymerization mechanism. Insights into
the polymerization mechanism were made possible through
evaluation of isolated P3HB samples (Mn, Đ, end-groups,
statistical analysis of microstructure) and reactivity studies
aimed at establishing the viability of relevant side-reactions
during the ROP of rac-BBL using the small molecule, (R)-3-
acetoxybutyric acid methylester [(R)-3-OAcBMe].
Stereocontrol. Statistical analysis of P3HB microstructure can
distinguish enantiomorphic site or chain-end stereocontrol
mechanisms based on the distribution of stereoerrors.35 Ber-
noullian analysis of the meso (m) and racemic (r) content in triad
distributions of P3HB, B ¼ 4(mm)(rr)/[(rm) + (mr)]2, predicts
a value of 1 for perfect chain-end control.35b A B value of 1.05 was
obtained from quantitative 13C-NMR of the methylene region of
P3HB generated by 1-La/TPPO at RT (Table 1, entry 6; Fig. S1†),
Fig.
5
31P{1H}-NMR studies in toluene-d8 at ꢂ30 ꢀC of: (a) 1-
La(TPPO)2 (25 mM) (b) 1-La(TPPO)2 + iPrOH (c) 1-La(TPPO)2 + iPrOH +
100 equiv. (rac)-BBL (38% conversion). All spectra are internally
referenced and intensity-normalized to PPh3 (4.0 mmol; Fig. S16b†).
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which is close to the theoretical prediction and conrms chain- limited to the independent studies of Kricheldorf (K catalysts)
end stereocontrol.3l,10e,36 While chain-end stereocontrol is and Coates (Zn beta-diketiminate catalysts).10f,42a Reactivity of
operative for several syndioselective catalysts,3l,37 this is the rst internal P3HB linkages were established by the use of small
example with an isoselective catalyst. Other catalysts which molecule models, which enabled detailed identication of the
produce isoenriched P3HB proceed through enantiomorphic resulting organic products. Despite the superior performance of
site-control3k,38 or their mechanism of stereocontrol have not yet many RE-based catalysts and the observation of crotyl forma-
been determined.
tion in several reports,3k,14g,24,45 investigations into elimination
End-group analysis. Additional insights into the polymeriza- pathways for RE-based catalysts are notably absent. Therefore,
tion mechanism were facilitated by end-group analyses using we examined the reactivity of 1-La and 1-La(TPPO)2 with a new
1H-NMR and MALDI-TOF techniques. ROP of rac-BBL and other small molecule model, (R)-3-acetoxybutyric acid methylester
b-lactones catalyzed by neutral metal alkoxides commonly [(R)-3-OAcBMe], to establish the viability of such side-reactions
proceed through coordination–insertion or anionic pathways.39 [e.g. pathway (iii)] during ROP.
The coordination–insertion mechanism proceeds through acyl
Addition of one equiv. iPrOH at RT to 1-La and 1-La(TPPO)2
cleavage (ester and alcohol end-groups), while the anionic cleanly generated the La isopropoxide species, 10-La and 10-
mechanism proceeds through alkyl cleavage (ether and La(TPPO)2, and one equiv. HN(SiHMe2)2 (:). 15 equiv. of (R)-3-
carboxylate end-groups). 1H-NMR spectra of isolated P3HB OAcBMe was added, and reactivity was monitored by H-NMR
1
samples revealed the presence of an isopropyl ester end-group aer 0.5 and 7 h (Fig. 6 and S25†). Our initial expectations
(Fig. S19 and S23†), while signals for an isopropyl ether were were that (R)-3-OAcBMe would react with 10-La and 10-La(TPPO)2
notably absent. These observations are consistent with a coor- through base-promoted elimination to form crotonate (trans-
dination–insertion mechanism for ROP with initiation occur- CrotMe), iPrOH, and a La acetate species. 10-La readily produced
ring from a metal-isopropoxide.
crotonate (0.5 h: 0.6 equiv.; 7 h: 1.2 equiv.); however, free iPrOH
Following a coordination–insertion mechanism, the other was not observed. Instead, the transesterication products,
end-group should be a terminal secondary alcohol, which would isopropyl butyrate/crotonate [(R)-3-OAcBiPr/trans-CrotiPr] and
be obtained upon hydrolysis of the propagating metal-alkoxide. methyl acetate (MeOAc), were readily identied (Fig. S25† for
As expected, the secondary alcohol end-group (–CHOHCH3) was detailed assignments). Transesterication between the La iso-
observed in a ꢁ1 : 1 molar ratio with respect to the ester end- propoxide and (R)-3-OAcBMe/trans-CrotMe would lead to a La
group (COOiPr). However, additional C–H resonances which methoxide and (R)-3-OAcBiPr/trans-CrotiPr
,
while trans-
correspond to a crotyl end-group were observed by 1H-NMR esterication between the La methoxide and the 3-acetoxy
spectroscopy (crotyl : CHOHCH3 : COOiPr; ꢁ1 : 1 : 1). Further group of (R)-3-OAcBiPr would generate MeOAc and a La 3-
evidence of the crotyl end-group was established by MALDI-TOF alkoxybutyrate species. The observed reactivity is consistent
measurements of P3HB obtained from ROP of 40 equiv. rac-BBL with reports of neutral La alkoxides as extremely efficient
using the 1-La(TPPO)2/iPrOH catalyst system. MALDI-TOF transesterication catalysts under mild conditions.46 In addi-
spectra corroborated 1H-NMR end-group assignments, and tion to the aforementioned products, quantiable amounts of
1
clearly supported crotyl end-group formation during the reac- free ligand (H2 L; 0.5 h: 0.1 equiv., 7 h: 0.6 equiv.) were also
tion (Fig. S22 and S23†).
detected. The formation of crotonate and the direct (conjugate
Elimination studies. Generation of crotyl end-groups aer acids) or indirect (transesterication) products of base-
polymerization could proceed through several possible path- promoted elimination provide clear evidence for pathway (iii)
ways: (i) elimination of water, hydroxide, or oxide from the occurring readily at RT with 10-La.
alcohol end-group under acidic or basic conditions respective-
In contrast to 10-La, 10-La(TPPO)2 generated less crotonate
ly,10g,40 (ii) thermal scission,41 or (iii) base-induced elimination (0.5 h: 0.14 equiv., 7 h: 0.73 equiv.) and only trace amounts of
1
of internal ester units,10f,42 (iv) terminal elimination from H2 L aer 7 h. These results highlight two additional and
a metal alkoxide. While pathway (i) has been proposed to benecial roles that strong neutral donor ligands (e.g. TPPO)
explain generation of crotyl end-groups aer quenching poly- can play in the ROP of rac-BBL. First, strong neutral donors can
merizations with weak acids,3k,10g this stands in contrast to the suppress elimination, as evidenced by the signicantly
stability of such 3-hydroxybutanoate monomer and oligomers decreased amount of crotonate formed with 10-La(TPPO)2
under strong-acid conditions.43 Furthermore, elimination from compared to 10-La. Supressing this side-reaction is critical, as
a metal alkoxide during the reaction would convert the the resulting La carboxylates would be inactive towards coor-
secondary alcohol end-group to an inactive crotyl end-group dination–insertion ROP at RT (i.e. dormant chains), while
and broaden Đ. The relative amounts of crotyl, secondary chain-scission would also broaden Đ and lower Mn. Second,
alcohol, and isopropyl ester end groups observed (ꢁ1 : 1 : 1, strong neutral donors can effectively suppress the kinetic
vide supra) and narrow Đ are inconsistent with expectations for basicity of the supporting ligand, as evidenced by signicant
1
this pathway. Pathway (ii) can be excluded due to the reaction amounts of H2 L generated with 10-La. While RE aryloxides have
temperatures evaluated in our studies (ambient or below).
been leveraged as efficient multi-functional catalysts through
Side-reactions such as deprotonation, transesterication, cooperative Lewis-acid/Lewis-base reactions (e.g. Michael, aldol,
and elimination were proposed in early reports for the ROP of hydrophosphination),47 RE aryloxides have been considered as
rac-BBL;40b,44 however, detailed examination of the elimination innocent supporting ligands for the ROP of rac-BBL. Although
pathway (iii) under mild temperatures (<100 ꢀC) has been rapid transesterication was observed for 1-La and 1-La(TPPO)2,
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i
1
Fig. 6 Reactivity studies of 1-La and 1-La(TPPO)2 in the presence of one equiv. PrOH and 15 equiv. (R)-3-OAcBMe followed by H-NMR after
0.5 h (a and d), 7 h (b and e). Dashed lines provided to help track the formation of H21L (c and f) during the reaction time course. * ¼ toluene (from
iPrOH stock solution), ** ¼ TPPO. Detailed assignments of full spectra provided as Fig. S25.†
the low Đ and high Pm support that this side-reaction is less a tethered donor group favors opposite polymer tacticities (2-
signicant under catalytic conditions. The pronounced RE: syndio, 1-RE: iso).
tendency towards transesterication should correspond to the
Proposed mechanism. Given the results of our catalytic and
lower steric-bulk of the methyl ester found in (R)-3-OAcBMe mechanistic studies, we propose the following mechanism for
compared to the more hindered ester linkages in P3HB.
the ROP of rac-BBL catalyzed by 1-La & 1-La(TPPO)2 (Fig. 7; L0 ¼
The effect of neutral donors on ROP catalyzed by 1-RE and 2-RE. THF or TPPO). Addition of iPrOH to 1-La or 1-La(TPPO)2 leads to
Given the observed benets of adding strong neutral donor a highly reactive initiator, 10-La or 10-La(TPPO)2. Ligand
ligands to 1-RE (vide supra), we set out to evaluate whether exchange of L0 for rac-BBL generates A, which can then undergo
similar enhancements would occur in structurally related insertion of the La alkoxide to generate B. Ring-opening would
catalysts with a tethered donor group (2-Y and 2-La). This was lead to C, which is involved in two competing ligand-exchange
motivated by reports of solvent-dependent10o and tethered- equilibria that gates productive (propagation) and unproduc-
donor dependent24,48 ROP reactivity for 2-RE and its deriva- tive (elimination) pathways. Upon binding of one equiv. L0 to C,
1
tives. H- and 31P{1H}-NMR studies indicate that TPPO readily the catalytic cycle is successfully completed with the regenera-
binds to 2-RE in solution (Fig. S18†); however, unlike 1-RE, rates tion of 10-La. Our low-temperature NMR studies of 1-La(TPPO)2
and selectivity for the ROP of rac-BBL were totally unaffected by support a mono-TPPO resting state during ROP, while our
added TPPO (Table 2, entries 3–5 and 8–10). While initially catalytic studies indicate that more than one equiv. of TPPO is
unanticipated, we suspect this is due to the much high required to achieve maximum rate and selectivity enhance-
concentrations of the weaker donor ligands (solvent) compared ments (Table S1,† entries 6–9). While we have depicted A, B, and
to our studies (two equiv.).3l,10o Under our experimental condi- C as mono-L0 adducts, we cannot exclude the possibility that
tions, the tethered donor of 2-RE dominates the observed one or more of these intermediates may be bis-L0 adducts.
reactivity and stereoselectivity, indicating that propagation
from the corresponding TPPO adducts of 2-RE is a higher donor ligands, binding of ester linkages to C may become
energy pathway.
competitive with L0 to form the key intermediate for base-
Alternatively, at high reaction conversions or with weaker
The presence or absence of a tethered donor also manifests promoted elimination, D. Chain cleavage through elimination
opposite size-dependent reactivity and selectivity trends for 1- would generate two polymer fragments that are inactive for
RE and 2-RE. Smaller ions are more reactive and selective for 2- further ROP at RT: (i) a terminated polymer with ester and crotyl
RE,3l,25,37b while larger ions are more reactive for 1-RE/OPR3. end-groups, and (ii) a dormant polyester chain terminated by
While both catalysts display chain-end stereocontrol and rare-earth carboxylate and secondary alcohol end-groups. With
feature labile coordination sites cis to an initiator (two for 1-RE, weak and sterically unencumbered donors (e.g. L0 ¼ THF), both
1
one for 2-RE), amplied selectivity is only observed with the the propagating alkoxide chain and L could act as competent
largest and most coordinatively unsaturated catalyst, 1-La. bases, while the kinetic basicity of 1L is suppressed with strong
Furthermore, the presence (2-RE) or absence (1-RE/OPR3) of and bulky neutral donors (e.g. L0 ¼ TPPO). While intermediate D
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Table 2 Effects of TPPO on 1-RE and 2-RE ROP activity with rac-BBL
Timea (h)
Conv.b (%)
Mn,exp (kg molꢂ1
)
Đc,d
Pm
c
e
Entry
[Cat.]
[TPPO]/[RE]
1
2
3
4
5
6
7
8
9
1-La
1-La
2-La
2-La
2-La
1-Y2
1-Y2
2-Y
0
2
0
1
2
0
2
0
1
2
24
1
40
97
22
21
21
33
95
91
99
99
2.2
9.6
1.4
1.6
1.7
1.23
1.18
1.17
1.14
1.16
1.15
1.18
1.16
1.12
1.14
0.57
0.71
0.45
0.49
0.48
0.55
0.51
0.22
0.22
0.22
24
24
24
24
3
1
1
1
5.9
14.0
14.2
17.6
15.9
2-Y
2-Y
10
a
b
Reaction times not optimized. Determined by 1H-NMR integration of BBL and PHB methine resonances in the crude reaction mixture.
c
Determined by gel permeation chromatography (GPC) at 30 ꢀC in THF using polystyrene standards and corrected by Mark–Houwink factor of
d
e
0.54.51 Mw/Mn. Probability of meso-linkages between repeat units. Determined by integration of P3HB C]O resonances using inverse gated
(IG) 13C-NMR.
is depicted with coordination of a neighboring polyester chain, phosphine oxides containing aromatic (TPPO) or aliphatic
we expect that both intra- and inter-molecular pathways are (TOPO) substituents, which suggests other origins for the
viable.
unique isoselective chain-end stereocontrol. Rieger and
While the exact origin of the unique isoselectivity remains coworkers recently carried out an extensive computational
unresolved, we hypothesize that strong neutral donors such as study investigating the ROP of rac-BBL catalyzed by 2-Y.25 The
TPPO lead to a sterically crowded axial environment in 1- syndioselective pathway is favored kinetically and thermody-
La(TPPO)2 compared to 1-La and 2-RE (Fig. 7). Non-covalent C– namically by the propagating P3HB chain adopting a k3 binding
H/p (arene) interactions between ligand and substrate have mode. The authors suggest that alternative P3HB binding
been proposed to explain the high syndioselectivity for the ROP modes (e.g. k1 or k2) may lead to iso-enriched P3HB. Such
of rac-BBL with a yttrium catalyst supported by a cumyl- intermediates (Fig. 7: A or B) could be favored by the stronger
substituted tetradentate amino-bisphenolate ligand.37b In binding and enhanced steric bulk of phosphine oxides, opening
contrast, we observed similar reactivity and selectivity with up new pathways that are disfavored for 2-Y.
Fig. 7 Proposed mechanism for the ROP of rac-BBL catalyzed by 1-La and 1-La(TPPO)2.
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Finally, our mechanistic studies uncover new roles for
neutral donor ligands in ROP. Previous studies have provided
evidence for decreased transesterication19a,b,e,49 and control of
catalyst aggregation state19h,j,49a,50 with added neutral donor
ligands; however, their role in suppressing base-promoted
elimination (i.e. crotyl end-group) was previously unknown.
Our results suggest that neutral donor groups play a critical role
in suppressing or shiing ligand-exchange equilibria for both
productive and non-productive pathways in the ROP of rac-BBL,
and addition of these simple ligands provide a facile and
inexpensive way to further modulate catalyst performance.
Acknowledgements
We thank Brown University for support of this research. We
thank Savannah Snyder and Chrys Wesdemiotis, University of
Akron, for performing high-resolution MALDI-TOF measure-
ments used for chain-end analysis. We thank Patrick J. Carroll,
Eric J. Schelter, and Chris R. Graves for helpful discussions. X.
D. and J. R. R. are inventors on U.S. patent application 62/
950,702 submitted by Brown University, which covers the cata-
lysts and process described herein.
Notes and references
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In summary, we have synthesized, characterized, and evaluated
the reactivity of novel benzyl-substituted amino-bisphenolate
rare-earth complexes, 1-RE, as catalysts for the isoselective
ROP of rac-BBL. 1-RE display ROP rates and selectivities that are
tuned by the identity of exogenous neutral donor ligands (e.g.
OPR3). 1-La/OPR3/iPrOH display excellent reactivity and selec-
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octyl, Ph). The use of simple monodentate OPR3 to enhance
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Our preliminary mechanistic studies indicate that (i) 1-
La(TPPO)2 is a precatalyst for the isoselective ROP of rac-BBL,
(ii) La(TPPO)n (n ¼ 1, 2) are implicated as catalytically relevant
species, (iii) isoselective ROP proceeds with chain-end stereo-
control through a coordination–insertion mechanism, and (iv)
addition of neutral donor ligands can suppress elimination
side-reactions. This is the rst investigation into elimination
pathways of RE-based catalysts in the ROP of rac-BBL, and 1-
La(TPPO)2 is the rst catalyst to access isoenriched P3HB with
chain-end stereocontrol. While structurally related catalysts
with a tethered donor group (2-RE) also operate under chain-
end stereocontrol, ROP activity and selectivity of 2-RE (i) are
unaffected by added neutral donor ligands and (ii) display
opposite stereoselectivity (syndioselective) compared to 1-La/
OPR3. Our study uncovers new roles for neutral donor ligands in
stereospecic ROP, and begins to connect their effect on cata-
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enhancements may require catalysts with enhanced metal
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new opportunities in catalyst design and optimization. Exten-
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the stereoselective synthesis of other oxygenated (co)polymers,
and further mechanistic studies are currently underway.
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