WO2023187655A1

WO2023187655A1 - Synthesis methods for ultra-high molecular weight polylactides and ultra-high molecular weight polylactides made therefrom

Info

Publication number: WO2023187655A1
Application number: PCT/IB2023/053092
Authority: WO
Inventors: Sanjay Rastogi; Dario Romano; Feijie Li
Original assignee: King Abdullah University Of Science And Technology
Priority date: 2022-03-28
Filing date: 2023-03-28
Publication date: 2023-10-05

Abstract

A facile method for the preparation of ultra-high molecular weight of poly(lactone) (PL) with relatively narrow polydispersity index using a Bismuth based catalyst is provided. The methods avoid the cumbersome step of monomer purification and proceed without any addition of co-initiators. Ultra-high molecular weight PL made according to the disclosed methods are also provided.

Description

SYNTHESIS METHODS FOR ULTRA-HIGH MOLECULAR WEIGHT POLYLACTIDES AND ULTRA-HIGH MOLECULAR WEIGHT POLYLACTIDES MADE THEREFROM

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. Provisional Application No. 63/324,421 filed March 28, 2022, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention is generally in the field of methods for making UHMW polymers particularly, UHMW PLA and polymers made therefrom.

BACKGROUND OF THE INVENTION

Polylactide (PLA) has become a very important polymer because of its favorable biodegradability, biocompatibility and bioresorbable properties.^1-6 It is used as possible candidate to replace polyethylene in the packing applications. However, one of the main shortcomings of PLA is its brittleness in nature and relatively poor mechanical properties, which often limits its further application.^7-10 It is generally accepted for polymeric materials that some mechanical properties of oriented structures can be improved as the molecular weight of PLA increases.^11-13 At present, ring-opening polymerization (ROP) of lactides is the preferred method over classic polyaddition of lactic acid to obtain high molecular weights ¹⁴ However, the purity of the monomer, catalyst, coinitiator, polymerization temperature and time play a critical role in achieving the ultra-high molecular weight (UHMW) PLA; where the monomer purity is probable the most critical aspect. Although many works on the synthesis of PLA have been published, there is a serious lacking of findings focusing on the synthesis of UHMWPLLA and UHMWPDLA.¹¹’^{15 16} So far, tin ( II and IV) complex catalysts are the most widely employed catalysts for the synthesis of relatively high molecular weight of PLA in academic research and industrial production.^{9 17-20} Some of the main drawbacks of tin-based catalysts consist in the tendency of transesterification, high tendency to racemize L-lactide and its severe cytotoxic to almost all kinds of living cells, which also limits its further use for medical application.^20-23 Beside tin octanoate, a previous study reported the capability of Me2Al[O-2-tert-Bu-6-(C6F5N=CH)C6H3] to promote the synthesis of UHMW-PLAs where weight-average molecular weights (AU) of 1.3 and 1.4 million g/mol with a poly dispersity index (£)) of 1.8-2.0 have been achieved for UHMWPLLA and UHMWPDLA respectively.²⁴ In both cases, the monomer purification step prior to polymerization is found to be the crucial requirement in order to obtain molecular masses above one million g/mol. The monomer purification contains multiple recrystallizations and/or sublimations to remove the water content responsible for lowering the molecular weight of the polymer produced. Even though the monomer purification is a critical requirements to achieve the UHMWs, it is very troublesome and costly, making this method only applicable to laboratory scale and not to commercial production.²⁵ Therefore, fundamental advancements on the synthesis of UHMWPLAs targeting to reduce the water content or to find catalysts capable to synthesize UHMWPLAs without monomer purification are sought and seen as a necessary requirement to develop the fundamental know how on the large scale synthesis of performing biopolymers meeting the societal requirements.

It is an object of the present invention to provide improved methods of making UHMWPLAs.

It is a further object of the present invention to provide PLA's with improved properties such as weight average molecular weight.

SUMMARY OF THE INVENTION

Methods for the preparation of ultra-high molecular weight (“UHMW”) of poly(lactone) (PL) are provided. The methods use Bismuth based catalyst as catalyst, such as BiPlnBr or BiPh ,. Typically, the UHMW PL produced using the disclosed methods has a weight average molecular weight of at least UK)⁶ g/mol, at least 1.2xl0⁶ g/mol, or at least 1.5xl0⁶ g/mol. The produced UHMW PL can also have a narrow polydispersity (ranging from 1.5 to 2.3). Examples of UHMW PL that can be produced using the disclosed method include, but are not limited to, UHMW poly(L-lactide) (“PLLA”), UHMW poly(D-lactide) (“PDLA”), UHMW poly(caprolactone) (“PCL”), UHMW poly(glycolide) (“PGL”), UHMW poly(trimethylene carbonate) (“PTC”), or UHMW poly(ethylene carbonate) (“PEC”), or a copolymer thereof (such as lactide, caprolactone, glycolide, trimethylene carbonate, and/or ethylene carbonate copolymerized with an alkylene oxide).

The method advantageously avoids the labor-intensive step of monomer purification and can in some preferred forms, proceed without any addition of co-initiators. Without the monomer purification step that was required in previously reported methods for producing high molecular weight poly(lactones), water is preserved for the polymerization reaction. In contrast to the previous methods that remove or reduce the water content in a polymerization reaction system to below at least 64 ppm, the disclosed methods proceed in the presence of at least 60 ppm, at least 64 ppm, at least 70 ppm, at least 80 ppm, at least 90 ppm, at least 100 ppm, at least 200 ppm, at least 300 ppm, at least 400 ppm, in a range from 64 ppm to 1000 ppm, from 64 ppm to 800 ppm, or from 64 ppm to 700 ppm water in the polymerization reaction system and produce PE having a desired AL.

Generally, the method disclosed herein includes (i) adding a monomer for the UHMW PL into a catalyst solution comprising a Bismuth based catalyst and a solvent (such as toluene) to form a reaction mixture; and (ii) heating the reaction mixture at a suitable temperature for a time period sufficient to produce a product composition comprising the UHMW PL. A solution polymerization reaction occurs in step (ii). Following the polymerization reaction in step (ii), the UHMW PL is produced with a yield of at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 are graphs describing the evolution of the molecular weight and the respective yield of the synthesized PLLA and PDLA, as a function of the LA/Bi molar ratio without addition of alcohol as co-initiator. In Figure 1,

(left axes) and yield (right axes) is shown as a function of LA/Bi molar ratio (Figure 1A), polymerization time (Figure IB), polymerization temperature (Figure 1C) and co-initiator (Figure ID).

Figure 2 are high temperature 'H NMR spectra (600 MHz, 120 °C) of the catalyst in DMSO-d6 (Figure 2A) and the catalyst with monomer in DMSO- d6 (Figure 2B).

Figures 3A and 3B are FT-ICR-MS spectra of polymerization solution before the precipitation from Table 4, entry 9 (Figure 3 A) and enlargement of the informative region (Figure 3B).

Figure 4 is a molecular model showing the energy pathway starting from the complex BiPh₂Br to the growing chain. Energy was calculated using the DFT method, level of theory B3LYP, basis set LANL2DZ. Purple = bismuth, gray = carbon, red = oxygen, dark red = bromine, white = hydrogen.

Figures 5A and 5B are representative thermograms of examples of PLAs and PCL polymers described in Table 4.

Figure 6 is a MALDI-TOF-MS spectrum of the polymer from Table 4 entry 9 (left) and entry 19 (right).

Figure 7 is the 'H NMR spectra catalyst characterization (300 MHz, 298K, CDCh) of Ph₂BiBr.

Figure 8A is a graph showing M, as a function of different molar ratio of LA/Bi. Figure 8B is a graph showing H₂O/Bi as a function of AL.

Figure 9 is a GPC chromatogram of the polymers of Table 4, entry 1 to 8.

Figure 10 is a GPC chromatogram of the polymers of Table 4, entry 5 and entry 9 to 11. Figure 11 is a GPC chromatogram of the polymers of Table 4, entry 5 and entry 13 to 15.

Figure 12 is a GPC chromatogram of the polymers of Table 4, entry 5 and entries 16 to 18.

Figure 13 is a GPC chromatogram of the polymers of Table 4, entry 5, entry 8, entry 19 and entry 20.

Figure 14 is a DSC thermogram of the polymers of Table 4, entry 5, and entries 9 to 11.

Figure 15 is a DSC thermogram of the polymers of Table 4, entry 5, and entries 13 to 15.

Figure 16 is a DSC thermogram of the polymers of Table 4, entry 5 and entries 16 to 18.

Figure 17 is a ^JH NMR spectrum (400 MHz, CDCh) of condensate from the polymerization reactors of Table 4, entry 9 (Figure 17A) and entry 19 (Figure 17B).

Figure 18 is a 'H NMR spectrum (600 MHz, 25 °C) of d6-DMSO.

Figure 19 is a ¹ H NMR spectrum (600 MHz, 25 °C) of PlnBi Br catalyst in d6-DMSO.

Figure 20 is a 'H NMR spectrum (600 MHz, 120 °C) of PlnBiBr in d6- DMSO.

Figure 21 is a 'H NMR spectrum (600 MHz, 25 °C) of PFnBiBr and L- lactide in d6-DMSO.

Figure 22 is a 'H NMR spectrum (600 MHz, 120 °C) of PlnBiBr and L- lactide in d6-DMSO.

Figure 23 is a complete FT-ICR-MS spectra of polymerization solution before the precipitation from Table 4, entry 9 (Figure 23A) and enlargement of the informative region (Figures 23B to 23F). DETAILED DESCRIPTION OF THE INVENTION

Methods for making ultra-high molecular weight (“UHMW”) poly(lactone) (“PL”) using bismuth (“Bi”) based catalysts are described herein. The disclosed methods allow ring opening polymerization (“ROP”) of lactones mediated by the diphenyl bismuth bromide to obtain UHMW-PLAs and UHMW-PCL without any monomer purification (such as to reduce or remove water content and optionally impurities in the monomer), which was previously unobtainable. UHMW PL typically refers to a PL having a weight average molecular weight (A/_w) of at least 1 *10⁶ g/mol. The M, of a PL can be determined using methods known in the art, such as by gel permeation chromatography (GPC) on a Shimadzu LC-2030 GPC system.

For example, Kricheldorf et al. reported a variety of Bi-based catalysts in the ROP of lactones, in which the catalytic system diphenyl bismuth bromide (BiPh2Br) synthesized relatively high molecular weight poly(s-caprolactone) (Mn=740 kg/mol) and poly(trimethylene carbonate) (A/_w=600 kg/mol). To achieve the high molar masses, the water content in the s-caprolactone (s-CL) was reduced by distillation over powdered calcium hydride followed by distillation over P4O10, while trimethylene carbonate (TMC) was recrystallized from ethyl acetate at least two times. The same Bismuth catalyst when used by Yiyang Lu et al. produced high molecular weight polyglycolide (Mn=245 kg/mol). To achieve these high molar masses, the polymerization using the BiPluBr catalyst was performed for 20 min at 140 °C, where the monomer diglycolide was recrystallized twice from dry toluene to reduce the water content.

Further, the disclosed methods allow ROP kinetics of monomer for PL (such as L-lactide and D-lactide) with the Bi based catalyst (such as BiPluBr) with or without the addition of initiator(s) (such as alcohols) to promote the synthesis of UHMW PL (such as UHMW PLLA, UHMW PDLA, and UHMW PCL). Without being bound to any theories, it is hypothesized that the presence of water content in the polymerization reaction mixture influences the molecular weights of the polymer produced. It may be that the activation of the Bi based catalyst (such as BiPl Br) takes place using the water in the monomer, which in turn generates active species (such as BiPluOH and BiPh(OH)Br). The active species during the ROP of the monomer for PL (such as lactides) can be evaluated using MALDLTOF-MS, low and high-temperature 1H NMR, Fourier- Transform lon-Cyclotron-Resonance Mass Spectrometry, and Density function theory (DFT) calculation, and combinations thereof.

I. Methods for Making Ultra-High Molecular Weight Poly(lactone)

The method disclosed herein is the first example of the synthesis of UHMW PLs (such as UHMW poly(lactide) (“PLA”) and UHMW poly(caprolactone) (“PCL”)) using a Bi based catalyst without monomer purification and without alcohols as initiator. In particular, the method is performed without purifying the monomer such as to reduce the water content to a low level (e.g., at least below 64 ppm) and optionally to also remove the impurities in the monomer. Without being bound to any theories, it is hypothesized that the presence of water content in the polymerization reaction mixture can activate the Bi based catalyst, without any initiator.

Generally, the disclosed method includes (i) adding a monomer for the PL into a catalyst solution containing a Bismuth based catalyst and a solvent to form a reaction mixture; and (ii) heating the reaction mixture at a temperature for a time period sufficient to produce a product composition containing the PL.

A. Adding Monomer for PL into Catalyst Solution

Typically, the solvent of the catalyst solution used in step (i) is an organic solvent that can dissolve the Bi based catalyst (such as a solubility of at least 0. Ig/L in the organic solvent). Examples of organic solvent suitable for forming the catalyst solution include, but are not limited to, toluene, paraffin, xylene, 2,2,5,5-tetramethyloxolane, tetrahydrofuran, benzene, and para-cresol, and combinations thereof. In preferred forms, the solvent of the catalyst solution is toluene. The use of a solvent in the disclosed method allows polymerization to occur in a solution (also referred to herein as “solution polymerization”). Without being bound to any theories, it is believed that the use of a catalyst solution in the disclosed method helps securing the PL having desired ultra-high molecular weight. For example, when synthesizing a PL under the same conditions as the disclosed method (e.g., such monomer, same monomer concentration, same catalyst, same catalyst concentration, same temperature, same time period, etc.), except for the use of a solvent (such as toluene), the polymerization reaction (also referred to herein as “bulk polymerization”) cannot produce PL having ultra-high molecular weight (such as a PL having M, of less than 0.5xl0⁶ g/mol). For example, Fernandez, et al., RSC Adv. 2016, 6, 3137-3149 and Fernandez, et al., Polymers 2015, 81, 12-22 uses triphenyl bismuth as catalyst to prepare poly(caprolactone) and pentadecalactone-co- decalactone copolymers in a bulk polymerization reaction, which produced the polymers having AL of less than 0.5xl0⁶ g/mol. A specific comparative example is described in Example 2 below.

In some forms, the Bi based catalyst used in the disclosed method can be represented by Bi(Ph)_pX_q, wherein p can be an integer from 1 to 3, X can be a halide (such as fluoride, chloride, bromide, or iodide), and q can be an integer from 0 to 2, and wherein p+q equals to 3. For example, the Bi based catalyst used in the disclosed method is BiPl Br or BiPhy or a combination thereof. As described above, it is hypothesized that the presence of water in the polymerization reaction mixture may activate the Bi based catalyst (such as BiPluBr), which in turn generates active species (such as BiPl OH and BiPh(OH)Br) to facilitate the polymerization reaction.

Typically, the monomer for PL used in the disclosed method is a cyclic ester (such as a lactone) or cyclic carbonate ester. In some forms, the reaction mixture contains more than one monomer, such as more than one cyclic ester (such as lactone), more than one cyclic carbonate ester, or a combination of cyclic ester(s) and cyclic carbonate ester(s). In some forms, the monomer in the reaction mixture or each monomer (when two or more monomers are used in the reaction mixture) can have a structure of Formula I or II:

Formula I Formula II wherein m can be 1, 2, or 3; Ai can

can be independently an integer from 1 to 4, from 1 to 3, or 1 or 2; n2 and n3 can be independently an integer from 0 to 4, from 0 to 3, or from 0 to 2, such as 0, 1, 2, or 3; and Ri-Rs can be independently hydrogen or a Ci-Ce unsubstituted.

When any of Ri-Rs is a Ci-Ce unsubstituted alkyl, the Ci-Ce unsubstituted alkyl can be a linear, branched, or cyclic alkyl, such as methyl, ethyl, 1 -propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tertbutyl, 1 -pentyl, tertpentyl, neopentyl, isopentyl, sec-pentyl, 3 -pentyl, sec-isopentyl, active pentyl, 1- hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. In some forms, when any of Ri-Rs is a cyclic Ci-Ce unsubstituted alkyl, the cyclic alkyl may be formed between the R group and the carbon atom to which it attaches. In some forms, when any of Ri-Rs is a Ci-Ce unsubstituted alkyl, the Ci-Ce unsubstituted alkyl can be methyl, ethyl, 1 -propyl, isopropyl, n-butyl, isobutyl, or tertbutyl, such as methyl or ethyl.

In some forms, the monomer in the reaction mixture or each monomer (when two or more monomers are used in the reaction mixture) can be lactide (i.e., L-lactide or D-lactide, or a combination thereof), caprolactone, trimethylene carbonate, ethylene carbonate, or glycolide. In some forms, two or more monomers can be used in the reaction mixture, and each monomer can be an enantiometric form. When two or more monomers are used, the monomers can be added into the catalyst solution sequentially or simultaneously to form a reaction mixture in step (i). In some forms, two or more monomers are sequentially added into the catalyst solution to form a reaction mixture in step (i). For example, two or more monomers are used in the reaction mixture by sequential addition into the catalyst solution, where a first monomer is L-lactide and a second monomer is D-lactide. When two or more monomers are used in the reaction mixture such as by sequential addition into the catalyst solution, the monomers can have any suitable molar ratio for producing a PL having a desired arrangement of blocks.

In the reaction mixture formed in step (i), the monomer and catalyst are at a suitable molar ratio for the polymerization reaction to produce PL having the desired ultra-high molecular weight. Generally, the molar ratio between the monomer and catalyst in the reaction mixture is at least 600, at least 1000, in a range from 600 to about 12000, from about 1000 to about 12000, from about 1000 to about 10000, from about 2000 to about 10000, or from about 2000 to about 8000. For example, for preparing poly (caprolactone), the molar ratio between the monomer and catalyst in the reaction mixture is at least 600, at least 1000, in a range from 600 to about 12000, from about 600 to about 10000, or from about 600 to about 8000. For example, for preparing poly(lactide), the molar ratio between the monomer and catalyst in the reaction mixture is at least 1000, in a range from 1000 to about 12000, from about 1000 to about 10000, from 2000 to about 12000, from about 2000 to about 10000, from 1000 to about 8000, or from about 2000 to about 8000. When more than one monomer is used to form the reaction mixture, the molar ratio between the total of the monomers and catalyst can be at least 600, at least 1000, in a range from 600 to about 12000, from about 1000 to about 12000, from about 1000 to about 10000, or from about 2000 to about 8000. The “total of the monomer” refers to the sum of the moles of monomers used to form the reaction mixture. In some forms, the disclosed method further includes adding a comonomer into the catalyst solution, prior to step (i) adding a monomer into a catalyst solution to form a reaction mixture, during step (i), or after step (i) and before step (ii) heating the reaction mixture. For example, the co-monomer is mixed with the monomer and then the mixture of monomer and co-monomer is added into the catalyst solution. For example, the co-monomer is added into the catalyst solution after addition of the monomer into the catalyst solution. The co-monomer can be any suitable molecule for reacting with the monomer to produce a PL. Examples of co-monomer for use in the disclosed method include, but are not limited to, alkylene oxides, such as ethylene oxide and propylene oxide.

The disclosed method may further include mixing an initiator, and optionally one or more co-initiators, with the catalyst solution, prior to step (i) adding a monomer into a catalyst solution to form a reaction mixture, during step (i), or after step (i) and before step (ii) heating the reaction mixture. Preferably, the initiator, and optionally one or more co-initiators, is mixed with the catalyst solution prior to step (i). For example, prior to the addition of monomer and optionally co-monomer into the catalyst solution, an initiator and optionally one or more co-initiators is mixed with the catalyst solution.

The use of initiator and optionally co-initiator(s) may assist the activation of the catalyst and further facilitate the polymerization reaction to produce PL having the desired UHMW. However, the disclosed method can produce the desired UHMW PL without the use of any initiator and co- initiator(s). The initiator and co-initiator are preferably alcohols, such as any Ci- Ce alcohols and aromatic alcohols, for example, methanol, ethanol, 1 -propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butyl alcohol, benzyl alcohol, 1,4-benzenedimethanol (1,4-BDM), tryptophol, tyrosol, phenethyl alcohol, etc. For example, when used in the method, the initiator is ethanol and the co-initiator or each co-initiator is butanol, benzol alcohol, or 1,4-BDM. The mixing step can be performed at a suitable temperature for a time period sufficient for the initiator and optionally the co-initiator(s) to react with the catalyst. For example, prior to step (i), an initiator and optionally one or more co-initiators is mixed with the catalyst solution at room temperature and reacted for a time period ranging from about 10 minutes to about 1 hour or from about 30 minutes to about 1 hour.

The initiator and optionally the co-initiator(s) is typically at a suitable ratio for reacting with the Bi based catalyst in the catalyst solution. Generally, when initiator and optionally co-initiator(s) are used in the method, the molar ration between the initiator and the catalyst can be in a range from 1 : 10 to 10:1, from 1 :5 to 5: 1, from 1 :2 to 2: 1, such as 1:1; and the molar ratio between the coinitiator or each co-initiator (when present) and the catalyst can have a molar ratio in a range from 1:10 to 10:1, from 1:5 to 5: 1, from 1:2 to 2: 1, such as 1 :1.

As described above, the disclosed method typically does not include purifying the monomer, which was required in previously reported methods. The main purpose of a monomer purification step is to remove or reduce the water content of the monomer to a low level (such as at least less than 64 ppm), which was believed as required to achieve poly(lactone) of high molecular weight. In contrast, the omission of such a monomer purification step in the disclosed method results in a water content in the reaction mixture formed in step (i), such as a water content of at least 60 ppm, at least 64 ppm, at least 70 ppm, at least 80 ppm, at least 90 ppm, at least 100 ppm, at least 200 ppm, at least 300 ppm, at least 400 ppm, in a range from 64 ppm to 1000 ppm, from 64 ppm to 800 ppm, or from 64 ppm to 700 ppm. The water content in the reaction mixture refers to the total amount of water in the reaction mixture, which is the sum of the water in the monomer, the solvent, the co-monomer (when present), the initiator (when present), and the co-initiator. The amount of water in each component of the reaction mixture can be determined using methods known in the art, such as by titration using Karl Fischer Titration C30S from Mettler Tledo Corporation. The presence of water in the reaction mixture may facilitate activation of the catalyst, without an initiator. Generally, in the reaction mixture, the water content and the catalyst can have a molar ratio of at least 2, at least 5, in a range from 2 to about 40, from 2 to about 30, from 5 to about 40, or from 5 to about 30.

B. Heating Reaction Mixture

In step (ii) of the disclosed method, polymerization occurs under suitable reaction conditions. Typically, in step (ii), the reaction mixture formed in step (i) is heated at a suitable temperature for a time period sufficient to perform solution polymerization and produce a product composition containing the PL.

The temperature for heating the reaction mixture is selected depending on the specific type of PL being synthesized. For example, the temperature for heating the reaction mixture is typically above the melting temperature of the monomer for the PL. For example, for preparing poly(lactide) ("PLA"), the polymerization is performed above the melting temperature of the monomer for PL and below the equilibrium melting temperature of the polymer. For example, for preparing poly(caprolactone) (“PCL”), the polymerization is performed above the melting temperature of the polymer. For example, in step (ii), the temperature for heating the reaction mixture is at least 90 °C, at least 100 °C, in a range from 90 °C to about 140 °C, from 90 °C to about 120 °C, from 100 °C to about 140 °C, or from 100 °C to about 120 G.

The time period for heating the reaction mixture is typically at least 24 hours or at least 36 hours, such as in a range from 24 hours to about 100 hours, from 24 hours to about 72 hours, from 36 hours to about 100 hours, or from 36 hours to about 72 hours.

For example, in step (ii), the reaction mixture is heated at a temperature of at least 90 °C, at least 100 °C, in a range from 90 °C to about 140 °C, from 90 °C to about 120 °C, from 100 °C to about I40G, or from 100 °C to about 120 °C. for at least 24 hours, at least 36 hours, in a range from 24 hours to about 100 hours, from 24 hours to about 72 hours, from 36 hours to about 100 hours, or from 36 hours to about 72 hours, to produce a product composition containing the PL.

Optionally, the disclosed method further includes purifying the PL in the product composition after step (ii). For example, the PL in the product composition is purified by dissolving the product composition in a purification solvent and precipitating the PL from the product composition in a precipitation solvent. The purification solvent can be any organic solvent that is capable of dissolving PL, such as chloroform, 1,1, 1,3, 3, 3 - hexafluoro isopropanol (HFIP), or tetrahydrofuran (THF), or a combination thereof. The precipitation solvent can be any solvent that can cause the PL to precipitate out from the purification solvent, such as cold methanol, cold ethanol, cold propanol, and non-solvents at a cold temperature. A cold solvent refers to a solvent having a temperature less than 23 °C. A cold temperature refers to a temperature below 23 °C. The cycle of dissolution and precipitation may be repeated one or more times. After one or more cycles of purification, such as one or more cycles of dissolving the product composition and precipitating the PL, the purified Pl may be dried using any known method, such as drying in a vacuum oven.

1. Ultra-High Molecular Weight Poly(lactone)

In step (ii), ultra-high molecular weight (“UHMW”) poly(lactone) (“PL”) is produced by solution polymerization. For example, UHMW poly(L- lactide) (“PLLA”), poly(D-lactide) (“PDLA”), poly(caprolactone) (“PCL”), poly(glycolide) (“PGL”), poly(trimethylene carbonate) (“PTC”), or poly(ethylene carbonate) (“PEC”), or a copolymer thereof (such as lactide, caprolactone, glycolide, trimethylene carbonate, and/or ethylene carbonate copolymerized with an alkylene oxide) is produced in step (ii) of the disclosed method. In some forms, when different enantiometric monomers are used to produce the UHMW PL, the PL produced can contain two or more blocks, where each block can be formed from an enantiometric monomer. For example, when D-lactide and L-lactide are used to produce UHMW poly(lactide) (“PLA”), the PLA can contain two or more blocks, where each block is formed from D-lactide or L-lactide, such as poly(L-lactide)-/>-poly(D-lactide) (PLLA-/?- PDLA), poly(D-lactide)-/?-poly(L-lactide)-/?-poly(D-lactide) (PDLA-/?-PLLA-/?- PDLA), poly(D-lactide)-/>-poly-s-caprolactone (PDLA-/?-PCL), and poly(L- lactide)-/?-poly-8-caprolactone (PLLA-/?-PCL).

The UHMW PL produced using the disclosed method has a weight average molecular weight of at least l 10⁶ g/mol, at least 1.2 10⁶ g/mol, or at least 1.5x10⁶ g/mol. Further, the poly dispersity of the UHMW PL is narrow (i.e., a polydispersity in a range from 1.5 to 2.3 or from 1.8 to 2.0).

For example, the disclosed method produces UHMW PLLA, UHMW PDLA, UHMW PCL, UHMW PGL, UHMW PTC, and/or UHMW PEC having a weight average molecular weight of at least 1 x 10⁶ g/mol, at least 1 ,2x 10⁶ g/mol, or at least 1.5xl0⁶ g/mol, and/or a polydispersity in a range from 1.5 to 2.3 or from 1.8 to 2.0. For example, the disclosed method produces UHMW PLLA, UHMW PDLA, and/or UHMW PCL, having a weight average molecular weight of at least 1 xlO⁶ g/mol, at least 1.2xl0⁶ g/mol, or at least 1.5xl0⁶ g/mol. For example, the disclosed method produces UHMW PLLA, UHMW PDLA, and/or UHMW PCL, having a weight average molecular weight of at least I xlO⁶ g/mol, at least 1.2xl0⁶ g/mol, or at least 1.5xl0⁶ g/mol and a polydispersity in a range from 1.5 to 2.3 or from 1.8 to 2.0.

Using the disclosed method, the UHMW PL, such as those listed above, can be produced with a high yield (i.e., at least 40%). For example, the UHMW PL produced in step (ii) of the disclosed method has a yield of at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, in a range from 40% to 99%, from 50% to 99%, or from 60% to 99%. The yield of the UHMW PL is calculated using the formula: ((weight of PL)/(weight of starting monomer)) x 100%.

The UHMW PL produced using the disclosed method may be characterized by additional parameters, such as glass-transition temperature, melting temperature/crystallization, enthalpy of melting/crystallization, using methods known in the art, to further support the UHMW of the produced PL. Specific examples of parameters and measuring methods of exemplary UHMW PL produced using the disclosed method are described in the Examples below.

The disclosed methods and UHMW PLs can be further understood through the following numbered paragraphs.

1. A method for making ultra-high molecular weight (“UHMW”) of poly(lactone) (“PE”) comprising:

(i) adding a monomer for the UHMW PL into a catalyst solution comprising a Bismuth based catalyst and a solvent to form a reaction mixture; and

(ii) heating the reaction mixture at a temperature for a time period sufficient to produce a product composition comprising the UHMW PL.

2. The method of paragraph 1 , wherein the solvent of the catalyst solution is toluene, paraffin, xylene, 2,2,5,5-tetramethyloxolane, tetrahydrofuran, benzene, and para-cresol, and a combination thereof.

3. The method of paragraph 1 or 2, wherein the Bismuth based catalyst is represented by Bi(Ph)_pX_q, wherein p is an integer from 1 to 3, X is a halide (such as fluoride, chloride, bromide, or iodide), and q is an integer from 0 to 2, and wherein p+q equals to 3.

4. The method of any one of paragraphs 1-3, wherein the Bismuth based catalyst is BiPluBr or BiPhy or a combination thereof.

5. The method of any one of paragraphs 1-4, wherein the monomer for UHMW PL is a cyclic ester or cyclic carbonate ester.

6. The method of any one of paragraphs 1-5, wherein the monomer for

UHMW PL has a structure of Formula I or II:

Formula I Formula II wherein

are independently an integer from 1 to 4, from 1 to

3, or 1 or 2; n2 and n3 are independently an integer from 0 to 4, from 0 to 3, or from 0 to 2; Ri-Rs are independently hydrogen or a Ci-Ce unsubstituted alkyl.

7. The method of any one of paragraphs 1 -6, wherein the monomer for UHMW PL is lactide (D-lactide or L-lactide), caprolactone, trimethylene carbonate, ethylene carbonate, or glycolide.

8. The method of any one of paragraphs 1-7, further comprising adding a co-monomer into the catalyst solution, prior to step (i), during step (i), or after step (i) and before step (ii), optionally wherein the co-monomer is mixed with the monomer for UHMW PL prior to step (i), and optionally wherein the comonomer is an alkylene oxide (such as ethylene oxide or propylene oxide).

9. The method of any one of paragraphs 1-8, wherein in the reaction mixture, the monomer for UHMW PL and the catalyst has a molar ratio of at least 600, at least 1000, in a range from 600 to about 12000, from about 1000 to about 12000, from about 1000 to about 10000, or from about 2000 to about 8000.

10. The method of any one of paragraphs 1-9, further comprising mixing an initiator and optionally one or more co-initiators with the catalyst solution at room temperature for a time period sufficient for the initiator and optionally the co-initiator(s) to react with the catalyst, prior to step (i), and optionally wherein the initiator and the one or more co-initiators (when present) are alcohols (such as Ci-Ce alcohols).

11. The method of paragraph 10, wherein the initiator and optionally the one or more co-initiators is reacted with the catalyst from about 10 minutes to about

1 hour or from about 30 minutes to about 1 hour. 12. The method of paragraph 10 or 11, wherein the initiator and the catalyst has a molar ratio in a range from 1: 10 to 10:1, from 1:5 to 5: 1, from 1:2 to 2:1, such as 1: 1, and optionally wherein the co-initiator or each co-initiator and the catalyst has a molar ratio in a range from 1 : 10 to 10:1, from 1 : 5 to 5 : 1 , from 1 : 2 to 2: 1, such as 1: 1.

13. The method of any one of paragraphs 10-12, wherein the initiator is ethanol and the co-initiator or each co-initiator, when present, is butanol, benzol alcohol, or 1,4-benzenedimethanol.

14. The method of any one of paragraphs 1-13, wherein the reaction mixture has a water content, and wherein the water content and the catalyst has a molar ratio of at least 2, at least 5, in a range from 2 to about 40, from 2 to about 30, from 5 to about 40, or from 5 to about 30.

15. The method of paragraph 14, wherein the water content in the reaction mixture is at least 60 ppm, at least 64 ppm, at least 70 ppm, at least 80 ppm, at least 90 ppm, at least 100 ppm, at least 200 ppm, at least 300 ppm, at least 400 ppm, in a range from 64 ppm to 1000 ppm, from 64 ppm to 800 ppm, or from 64 ppm to 700 ppm

16. The method of any one of paragraphs 1-15, wherein in step (ii), the temperature for heating the reaction mixture is above the melting temperature of the monomer for the PL.

17. The method of paragraph 16, wherein the temperature for heating the reaction mixture is at least 90 °C, at least 100 °C, in a range from 90 °C to about 140 °C, from 90 °C to about 120 °C, from 100 °C to about 140 °C, or from 100 °C to about 120 °C.

18. The method of any one of paragraphs 1-17, wherein in step (ii), the reaction mixture is heated for at least 24 hours, at least 36 hours, in a range from 24 hours to about 100 hours, from 24 hours to about 72 hours, from 36 hours to about 100 hours, or from 36 hours to about 72 hours. 19. The method of any one of paragraphs 1-18, wherein the UHMW PL has a weight average molecular weight of at least 1 * 10⁶ g/mol, at least 1.2 10⁶ g/mol, or at least 1.5 10⁶ g/mol.

20. The method of any one of paragraphs 1-19, wherein the UHMW PL has a poly dispersity in a range from 1.5 to 2.3 or from 1.8 to 2.0.

21. The method of any one of paragraphs 1-20, further comprising purifying the UHMW PL in the product composition after step (ii).

22. The method of paragraph 21, wherein the UHMW PL is purified by dissolving the product composition in a purification solvent and precipitating the PL from the product composition in a precipitation solvent, wherein the purification and precipitation are repeated one or more times, and optionally wherein the precipitated PL is dried.

23. The method of paragraph 22, wherein the purification solvent is chloroform and the precipitation solvent is cold methanol.

24. The method of any one of paragraphs 1-23, wherein the UHMW PL has a yield of at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, in a range from 40% to 99%, from 50% to 99%, or from 60% to 99%.

25. The method of any one of paragraphs 1-24, wherein the method does not include purifying the monomer(s) prior to step (i).

26. The method of any one of paragraphs 1-25, wherein the UHMW PL is a poly(L-lactide), poly(D-lactide), poly (caprolactone), poly(L-lactide)-/>-poly(D- lactide) (PLLA-/?-PDLA), poly(D-lactide)-/?-poly(L-lactide)-/?-poly(D-lactide) (PDLA-/?-PLLA-/?-PDLA), poly(D-lactide)-/?-poly-8-caprolactone (PDLA-/?- PCL), or poly(L-lactide)-/?-poly-8-caprolactone (PLLA-/?-PCL).

27. An ultra-high molecular weight (“UHMW”) poly(lactone) (“PL”), having a weight average molecular weight (AL) of at least 1 *10⁶ g/mol, at least 1.2 10⁶ g/mol, at least 1.4 10⁶ g/mol, or at least 1.5 10⁶ g/mol.

28. The UHMW PL of paragraph 27, wherein the UHMW PL is a poly(L- lactide), poly(D-lactide), poly(caprolactone), poly(L-lactide)-/?-poly(D-lactide) (PLLA-LPDLA), poly(D-lactide)-/?-poly(L-lactide)-/?-poly(D-lactide) (PDLA- /?-PLLA-/?-PDLA), poly(D-lactide)-/?-poly-8-caprolactone (PDLA-/?-PCL), or poly(L-lactide)-/>-poly-s-caprolactone (PLLA-/?-PCL).

29. The UHMW PL of paragraph 27 or 28, wherein the UHMW PL has a polydispersity in a range from 1.5 to 2.3 or from 1.8 to 2.0.

30. An ultra- high molecular weight (“UHMW”) poly(lactone) (“PL”) made according to the method of any one of paragraphs 1 -26.

Particularly preferred embodiments are exemplified below.

EXAMPLES

Example 1

Materials and Methods

Materials

All the reactions and manipulations were conducted using Schlenk techniques under nitrogen/vacuum or in a glovebox (MBraun Unilab Plus). L- lactide and D-lactide ((S,S)-3,6-dimethyl-l,4-dioxane-2, 5-dione and (R,R)-3,6- dimethyl-l,4-dioxane-2, 5-dione, respectively) was obtained from Purasorb of Corbion Co., Ltd. s-caprolactone was purchased from Alfa Aesar. Toluene and tetrahydrofuran (THF) were purchased from LPS and purified by SPS Compact (Mbraun Solvent Purification System). Ethanol, 1 -butanol and benzyl alcohol were purchased from Sigma- Aldrich and purified over molecular sieve under nitrogen. Chloroform (stabilized with amylene) used for polymer dissolution was purchased from Biosolve, while the chloroform used for chromatogram analyses (HPLC grade) was purchased from HiPerSolv and used as received. Triphenyl bismuth and tribromide bismuth were purchased from Acros Organics and used as received. Deuterated chloroform (CDCh) was purchased from Cambridge Isotope Laboratories and used as received. Deuterated dimethyl sulfoxide (DMSO-d6) was purchased from Sigma, then was purified by CaH2 and then stored with 3 A molecular sieve which was activated at 350 °C in an oven for 12 hours. Polymerizations

Without co-initiators

Typical polymerization procedures were as follows. L- and D-lactide were polymerized as described in previous studies^31,32. Briefly, PLLA was obtained by ring-opening polymerization of L- lactide (LA) using BiPh2Br as catalyst and toluene as solvent. Schlenk vials for polymerization were dried in an oven at 130 °C overnight and quickly transferred in the glovebox. The Schlenk vials were loaded with the desired amount of LA. Separately, in a Schlenk vial, the Bi complex catalyst was dissolved with toluene as stock solution in the glove box at room temperature. The solution was stirred for 10 minutes, followed by the addition of the desired amount of LA in toluene. The reaction mixture was then placed into an oil bath preheated at the desired reaction temperature for the desired polymerization time. The resulting polymer was dissolved in chloroform and precipitated in cold methanol and dried until constant weight. The amount of CHCh and CH3OH used to dissolve and precipitate the PLAs were respectively 5 mL and 50 mL per gram of polymer obtained.

When the polymerization was conducted below the melting temperature of PLA and above the melting temperature of LA, the polymerization proceeded at the beginning in a toluene solution of the monomer. The viscosity of the mixture increased during the polymerization relatively fast and after approximately 5 hours, became grey gel-like. The polymerization further probably proceeded in the solid phase.

With alcohols as co-initiators

PLLA was obtained by ring-opening polymerization (ROP) of LA using BiPluBr as initiator and ethanol (EtOH), 1 -butanol (BuOH), benzyl alcohol (PhCPLOH), and 1 ,4-benzenedimethanol (1,4-BDM) as co-initiators with toluene as solvent. An equimolar amount of alcohol was mixed with the catalyst stock solution at room temperature and reacted for approximately 30 minutes. The rest of polymerization procedures was followed as described above. Polymerization characterizations

The number-average molecular weight (Mn), Mw and D of the PL As were determined by gel permeation chromatography (GPC) on a Shimadzu LC-2030 GPC system. Chloroform was used as eluent at a flow rate of 1.0 mL/minute. The temperature of the columns and detector were maintained at 40 °C. Molar masses were calculated against a reference curve performed using a calibration ranging from <10² to 2/ 10⁷ Da (A/_w) using polystyrene standard samples. GPC traces are provided Figures 9-13.

Differential scanning calorimetry (DSC) was performed on a TA Instruments DSC Q2000 to identify the glass- transition temperature, melting temperature/crystallization and enthalpy of melting/crystallization of the synthesized polymers. Heating and cooling runs were performed at a rate of 10 °C/minute. The melting temperature of the materials was determined from the second heating run. Crystallinity (%) values were calculated according to the formula: %c=(AHm-AHc/AHni⁰) x 100%, where AHm°= 93.6 J/g represents the theoretical heat of melting of 100% crystalline PLA, AH_m and AH_C corresponds to the melting and cold-crystallization enthalpies respectively^41-43.

'H NMR spectra was recorded with a Bruker Ultrashield 300 spectrometer (300 MHz magnetic field). NMR samples were prepared by dissolving ca. 10 mg of sample in 0.5 mL of CDCh. All spectra were referenced against the residual solvent peak in the deuterated solvent. ¹ H NMR characterization of the resultant catalyst is shown in Figure 7.

NMR measurements were carried out in deuterated dry DMSO (Sigma) at room temperature and 120 °C with a Bruker AVANCED III 600 spectrometer operating at 600 MHz.

Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT- ICR-MS) determines the m/z ratio of ions by measuring the cyclotron frequency of the ions in a fixed magnetic field. Samples were analyzed on a Bruker Daltonics FT-ICR mass spectrometer (9.4 T Solarix XR, Bremen, Germany). The samples were diluted in pure toluene and directly injected into the atmospheric pressure photo ionization (APPI) source. The FT-ICR mass spectra of samples were acquired using the positive APPI ionization mode with a mass range of m/z 154-2000.

MALDI-TOF MS experiments were carried out by using 2,5-Dihydroxy benzoic acid as the matrix in chloroform (CHCh) and sodium trifluoroacetate (NaTFA) as ionizing agent on a Bruker Ultrafex III MALDITOF mass spectrometer (Bruker Daltonik, Bremen, Germany).

The water content of monomers, solvents and alcohols were determined by Karl Fischer Titration C30S from Mettler Toledo Corporation. Samples, 50 mg/mL in THF; injection volume, 0.5 mL.

Quantum Chemical Calculations

Density functional theory calculations were performed to model the BiPluBr and possible activation structures with water (e.g. BiPhBr(OH), BiPh2(OH)), including the coordination with water and lactide using the GuassianO9/GaussView 5.0.9 software package. Different geometrical isomers for the non-coordinated complexes (pseudo-tetrahedral) and for coordinated complexes (distorted trigonal bipyramid) were calculated and energy difference calculations were conducted using the most stable geometrical isomers. The level of theory used for all the calculations was B3LYP with the basis set LANL2DZ used for all the atoms. Geometry optimizations were calculated using no constrains. All the optimized geometries show no imaginary frequency. Energies and structural distances were calculated on the optimized structures ⁴⁴.

Results and Discussion

Effect of water content in the polymerization systems

The resulting water content in the different chemicals used during the polymer syntheses are summarized in Table 1. Table 1: KFT characterization of the L- and D-lactide, solvents and alcohol.

Table 2: Water content in the polymerization systems at different molar ratio of LA/Bi

Other conditions: dry toluene, 120 °C, 72 hours. ^a Raw L-lactide as received (monomer). ^b Raw D-lactide as received (monomer). ^c Calculated as following: ((isolated weight of PLA)/(starting monomer amount)) x 100%. ^d GPC data in CH CT, vs. polystyrene standards. ^e The molar ratio of H2O (in the polymerization system) to Bi complex catalyst.

Table 3: Water content in the polymerization systems with different alcohols as co-initiator

Other conditions: LA (27.75 mmol), Bi (3.47 pmol), toluene, [LA]o = 5.55 mmol/ml, 120 °C, 72 hours. ^a Raw_L-lactide as received (monomer). ^b Without the addition of alcohol named as “None”, with alcohol as co-initiator, the molar ratio of Pin Bi Br/ROH = 1. ^c Calculated as following: ((isolated weight of PLA)/(starting monomer amount)) x l00%. ^d GPC data in CHCL, vs. polystyrene standards. ^e The molar ratio of H2O (in the polymerization system) to Bi complex catalyst.

L-D-lactide and s-caprolactone polymerizations using BiPli2Br catalyst: effect of M/1 molar ratios, polymerization time, temperature and monomer

To understand the effect of the catalyst concentration on the molecular characteristics and the polymerization kinetic, a series of reactions varying the amount of catalyst used as a changing variable were performed. Table 4 summarizes the results of the L-lactide polymerization, synthesized following ROP at different catalyst concentrations, polymerization time and temperature and using the best conditions found for the ROP of D- lactide. As shown in FIG. 1 A, the molecular mass of PLLA increases with catalyst concentration at the initial stage of polymerization, followed by a decrease in the subsequent stages. The highest molecular weight of PLLA as well as the highest polymer yield can be obtained for an LA/Bi molar ratio of 8000. Therefore, the kinetic study was performed using these molar ratios. Ultra-high molecular weight PDLA having molar mass of 1580 kg/mol was also achieved under the same polymerization conditions as ROP of L-lactide.

Table 4. Polymerization of L-lactide, D-lactide and s-caprolactone using different reaction conditions

Other conditions are as follows: dry toluene (5 mL). L-lactide, D-lactide and e- caprolactone used as received (monomer). ^a Monomer conversion determined by ’H NMR spectroscopy (CDCh, 298 K). ^b Calculated as following: ((isolated weight of PLA)/(starting monomer amount)) x 100%. ^c TON = (Molar amount of LA reacted)/(molar amount of Bi). ^d GPC data in CHCh vs. polystryrene standards. ^e Bulk polymerization, no toluene added.

Figure 1 describes the evolution of the molecular weight and the respective yield of the synthesized PLLA and PDLA, as a function of the LA/Bi molar ratio without addition of alcohol as co-initiator. PLLA can be synthesized for LA/A1 molar ratios up to 8000 resulting into the molecular weights of 1.75 x 10⁶ g/mol and polydispersity of 2.0. As expected from a single-site catalyst, the polydispersity index of the synthesized polymer is found to be relatively narrow (in the range of 1.5-2.3). Once higher LA/Bi molar ratios are used, the molecular weight of polymer decreases. The GPC spectrogram of each individual sample are shown in Figures 9-13.

Table 4 shows the polymerization conditions and molecular characteristics of the polymers synthesized by using BiPhiBr catalyst without any alcohol as co-initiator and without any monomer purification at fixed LA/Bi of 8000 performed at different polymerization time. The GPC chromatogram of each individual sample are shown in Figures 9-13. The relatively narrow polydispersity values (1.8 <£) > 2.0) of the resulting polymers are unimodal suggesting that a single species is responsible for the polymer production (or the unlikely case where more species have the exactly same kinetic profiles) with the distribution curves that shift to higher molecular weight values with increasing reaction time. Figure IB describes the evolution of the molecular weight and PLLA yield as a function of reaction times. The kinetic profile suggest that a polymerization time of 72 hours is required to yield a monomer conversion of around 84% while reaching a molecular weight plateau of approximately 1700 kg/mol. Thus, the chosen polymerization time is 72 hours in the next experiments.

Meanwhile, the polymerization conditions and molecular characteristics of PLLA synthesized using BiPFnBr catalyst at different polymerization temperatures were studied and listed in the Table 4 and Figure 1C. In this set of experiments, the LA/Bi molar ratios and the polymerization time were fixed based on previous findings. The GPC chromatogram of all samples from Table 4 are shown in Figures 9-13. The results in Figure 11 show a clear monomodal shift of the peak of the dispersity to higher AL (from 90 kg/mol to 1750 kg/mol) with increasing polymerization temperature. Figure 1C graphically summarizes the polymerization data of Table 4. The yield increases with the polymerization temperature. The most reasonable explanation to the increase in the yield can be attributed to the increased polymerization rate achieved at higher temperatures. Polydispersity of the synthesized polymer also increases with the polymerization temperature from a value of 1.3 up to 2.0. An increase in the poly dispersity, as a function of polymerization temperature, can be attributed to transesterification or hydrolysis that may result into different chains with different molecular weights. However, it cannot be excluded that depolymerization process might become relevant at higher polymerization temperatures. This temperature dependence is reflective of previously reported studies on ROPs.

It was found that a high molecular weight of PLA with a value of 0.5 million and poly dispersity at 1.8 can be achieved by ROP of LA using BiPlnBr catalyst at 120 °C at 24 hours without monomer purification and alcohols added. These results indicate that ROP of L-lactide with BiPluBr proceeds relatively quickly, which is unexpected considering literature reports on ROP of s-CL and TMC with Bi catalysts ^31,32.

L-lactide polymerizations using BiPh2Br catalyst: effect of coinitiators

Table 4 also reports the polymerization conditions and molecular characteristics of PLLA synthesized using BiPFnBr catalyst in addition with different alcohols as co- initiators. In this set of experiments, the LA/Bi molar ratios and the polymerization time and temperature were fixed based on previous experiments. The GPC spectrogram of all samples from Table 4 are shown in Figures 9-13.

Figure ID depicts the evolution of the molecular weight and the respective yield of the synthesized PLLA as a function of the addition of different alcohols as co-initiator. The yield increases with the alcohols added, but the molecular weight decreases (Figure ID). A possible explanation is that the amount of active site increases with the addition of alcohols. BiPluBr is less reactive than BiPluOR, indicating favor of a polymerization proceeding via the coordination-insertion mechanism³¹.

As shown in the Table 4 and Figure ID, the resulting polymers show a relatively high temperature peak at about 178 °C, corresponding to the fusion of homochiral crystals of optically pure PLLA type samples. In addition, the reactions with BiPl Br give access to resulting polymers with a wide variety of molecular weights. These results prompted the investigation of the influence of on the thermal behavior via DSC measurements in as shown in Table 6. The melting temperature (T_m) shows no significant variation with AL.

The polymerization data reported in Table 1 demonstrate that BiPlnBr is a useful catalyst for the synthesis of ultra-high molecular weight polylactones (PLLA, PDLA and PCL) without any monomer purification. The catalyst can be used without the use of a co-initiator as well as when used in combination with different alcohols. Both rates of polymerization and molar mass of PLA depend on the initiator concentration but not in a simple proportional manner. As reported in previous studies^{9 17-20} and by inventors’ own work²⁴ the ultra- high molecular weight-PLAs can be obtained using the commercial catalyst Sn(Oct)2 and phenoximine- Al catalysts where the monomer purification by recrystallization for several times is a required step. The process of recrystallization is challenging and costly, thereby only applicable to laboratory settings and not easily adaptable for more stringent industrial settings. From the polymerization data of Table 4, it is clear that ultra-high molecular weight PLLA and PDLA can be obtained without the addition of any alcohols as coinitiator and without any monomer purification step. This not only reduces the amount of solvent used for the monomer purification, but eliminated the need of solvent purification, thereby making the reported protocol easily adoptable on the commercial scale.

Catalyst Activation Mechanism

It is hypothesized that the catalyst activation mechanism takes place using the water in the monomer to form the necessary M-OR (here R = H) for the polymerization to initiate when the catalyst is used without any co-initiator. The hypothesis is in supports previous results reported for the synthesis of polycaprolactone and poly(trimethylene carbonate) using the same catalyst without the addition of any alcohols as co-initiator^31-33.

In previous reaction mechanism studies of ROPs of lactones (lactides, s- caprolactone, trimethylene carbonate, glycolide) catalyzed by diphenyl bismuth bromide catalyst, previous studies ^{19 31 34 39} reported that BiPluBr is activated by HOR, followed by the formation of HBr, in agreement with Equation 1 below. Also, it has been found that the initial formation of a Bi-alkoxide group was followed by the normal coordination-insertion mechanism which was shown by previous studies to be valid for most covalent metal alkoxides^31,45. Considering the strong enthalpic driving force in the formation of Ph-H (103 Kcal/mol)^46,47 by the hydrolysis of Bi-Ph, herein it was questioned whether the reaction of the complex with water can or cannot occur (Equation 2) as a possible coactivation or primary catalyst activation mechanism. The following section is aimed to understand the catalyst activation mechanism for the BiPlnBr in similar polymerization conditions.

BiPh/Br + HOR — PluBi - OR + HBr (Equation 1 )

BiPh/Br + HOR — PhBi(Br) - OR + PhH (Equation 2)

5 In order to understand the catalyst activation mechanism and the active species of the BiPh/Br, a series of polymerizations were conducted using two additional Bi-based initiators (e.g., BiBn and BiPht). Polymerization data are summarized in the Table 5. High molecular weight PLA (782 Kg/mol) with a very high conversion (97%) can be obtained by using the BiPht complex in the 0 reaction conditions used. These findings further strengthen the ability of the Bi- Ph bond to be hydrolyzed by the water in the monomer. When the BiBn complex is employed, no polymer is obtained; however, the BiBn complex was not soluble in the toluene solution of the lactide at room temperature as well as 120 °C. Regarding the BiBn, it was difficult to discern information on the 5 ability of the Bi-Br bond to be hydrolyzed by water due to the insolubility of the BiBn.

Table 5. Comparison of the reactivity of three Bi-based catalysts: effect of three different catalysts on the ROP of L- lactide

a Other conditions: raw L-lactide as received (27.75 mmol), Bi (3.47 pmol), 0 LA/Bi=8000, dry toluene (5 mL), 120 °C, 72 hours b Monomer conversion determined by ¹ H NMR spectroscopy (CDCL, 298 K) c Calculated as following: ((isolated weight of resulting polymer)/(starting monomer amount)) x 100% d TON =(Molar amount of monomer reacted)/(molar amount of Bi) 5 ^e TOF=TON/reaction time f Theoretical molecular weight calculated using /thcor) = Conv. x [M]o /[Bi] x Mu

⁸ GPC data in CH CT, vs. polystyrene standards h Melting enthalpy of 100% crystalline PLA and PCL is 93.6 J/g.⁴¹ 0 High temperature ¹ H NMR results of the BiPh/Br complex in Figure 2A do not show large changes, excluding any thermal complex modification. Once placed in combination with the L-lactide in Figure 2B and Figures 18-22, a proton corresponding to an -OH group from the active species BiPh2(OH) or BiPh(OH)Br has been detected at 4.22 ppm, which suggests that the BiPFnBr reacts with the water contained in the monomer leading to active specie (s) for the ROP (e.g. species containing a Bi-0 bond). The 'H NMR of the complex BiPluBr with L-lactide recorded at room temperature (Figure 21) does not show a peak at 4.22 ppm. This peak was detected only after raising the temperature to 120 °C, indicating the endothermic nature of the hydrolysis.

Figure 17 shows the 'H NMR results (300 MHz, 25 °C, CDCk) of a condensate found on the stopper of the Schlenk vial used for the ROP of L- lactide (see Table 4, Entry 9) and s-caprolactone (see Table 4, Entry 19). Beside the condensed monomer (peaks at 5.04 ppm and 1.65 ppm from L- lactide; peak at 4.23 ppm from s-caprolactone), the single peak in the aromatic region at 7.34 ppm in Figure 17A and 7.36 ppm in Figure 17B was found to be benzene, which indicates the hydrolysis of the Ph-Bi by the water from the polymerization system, in accordance with Equation 2. The ¹ H NMR results support the prediction of the hydrolysis of the Bi-Ph bond indicating that the reaction mechanism is more complex than previously reported.

So far, ¹ H NMR revealed the hydrolysis of the Bi-Ph bond, but does not indicate if the resulting species BiPhBr(OH) is active in the ROP of the lactide. To answer this question, FT-ICR-MS analyses of the polymer produced are performed in order to detect the polymeric chain with the active species still connected. Figure 3 (and Figure 23) show the FT-ICR-MS characterization of the polymer of Table 5, entry 9.

Figure 3 shows the FT-ICR- MS characterization where the dimer of the lactide having -OH as the end group was found to be bound to PhBrBi- and PluBi- corresponding to the activated species BiPhBr(OH) and BiPh2(OH) respectively. For the case of BiPhBr((OC(=O)CH(CH3))4OH), the presence of two peaks with same intensity at m/z (653 g/mol) and m/z+2 (655 g/mol) attributed to the two isotopes of the bromine are detected, further strengthening the structural assignment. Therefore, from the combination of the ¹ H NMR and FT-ICR-MS experiments, it can be concluded that BiPFnBR can be activated by the water in the lactide, thereby generating two active species (e.g. BiPh2(OH) and BiPhBr(OH)) capable of opening the lactide. Given that PCL is also obtained using the same catalytic system in the same conditions, it is reasonable to extend these findings to other lactones.

Quantum Chemical Calculations

To elucidate the reason behind the Bi-based catalyst ability to promote the synthesis of ultra-high molecular weight polylactones without any monomer purification, a series of Density function theory (DFT) calculations on the complex BiPFnBr, the active species (e.g. BiPh2(OH) and BiPhBr(OH)) and their water and lactide coordinated species were performed. Figure 4 shows the energy pathway for the formation of the growing chain starting from the BiPhBr(OH) complex.

Starting from the active species BiPhBr(OH), both water and lactide are energetically favorable processes where the water coordination is 5-7 Kcal/mol more energetically favorable compared to the lactide coordination (Figure 4). Once the lactide coordinate the BiPhBr(OH), the ROP can take place with a release of 6 Kcal/mol (Figure 4). From here, further addition ROP steps were not energetically demanding (0 Kcal/mol for the most stable geometrical isomer, while it is 2 Kcal/mol favorable process considering the second most stable geometrical isomer) (Figure 4). However, the hydrolysis was energetically demanding, requiring 25 Kcal/mol. Possibly, the difference of 25 Kcal/mol between the ROP and the chain transfer of the growing chain to the water may underlie the ability to tolerate small amounts of water and the ability to promote the synthesis of ultra-high molecular weight polylactones using undried monomer.

Polymer characterization

Figure 4 (and Figures 14-16) shows a series of typical thermograms of the PLAs produced from Table 4. All the polymers demonstrated high melting temperatures (up to 178 °C) and crystallinities (up to 67%), indicating the high stereo-regularity of the PLLA and PDLA synthesized, corresponding to the fusion of homochiral crystals of optically pure PLLA and PDLA polymers. Thermal characterization of the polymer produced support previous reported data of glass transition temperature, melting point, and crystallization^{2 13}’²⁴. Figures 5A and 5B also show PCL thermograms and typical melting points of 61 °C and a crystallinity of 49%, in line with previously reported results⁴⁸.

Table 6 summarizes the main thermal characteristics of the synthesized polymers.

Table 6. DSC Data of PLAs and PCL Polymers Described in Table 4

Obtained by DSC. Melting enthalpy of 100% crystalline PLA is 93.6 J/g.41

MALDI-TOF-MS analysis of the polymer produced was performed to elucidate possible structures and distribution in the polymers produced. Figure 6 is an example of MALDI-TOF-MS spectrum of the polymer synthesized without using any initiator. In both PLA and PCL, linear as well as cyclic structures were observed.

It corresponding to the results of FT- ICR-MS in Figures 3A and 3B. Moreover, the characterized polymers have molecular weight above 1 million g/mol, while the detection range of the MALDI-TOF-MS was limited to a few thousands g/mol. Therefore, the observed cyclic structure could also arise from backbiting of the long macromolecules, generating small cyclic structures ^44,49.

These results together indicate that the initial rapid and kinetically controlled polymerizations are more influenced by thermodynamically controlled equilibration reactions and catalyst concentration, polymerization time and reaction temperature, the main reasons for the increase of the average molar masses.. Second, the results from the present mechanism studies completes the unclear reaction mechanism as previously reported.

Discussion

In this work, it is reported for the first time the synthesis of ultra-high molecular weight (UHMW) PLAs and UHMW-PCL mediated by a BiPlnBr catalyst. Moreover, the synthesis of UHMW-PLLA, UHMW-PDLA and UHMW-PCL were achieved without any monomer purification, making the reported synthetic procedure time, and cost effective for larger scale production. The achieved molecular weights of the polymers generated were as follows: PLLA (AL=1.75xlO⁶ g/mol), PDLA (A/_w=1.58xl0⁶ g/mol) and PCL (A/w=1.58xl0⁶ g/mol). The presence or absence of an alcohol allows for control of polydispersity, molar mass, and structure of the end groups. The synthesis of UHMW-PLAs is affected by the polymerization temperature and time, catalyst concentration, and addition of co-initiators. Possibly, the water content of the monomer within a certain range plays an important role in catalyst activation as well as controlling the molecular weights of the polymers. Additionally, diphenyl bismuth bromide catalyst can be activated by water from the monomer, thereby forming two active species, thereby completing the activation mechanism of the Bi-based catalyst.

Example 2: Comparative data

The reported data in the literature using the Bismuth catalyst makes use of bulk polymerization for the synthesis of polylactones. However, when this method is replicated for the synthesis of PLAs, it results in very low molar mass compared to the polylactones. The modification done in the synthesis step, addition of the toluene, helps in securing the desired high molar masses. The conditions are summarized in the Comparative Example 1 , where the entry 5 refers to the modified synthesis step having toluene with the monomer (Solution polymerization) and entry 22, refers to the bulk polymerization (without any toluene, only monomer).

Comparative Example 1

Table 7: Data for Comparative Example 1. Solution (entry 5, monomer +toluene) vs bulk polymerization (entry 22, monomer only).

Other conditions: monomers as received, polymerization time 72 hours, polymerization temperature 120 °C, LA/Bi = 8000, no initiator, a Monomer conversion determined by ’H NMR spectroscopy (CDCb, 298 K). b Calculated as following: ((isolated weight of PLA)/(starting monomer amount)) x 100%. c TON=(Molar amount of LA reacted)/(molar amount of Bi). dGPC data in CHCh vs. polystyrene standards. e Obtained by DSC. fObtained by DSC. Melting enthalpy of 100% crystalline PLA and PCL is 93.6 J/g and 139 J/g, respectively.

The data in Table 7 shows that the polymerization for the entry 5 and 22 was conducted in the same conditions, with the exception that the entry 5 is conducted in the presence of 5 mL solvent (toluene) together with the monomer. The entry 5 results in a polymer having weight average molar mass (A/w) of 1749 Kg/mol. The absence of toluene in the entry 22 as the reaction medium causes reduction in the molar mass of the synthesized PLA by approximately 11 times 154 Kg/mol. The polymerization is conducted at 120 °C, which is below the melting temperature of PLA and above the melting temperature of the monomer LA. The presence of toluene favors the polymerization. Comparative Example 2

Table 8: Data for Comparative Example 2: Bi- vs reported Al-based catalyst

Other conditions: monomers as received, polymerization time 72 hours, dry toluene (5 mL), polymerization temperature 120 °C, LA/M = 8000, no initiator, ^a Monomer conversion determined by ¹ H NMR spectroscopy (CDCls, 298 K). b Calculated as following: ((isolated weight of PLA)/(starting monomer amount)) x 100%. c TON=(Molar amount of LA reacted)/(molar amount of M). dGPC data in CHCh vs. polystyrene standards. e Obtained by DSC. f Obtained by DSC. Melting enthalpy of 100% crystalline PLA and PCL is 93.6 J/g and 139 J/g, respectively.

The data in Table 8 shows performance of the Bi- vs Al-based catalyst. Under the same polymerization conditions, the Al-based catalyst does not yield UHMWPLA. The weight average molecular weight of the PLA synthesized by the Bi-based catalyst (1749 Kg/mol) is approximately twice compared to the Al- based catalyst (902 Kg/mol). To add, the normally used Sn-based catalyst does not yield the desired molecular weight under the same reaction conditions of the comparative example 2.

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Claims

We claim:

1. A method for making ultra-high molecular weight (“UHMW”) of poly(lactone) (“PL”) comprising:

2. The method of claim 1 , wherein the solvent of the catalyst solution is toluene, paraffin, xylene, 2,2,5,5-tetramethyloxolane, tetrahydrofuran, benzene, or para-cresol, or a combination thereof.

3. The method of claim 1 or 2, wherein the Bismuth based catalyst is represented by Bi(Ph)_pX_q, wherein p is an integer from 1 to 3, X is a halide (such as fluoride, chloride, bromide, or iodide), and q is an integer from 0 to 2, and wherein p+q equals to 3.

4. The method of any one of claims 1-3, wherein the Bismuth based catalyst is BiPluBr or BiPhy or a combination thereof.

5. The method of any one of claims 1-4, wherein the monomer for UHMW PL is a cyclic ester or cyclic carbonate ester, optionally wherein the monomer for UHMW PL is a lactone.

6. The method of any one of claims 1-5, wherein the monomer for UHMW PL has a structure of Formula I or II:

Formula I Formula II wherein

are independently an integer from 1 to 4, from 1 to

7. The method of any one of claims 1 -6, wherein the monomer for UHMW PL is lactide (D-lactide or L-lactide), caprolactone, trimethylene carbonate, ethylene carbonate, or glycolide.

8. The method of any one of claims 1-7, further comprising adding a comonomer into the catalyst solution, prior to step (i), during step (i), or after step (i) and before step (ii), optionally wherein the co-monomer is mixed with the monomer for UHMW PL prior to step (i), and optionally wherein the comonomer is an alkylene oxide (such as ethylene oxide or propylene oxide).

9. The method of any one of claims 1-8, wherein in the reaction mixture, the monomer for UHMW PL and the catalyst has a molar ratio of at least 600, at least 1000, in a range from 600 to about 12000, from about 1000 to about 12000, from about 1000 to about 10000, or from about 2000 to about 8000.

10. The method of any one of claims 1 -9, further comprising mixing an initiator and optionally one or more co-initiators with the catalyst solution at room temperature for a time period sufficient for the initiator and optionally the co-initiator(s) to react with the catalyst, prior to step (i), and optionally wherein the initiator and the one or more co-initiators (when present) are alcohols (such as Ci-Ce alcohols).

11. The method of claim 10, wherein the initiator and optionally the one or more co-initiators is reacted with the catalyst from about 10 minutes to about 1 hour or from about 30 minutes to about 1 hour.

12. The method of claim 10 or 11, wherein the initiator and the catalyst has a molar ratio in a range from 1 : 10 to 10: 1, from 1 : 5 to 5 : 1 , from 1 :2 to 2: 1 , such as 1: 1, and optionally wherein the co-initiator or each co-initiator and the catalyst has a molar ratio in a range from 1: 10 to 10:1, from 1:5 to 5: 1, from 1:2 to 2:1, such as 1: 1.

13. The method of any one of claims 10-12, wherein the initiator is ethanol and the co-initiator or each co-initiator, when present, is butanol, benzol alcohol, or 1 ,4-benzenedimethanol.

14. The method of any one of claims 1-13, wherein the reaction mixture has a water content, and wherein the water content and the catalyst has a molar ratio of at least 2, at least 5, in a range from 2 to about 40, from 2 to about 30, from 5 to about 40, or from 5 to about 30.

15. The method of claim 14, wherein the water content in the reaction mixture is at least 60 ppm, at least 64 ppm, at least 70 ppm, at least 80 ppm, at least 90 ppm, at least 100 ppm, at least 200 ppm, at least 300 ppm, at least 400 ppm, in a range from 64 ppm to 1000 ppm, from 64 ppm to 800 ppm, or from 64 ppm to 700 ppm

16. The method of any one of claims 1-15, wherein in step (ii), the temperature for heating the reaction mixture is above the melting temperature of the monomer for the PL.

17. The method of claim 16, wherein the temperature for heating the reaction mixture is at least 90 °C, at least 1001C, in a range from 90 °C to about 140 °C, from 90 °C to about 120 °C, from 1001C to about 140 °C, or from 100 °C to about 120 °C.

18. The method of any one of claims 1-17, wherein in step (ii), the reaction mixture is heated for at least 24 hours, at least 36 hours, in a range from 24 hours to about 100 hours, from 24 hours to about 72 hours, from 36 hours to about 100 hours, or from 36 hours to about 72 hours.

19. The method of any one of claims 1-18, wherein the UHMW PL has a weight average molecular weight of at least 1 * 10⁶ g/mol, at least 1.2 10⁶ g/mol, or at least 1.5 10⁶ g/mol.

20. The method of any one of claims 1-19, wherein the UHMW PL has a polydispersity in a range from 1.5 to 2.3 or from 1.8 to 2.0.

21. The method of any one of claims 1-20, further comprising purifying the UHMW PL in the product composition after step (ii).

22. The method of claim 21, wherein the UHMW PL is purified by dissolving the product composition in a purification solvent and precipitating the PL from the product composition in a precipitation solvent, wherein the purification and precipitation are repeated one or more times, and optionally wherein the precipitated PL is dried.

23. The method of claim 22, wherein the purification solvent is chloroform and the precipitation solvent is cold methanol.

24. The method of any one of claims 1-23, wherein the UHMW PL has a yield of at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, in a range from 40% to 99%, from 50% to 99%, or from 60% to 99%.

25. The method of any one of claims 1-24, wherein the method does not include purifying the monomer(s) prior to step (i).

26. The method of any one of claims 1-25, wherein the UHMW PL is a poly(L-lactide), poly(D-lactide), poly (caprolactone), poly(L-lactide)-/>-poly(D- lactide) (PLLA-/?-PDLA), poly(D-lactide)-/?-poly(L-lactide)-/?-poly(D-lactide) (PDLA-/?-PLLA-/?-PDLA), poly(D-lactide)-/?-poly-8-caprolactone (PDLA-/?- PCL), or poly(L-lactide)-/?-poly-8-caprolactone (PLLA-/?-PCL).

27. An ultra-high molecular weight (“UHMW”) poly(lactone) (“PL”), having a weight average molecular weight ( /_w) of at least 1 *10⁶ g/mol, at least 1.2 10⁶ g/mol, at least 1.4 10⁶ g/mol, or at least 1.5 10⁶ g/mol.

28. The UHMW PL of claim 27, wherein the UHMW PL is a poly(L- lactide), poly(D-lactide), poly(caprolactone), poly(L-lactide)-/?-poly(D-lactide) (PLLA-/?-PDLA), poly(D-lactide)-/?-poly(L-lactide)-/?-poly(D-lactide) (PDLA- /?-PLLA-/?-PDLA), poly(D-lactide)-/?-poly-8-caprolactone (PDLA-/?-PCL), or poly(L-lactide)-/>-poly-s-caprolactone (PLLA-/?-PCL).

29. The UHMW PL of claim 27 or 28, wherein the UHMW PL has a polydispersity in a range from 1.5 to 2.3 or from 1.8 to 2.0.

30. An ultra- high molecular weight (“UHMW”) poly(lactone) (“PL”) made according to the method of any one of claims 1-26.