The present invention relates to a compound having the formula LaM(OR1)bR2cXd wherein M is a metal selected from Ti, Zr and Hf; L is a ligand selected from permethylpentalene, (hydro)permethyl-pentalene, (hydro)pentalene, cyclopentadiene, indene and ethylene- or silane-bridged indene, preferably (bis)indene; R1 is a 1-6C alkyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted phenylalkylene group; R2 is Me or Et; X is halogen; a=1 to 3, b=1 to 3, c=0 or 1 and d=0, 1, 2 or 3; and dimers thereof, the use of the compound as an initiator in the polymerization of lactide monomer and a process for producing a polylactide performed by contacting a lactide monomer with the compound.

RELATED APPLICATIONS

This application is a § 371 national stage application based on Patent Cooperation Treaty Application serial number PCT/EP2015/057581, filed Apr. 8, 2015, which claims the benefit of priority to GB 1406406.7, filed Apr. 9, 2014.

The present invention relates to the production of poly(lactic acids). It, further, relates to metal complexes that are useful as catalysts/initiators in lactide polymerisation.

Poly(lactic acids) (PLAs) have been studied intensely during the past few decades because of their biodegradability and biocompatibility. PLA possesses versatile physical properties and has been used in medical applications and tissue engineering such as media for controlled drug release. Ring opening polymerisation (ROP) of lactide (LA) by single-site initiators is the most efficient route to PLAs with controlled molecular weight and narrow molecular weight distribution. The two stereogenic centres in one lactide molecule results in three distinct configurational isomers (S,S)-LA, (L-LA); (R,R)-LA, (D-LA) and (R,S)-LA, (meso)-LA. The 1:1 mixture of (S,S)-LA and (R, R)-LA is referred to as rac-LA.

Metal complexes useful for initiating ring opening polymerisation of lactides are known.

Wenshan Ren et al, Inorganic Chemistry Communications, 30, (2013), 26-28 report that benzyl thorium metallocenes [η5-1,3-(Me3C)2C5H3]2Th(CH2Ph)2(1) and [η5-1,2,4-(Me3C)3CH2H2]2Th(CH2Ph)2(2) can initiate the ring opening polymerisation (ROP) of racemic-lactide (rac-LA) under mild conditions. Complete conversion of 500 equiv of lactide occurs within 5 h at 40° C. in dichloromethane at [rac-LA]=1.0 mol L−1, and the molecular weight distribution is very narrow (ca.1.15) over the entire monomer-to-initiator range, indicating a single-site catalyst system.

The present invention is based on the discovery of a different class of compounds which have use as initiators for the polymerisation of lactide monomers.

The present invention provides a compound having the formula
LaM(OR1)bR2cXd
wherein
M is a metal selected from Ti, Zr and Hf;
L is a ligand selected from permethylpentalene (Pn*=C8Me6), (hydro)permethylpentalene(Pn*(H)=C8Me6H), (hydro)pentalene (Pn(H)=C8H8), cyclopentadiene (Cp=C5H5), indene (C7H7) and ethylene- or silane-bridged indene;
R1is a 1-6 C alkyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted phenylalkylene group;
R2is Me or Et
X is halogen
a=1 to 3, b=1 to 3, c=0 or 1 and d=0, 1, 2 or 3
and dimers thereof.

Pentalenes, referred to above, have the structures shown below:

The silane-bridge can be optionally substituted with a range of alkyl groups. The SBI ligand refers to the di-methyl silane bridged indenyl ligand.

The present invention, further, provides the use of a compound of the invention as an initiator in the polymerisation of a lactide monomer.

The present invention, yet further, provides a process for producing a polylactide which comprises contacting a lactide monomer with a compound of the invention.

As stated above, compounds of the present invention have the general formula
LaM(OR1)bR2cXd
where L, M, R1, R2, X, a, b, c and d are as defined above, and dimers thereof.

M is a Group IV transition metal selected from titanium, zirconium and hafnium. According to one preferred embodiment, M is titanium. According to another preferred embodiment, M is zirconium. According to a different embodiment, M is hafnium.

L is a ligand selected from permethylpentalene(Pn*), (hydro)permethylpentalene(Pn*(H)), (hydro)pentalene(Pn(H)), cyclopentadiene (Cp), indene and ethylene-bridged indene (EBI) and dimethylsilane-bridged indene (SBI). According to one preferred embodiment, the ligand group L is permethylpentalene. According to a different embodiment, the ligand group L is indene or EBI when M is Zr.

The compounds of the present invention are alkoxide, phenyloxide or phenylalkyleneoxide metal complexes based on the ligand group L. R1of the OR1group attached to the metal M is selected from 1-6C alkyl, substituted or unsubstituted phenyl and substituted or unsubstituted phenylalkylene. Preferably, the 1-6C alkyl group, for R1, is a tertiary butyl group. Preferably, when R1is a phenyloxide group, it is a dialkylphenyloxide group of the formula —C6H3(R3)2where R3is a 1-4C alkyl group, especially Me,iPr oriBu. According to a preferred embodiment, R1is selected from 2,6-dimethylphenyl, 2,6-diisopropylphenyl and 2,6-ditertiarybutylphenyl.

R1may, according to a different embodiment, be a substituted or unsubstituted phenylalkylene group as mentioned above. Examples include —CH2C6H5and —CH(Me)C6H5.

The metal complexes of the invention may contain one R2group attached to the metal M. If present, R2is selected from Me and Et. If R2is present in the complex, it is preferably methyl.

The metal complexes of the invention may contain a halogen group X attached to M. Preferably, if present, X is Cl. Typically, if X is present in the complex, the value of d is 1 or 2.

According to a preferred embodiment, the compound of the invention is a (half)metallocene complex being

η5-Pn*(H)Ti(OtBu)3; or

η5-Pn*(H)Zr(OtBu)3; or

η5-Pn*(H)Zr(O—CH2C6H5)3; or

η5-Pn*(H)Zr(O—S—CH(CH3)C6H5)3; or

rac-η5-Pn*(H)Zr(O-rac-CH(CH3)C6H5)3; or

η5-Pn*(H)Zr(O-2,6-Me-C6H3)3; or

η5-Pn*(H)Zr(O-2,6-iPr-C6H3)3; or

η5-Pn*(H)ZrCl2(O-2,6-tBu-CH); or

η5-Pn*(H)Hf(O-2,6-Me-C6H3)3; or

η5-Pn*(H)HfCl(O-2,6-iPr-C6H3)2; or

The compounds above may be made, for instance, by the reaction of η5-Pn*(H)SnMe3with the corresponding metal chloride, e.g. TiCl4, ZrCl4or HfCl4, in benzene at 80° C. for 2-72 h and then with the appropriate potassium alkoxide, potassium phenyloxide or potassium phenylalkyleneoxide at room temperature in benzene or toluene. However, any suitable process for preparing the compounds known in the art may be used for preparation thereof.

According to a different preferred embodiment, the (half)metallocene complex of the invention is

[(Pn*)Ti(O-2,6-Me-C6H3)Cl]; or

[η8-(Pn*)Ti(O-2,4-tBu-C6H3)Cl]; or

[η8-(Pn*)Ti(O-2,6-Me-C6H3)2]; or

[η8-(Pn*)Ti(OtBu)Cl]; or

[η8-(Pn*)Ti(OtBu)2; or

[η5-(Pn*H)Ti(O-2,6-Me-C6H3)Cl2]; or

The above compounds may be produced, for example, by the reaction of one equivalent of [η8-(Pn*)TiCl(μ-Cl)]2with two equivalents of KOR (where R=2,6-MeC6H3or 2,4-tBuC6H3) at room temperature in toluene for 24-48 h. However, any suitable process for preparing the compounds known in the art may be used for preparation thereof.

According to yet a further preferred embodiment, the (half)metallocene complex of the invention is

[(EBI)Zr(O-2,6-Me-C6H3)Cl]; or

[Ind2Zr(O-2,6-Me-C6H3)Me]; or

[Ind2Zr(O-2,6-Me-C6H3)Cl]; or

[Ind2Zr(O-2,6-Me-C6H3)2]; or

[Cp2Zr(O-2,6-Me-C6H3)2]; or

[Cp2Zr(O-2,6-Me-C6H3)Cl]; or

The above EBI Zr compounds may be produced by reacting stoichiometric amounts of [K(O-2,6-Me-C6H3)] and rac-[(EBI)ZrCl2] in toluene with stirring for 18 h at room temperature. A modified procedure for preparing [(Ind)2Zr(OtBu)Me] involves reacting stoichiometric amounts of [(Ind)2ZrMe2] and tert-butanol in toluene with stirring at room temperature for 18 h, followed by concentration in vacuum. [(Ind)2Zr(O-2,6-Me-C6H3)Me] can be prepared by reacting stoichiometric amounts of [(Ind)2ZrMe] and 2,6-dimethylphenol in toluene with stirring at room temperature for 18 h, followed by concentration in vacuo. However, any suitable process for preparing the compounds known in the art may be used for preparation thereof.

The compounds of the invention are useful as initiators in the polymerisation of a lactide monomer. Accordingly, the present invention also relates to the use of a compound as hereinbefore described as an initiator in the polymerisation of a lactide monomer.

According to a further aspect, the invention provides a process for producing a polylactide which comprises contacting a lactide monomer with a compound as hereinbefore described.

In a preferred embodiment of the process, the lactide monomer is L-lactide and the resulting polylactide is isotactic polylactide. In another preferred embodiment of the process, the lactide monomer is rac-lactide and the resulting polylactide is atactic polylactide.

Experimental Detail I—Relating to Permethylpentalenes

General Procedure

All organometallic syntheses were performed under an inert atmosphere of nitrogen gas, utilizing standard Schlenk techniques on a dual vacuum-inlet gas manifold or Braun glove box. Where necessary, solvents were dried SPS drying system (hexane, pentane, toluene). Deuterated NMR solvents were dried over NaK (benzene-d6, toluene-d8) or CaH2(chloroform-d1), vacuum transferred and free-pump-thaw-degassed three times prior to use. Elemental analyses were conducted by Mr Stephen Boyer at the elemental analysis service at London Metropolitan University. NMR spectra were recorded using Young's tap NMR tubes on a Varian Mercury VX-Works 300 MHz spectrometer.1H and13C{1H} NMR spectra were referenced via the residual protio-solvent peak. Potassium tert-butoxide was purchased from Sigma-Aldrich and used as received. L- and rac-lactide were purchased from Alfa Aesar and re-crystallized and sublimed (10−2mbar, 50° C.) prior to use. [K(O-2,6-Me-C6H3)] and [K(O-2,4-tBu-C6H3)] were prepared by stirring potassium bis(trimethylsilyl)amide with the appropriate alcohol in THF at room temperature.

Crystals were mounted on glass fibres using perfluoropolyether oil, transferred to a goniometer head on the diffractometer and cooled rapidly to 150K in a stream of cold nitrogen using an Oxford Cryosystems CRYOSTREAM unit. Data collections were performed using an Enraf-Nonium FR590 KappaCCD diffractometer, utilising graphite-monochromated Mo KαX-ray radiation (λ=0.71073 Å). Intensity data were processed using the DENZO-SMN package. Structures were solved using the direct-methods program SIR92, and refined using full-matrix least squares refinement on all F2data using the CRYSTALS program suite.

Polymerisation Procedure

All polymerizations were carried out in Young's tap NMR tubes containing 0.4 mL of a benzene-d6solution of lactide with an initial lactide concentration of [LA]0=0.104 M and 0.1 mL of a benzene-d6solution of catalyst (of a concentration to ensure [LA]0/[init.]0=50). Lactide conversion was subsequently calculated by comparing the integration values of the methane signal of PLA and lactide monomer in the1H NMR spectrum. The temperature at which a given polymerisation was carried out varied in the temperature range 80 to 100° C. and is noted in the appropriate section.

Synthesis of [(Pn*)Ti(O-2,6-Me-C6Me2)Cl]

Synthesis of [η8-(Pn*)Ti(O-2,4-tBu-C6H3)Cl]

Synthesis of [η8-(Pn*)Ti(O-2,6-Me-C6H3)2]

Synthesis of [η8-(Pn*)Ti(OtBu)Cl]

Synthesis of [η8-(Pn*)Ti(OtBu)2]

Synthesis of [η5-(Pn*H)Ti(O-2,6-Me-C6H3)C)2]

Synthesis of [η5-(Pn*H)Ti(O-2,6-Me-C6H3)3]

Crystallographic Details

Experimental Detail II—Relating to (Hydro)Permethylentalenes

General Procedure

All organometallic syntheses were performed under an inert atmosphere of nitrogen gas, utilizing standard Schlenk techniques on a dual vacuum-inlet gas manifold or Braun glove box. Where necessary, solvents were dried by reflux over the appropriate drying agent: NaK (Et2O), sodium (THF) and SPS drying system (hexane, pentane, soluene). Solvents were distilled from the desiccant under a flowing stream of nitrogen and transferred using a siphoning technique via steel cannulae and stored in flame-dried glass ampoules under an atmosphere of nitrogen. Deuterated NMR solvents were dried over NaK (benzene-d6, toluene-d8) or CaH2(pyridine-d5), vacuum transferred and freeze-pump-thaw-degassed three times prior to use. Elemental analyses were conducted by Mr Stephen Boyer at the elemental analysis service at London Metropolitan University. NMR spectra were recorded using Young's tap NMR tubes on a Varian Mercury VX-Works 300 MHz spectrometer.1H and13C{1H} NMR spectra were referenced to the residual protio-solvent peak.

Crystals were mounted on glass fibres using perfluoropolyether oil, transferred to a goniometer head on the diffractometer and cooled rapidly to 150 K in a stream of cold nitrogen using an Oxford Cryosystems CRYOSTREAM unit. Data collections were performed using an Enraf-Nonius FR590 KappaCCD diffractometer, utilising graphite-monochromated Mo KαX-ray radiation (λ=0.71073 Å). Intensity data were processed using the DENZO-SMN package. Structures were solved using the direct-methods program SIR92, and refined using full-matrix least squares refinement on all F2 data using the CRYSTALS program suite.

Polymerisation Procedure

The lactide monomer (40 mg) and the complex were introduced in an NMR tube following the desired monomer:initiator ratio. Then 0.57 mL of chloroform-d1was added to the compounds, leading to an initial monomer concentration of [LA]0=0.5 M. The solution was monitored by1H NMR spectroscopy. The conversion was determined by integration of the methane area of the polymer versus the monomer.

Synthesis of Pn*(H)SnMe3

Synthesis of Pn*(H)TiCl3

Synthesis of [Pn*(H)ZrCl3]2

Synthesis of [Pn*(H)HfCl3]2

Synthesis of η5-Pn*(H)Ti(OtBu)3

Synthesis of η5-Pn*(H)Zr(OtBu)3

Synthesis of η5-Pn*(H)Zr(O—CH2C6H5)3

Synthesis of η5-Pn*(H)Zr(O—S—CH{CH3}C6H5)3

Synthesis of η5-Pn*(H)Zr(O-rac-{CH3}C6H5)3

Synthesis of η5-Pn*(H)Zr(O-2,6-Me-C6H3)3

Synthesis of η5-Pn*(H)Zr(O-2,6-iPr-C6H3)3

Synthesis of η5-Pn*(H)ZrCl2(O-2,6-tBu-C6H3)

Synthesis of η5-Pn*(H)Hf(O-2,6-Me-C6H3)3

Synthesis of η5-Pn*(H)HfCl(O-2,6-iPr-C6H3)2

Synthesis of η5-Pn*(H)HfCl2(O-2,6-tBu-C6H3)

Experimental Detail III—Relating to Indenyl-Base Catalysts

General Details

Air and moisture sensitive compounds were manipulated under an inert atmosphere of nitrogen, using standard Schlenk line techniques on a dual manifold vacuum/nitrogen line or a Braun Unilab glove box. Reaction solvents (pentane, hexane, and toluene) were dried using an MBraun SPS-800 solvent purification system. Hexane, toluene, and pentane were stored over pre-activated 3 Å molecular sieves. Dry solvents were stored in oven-dried ampoules under an atmosphere of nitrogen, sealed with either Rotoflo or Young's taps. Deuterated solvents used in NMR analysis of air-sensitive compounds were dried over the appropriate drying agent, freeze-thaw degassed and vacuum transferred prior to use: chloroform-d1(Sigma-Aldrich) was stored over pre-activated 3 Å molecular sieves. NMR spectra were recorded on a 300 MHz Varian Mercury VX-Works spectrometer.1H (300.27 MHz) and13C{1H} (75.50 MHz) spectra were recorded at 25° C. unless otherwise stated, and referenced internally to the residual protio-solvent peak in the deuterated solvent used.1H and13C{1H} chemical shifts, δ, are given in parts per million (ppm), are given relative to the residual solvent peaks. Air sensitive samples were prepared under an inert atmosphere in a glove box, using dried solvents in Young's taps NMR tubes. [(Ind)2ZrMe2], and complex were synthesised according to literature procedures. [(EBI)ZrCl2] (Strem Chemicals) was hot re-crystallised in toluene.

Polymerisation Procedure

All polymerisations were carried out in Young's tap NMR tubes containing 40 mg of lactide in a chloroform-d1solution of initiator (20 mg initiator in 4 mL chloroform-d1), ensuring that the lactide:initiator ratio was 50:1. chloroform-d1was then added to ensure the initial lactide concentration was [LA]0=0.50 M. Polymerisations involving addition tert-butanol were prepared as usual, and tert-butanol was added to the chloroform-d1solution via microsyringe, ensuring the lactide:initiator:tert-butanol ratio was 50:1:1.

Crystals were mounted on MiTeGen MicroMants using perfluoropolyether oil, and cooled rapidly to 150 K in a stream of cold nitrogen using an Oxford Cryosystems CRYOSTREAM unit. Data collections were performed using an Enraf-Nonius FR590 KappaCCD diffractometer, utilising graphite-monochromated Mo KαX-ray radiation (λ=0.71073 Å). Raw frame data were collected at 150(2) K using a Nonius KappaCCD diffractometer, reduced using DENZO-SMN and corrected for absorption using SORTAV. The structure was solved using SuperFlip and refined using full matrix least-squares using CRYSTALS.

Crystallographic Data of [EBI)Zr(O-2,6-Me-C6H3)Cl]

Synthesis of [(EBI)Zr(O-2,6-Me-C6H3)Cl]

Synthesis of [Ind2Zr(O-2,6-Me-C6H3)Me]

Polymerisation of L- and Rac-Lactide

To study the difference between the aryloxide group, pseudo-first order kinetic data of the polymerisation of lactide monomers were carried out with a monomer:initiator: ratio of 50 at 100° C. in chloroform-d1. The results are shown in Table 1 and illustrated inFIG. 1. The observed propagation rates, kobs, were determined by analysis of a semi-logarithmic plot of 1n([LA]0/[LA]t) vs. time, where [LA]0=0.50 mol/L.

As can be seen inFIG. 1, the four complexes based on dimethyl and diisopropyl aromatic group with zirconium and hafnium (7, 8, 10 and 11) led to the highest constant of propagation (0.364<kobs<0.479 h−1). Both tert-butyl complexes (9 and 12) demonstrated the lowest rate of polymerisation (with kobsof 0.043 h−1for η5-Pn*(H)ZrCl2(O-2,6-tBu-C6H3) and kobsof 0.086 h−1for η5-Pn*(H)HfCl2(O-2,6-tBu-C6H3)). When varying the metal using dimethylphenoxide type complexes, it appears that zirconium is faster than hafnium than titanium (kobsof 0.479, 0.391 and 0.113 h−1respectively). These rates are within the literature range.

The polydispersities are relatively high (1.45<Mw/Mn<1.74) certainly due to high temperature of polymerisation. The molecular weights are slightly higher than the theoretical ones (7,547<Mn<11,680 g/mol).

The effect of variation of the alkoxide group substituent on the polymerisation of L-lactide has been studied at 100° C., with a monomer:initiator: ratio of 50 in chloroform-d1. When complexes η5-Pn*(H)Ti(OtBu)3, 1, and η5-Pn*(H)Zr(OtBu)33, were used no conversion was achieved after 1 h. However, changing the tert-butyl group for a benzylic type substituent dramatically increased the rate of the polymerisation with conversion above 90% for η5-Pn*(H)Ti(O—CH2Ph)3, 4, η5-Pn*(H)Zr(O—S—CH{CH3}C6H5)3, 5, η5-Pn*(H)Zr(O-rac-CH{CH3}C6H5)3, 6, (93, 96 and 97% respectively).

To study the effect of the chirality on the initiating group, pseudo-first order kinetic data of the polymerisation of lactide monomers were carried out with a monomer:initiator: ratio of 50 at 100° C. in chloroform-d1. The results are shown in Table 2 and illustrated inFIGS. 2-3and SI.

Both complexes η5-Pn*(H)Zr(O—S—CH{CH3}C6H5)3, 5, η5-Pn*(H)Zr(O-rac-CH{CH3}C6H5)3, 6 demonstrated very high rate of polymerisation for L- and rac-lactide (1.885<kobs<3.442 h−1) at 100° C. Over the three temperatures (60, 80 and 100° C.), the racemic complex polymerised faster both lactide monomers. At 60° C., the observed propagation rates when using rac-η5-Pn*(H)Zr(O—CH{CH3}C6H5)3, 6 are around 70% faster (kobsof 0.850 h−1for L-lactide and 0.767 h−1for rac-lactide) than when η5-Pn*(H)Zr(O—S—CH{CH3}C6H5)35 was used (kobsof 0.484 h−1for L-lactide and 0.491 h−1for rac-lactide). L- and rac-lactide appears to be polymerised at similar rates of polymerisation.

The polydispersities decreased with decreasing temperature (1.27<Mw/Mn<1.44 for 100° C. and 1.15<Mw/Mn<1.24 for 80° C.). The molecular weight experimental are half of the theoretical (2,693<Mn<4,549 g/mol).

The activation parameters for the ring-opening polymerisation of L- and rac-lactide initiated using η5-Pn*(H)Zr(O—S—CH{CH3}C6H5)3, 5, η5-Pn*(H)Zr(O-rac-CH{CH3}CH5)3, 6 were determined using Eyring plots and found to be 30.4<ΔH#<46.6 kJ/mol and 411.4<ΔS#<640 J/(mol K),FIG. 4and SI.

Pseudo-first order kinetic data of the polymerisation of L-lactide to study the effect of variation of the concentration of the monomer:initiator ratio at 100° C. in chloroform-d1using η5-Pn*(H)Zr(O-2,6iPr—C6H3)3, 8. The results are collated in Table 3 and illustratedFIG. 5.

As expected the rate of the polymerisations of L-lactide at 100° C. in chloroform-d1increased with decreasing monomer:initiator ratio (kobsof 0.235, 0.377, 0.391 and 0.521 h−1for [LA]0/[Zr]0of 200, 100, 50 and 25 respectively). Furthermore, the molecular weights, Mn, increased with increasing concentration from 6,920 to 17,042 g/mol for initial monomer:initiator ratio of 25 to 200 respectively. The polydispersities, Mw/Mn, are varying between 1.40<Mw/Mn<1.74.

The observed rate of the propagation of L-lactide using η5-Pn*(H)Zr(O-2,6-Pr—C6H3)3, 8, demonstrated a pseudo first-order kinetic as a function of the initiator (FIG. 6).

Pseudo-first order kinetic data of the polymerisation of L-lactide to study the effect of temperature with monomer:initiator ratio of 50 in chloroform-d1using η5-Pn*(H)Zr(O-2,6-Pr—C6H3)3, 8. The results are collated in Table 4 and illustratedFIG. 7.

As expected the rate of the polymerisations of L-lactide in chloroform-d1decreased with decreasing temperature (kobsof 0.391, 0.151 and 0.092 h−1for T of 100, 90 and 80 respectively). The molecular weights, Mn, remain constant between 6,348 to 7,751 g/mol which are very close to the theoretical ones. However, the polydispersities, Mw/Mn, decreased with decreasing temperature from 1.72 to 1.58 for 100 to 80° C. respectively.

The activation parameters for the ring-opening polymerisation of L-initiated using η5-Pn*(H)Zr(O-2,6-Pr—C6H3)3, 8 were determined using Eyring plots and found to be ΔH#=75.9 kJ/mol and ΔS#=1847 J/(mol K),FIG. 8.

The synthesized polylactides were characterised by1H,1H{1H} and13C{1H} NMR spectroscopy. The NMR spectra demonstrated no epimerisation when L-lactide was polymerised and an isotactic biased PLA when rac-lactide was polymerised.

They have also been characterised by MALDI-TOF and13C{1H} NMR spectroscopy to determine the end of chains. It was shown that the lactide monomers inserted in the metal-oxygen bond.

Pseudo-first order kinetic data of the polymerisation of L-lactide at 80° C. in beneze-d6, with an initiator: monomer ratio of 1:50, using selected permethylpentalene complexes are shown inFIG. 9. The kinetic data for all polymerisations displayed an induction period that varied depending on the initiating complex. As such, the data inFIG. 9is given from 32 h, by which time all induction periods had ended.

The complex that exhibited by far the highest activity towards the ring-opening polymerisation of lactide isomers was [η5-(Pn*)Ti(O-2,6-Me-C6H3)2]. It demonstrates a rate of polymerisation similar to published titanium complexes (kobs=69.9×10−3h−1)37and ten times faster than the complexes [η8-(Pn*)Ti(O-2,6-Me-C6H3)Cl] and [η8-(Pn*)Ti(O-2,4-Bu-C6H3)Cl] at 80° C. which demonstrated similar rates of propagation, (kobs=7.2×10−3h−1and 7.0×10−3h−1respectively). These rates of propagation being 3.5 times faster than when [η5-(Pn*)Ti(O-2,6-Me-C6H3)Cl2] was used (kobs=1.9×10−3h−1).

As is shown inFIG. 10, at 90° C., when initiated by [η8-(Pn*)Ti(O-2,6-Me-C8H3)2], rac- and L-lactide polymerise at the same rate (kobs≈110×10−3h−1). This is presumably because the achiral initiator cannot distinguish between both lactide enantiomers and has incorporated each at the same rate. This absence of stereochemical preference suggests that the polymerisation goes by a chain-end controlled mechanism.

Polymerisations of L-lactide using [η8-(Pn*)Ti(O-2,6-Me-C6H3)2] were carried out in the temperature range of 80 to 100° C. and the results were collated to an Eyring plot. From the Eyring plot an estimation of the activation parameters were obtained: ΔH#=75.15 kJ mol−1, ΔS#=−125.85 J K−1mol−1, ΔG#(100° C.)=87.74 kJ mol−1. The modest value of ΔH#is typical for attack on a carbonyl group coordinated to a metal centre and the negative and relatively high value of ΔS#implies a high degree of order in the transition state. As such, all parameters are consistent with a coordination insertion mechanism displaying a highly ordered transition state. The polymerisation of L-lactide leads to isotactic PLA and rac-lactide to atactic PLA.

Pseudo-first order kinetic data of the polymerisation of L-lactide using [(EBI)Zr(O-2,6-Me-C6H3)Cl], [(Ind)2Zr(OtBu)Me], and [(Ind)2Zr(O-2,6-Me-C6H3)Me] are shown inFIG. 11. All initial polymerisation studies were carried out at 80° C. in chloroform-d1, with an L-LA:initiator ratio of 50:1, ensuring [LA]0—0.50 M.

FIG. 12shows semi-logarithmic plots of L-lactide conversion vs time, [LA]0/[Init]0=50, [LA]0=0.50 M, T=80° C., chloroform-d1(0.5 mL), polymerisation using [(EBI)Zr(O-2,6-Me-C6H3)Cl], (dotted line), [(Ind)2Zr(OtBu)Me], (solid line), [(Ind)2Zr(O-2,6-Me-C6H3)Me], (dashed line).FIG. 12shows that complex [(Ind)2Zr(OtBu)Me] displayed the highest activity with 84% conversion in eight hours (kobs=0.24 h−1) and no initiation period. This is comparable to moderate activities of zirconium initiators in the literature. A significantly lower activity was displayed by [(Ind)2Zr(O-2,6-Me-C6H3)Me] which achieved 74% conversion after 28 h (kobs=0.05 h−1), at a rate 4.5 times slower than [(Ind)2Zr(OtBu)Me]. Interestingly, [(Ind)2Zr(O-2,6-Me-C6H3)Me] displayed an initiation period of around half an hour. These observations are rationalised by the increased bulk of the aryl-oxide substituent of [(Ind)2Zr(O-2,6-Me-C6H3Me] compared to the tert-butoxide substituent of [(Ind)2Zr(OtBu)Me]. In comparison, [(EBI)Zr(O-2,6-Me-C6H3)Cl]exhibited the lowest catalytic activity, managing 4.2% conversion in 28 h (kobs=0.002 h−1) which is comparable to rac-[(EBI)Zr(OC{OiPr}=CMe2)] (7% conversion in 18 h at 80° C. in toluene) synthesised by Ning et al, Organometallics, 2008, 27, 5632. The rate of [(EBI)Zr(O-2,6-Me-C6H3)Cl] is two orders of magnitude less than [(Ind)2Zr(OtBu)Me] and [(Ind)2Zr(O-2,6-Me-C6H3)Me], probably due to both the increased bulk of the aryloxide compared to the tert-butoxide and the increased rigidity conferred by the ansa-bridged ligand, preventing reorientation of the indenyl moieties.

As [(Ind)2Zr(OtBu)Me] showed the highest rate of polymerisation, further studies were carried out to investigate its stereoselectivity and estimate its activation. Polymerisations using [(Ind)2Zr(OtBu)Me] as the initiator were carried out between 60° C. and 100° C., with the same LA:initiator ratios and [LA]0as used previously. The enthalpy of activation (ΔH‡) and the entropy of activation (ΔS‡) were calculated from a plot of ln(kobs/T) vs. (1/T) (FIG. 12), giving ΔH‡=46.9 kJ·mol−1and ΔS‡=−193.9 J·K−1·mol−1. These values are consistent with the literature; typical for a bimolecular reaction, and a coordination-insertion mechanism.

Furthermore, it was found that polymerisation of L-LA (kobs=0.24 h−1) was twice as fast as rac-LA (kobs=0.11 h−1) with [(Ind)2Zr(OtBu)Me] at 80° C. with similar [LA]0:[2]0ratio of 50:1 (FIG. 13). This is probably due to the energy barrier required to invert the chiral configuration at the metal centre, which is indicative of a chain-end control mechanism.

The1H{1H} NMR spectrum of the polymerisation of rac-LA using [(Ind)2Zr(OtBu)Me] as initiator demonstrated a bias towards isotactic PLA, Piof 72%.

Polymerisations of L-LA and rac-LA were repeated at 80° C. with the addition of tert-butanol in stoichiometric amounts with [(Ind)2Zr(OtBu)Me]. The addition of tert-butanol has little effect on kobsfor both L-LA and rac-LA. The rate of polymerisation for L-LA without alcohol is similar to the one with (kobsof 0.24 h−1and 0.23 h−1respectively). Similarly the rates for the polymerisations of rac-LA were (kobsof 0.11 h−1and 0.10 h−1respectively). The molecular weights and polydispersities of the polymerisation of L-LA and rac-LA with and without tert-butanol are collated in Table 5. As an initiator, [(Ind)2Zr(OtBu)Me]demonstrated highly controlled polymerisation of L-LA and rac-LA at 80° C. with a LA:initiator ratio of 50:1 in chloroform-d1, as shown by low polydispersities (1.08<Mw/Mn<1.12). The addition of tert-butanol does not affect the polydispersities; however, the experimental molecular weights appear more controlled in the presence of the alcohol, as expected of immortal polymerisation.