WO2013128175A1 - Aluminum salen and salan catalysts for ring-opening polymerisation of cyclic esters - Google Patents

Abstract

The present application includes new aluminum salen and salan catalysts for the living and/or immortal ring-opening polymerization of suitable cyclic ester monomers such as lactide, β-butyrolactone and ε-caprolactone. The present application also includes processes comprising the ROP of a suitable cyclic ester monomer, optionally in combination with one or more suitable cyclic ester comonomers in the presence of said new aluminum salen and salan catalysts. The present application further includes processes comprising the ROP of β-butyrolactone, optionally in combination with one or more suitable cyclic ester comonomers, in the presence of an aluminum salen or salan catalyst, to form poly(3-hydroxybutyrate) homopolymers and copolymers comprising 3-hydroxybutyrate monomeric units, respectively.

Description

TITLE: ALUMINUM SALEN AND SALAN CATALYSTS FOR RING- OPENING POLYMERIZATION OF CYCLIC ESTERS

FIELD OF THE APPLICATION

[0001] The present application relates to new aluminum salen and salan catalysts useful for the living and/or immortal ring-opening polymerization (ROP) of suitable cyclic ester monomers such as lactide, β- butyrolactone and ε-caprolactone, to processes comprising the ROP of a suitable cyclic ester monomer, optionally in combination with one or more suitable cyclic ester comonomers in the presence of said new aluminum salen and salan catalysts, and to processes comprising the ROP of β-butyrolactone, optionally in combination with one or more suitable cyclic ester comonomers, in the presence of an aluminum salen or salan catalyst to form poly(3- hydroxybutyrate) homopolymers and copolymers comprising 3- hydroxybutyrate monomeric units, respectively.

BACKGROUND OF THE APPLICATION

£0002] Research into biodegradable aliphatic polyesters and exploration of their properties continues to flourish. The bioassimilabie and renewable nature of these aliphatic polymers makes them attractive as alternatives for traditional non-biodegradable plastics, and as new materials for use in the biomedical and pharmaceutical industries.¹

[0003] Particular emphasis has been placed on the development of poly(!actic acid) (PLA), produced through the ring-opening polymerization (ROP) of lactide; the cyclic diester of lactic acid.^2,3 High molecular weight PLA can easily be prepared by ROP; and by careful choice of lactide diastereomer (DL-, LL- or DD-) and judicious choice of catalyst, the microstructure of the resulting PLA may be manipulated to fine tune the polymer's properties.

[0004] Metal catalysts supported by a variety of ligand frameworks have been fashioned for the ROP of lactide; particularly those based upon Al, Ca, Mg, Y and Zn.^{4, 5,6,7} Initiation by these catalysts occurs most often by preparation or in situ generation of a metal-alkoxide species, which then catalyzes the ROP of lactide by a coordination-insertion mechanism. Aluminum has shown particular affinity for the stereospecific ROP of rac- lactide. Typically, ligand frameworks based upon nitrogen donors including amino-£>/s(phenolates) ⁹ ' ¹⁰ , Schiff-base ligand frameworks such as bis- iminopyridyl (BIMPY) ¹ and salen (salen = W,W-6/s{salicylaidimine)-1 ,2- ethylenediamine)^12,13,14 derivatives remain the most popular.

[0005] Al-based salen catalysts were first utilized by Spassky to initiate the ROP of rac-lactide to form isotactic stereocomplexed PLA with narrow molecular weight distributions.¹⁵ Since then, a significant effort has been invested in exploring this type of catalyst. In particular, aluminum salen and salan (salan = /\/,/\/'-£i/s(o-hydroxybenzyl)-1 ,2-diaminoethane) catalysts developed by Gibson et al. have shown high activity under mild polymerization conditions and produce highly isotactic (P_m = 0.83 and 0.88 for catalysts l(c) and l(d), respectively)¹⁶ and heterotactic (P_r = 0.96 for catalyst 1(e))¹⁷ PLA (Scheme 1).

1(c) l{d) l(e)

Scheme 1

[0006] While PLA and its copolymers remain of great interest, the development of catalysts which effectively control the ROP of other cyclic esters to increase the number of biodegradable aliphatic polyesters accessible has only recently been explored.¹⁸ Gaining momentum as potential alternatives to PLA for uses as biomedical devices are the poly(hydroxyalkanoates) (PHA), which have traditionally been synthesized by using various bacteria.

[0007] Among PHAs, Poly(3-hydroxybutyrate) (PHB), which can be accessed through ROP of β-butyrolactone (β-BL), has been receiving increased attention.¹ Similar to PLA, by virtue of its stereogenic center, variability of PHB properties may be introduced by precise control of polymer microstructure. Traditionally, PHB producing bacteria has been the most widely used route to obtain high molecular weight PHB with high isotactic stereo regularity.

[0008] However, despite being a highly strained four-membered ring structure, it appears as though there are few catalysts which will initiate and effectively control the ROP of β-BL.¹⁹ Exceptional activity and stereospecificity for the ROP of β-BL has been reported for yttrium coordinated to aminoalkoxy-Jb/s(phenolate) ligands ⁶ However, reports of aluminum initiators successfully initiating the ROP of β- butyro!actone with exemplary control remain scarce.

[0009] Kurcok et al. have reported the ROP of β-butyrolactone in toluene using AI(0'Pr)₃ as an initiator ²⁰ The ROP of rac^-butyrolactoneusing an AI(OTf)₃ initiator or an AI(OTf)₃/BnOH system has also been reported.²¹ The ROP of β- butyrolactones by aluminum porphyrins, optionally using methylaluminum bis(2,6- di-ferf-butyl-4-methyipheno!ate) to accelerate the polymerization has been disclosed, for example, by Isoda et al.²²

[0010] The oligomerization of ε-caprolactone using aluminium complexes containing the ligands tbmSalen [tbmSalen = N,N'-ethyienebis(3-ferr-butyl-5- methylsalicylideneiminato)] and tbmSalcen [tbmSalcen = /V,/V -trans-1 ,2- cyclohexanediyl-bis(3-ferf-butyl-5-methylsalicyclideneiminato) ] hasalso been reported.²³

[0011] Biodegradable thermoplastics with temperature dependent properties also present an avenue for future development. The ideal material in this sense is very rigid at a given temperature, while at another temperature the material is quite flexible. These unique thermoplastic properties are traditionally achieved through an ABA trib!ock copolymer where long segments or blocks of monomer A are built around a central block of monomer B. However, fully degradable and renewable ABA triblock copolymers have been inaccessible through traditional methods due to catalyst incompatibilities and differential reactivities. [0012] Block copolymers of poly(lactic acid) are especially appealing because of the brittleness and shallow range of physical properties of PLA materials. However, while lactide has previously been incorporated into block copolymers of an array of different monomers, the central core is either not biodegradable or expensive or both. Further, existing methods for the preparation of ABA triblock copolymers may require multiple catalysts, and the core first method is inherently inflexible. Presently known ABA trtblock copolymers cannot, for example, be made in one pot, they may not be fully degradable and their thermal properties cannot be tuned by changing tacticity biases.

[0013] The synthesis of ABA block copolymers where A = PLA and B = PHB would have desirable properties due to the significantly lower glass transition temperature {T_g) of atactic PHB with respect to the T_g of isotactic PLA. However, the synthesis of block copolymers from isotactic PLA and atactic PHB presents a secondary challenge in that a single catalyst would be required to direct two different types of tacticity control in a single chain.

[0014] No previous reports of PLA-PHB-PLA triblock copolymers have been found. PCT Publication No. WO 2010/066597 to Carpentier et al. discloses di-, tri- and multi-block polyester/polycarbonate copolymers comprising, for example, PLA or PHB blocks along with a polycarbonate block via ring-opening polymerization in the presence of a catalyst system in combination with a polycarbonate macroinitiator comprising one or more hydroxy! functional groups.

SUMMARY OF THE APPLICATION

[0015] The present application reports new aluminum salen and salan catalysts useful for the ring-opening polymerization of β-butyrolactone and other suitable monomers, such as lactide. The aluminum catalyst of Formula l(a) has the highest reported isotacticity bias for the polymerization of PLA.

[0016] Accordingly, the present application includes a compound of Formula I:

wherein

— represents a single or double bond;

R¹ is methyl;

R² is Ad;

R³ is methyl or -CH₂Ph, except when— represents a double bond, then R³ is not present; and

Z is selected from C₂-₃ alkylene, optionally substituted by 1 or 2 methyl roups,

wherein R⁴ is H, chloro, bromo, Ci_-6 alkyl OR⁵ or NR⁵, where R⁵ is/are independently selected from aikyl; and * represents the site of attachment to the N atom.

[0017] In the present application, it has also been demonstrated that aluminum- based saien and salan catalysts are useful for the polymerization of β- butyroiactone, optionally in combination with one or more suitable cyclic ester comonomers, to form poly(3-hydroxybutyrate) homopolymers and copolymers comprising 3-hydroxybutyrate monomeric units, respectively. In particular, this invention solves the issue of how to access block copolymers of PLA with a second, biodegradable block of a lower T_g by combining it with PHB, for example.

[0018] Accordingly, the present application also includes a process for producing a polymer comprising 3-hydroxybutyrate monomeric units, the process comprising the ring-opening polymerization of β-butyrolactone, optionally in combination with one or more suitable cyclic ester comonomers, in the presence of a compound of Formula I:

wherein

— represents a single or double bond;

R¹ is H, chloro, bromo or Ci.₆ alkyl;

R² is selected from H, bromo, chloro, C_1-6 alkyl and Ad;

R³ is methyl or -CH₂Ph, except when— represents a double bond, then R³ is not present; and

Z is selected from C2-3 alkylene, optionally substituted by 1 or 2 methyl groups,

wherein R is H, chloro, bromo, C-,.₆ alkyl OR⁵ or NR⁵, where R⁵ is/are independently CL₆ alkyl; and

* represents the site of attachment to the N atom, under conditions suitable for the formation of a polymer comprising 3- hydroxybutyrate monomeric units.

[0019] in the present application, it has further been demonstrated that suitable cyclic ester monomers such as rac- -butyrolactone, rac-lactide and ε-caprolactone can be polymerized in the presence of compounds of Formula l(a) and l(b).

[0020] Accordingly, the present application also includes a process comprising the ring-opening polymerization of a suitable cyclic ester monomer, optionally in combination with one or more suitable cyclic ester comonomers, in the presence of a compound of Formula I:

wherein

— represents a single or double bond;

R¹ is methyl;

R² is Ad;

R³ is methyl or -CH₂Ph, except when— represents a double bond, then R³ is not present; and

Z is selected from C_2-3 alkylene, optionally substituted by 1 or 2 methyl groups,

wherein R⁴ is H, chloro, bromo, C_LB alky) OR⁵ or NR⁵, where R⁵ is/are independently Ci.₆ alkyl; and ^* represents the site of attachment to the N atom, under conditions suitable for the formation of polymer.

[0021] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating embodiments of the application are given by way of illustration only, since various changes and modifications within the spirit and scope of the application will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The present application will now be described in greater detail with reference to the drawings in which: [0022] Figure 1 shows a plot of ln([rac-p-BL]o/[rac-p-BL]_t) versus time (min) for ROP of rac-p-BL in the presence of the compound of Formula i(a) at 7Q°C in benzene-cf₆ with [M]/[A!] =100.

[0023] Figure 2 shows a plot of M_n versus percent conversion (solid line represents theoretical molecular weight) for ROP of rac-p-BL in the presence of the compound of Formula l(a) at 70°C in benzene- cf₆ with [M]/[AI] = 100.

[0024] Figure 3 shows a plot of ln([rac-p-BL]o/[rac-p-BL]_t) versus time (min) for ROP of rac-p-BL in the presence of the compound of Formula l(c) at 70°C in benzene-c/₆ with [M]/[AI] =100.

[0025] Figure 4 shows a plot of M_n versus percent conversion (solid line represents theoretical molecular weight) for ROP of rac-p-BL in the presence of the compound of Formula l(c) at 70°C in benzene-d6 with [M]/[Ai] = 00.

[0026] Figure 5 shows a plot of ln([rac-p-BLy[rac-p-BL]_t) versus time (min) for ROP of rac-p-BL in the presence of the compound of Formula l(e) at 70°C in benzene-de with [M]/[Al] = 100.

[0027] Figure 6 shows a plot of M_n versus percent conversion (solid line represents theoretical molecular weight) for ROP of rac-p-BL in the presence of the compound of Formula l(e) at 70°C in benzene-d6 with [M]/[AI] =100.

[0028] Figure 7 shows a plot of ln([M]₀/[M]_t) versus time (h) for rac-p-BL in the presence of the compound of formula l(c) with [p-BL]/[AI] =100 in 3 mL

toluene using BnOH as an initiator.

[0029] Figure 8 shows an exemplary ¹H{ H}NMR spectrum for isotactic PLA (M_n =10600, PDI =1 ,07) after ROP of rac-iactide in the presence of the compound of Formula l(a) at 70°C in toluene.

[0030] Figure 9 shows a plot of M_n vs [M]/[AI] for the ROP of rac-lactide in the presence of the compound of Formula I (a) at 70°C in toluene. [0031] Figure 10 shows the molecular structure of the compound of Formula l(a) as determined by single crystal x-ray crystallography. Hydrogens have been removed for clarity.

[0032] Figure 1 1 shows plots of !n([M]₀/[M]_t) vs time (min) for the copolymerization of rac-p-BL (PHB = diamonds) and rac-lactide (PLA = squares) by catalysts of (a) Forumla 1(e) and (b) Formula 1 (a) (right) at 85°C in toiuene-c ₈ with [rac- -BL]:[rac- lactide]:[AI] of 50:50:1.

DETAILED DESCRIPTION OF THE APPLICATION

I. Definitions

[0033] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the application herein described for which they are suitable as would be understood by a person skilled in the art.

[0034] As used in this application, the singular forms "a", "an" and "the" include plural references unless the content clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to present certain aspects with one compound, or two or more additional compounds.

[0035] In embodiments comprising an "additional" or "second" component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A "third" component is different from the other, first, and second components, and further enumerated or "additional" components are similarly different.

[0036] The term "suitable" as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the molecule(s) to be transformed, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.

[0037] In embodiments of the application, the compounds described herein have at least one asymmetric centre. Where compounds possess more than one asymmetric centre, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (e.g. less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the application having alternate stereochemistry.

[0038] In understanding the scope of the present disclosure, the term "comprising" and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The foregoing also applies to words having similar meanings such as the terms, "including", "having" and their derivatives. The term "consisting" and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The term "consisting essentially of, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and/or steps.

[0039] Terms of degree such as "substantially", "about" and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least +5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0040] The term "alkyl" as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The term Ci-ealk l means an alkyl group having 1 , 2, 3, 4, 5, or 6 carbon atoms.

[0041] The term "alkylene" as used herein, whether it is used alone or as part of another group, refers to a bivalent alkyl group.

[0042] Ad as used herein refers to the group adamantyl.

[0043] Bn as used herein refers to the group benzyl.

[0044] OTf as used herein refers to the group triflate, CF3SO3^".

[0045] β-BL as used herein refers to β-butyrolactone:

[0046] LA as used herein refers to lactide:

[0047] The term "glycoiide" as used herein refers to a compound of the following structure:

[0048] PHB as used herein refers to poly{3-hydroxybutyrate):

[0049] PLA as used herein refers to poly(lactic

[0050] The term "salen" as used herein refers to a ligand of the formula N,A/'-b/s(salicylaidimine)-1 ,2-ethylenediamine:

or a derivative thereof.

[0051] The term "salan" as used herein refers to a saturated sa!en ligand; i.e. a ligand of the formula N,W'-jb/s(o-hydroxybenzyl)-1 ,2- diaminoethane:

or a derivative thereof.

[0052] A "derivative" of a salen or salan ligand herein includes a salen or salan ligand substituted at the ortho- and para-hydroxy positions of the aromatic rings by a radical R² or R as defined herein, a salan ligand substituted at the nitrogen atoms by a radical R³ as defined herein, a salan or salen ligand with a bridge between the nitrogen atoms Z as defined herein, and, in aluminum salen or salan complexes, to a salen or salan ligand wherein the hydrogens of the hydroxy moieties are replaced by a bond to aluminum.

[0053] The prefix "rac-" as used herein refers to a racemic mixture. For example, the term Vac-lactide" as used herein refers to a racemic mixture consisting of D-lactide and L-lactide:

D-lactide L-lactide

[0054] The abbreviation T_g as used herein refers to the term "glass transition temperature" which is used herein to refer to the temperature at which a polymer changes from a brittle vitreous state to a plastic state.

[0055J The term "monomer" as used herein refers to a molecule that can undergo polymerization to form a polymer. The portion contributed by each monomer to the polymer chain is herein referred to as a "monomeric unit".

[0056] The term "homopoiymer" as used herein refers to a polymer that is derived from one species of monomer.

[0057] The term "copolymer" as used herein refers to a polymer that is derived from more than one species of monomer.

[0058] The term "block copolymer" is used herein to refer to a copolymer wherein the polymer chain consists of more than one "block", wherein each block consists of repeating monomeric units, and no two adjacent blocks consist of the same type of monomeric units.

[0059] The term "dibiock copoiymer" as used herein refers to a block copolymer consisting of two blocks. One block, which may be herein designated "A" consists of monomeric units of one type and the other block, which may be herein designated "B" consists of monomeric units of a different type. For this reason, dibiock copolymers are sometimes referred to herein as "AB block copolymers" or "AB dibiock copolymers" and the like.

[0060] The term "triblock copolymer" as used herein refers to a block copolymer consisting of three blocks. It is an embodiment that two of the blocks consist of monomeric units of the same type, which may be designated "A" and the other block consists of monomeric units of a different type, which may be designated "B". Such triblock copolymers are sometimes referred to herein as "ABA block copolymers" or "ABA triblock copolymers" and the like.

[0061] The term "alternating block copolymer" as used herein refers to a block copolymer consisting of alternating blocks of two different types of monomeric units.

[0062] The term "comonomer" as used herein refers to one or more of the monomers polymerized to form a copolymer. Suitable comonomers include rac-lactide, β-butyrolactone and ε-caproiactone, and the like. The selection of a suitable comonomer can be made by a person skilled in the art.

[0063] The term "ring-opening polymerization" (ROP) as used herein refers to a polymerization in which a cyclic monomer is converted into a polymer wherein the monomeric units contain at least one cyclic unit less than the cyclic monomer. In an embodiment, the polymer formed by the ring- opening polymerization of a cyclic monomer consists of acyclic monomeric units.

[0064] The terms "cyclic ester monomer" and "cyclic ester comonomer" as used herein refer to cyclic compounds with one or more ester linkages within the ring which are polymerizable via ring-opening polymerization under conditions suitable for the formation of polymer. The "cyclic ester monomer" or "cyclic ester comonomer" can be a "cyclic monoester" which herein refers to a compound with one ester linkage within the ring such as β-butyrolactone or ε- caprolactone, for example. The "cyclic ester monomer" or "cyclic ester comonomer" can also be a "cyclic diester" which herein refers to a compound with two ester linkages within the ring such as Iactide or glycolide, for example. The selection of a suitable "cyclic ester monomer" or "cyclic ester comonomer" can be made by a person skilled in the art.

[0065] The term "living polymerization" as used herein refers to a type of polymerization wherein there is one polymer chain growing per catalyst active site, and no chain-breaking processes such as chain transfer or termination. [0066] The term "immortal polymerization as used herein refers to a type of polymerization employing a bi-component system comprising a catalyst and an external nucleophile acting simultaneously as the initiator and chain transfer agent. In an immortal polymerization, the number of growing polymer chains is equal to the initial amount of chain transfer agent, which typically exceeds the number of catalyst active sites. Immortal polymerizations are described, for example, in Ajellal et al., "Metal-catalyzed immortal ring- opening polymerization of lactones, lactides and cyclic carbonates" Dalton Transactions, 2010, 39, 8363-8376.

[0067] The expression "proceed to a sufficient extent" as used herein with reference to the reactions or process steps disclosed herein means that the reactions or process steps proceed to an extent that conversion of the starting material or substrate to product is maximized. Conversion may be maximized when greater than about 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% of the starting material or substrate is converted to product.

II. Catalysts of the Application

[0068] In the present application, methyl/adamantyl substituted salen and salan catalysts were synthesized in good yields. The methyl/adamantyl substituted Al-salen complex showed excellent control in the ROP of rac- -BL and rac-lactide, yielding atactic PHB and highly isotactic PLA (P_m = 0.92). H NMR spectroscopic experiments displayed pseudo-first order reaction kinetics and a linear relationship between molecular weight and increasing percent conversion, indicating living ROP for both rac- -BL and rac-iactide.

[0069] Accordingly, the present application includes a compound of Formula I:

I

wherein:™ represents a single or double bond;

R¹ is methyl;

R² is Ad;

R³ is methyl or -CH₂Ph, except when— represents a double bond, then R³

is not present; and

wherein R⁴ is H, chloro, bromo, C_1-6 alkyl OR⁵ or NR⁵, where R⁵ is/are independently C _-6 alkyl; and ^* represents the site of attachment to the N atom.

[0070] In an embodiment,™ represents a single bond. In another embodiment,— represents a double bond.

[0071] In an embodiment, R³ is -CH₂Ph.

[0072] In another embodiment of the application, Z is unsubstituted C₂.₃ alkylene. It is a further embodiment that Z is ^*-CH₂CH₂-^*, wherein ^* represents the site of attachment to the N atom.

[0073] In an embodiment, the compound of Formula I is selected from a compound of Formula l(a) and l(b):

III. Processes of the Application

[0074] In the present application, it has also been demonstrated that in addition to mediating the ring-opening polymerization (ROP) of rac-iactide, aluminum-based salen and salan complexes mediate the ROP of rac-β- butyrolactone (rac- ~BL) and ε-caprolactone. All catalysts gave modest control in the ROP of ε-caprolactone. Al-salen complexes showed great control in the ROP of rac- -ΒΙ, with excellent correlation between theoretical and experimental molecular weights and narrow molecular weight distributions of < 1.15. Al-salan complexes also showed superb control, with good molecular weight correlations and narrow molecular weight distributions of <1.05, marking the greatest control observed to date by an aluminum catalyst in the ROP of rac-^-BL.

[0075] All poly(3-hydroxy butyrate) (PHB) isolated using Al-salen and salan complexes contained an atactic microstructure. Kinetic studies of rac-β- BL ROP by ¹H NMR spectroscopy revealed pseudo-first order reaction kinetics and a linear relationship between molecular weight and increasing percent conversion, indicating living ROP. Al-salan catalysts were also shown to mediate the ROP of rac-β-Βί. by an immortal mechanism through the addition of excess benzyl alcohol of up to 50 mol eq. at [M]/[AI] = 500 with no loss of control.

[0076] Accordingly, the present application also includes a process for producing a polymer comprising 3-hydroxybutyrate monomeric units, the process comprising the ring-opening polymerization of β-butyrolactone, optionally in combination with one or more suitable cyclic ester comonomers, in the presence of a compound of Formula I:

R³ wherein:™ represents a single or double bond;

R¹ is H, chloro, bromo or Ci-₆ alkyl;

R² is H, chloro, bromo, C_1-6 alkyl or Ad;

R³ is methyl or -CH₂Ph, except when— represents a double bond, then R³ is not present; and

Z is selected from C₂.₃ alkylene, optionally substituted by 1 or 2 methyl groups,

wherein R⁴ is H, chloro, bromo, C_1-6 alkyl OR⁵ or NR⁵, where R⁵ is/are independently ^e alkyl; and * represents the site of attachment to the N atom,

under conditions suitable for the formation of a polymer comprising 3- hydroxybutyrate monomeric units.

[0077] In an embodiment,— represents a single bond.

In another embodiment,™ represents a double bond.

[0078] In an embodiment, R¹ is selected from chloro and C- alkyl. In another embodiment, R is selected from chloro, methyl and terl-butyl.

[0079] In an embodiment, R² is selected from chloro, aikyl and Ad.

In another embodiment, R² is selected from chloro, methyl, fe t-butyl and Ad.

[0080] In an embodiment, R³ is -CH₂Ph.

[0081] In an embodiment of the application, Z is unsubstituted C_2-3 alkylene. It is a further embodiment that Z is *-CH₂CH₂-*, wherein * represents the site of attachment to the N atom.

[0082] It an embodiment that the β-butyrolactone is rac-p-butyrolactone.

[0083] In an embodiment, the compound of Formula I is selected from

a compound of Formula l(a), l(b), l(c), l(d) and l(e):

1(d) 1(e)

[0084] In an embodiment, the conditions suitable for the formation of a polymer comprising 3-hydroxybutyrate monomeric units are selected from conditions suitable for living polymerization and conditions suitable for immortal polymerization.

[0085] In an embodiment of the application, the process comprises the ring-opening polymerization of β-butyrolactone under conditions suitable to produce poly(3-hydroxybutyrate) homopolymer.

[0086] In an embodiment of the application, the process comprises the ring-opening polymerization of β-butyrolactone in combination with one or more suitable cyclic ester comonomers under conditions suitable to produce a copolymer comprising 3-hydroxybutyrate monomeric units. In another embodiment of the application, the copolymer is a block copolymer. In a further embodiment, the block copolymer is an alternating block copolymer. It is an embodiment that the block copolymer is selected from a diblock copolymer and a triblock copolymer.

[0087] In an embodiment of the application, the suitable cyclic ester comonomer is a suitable cyclic monoester. In another embodiment, the suitable cyclic monoester is ε-caprolactone.

[0088] In an embodiment of the application, the suitable cyclic ester comonomer is a suitable cyclic diester. In another embodiment, the suitable cyclic diester is selected from lactide and giycolide. It is an embodiment that the suitable cyclic diester is rac-lactide. [0089] In an embodiment of the application, the process comprises the ring-opening polymerization of β-butyrolactone in combination with rac-lactide under conditions suitable to produce an AB diblock copolymer, wherein A is a block consisting of poly(lactic acid) and B is a block consisting of poly(3- hydroxybutyrate).

[0090] In another embodiment of the application, the process comprises the ring-opening polymerization of β-butyroiactone in combination with rac-lactide under conditions suitable to produce an ABA triblock copolymer, wherein A is a block consisting of poly(lactic acid) and B is a block consisting of poly(3-hydroxybutyrate).

[0091] In the present application, it has further been demonstrated that suitable cyclic ester monomers such as rac-P-butyrolactone, rac-lactide and ε- caprolactone can be polymerized in the presence of compounds of Formula l(a) and l(b).

[0092] Accordingly, the present application also includes a process comprising the ring-opening polymerization of a suitable cyclic ester monomer, optionally in combination with one or more suitable cyclic ester comonomers, in the presence of a compound of Formula I:

wherein

— represents a single or double bond;

R¹ is methyl;

R² is Ad;

R³ is methyl or -CHkPh, except when™ represents a double bond, then R³ is not present; and

Z is selected from C2-3 alkylene, optionally substituted by 1 or 2 methyl groups,

wherein R⁴ is H, chloro, bromo, C_1-6 alkyl OR⁵ or NR⁵, where R⁵ is/are independently C1-6 alkyl; and * represents the site of attachment to the N atom,

under conditions suitable for the formation of a polymer.

[0093] In an embodiment, ™ represents a single bond. In another embodiment,— represents a double bond.

[0094] In an embodiment, R³ is -CH₂Ph.

[0095] In another embodiment of the application, Z is unsubstituted C₂.₃ aikylene. It is a further embodiment that Z is *-CH₂CH₂ *, wherein * represents the site of attachment to the N atom.

[0096] In an embodiment, the compound of Formula I is selected from a compound

[0097] In an embodiment, the conditions suitable for the formation of polymer are selected from conditions suitable for living polymerization and conditions suitable for immortal polymerization.

[0098] In an embodiment of the application, the process comprises the ring-opening polymerization of a suitable cyclic ester monomer under conditions suitable to produce homopolymer.

[0099] In an embodiment of the application, the process comprises the ring-opening polymerization of a suitable cyclic ester monomer in combination with one or more suitable cyclic ester comonomers under conditions suitable to produce copolymer. In another embodiment of the application, the copolymer is a block copolymer. In a further embodiment, the block copolymer is an alternating block copolymer. It is an embodiment that the block copolymer is selected from a diblock copolymer and a triblock copolymer.

[00100] In an embodiment of the application, the suitable cyclic ester monomer and/or suitable cyclic ester comonomer is a suitable cyclic monoester. In another embodiment, the suitable cyclic monoester is selected from β-butyrolactone and ε-caprolactone. It is an embodiment that the suitable cyclic monoester is rac- -butyrolactone.

[00101] In an embodiment of the application, the suitable cyclic ester monomer and/or suitable cyclic ester comonomer is a suitable cyclic diester. In another embodiment, the suitable cyclic diester is selected from lactide and glycolide. It is an embodiment that the suitable cyclic diester is raolactide.

[00102] The following non-iimiting examples are illustrative of the present application:

EXAMPLES

Example 1 : Synthesis of compounds of the Formula l(a) and l(b)

[00103] New aluminum salen and salan catalysts of the Formulae \{a) and l(b), respectively, possessing bulky adamantyl substituents at the o- hydroxy positions were synthesized. The synthesis of the ligands and complexes were adapted from literature procedures. ^25,26

(a) Synthesis of new aluminum saien catalyst of the Formula 1(a)

[00104] 3-adamantyl-2-hydroxy-4-methylbenzaldehyde was synthesized according to literature procedure^25,26 and a formic acid catalyzed imine condensation with 1 ,2-diaminoethane in ethanol produced the methyl/adamantyl substituted salen ligand of Formula II in moderate yields. Subsequent treatment of the compound of Formula II with AI e₃ in toluene at 110 °C for 24 h allowed access to pure catalyst of the Formula i(a) in high isolated yields.

(i) Synthesis and characterization of methyl/adamantyl salen ligand of Formula II

[00105] In an exemplary procedure, 0.869 g (3.21 mmol) of 3- adamantyl-2-hydroxy-4-methylbenzaldehyde was dissolved in 10 mL of 100% ethanol. To this solution 0.0965 g (1.61 mmol) 1 ,2-diaminoethane was added followed by several drops of formic acid, and the mixture was refluxed for 4 hours with a yellow precipitate observed generally within the first 30 minutes. After 4 hours, heating was ceased, and the mixture was allowed to coo! to room temperature. The yellow precipitate was filtered and washed with cold 100% ethanol with 0.663 g (73%) of the compound of Formula II isolated as a yellow powder.

[00106] ¹H NMR (300 MHz, CDCI₃): 13.67 (s, -OH, 2H), 8.34 (s, ArCH=N, 2H), 7.06 (s, ArH, 2H), 6.88 (s, ArH, 2H), 3.91 (s, N-CH₂CH₂-N, 4H), 2.17 (m, AdH and ArCH₃, 30H), 1.80 (bs, AdH, 15H) ppm. ¹ C NMR (100 MHz, CDCI₃): 167.8, 158.8, 137.7, 131.0, 129.9, 127.1 , 118.7, 59.9, 40.7, 37.6, 37.4, 37.3, 29.5, 21.1 ppm. Anal. For C38H48N2O2 Calcd.: C, 80.81%; H, 8.57%; N, 4.96%. Found: C, 81.12%; H, 8.40%; N, 5.10%.

(ii) Synthesis and characterization of methyl/adamantyl saien compound of Formula 1(a)

II 1(a)

[00107] In an exemplary procedure, in a nitrogen filled glovebox, 0.900 g (1.59 mmol) of the compound of Formula II was dissolved in 10 mL of toluene in an oven-dried ampoule. With vigorous stirring, 0.552 g (1.59 mmol) trimethylaluminum was added dropwise. Effervescence was observed, and the ampoule was sealed, removed from the glovebox and heated to 110 °C for 24 hours. After 24 hours a yellow precipitate formed and the ampoule was allowed to cool to room temperature. The precipitate was filtered, and was washed with pentane yielding 0.414 g (43%) of the compound of Formula l(a) as a yellow powder.

[00108] H NMR (300 MHz, C₆D₆): 7.33 (s, ArCH=N, 2H), 7.32 (s, ArH, 2H), 6.60 (d, ArH, 2H, J = 1.8 Hz), 2.93 (q, N-CH₂CH₂-N, 2H, J = 6.3, 12.3 Hz), 2.51 (br, AdH and N-CH₂CH₂-N, 14 H), 2.28 (s, ArCH₃, 6H) 2.18 (br, AdH, 6H), 1.87 (bm, AdH, 14H) -0.41 (s, AICH₃, 3H). ¹³C NMR (100 MHz, C₆D₆): 168.2, 165.4, 142.2, 138.2, 135.0, 131.3, 129.7, 126.0, 124.5, 120.1 , 54.0, 41.5, 38.3, 38.0, 30.2, 21.7, 21.1 ppm.

(b) Synthesis of new aluminum satan catalyst of the Formula 1(b)

[00109] Aluminum salan catalyst of Formula l(b) was synthesized by first combining 2-adamantyl-4-methylphenol, ΜΛ/'-dibenzylethylenediamine _antj excess para-formaldehyde to yield the methyl/adamantyl substituted salan ligand of Formula III in low yields, followed by treatment with AIMe₃ in toluene at 10 °C for 24 h to give the catalyst of Formula l(b) in high yields.

(i) Synthesis and characterization of methyl/adamantyl salan ligand of Formula III

[00110] In an exemplary procedure, 2.25 g (9.28 mmol) of 2-adamantyl- 4-methylphenol was dissolved in 10 mL of 100% ethanol. To this solution 1.12 g (4.64 mmol) Λ/,Λ -dibenzyi-1 ,2-diaminoethane was added followed by 0.962 g (9.28 mmol) of paraformaldehyde, and the mixture was refluxed for 18 hours. After 18 hours, heating was ceased, and the mixture was allowed to cool to room temperature. A white precipitate formed and was filtered followed by washing with cold 100% ethanol with 2.45 g (35%) of the compound of Formula III isolated as a white powder.

[00111] ¹H NMR (300 MHz, CDCI₃): 10.36 (bs, -OH, 2H), 7.31 (m, ArH, 0H), 6.92 (s, ArH, 2H), 6.59 (s, ArH, 2H), 3.61 (s, ArCH₂, 4H), 3.50 (s, PhCH₂N, 4H), 2.65 (s, ArCH₃, 6H) ppm. ¹³C NMR (100 MHz, CDC ): 154.4, 136.9, 129.8, 128.7, 127.7, 127.5, 126.9, 122.1 , 59.0, 58.3, 49.8, 41.5, 40.6, 37.4, 37.3, 36.9, 29.4, 29.3, 21.0 ppm. Anal. For C52H64N2O2 Calcd.: C, 83.38%; H, 8.61 %; N, 3.74%. Found: C, 83.18%; H, 8.44%; N, 4.02%.

(ii) Synthesis and characterization of methyi/adamantyl salan compound Of Formula 1(b)

[001123 In an exemplary procedure, in a nitrogen filled glovebox, 0.815 g (1.08 mmol) of the compound of Formula III was dissolved in 10 mL of toluene in an oven-dried ampoule. With vigorous stirring, 0.078 g (1.08 mmol) trimethylaluminum was added dropwise. Effervescence was observed, and the ampoule was sealed, removed from the glovebox and heated to 110°C for 24 hours. After 24 hours a white precipitate formed and the ampoule was allowed to cool to room temperature. The precipitate was filtered, and was washed with pentane yielding 0.564 g (66%) of the compound of Formula l(b) as a white powder.

[00113] ¹H N R (300 MHz, C₆D₆): 7.23 (s, Artf, 2H), 7.05 (m, ArW, 10H), 6.49 (s, ArH, 2H), 4.10-3.52 (br, ArCH₂ and ArCH₂N, 6H), 2.50 (m, AdH, 14H), 2.34 (s, ArCH₃, 6H), ¹³C NMR (100 MHz, C₆D₆): 157.5, 140.0, 132.8, 129.7, 129.2, 129.1 , 120.9, 41.2, 38.1 , 37.9, 30.4, 21.5 ppm. Anal. For C₅3He5AIN₂0₂ Calcd.: C, 80.67%; H, 8.30%; N, 3.55%. Found: C, 80.52%; H, 8.13%; N, 3.48%.

Example 2: Ring-opening polymerization (ROP) of rac-p-butyrolactone using catalysts of the Formulae l(a) to 1(e)

[00114] The aluminum salen catalysts of Formula l(a), l(c) and i(d) and the aluminum salan catalysts of Formula l(b) and l(e) were explored for their ability to facilitate the ROP of racemic β-butyrolactone (rac-β-ΒΙ.) to form PHB. (a) ROP of rac-β-Βί. using new aluminum salen catalyst of Formula 1(a)

[00115] The aluminum salen catalyst of the Formula l(a) was effective in mediating the ROP of rac-(3-BL (Table 6). The polymerization rates were noticeably lower than the catalyst of Formula l(c) but no difference in control was observed. Contrary to the catalyst of Formula l(c), an increase in [M]/[AI] did not produce PHB of the corresponding higher molecular weight. ¹³C{¹H} NMR spectra contained only diads corresponding to atactic PHB. Kinetic studies by ¹H NMR spectroscopy showed pseudo-first order reaction kinetics with respect to monomer concentrations, and a linear increase of molecular weight with increasing percent conversion {Figures 1 and 2).

(b) ROP of rac-β-Βί. using new aluminum salan catalyst of Formula 1(b)

[00116] There was an increase in steric bulk for the salen catalyst of Formula l(a) in comparison to the catalyst of Formula l{c). However, there was a significant change in both sterics and electronics when comparing the catalyst of Formula l(b) to the catalyst of Formula l(e) therefore a considerable difference in reactivity was expected. Only trace amounts of PHB were isolated after 24 h under polymerization conditions as the compound of Formula l(b) requires longer reaction times. Reaction times of 72-144 hours under polymerization conditions were used to get productive polymerization.

(c) ROP of rac^-BL using aluminum salen catalyst of Formula 1(c)

[00117] Upon treatment with 1 mol eq. of benzyl alcohol to generate the active alkoxide initiating species in situ, the catalyst of Formula l(c) successfully initiated the ROP of rac- -BL reaching high conversion and maintaining molecular weight distributions <1.15 (Table 2).

[00118] While initiation was poor in toluene and THF at 25 °C, with only trace quantities of PHB being isolated after 48 hours, increasing the polymerization temperature to 70 °C increased the initiation efficiency greatly. Polymerization rates decreased drastically when polymerizations were carried out in THF compared to those carried out in toluene or under neat conditions, albeit with no loss of control, and this was attributed to competitive solvent coordination at the Al centre. Of note, when the ratio of [M]/[A1] was increased and polymerization times extended, high molecular weight shoulders were observed in PHB GPC traces, presumably due to catalyst degradation at these longer polymerization times. While not wishing to be limited by theory, it is assumed that catalyst degradation begins to take place at higher percent conversion, causing a loss of control evidenced by these increased molecular weight distributions.

[00119] Upon investigation of the methylene and the carbonyl region ¹³C{¹H} NMR spectra for isolated PHB, it was observed that no tacticity control was brought about by the catalyst of Formula l(c) regardless of solvent or temperature. As an atactic microstructure has the lowest possible T_g for linear PHB, this result proves advantageous in respect of a thermoplastic block copolymer consisting of PHB and PLA, for example.

[00120] Further study of the ROP was conducted through kinetic studies by ¹H NMR spectroscopic measurements conducted at 70 °C in benzene-cfe. Pseudo-first order reaction kinetics with respect to monomer were observed in plots of ln([M]₀/[M]t) versus time (Figure 3). Additionally, a plot of M_n versus percent conversion revealed a linear relationship (Figure 4). Together, these demonstrate that the ROP of rac-β-ΒΙ- by the catalyst of Formula l(c) proceeds by a living polymerization mechanism.

(d) ROP of rac-β-Βί. using aluminum salen catalyst of Formula 1(d)

[00121] The aluminum salen catalyst of Formula l(d) was also screened and examined for its activity (Table 3). Previous reports have indicated that the propylene-backbone of this catalyst allows for more favourable biting angle and promotes tighter binding to the Al centre, giving a greater degree of steric crowding than the catalyst of Formula l(c).⁸ High activity and narrow molecular weight distributions were observed, and an increase in [M]/[AI] gave PHB of increased molecular weight. Similar to the catalyst of Formula l(c), high molecular weight shoulders were observed in GPC traces of this higher M_n PHB. Additionally, harsher polymerization conditions of increased temperature were marked by a large increase in molecular weight distribution, indicating that this facilitated degradation of the catalyst of Formula 1(d).

(e) ROP of rac~ -BL using aluminum salan catalyst of Formula 1(e)

[00122] The aluminum salan catalyst of Formula l(e) was also explored as a pre-initiator for the ROP of rac- -BL. This catalyst proved to be an exceptional mediator for this polymerization, as the alkoxide species polymerizes rac-β-ΒΙ, providing remarkable control as there is excellent agreement between theoretical and experimental molecular weights and narrow molecular weight distributions of <1.05 even under harsh polymerization conditions (Table 4).

[00123] Increasing the [M]/[AI] to 250 and 500 produced PHB of the corresponding increased molecular weight. Altering the polymerization solvent from toluene to THF showed no significant change in rate; however, neat conditions required lowered polymerization times to reach high conversion. Kinetic studies by ¹ H NMR spectroscopy of the catalyst of the Formula 1(e) at 70 °C in benzene-cfe revealed pseudo-first order kinetics with respect to [rac- β-BL], and a linear increase of M_n with increasing percent conversion (Figures 5 and 6). All PHB chains synthesized contained an atactic microstructure.

[00124] In comparison to the catalysts of Formulae l(c) and l(d), the catalyst of Formula l(e) shows a greater degree of control under an assortment of polymerization conditions with higher activity. It is evident that the catalyst of Formula l(e) exhibits the greatest control shown by an aluminum-based catalyst for living ROP of rac-β-ΒΙ. to date. This control is accompanied by high activity compared to other aluminum catalysts, and the capability to synthesize high molecular weight PHB.

Example 3: Immortal ROP of rac-p-BL by the catalyst of Formula l(c)

[00125] Following the outstanding results for the catalyst of Formula l(c) by a living ring-opening polymerization mechanism for rac- -Bl, the versatility of this catalyst by introducing an excess of benzyl alcohol, which would allow for an immortal ROP mechanism to occur, was investigated (Table 5, Figure 7).

[00126] Experimental molecular weights calculated from GPC chromatograms agreed with theoretical molecular weights when the ratio of benzyl alcohol was increased from 2 to 50 with respect to a constant [ ]/[AI] ratio of 500. Through this, it was hoped to effectively measure when the excess of benzyl alcohol would no longer effectively serve as a chain transfer agent, and instead act as quenching reagent in the polymerization.

[00127] High activity was observed, with conversion >80% after 24 hours at 70 °C in 3 ml_ of toluene. No significant loss of control was observed, as shown by the lack of change in molecular weight distributions. Thus, benzyl alcohol serves as an excellent chain transfer agent for this system. These results mark the greatest control and highest ratio of chain-transfer agent:cataiyst achieved in an immortal type ROP of rac-$-BL utilizing an aluminum-based catalyst.^{21 ,22}

Example 4: ROP of ε-caprolactone using aluminum salen and salan catalysts

[00128] The polymerization of ε-caprolactone, a seven-membered lactone that upon ROP yields poly(E-caprolactone) (PCL) was also explored in the presence of aluminum salen catalysts of Formula l(a), l(c) and l(d) and the aluminum salan catalyst of Formula l(e). Aluminum-based catalysts have shown activity towards ε-caprolactone ROP.^{1 ,27 28} However, while complexes of Formulae l(c) to l(e) were active, only modest control was achieved. Significantly broader molecular weight distributions along with poor correlation between theoretical and experimental molecular weights were observed (Table 5). This is not entirely unexpected as ε-caprolactone is significantly less bulky than rac-p-BL or rac- lactide, and thus would be a more reactive monomer when coordinated at the metal centre. However, attempts to lower reactivity by decreasing polymerization temperature resulted in poor initiation, which effectively broadened molecular weight distributions further. Similar to the catalyst of Formula l(c), methylladamantyl substituted aluminum salen catalyst of Formula l(a) provided only modest control in the ROP of ε-caprolactone (Table 1).

Example 5: ROP of rac-lactide using catalysts of Formulae l(a) and l(b)

[00129] To maximize the properties of a thermoplastic block copolymer of, for example, PHB and PLA, the PLA blocks must have a high T_g as is observed in highly isotactic PLA. Catalysts of Formulae l(c) and [(e) induce stereocontrol bias in PLA polymerizations. However, while the ierf-butyl groups of the catalyst of Formula i(c) provide high isotactic bias (P_m =0.83) from rac-lactide, there is still potential for improvement.

[00130] Catalysts of the Formulae l(a) and l(b), with adamantly substitutions at the positions ortho to the aluminum center have a significantly more crowded coordination sphere, promoting a more highly isotactic PLA.

[00131] ethyl/adamantyl-substituted aluminum salen catalyst of Formula l(a) was effective in mediating the ROP of rac-lactide (Table 1 , Figure 8). ROP of rac-lactide yielded highly isotactic PLA with a P_m value of 0.92 with good agreement between theoretical and experimental molecular weights and narrow molecular weight distributions. This represents isotactic stereospecificity among the highest reported for aluminum-based catalysts in the ROP of rac-lactide. increasing the [M]/[AI] ratio produced the corresponding PLA of higher molecular weight. A plot of M_n vs. [M]/[AI] supports the living nature of these polymerizations (Figure 9).

[00132] Only trace amounts of PLA were isolated after 24 h under polymerization conditions with the catalyst of Formula l(b) as it requires longer reaction times. Reaction times of 72-144 hours under polymerization conditions were used to get productive polymerization.

Example 6: General procedure for co-polymerization of lactide and β-BL

[00133] In an exemplary procedure, 0.500 g rac-lactide, 0.299 g rac-p-BL, 0.02919 g of the catalyst of Formula l(e) and 3.6 pL BnOH were added to an oven-dried ampoule in a nitrogen-filled glovebox. The ampoule was sealed and heated to 120°C for 6 hours. The ampoule was cooled to room temperature, and the residue was dissolved in 10:1 dichloromethane:methanoi. After stirring at room temperature for 30 minutes, a crude sample was removed for GPC/NMR analysis to ensure that polymers were monomodal and that initiation was efficient, and the solution was precipitated into 100 mL of cold MeOH. The solution was filtered, yielding a white precipitate which was dried under vacuum for 24 hours. Tables 7, 8 and 12 contain data relating to exemplary purified polymers. Kinetic data on the polymerisations are shown in Figure 11.

Example 6a: Alternative procedure for co-polymerization of lactide and β-BL

[0134] In a nitrogen filled glovebox, rac-lactide (0.500 g, 3.46 mmol), /¾ο-β-ΒΙ_ (0.299 g, 3.46 mmol), catalyst of Formula l(e) (0.02 9 g, 0.035 mmol) and benzyl alcohol (3.6 μΙ_, 0.035 mmol) were dissolved in toluene or d⁸-toluene (1-3 mL) and the solution added to an ampoule. The ampoule was sealed, removed from the glovebox and heated at 85°C to reach the desired conversion. Conversion was monitored by removal of samples from the ampoule or, in the case of d⁸-toluene, monitored directly by ¹H NMR spectroscopy. The sample was then cooled to room temperature and the residue was dissolved in a 10:1 (v/v) mixture of CH₂CI₂:MeOH, precipitated into cold methanol (100 mL), filtered and dried under vacuum to constant weight.

Example 7: General procedure for the preparation of AB block copolymers

[0135] In an exemplary procedure, 0.0532 g IsoPLAio was dissolved in 2 mL of toluene in a nitrogen-filled glovebox. To this solution, 0.0229 g of the catalyst of Formula l(e) dissolved in 1 mL toluene was added, and the combined solutions were added to an oven-dried ampoule. Next, 0.125 g of rac-p-BL was added to the ampoule. The ampoule was sealed and heated to 120°C for 4 hours. The ampoule was cooled to room temperature, and 0.5 mL of MeOH was added. After stirring at room temperature for 30 minutes, a crude sample was removed for GPC/NMR analysis to ensure that polymers were monomodal and that initiation was efficient, and the solution was precipitated into 100 mL of cold MeOH. The solution was filtered, yielding a white precipitate which was dried under vacuum for 24 hours. Tables 9 and 0 contain data relating to the experimental conditions and product characterization.

Example 7a: Alternative procedure for the preparation of AB block copolymers

[0136] In a nitrogen filled glovebox, 2.44 mmol of lactide monomer contained within an oven-dried ampoule and magnetic stirbar was dissolved in 6 mL of toluene. 0.012 g (0.019 mmol) of catalyst of Formula l(e) was added to the solution, and the solution stirred at 85°C for 4 hours. To this mixture, 0.210 g (2.44 mmol) of rac-p-BL was added to the mixture. The ampoule was sealed, and heated to 85 °C for 12 h. At this time, the ampoule was allowed to cool to ambient temperature, and samples of the polymerization mixture were removed for analysis by GPC and 1 H NMR.

Example 8: General procedure for the preparation of ABA block copolymers

[00137] In an exemplary procedure, 0.0532 g lsoPLA₁₀ was dissolved in 2 mL of toluene in a nitrogen-filled glovebox. To this solution, 0.0229 g of the catalyst of Formula l(e) dissolved in 1 mL of toluene was added, and the combined solutions were added to an oven-dried ampoule. Next, 0. 25 g of rac- -BL was added to the ampoule. The ampoule was sealed and heated to 120°C for 4 hours. The ampoule was cooled to room temperature, a crude sample was removed, and 0.0523 g rac-lactide was added to the ampoule. The ampoule was then heated to 120 QC for 4 hours. At this time, 0.5 mL of MeOH was added. After stirring at room temperature for 30 minutes, a crude sample was removed for GPC/NMR analysis to ensure that polymers were monomoda! and that initiation was efficient, and the solution was precipitated into 100 mL of cold MeOH. The solution was filtered, yielding a white precipitate which was dried under vacuum for 24 hours. Table 10 contains data relating to the experimental conditions and an exemplary purified polymer.

Example 8a: Alternative procedure for the preparation of ABA block copolymers

[0138] To the reaction of example 7a, without workup, 0.217 g (1.50 mmol) of rac- lactide was added to the polymerization mixture, the ampoule was sealed, and heated at the prescribed temperature for an additional 12 h. Crude samples of the polymerization mixture were again removed for analysis by GPC and 1 H NMR, and 1 mL of MeOH was added. The mixture was left to stir for 30 min, after which the mixture was precipitated into 00 mL of co!d MeOH. The solution was filtered, and the polymer dried under vacuum until constant weight.

[0139] This procedure of examples 7a and 8a provides for a 1-pot direct synthesis of the block copolymer, rac-lactide polymerized at 85°C in toluene, and sequential addition of 50 mol eq. of rac-p-BL and an additional portion of 50 mol eq. of rac-lactide. Monomer conversion was > 90% for each block, and PDIs of < 1.1 were measured (at each step, and in the final product). The resulting block copolymers give 2:1 statistical integration of the two monomers (verified by ¹H NMR) and maintained high levels of stereocontrol, producing highly isotactic and heterotacttc PLA blocks depending upon catalyst choice.

Example 9: Single crystal x-ray crystallography of the compound of Formula 1(a)

[00140] Crystals of the compound of Formula l(a) were grown by slow evaporation of a concentrated solution of the compound using toluene at 25°C. Single crystals were coated with Paratone-N oil, mounted using a polyimide MicroMount and frozen in the cold nitrogen stream of the goniometer. A hemisphere of data was collected on a Bruker AXS P4/SMART 1000 diffractometer using ω and Θ scans with a scan width of 0.3° and 10 s exposure times. The detector distance was 5 cm. The data were reduced (SAINT)²⁹ and corrected for absorption (SADABS)³⁰ The structure was solved by direct methods and refined by full-matrix least squares on F²(SHEI_XTL)³¹. All non-hydrogen atoms were refined using anisotropic displacement parameters. Hydrogen atoms were included in calculated positions and refined using a riding model. The lattice contained toluene which was disordered over multiple overlapping positions and could not be modelled properly. The solvent molecule was modeled using disordered electron density. F(000),p, W and d were corrected accordingly. See Table 1 1 for crystal data and structure refinement, and Figure 10 for the molecular structure of the compound of Formula l(a).

[00141] While the present application has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the application is not limited to the disclosed examples. To the contrary, the application is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

[00142] AN publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term. FULL CITATIONS FOR DOCUMENTS REFERRED TO IN THE

SPECIFICATION

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Table 1

Monomer [M]/[AI] Solvent³ Temp Time (h) M_n ^c PDI^C % Conv.^d Tacticity p f

ε-caprolactone 100 toluene 70 5 8054 9076 1.52 70 — — a) Polymerizations were conducted in 3 mL of solvent.

b) Calculated by ([M]/[AI]) x MW(monomer) x (% conv.) + MW(endgroup).

c) Determined by SEC (GPC) in THF at 50 °C using polystyrene standards (conv. factor = 0.70 PHB, 0.58 PLA, 0.57 PCL). d) Determined by gravimetric analysis.

e) Determined by examination of the carbonyl and methylene regions of the ¹³C N R spectrum.

f) Probability of a meso linkage determined by examination of the methine region of selective ¹H{ H} NMR spectra.

Table 2

[M]/[AI] Solvent³ Temp (°C) Time (h) M_n,_h ^D PDI° % Conv.⁰ Tactlcity^e

100 neat 25 72 3661 3065 3213 1.05 42 atactic

100 toluene 25 48 — — — — Trace atactic

100 THF 25 48 — — — — Trace atactic

100 THF 50 18 1917 1897 1979 1.04 22 atactic

100 neat 70 3 5046 5110 1.08 58 atactic

100 neat 70 12 5606 5915 6666 1.13 65 atactic

100 toluene 70 6 7235 5888 1.09 83 atactic

100 toluene 70 20 7235 6374 6927 1.09 83 atactic

250 to -_|l-u|_e_|pne 70 36 19019 16167 1.12 88 atactic

100 70 6 2088 2167 1.04 24 atactic

100 toluene 120 12 6450 2236 3487 1.56 74 atactic

250 THF 70 6 7564 4817 5003 1.03 35 atactic

500 THF 70 24 11621 5036 5235 1.04 27 atactic a) Polymerizations were conducted in 3 mL of solvent where applicable.

b) Calculated by ([M]/[AI]) x W(rac-p-BL) x (% conv.) + MW(endgroup).

c) Determined by SEC (GPC) in THF at 50 °C using polystyrene standards (conv. factor = 0.70). d) Determined by gravimetric analysis.

e) Determined by examination of the carbonyl and methylene regions of the ¹³C NMR spectrum.

Table 3

[M]/[AI] Solvent³ Time (h) M_n,_h ^D _n ^c p_D|C % Conv.^a Tacticity^e

100 neat 3 5046 5921 1.08 58 atactic

100 toluene 6 5045 5110 1.06 58 atactic

100 toluene¹ 6 7134 7443 1.35 82 atactic

250 toluene 18 20315 16572 1.14 94 atactic

500 toluene 36 35368 25750 1.09 82 atactic a) Polymerizations were conducted in 3 mL of solvent where applicable. b) Calculated by ([M]/[AI]) x MW(rac-p-BL) x (% conv.) + MW(endgroup). c) Determined by SEC (GPC) using polystyrene standards (conv. factor = d) Determined by gravimetric analysis.

e) Confirmed by ³C{¹H} NMR spectroscopy.

f) Polymerization at 120 °C.

Table 4

[ ]/[All^a Solvent¹¹ Temp (°C) Time (h) Mn.th^c M_n° PDI^d % Conv.^e

100 Neat 25 24 6350 6171 1.03 73

100 Toluene 25 48 4846 6371 1.03 58

100 THF 25 48 6589 6453 1.03 75

100 Neat 70 3 6264 6086 1.04 72

100 Toluene 70 6 8612 8557 1.03 99

100 THF 70 6 7819 8150 1.03 89

100 Toluene 120 2 8258 7391 1.05

250 Toluene 70 10 17505 19600 1.03 81

500 Toluene 70 20 38819 35693 1.04 90 a) All PHB isolated was atactic confirmed by ³C{¹H} NMR spectroscopy. b) Polymerizations were conducted in 3 mL of solvent where applicable. c) Calculated by ([M]/[AI]) x MW(rac- -BL) x (% conv.) + MW(endgroup). d) Calculated by SEC(GPC) using polystyrene standards with a conversion factor of 0.70 for PHB.

e) Determined by gravimetric analysis.

Table 5

[M]:[AI]:[BnOH]^a M_n.th^D M„^c PDI^C % Conv.^G

500:1 :2 19840 16294 1.05 92

500:1 :5 7362 7461 1.03 85

500:1 :10 3529 3171 1.11 82

500:1 :25 1446 1556 1.08 84

500:1 :35 1205 1229 1.05 98

500:1 :50 844 840 1.10 98 a) All polymerizations were conducted in 3 mL of toluene at 70 °C for 24 h. b) Calculated by ([M]/[AI]) x MW(monomer) x (% conv.) + MW(endgroup). c) Determined by SEC(GPC) using polystyrene standards with a conversion factor of 0.70 for PHB.

d) Determined gravimetrically.

Table 6

Catalyst [ J/[AI] Solvent³ Temp (°C) Time (h) _n,h^b M_n ^c PDI^C % Conv.^d

1(c) 100 Neat 70 7 8521 6756 1.54 74

1(c) 100 Toluene 70 6 7791 4034 1.35 67

1(c) 100 THF 50 5 9089 3261 1.67 79

1(c) 100 Toluene 50 5 9020 13604 1.65 81

1(c) 250 Toluene 70 8 17176 9773 1.19^e 60

1(e) 100 Toluene 70 5 7675 3633 1.40 66

1(e) 100 THF 70 5 9217 5499 1.53 80

lie) 100 -j"|_jp 50 5 9549 4774 1.28^e 83

1(e) 100 Toluene 70 5 9434 8808 1.48^e 82

1(e) 250 Toluene 70 8 22902 22194 1.80 80 a) Polymerizations were conducted in 3 mL of solvent where applicable.

b) Calculated by {[M]/[Al]) x MW(rac^-BL) x (% conv.) + W(endgroup).

c) Calculated by SEC (GPC) using polystyrene standards with a conversion factor of 0.57 for PCL. d) Determined by gravimetric analysis.

e) Bimodai molecular weight distribution.

Table 7

Initial feed Catalyst Solvent Temp (°C) Time (h) _n ^a PDI^a GPC trace lactide:p-BL

100:100 1(e) neat 120 6 19259 1.20 monomodal

100:100 Kc) neat 120 6 13717 1.45 bimodal

100:100 Ka) neat 120 6 38029 1.55 monornodal a) Determined by GPC using polystyrene standards. M_n values are uncorrected.

Table 8

Initial feed Catalyst Solvent Temp (°C) Time (h) PLA:PHB PDI^b GPC trace lactide^-BL (polymer)³

100:100 lie) neat 120 6 3:1 19259 1.20 monomodal

100:50 lie) neat 120 6 6:1 26142 1.12 monomodal

200:50 lie) neat 120 6 19:1 31603 1.14 monomodal

300:50 lie) neat 120 6 39:1 27270 1.18 monomodal

50:100 lie) neat 120 6 1 :1 13521 1.18 monomodal

50:200 lie) neat 120 6 1 :1.2 18278 1.18 monomodal

50:300 lie) neat 120 6 1:2 18288 1.13 monomodal a) Determined by NMR.

b) Determined by GPC using polystyrene standards. M_n values are uncorrected.

Table 9

Initiator³ Catalyst Initial Solvent Temp Time Mn.th PDI" % conv. GPC trace

polymer: monomer (°C) {h> β-BL

lsoPLA₁₀

n = 5598 1(c) 1 :100 toluene 120 6 5598 11365 1.11 48 monomodal PDI = 1.23

lsoPLA₁₀

aPHB

M_n = 1930 1(e) 1:100 toluene 120 6 6037 4019 1.07 57 monomodal PDI = 1.05 a) IsoPLAio and lsoPLA₃₅ values refer to the number of lactide units (10 or 35) in the starting segment (i.e. the first "A" block in the chain.

b) Determined by GPC using polystyrene standards. M_n values are uncorrected.

Table 10

Initiator³ Block type Catalyst Initial Solvent Temp (°C) Time (h) _pD|b GPC trace

polymer:monomer

lsoPLA₁₀

M_n = 1 66 AB l(e) 1 :40 toluene 120 4 5134 1.20 monomodal

PDI = 1.23

AB- Woc f-copoly m e r

M_n = 5134 ABA l(e) 1 :40 toluene 20 4 8789 1.16 monomodal PDI = 1.20 a) IsoPLAio and lsoPLA₃₅ values refer to the number of lactide units (10 or 35) in the starting segment (i.e. the first "A" block in the chain.

b) Determined by GPC using polystyrene standards. M_n values are uncorrected

Table 11

Empirical formula C46 H57 Al N2 02

Moiety formula C39H 9AIN2O2 · CH3C6H5

Formula weight 696.92

Temperature 198(1) K

Wavelength 0.71073 A

Diffractometer used Bruker AXS P4/SMART 1000

Detector distance 5 cm

Monochromator used Graphite

Crystal size 0.45 x 0.35 x 0.20 mm³

Colour and habit Colorless, irregular

Crystal system Triclinic

Space group P-1

Unit cell dimensions a = 10.7051(16) A a = 87.922{2)° b = 11.9608(18) A β = 74.211(2)° c = 16.609(3) A 7 = 69.566(2)°

Volume 1913.6(5) A^a

Z 2

Density (calculated) 1.210 Mg/m^a

Absorption coefficient 0.094 mm^"1

F(000) 752

Theta range for data collection 1.82 to 27.50°

Completeness to theta = 25.00° 99.6 %

Scan type ω and φ

Scan range 0.3°

Exposure time 10 s

Index ranges -13 < h < 12, -14 < k < 15, -20 < I < 21

Standard reflections 50 frames at beginning and end

of data collection

Crystal stability no decay

Reflections collected 13400

Independent reflections 8319 [R(int) = 0.0150]

Solution Direct methods

Hydrogen atoms Calculated positions, riding model

Absorption correction SADABS

Max. and min. transmission 0.9815 and 0.9590

Refinement method Full-matrix least-squares on F

Data / restraints / parameters 8319 / 0 / 400

Goodness-of-fit on F* 1.096

Final R indices [l>2sigma(l)] R1 = 0.0427, wR2 = 0.1217

R indices (all data) R1 = 0.0526, wR2 = 0.1295

Largest/mean shift/esd 0.000/0.000

Largest diff. peak and hole 0.393 and -0.250 e.A ^a wR2 = (∑[w(Fa²-Fe²)²]/∑[wFa⁴])¹'²

R1 =∑ 11 Fa 1 - IFe 1111 1 Fa I

Weight =11 [a²(Fa²) + (0.0784 ^* p)² + (0.1981 * P)]

where P = (max (Fa², 0) + 2 ^* Fe²)/3

Table 12

Entry [LA]:[p-BL] PLA:PHB" Mn,th^c PDI" T₃

(°C)

1 1 :1 (100:100) 3.5:1 14900 20100 1.09 32.0

2 2:1 ( 00:50) 9:1 16700 29400 1.05 43.6

3 4: 1 (200:50 ) 19:1 27000 18900 1.07 35.5

4 6:1 (300:50) 39:1 23000 29400 1.07 39.3

5 1 :2 (50:100) 1 :1 13600 15800 1.07 17.7

6 1 :4 (50:200) 1 :1.6 23900 17100 1.07 13.6

7 1 :6 (50:300) 1 :2 17300 14600 1.05 11.4

Polymerizations were conducted neat at 120°C and with 0.035 mmol of [Al] using 1 eq. benzyl alcohol to generate the active alkoxide.

" Ratio of poly(lactic acid) to poly(3-hydroxybutyrate) calculated using H NMR spectroscopy through integration of methyl signals associated with each polymer unit. ^c Calculated by ([M]/[AI] * MW(rac-p-BL) χ (% conv.) ) + ([M]/[AI] * W(rac-iactide) χ (% conv.)) + MW(endgroups). ^d Obtained from SEC(GPC) / MALS.

Claims

We claim:

1. A process comprising the ring-opening polymerization of a suitable cyclic ester monomer, optionally in combination with one or more suitable cyclic ester

comonomers, in the presence of a compound of Formula I:

I

wherein:™ represents a single or double bond;

R is methyl;

R² is Ad;

R³ is methyl or -CH₂Ph, except when ~ represents a double bond, then R³ is not present; and

wherein R⁴ is H, chloro, bromo, C_1-6 alky! OR⁵ or NR⁵, where R⁵ is/are independently

^* represents the site of attachment to the N atom;

under conditions suitable for the formation of polymer.

The process of claim 1 , wherein— represents one of: a single bond. A double bond.

The process of claim 1 or claim 2, wherein™ represents a single bond and R³ is -CH₂Ph.

4. The process of anyone of preceding claim, wherein Z is *-CH₂CH₂-*, wherein * represents the site of attachment to the N atom.

5. The process of claim 1 , wherein the compound of Formula I is selected from a compound of Formula l(a) and l(b):

l(a) l(b)

6. The process of any one preceding claim, wherein the conditions suitable for he formation of polymer are selected from conditions suitable for living polymerization and conditions suitable for immortal polymerization.

7. The process of any one preceding claim, wherein the process comprises the ring-opening polymerization of a suitable cyclic ester monomer under conditions suitable to produce homopolymer.

8. The process of any one preceding claim, wherein the process comprises the ring-opening polymerization of a suitable cyclic ester monomer in combination with one or more suitable cyclic ester comonomers under conditions suitable to produce copolymer.

9. The process of claim 8, wherein the copolymer is a block copolymer.

10. The process of claim 9, wherein the block copolymer is selected from; an alternating block copolymer, a diblock copolymer, a triblock copolymer.

11. The process of claim 10, wherein the block copolymer is one of: a diblock copolymer, a triblock copolymer.

12. The process of any one preceding claim, wherein the suitable cyclic ester monomer is a suitable cyclic monoester or diester. 2013/128175

51

13. The process of anyone of claims 1 to 7 and 9 to 12, wherein the suitable cyclic ester comonomer is a suitable cyclic monoester or diester.

14. The process of claim 12 or 13, wherein the suitable cyclic monoester is

selected from β-butyrolactone, rac-p-butyrolactone and ε-caprolactone.

15. The process of claim 12 or 13, wherein the suitable cyclic diester is selected from iactide, rac-!actide and glycoside. 6. A process for producing a polymer comprising 3-hydroxybutyrate monomeric units, the process comprising the ring-opening polymerization of β-butyrolactone, optionally in combination with one or more suitable cyclic ester comonomers, in the presence of a compound of Formula I:

wherein:™ represents a single or double bond;

R¹ is H, chloro, bromo or Ci_6 alkyi;

R² is H, chloro, bromo, Ci_-6 alkyl or Ad;

R³ is methyl or -CH₂Ph, except when™ represents a double bond, then R³ is not present; and

Z is selected from C_2-3 aikylene, optionally substituted by 1 or 2 methyl group

wherein R⁴ is H, chloro, bromo, C_1-6 alkyl OR⁵ or NR⁵, where R⁵ is/are independently Ci alkyl; and

* represents the site of attachment to the N atom;

under conditions suitable for the formation of polymer.

17. The process of claim 16, wherein™ represents one of; a single bond, a double bond.

18. The process of claim 16 or 17, wherein™ represents a single bond and R³ is -CH₂Ph.

19. The process of any one of claims 16 to 18, wherein R¹ is selected from; chloro and C alkyl, and optionally selected from chloro, methyl and terf-butyl.

20. The process of any one of claims 16 to 19, wherein R² is selected from chloro, d.₄ alkyl and Ad, and optionally selected from selected from chloro, methyl, terf-butyl and Ad.

21. The process of any one of claims 16 to 20, wherein Z is unsubstituted C₂-3

alkylene.

The process of claim 16, wherein the compound of Formula I is selected from a compound of Formula l(a), l(b), l(c), l(d) and l(e):

l(c) 2013/128175

53

1(e)

23. The process of any one of claims 16 to 22, wherein the process comprises the ring-opening polymerization of β-butyrolactone under conditions suitable to produce poly(3-hydroxybutyrate) homopolymer.

The process of anyone of claims 16 to 22, wherein the process comprises the ring-opening polymerization of β-butyrolactone in combination with one or more suitable cyclic ester comonomers under conditions suitable to produce a copolymer comprising 3-hydroxybutyrate monomeric units.

25. The process of claim 23, wherein the copolymer is a block copolymer.

26. The process of claim 24, wherein the block copolymer is selected from; an alternating block copolymer, a diblock copolymer, a triblock copolymer.

27. The process of claim 26, wherein the process comprises the ring-opening polymerization of β-butyrolactone in combination with rac-lactide under conditions suitable to produce an AB diblock copolymer, wherein A is a block consisting of poly(lactic acid) and B is a block consisting of poly(3hydroxybutyrate), or the process comprises the ring-opening polymerization of β-butyro!actone in combination with rac-lactide under conditions suitable to produce an ABA tribiock copolymer, wherein A is a block consisting of poly(lactic acid) and B is a block consisting of poly(3hydroxybutyrate).

The process of anyone of claims 16 to 22 and 24 to 26, wherein the suitable cyclic ester comonomer is one of; a suitable cyclic monoester, a suitable cyclic diester.

29. The process of claim 28, wherein the suitable cyclic monoester is ε- caprolactone.

30. The process of claim 28, wherein the suitable cyclic diester is rac-lactide.

3 . The process of any one of claims 16 to 38, wherein the p-butyro!actone is rac- /?-butyrolactone.

32. A compound of Formula I:

wherein:— represents a single or double bond;

R¹ is methyl;

R² is Ad;

R³ is methyl or -CH₂Ph, except when™ represents a double bond, then R³

is not present; and

Z is selected from C₂.3 alkyiene, optionally substituted by 1 or 2 methyl groups,

wherein R⁴ is H, chloro, bromo, d.₆ a!kyl OR⁵ or NR⁵, where R⁵ is/are independently

* represents the site of attachment to the N atom.

33. The compound of claim 1 , wherein ™ represents one of. a single bond, a double bond.

34. The compound of claim 32 or 33, wherein R³ is ~CH²Ph.

35. The compound of anyone of claims 32 to 34, wherein Z is *-CH₂CH *, wherein * represents the site of attachment to the N atom.

36. The compound of claim 1 , wherein the compound of Formula I is selected from a compound of Formula !(a) and i(b):

l(a) i(b)