Ring Opening Polymerization of Lactide for The synthesis of Poly (Lactic Acid)

Ring Opening Polymerization of Lactide for The synthesis of Poly (Lactic Acid) Reported by Keith A. Porter Date 2 March 2006 INTRODUCTION Poly (lactic acid) (PLA) shows promise as a valuable alternative to petroleum-based polymers for uses as plastics, fibers, and coatings. PLA is produced from renewable resources such as corn and sugar beets, and the material is biodegradable thus making it ideal for industrial use.1,2 PLA is derived from lactic acid, which exists as two enantiomers: L- and D-lactic acid, 1 and 2. Lactic acid forms PLA O HO upon polycondensation; however, this is an equilibrium reaction and O HO OH OH difficulties completely removing water can limit the maximum molecular CH3 CH3 weight attained due to hydrolysis of the ester bonds. A solution to this 1 2 problem is the use of the cyclic dimmer lactide. Lactide undergoes Ring Opening Polymerization (ROP) to give PLA. Since this is not a condensation polymerization, there is no need for the removal of water. Cargill Dow LLC has capitalized on the ROP of lactide to produce about 300 x 106 lbs/year of PLA.3 PLA belongs to a group of polymers known as polyesters, which are among the more versatile of organic polymers. The ROP of lactide is thermodynamically driven by the relief of angle strain and switching from (E) to (Z) ester conformation upon ring opening.4 There are three stereoisomers of lactide, D-lactide (3), L-lactide (4), and meso-lactide (5). This seminar will focus on the stereoselective synthesis of the different PLA microstructures and the properties that arise from stereohomogeneity. R O O O O S O R 3 O 4 RO O O S O O O S 5 BACKGROUND INFORMATION PLA is an aliphatic, hydrolyzable polyester (6). Upon exposure to heat and water, the polymer breaks down to low molecular weight oligomers.5 Further degradation can occur by the O action of microorganisms in the body and in the environment to produce lactic acid in the O CH3 6 n former and carbon dioxide and water in the latter. PLA has many properties similar to its petro-chemical based counterparts. PLA is glossy, transparent, and flavor-resistant, and it can be elastic or tough. The polymer has many uses ranging from bottles to high temperature plastic cooking dishes.6 25 STEREO-HOMOGENEITY OF PLA Four different stereoisomers of PLA are shown in Figure 1. Isotactic PLA is formed from either pure Dor L-lactide, and the sequential stereogenic carbons have the same absolute configuration. In contrast, O R O R O O O O O R O Isotactic O R O R O O O O R O S O S n O R O S O R Heterotactic O O O O n O S O S O R O O O O Syndiotactic O R O S n n O O O O O O O O Isotactic Stereoblock n m Figure 1. Different microstructures of PLA syndiotactic PLA has alternating configurations of the sequential stereocenters. Atactic PLA has a random distribution of configurations about the stereocenters while its heterotactic counterpart has regions of stereo-homogeneity.7 Isotactic stereoblock PLA is similar to isotactic PLA but differs in that rac-lactide is used instead of pure L- or D-lactide. Thakur, Munson and co-workers8 showed that the tacticity can be determined directly by 1H NMR analysis of the methine hydrogen. The most common method for determining the degree of crystallinity is by Differential Scanning Calorimetry (DSC).9 As stereoregularity increases, so does the overlap between PLA helices, thus increasing the number of stabilizing dipole-dipole interactions.10 The stronger the intermolecular forces, the greater the mechanical and thermal properties of the polymer.11 Since the properties arise from the stereochemistry7, the development of new types of stereocomplexes are vital to make stronger, more durable PLA. SYNTHESIS OF PLA WITH OPTICALLY ACTIVE LACTIDE Isotactic PLA is formed by the polymerization of either pure L or D-lactide. Several different types of metal catalysts such as zinc (II) and titanium(IV) have been evaluated, but tin (II) 2ethylhexanoate (Sn(Oct)2) (7) has been most widely used because of high reaction rates, the solubility in the monomer melt, and the ability to produce high molecular weights.1,12 The coordination-insertion 26 mechanism is shown in Figure 2. Molecular modeling suggests that two alcohols (these alcohols can be initiators such as MeOH or iPrOH or the propagating hydrolyzed lactide) exchange with the octoate ligands (8a) followed by the coordination of lactide to the metal center (8b). Insertion of the alcohol (8c) followed by ring-opening (8d) generates a linear monomer (8e) and starts propagation. The ROP of neat lactide with Sn(Oct)2 gives PLA having molecular weights up to 106 g/mol at 140 – 180 oC with catalyst concentration of 100-1000 ppm in 2-5 hours.5 A major drawback of the tin catalyst is the incorporation of the toxic metal on the polymer chain end and the resulting toxicity risk in biomedical applications. Another is the broad polydispersity index ranging from 1.5-2.0. The large range was attributed to the tin complex reacting with impurities in L-lactide to form new initiator species leading to an initiation rate that is slower than the propagation rate.13 O H O H O O 2 equiv ROH Sn O O O O R Lactide Sn R O H 7 O O Sn O R O H O OR O O O O H R Sn O H Lactide O O O O O O H O O O 8b O O O O OR O O O O 8a O R O O Sn O R H 8e O O O H R O O O Sn O O R O O H O 8d O 8c Figure 2. Coordination-insertion mechanism of Sn(Oct)2 catalyzed polymerization of L-lactide. SYNTHESIS OF PLA WITH rac-LACTIDE Kinetic Resolution of rac-Lactide and the Formation of Isotactic Stereoblocks The kinetic resolution of rac-lactide was accomplished with two different chiral aluminum complexes.14-16 Spassky and co-workers14a,b reported one of the most important discoveries in the stereocontrol of PLA; the use chiral Al(OiPr)[(R)-(SalBinap)] ((R)-9) catalyst promoted high selectivity in the kinetic resolution of rac-lactide. (R)-9 showed a 20:1 preference for the polymerization of D- 27 lactide over L-lactide (Figure 3). This was a major advance in the stereocontrolled polymerization of PLA because the separation of rac-lactide to yield enantiopure lactide is expensive and tedious. O O O O O O O (R)-9 O O R O O O O R n O O L L D O 20:1 ratio Figure 3. Kinetic resolution of rac-lactide. At 60 % conversion, the product was identified by circular dichroism (CD) as poly(D-lactic acid) with a Tm of 170 oC. At 100% conversion, the Tm rose to 187 oC, indicating that eventually, isotactic stereoblock PLA was synthesized. Feijen and co-worers16 reported the first neat ROP of rac-lactide using a chiral catalyst, (R, R) salen-Al catalyst (10) in the synthesis of isotactic stereoblock PLA. Aluminum catalyst (R, R)-10 was prefered the ROP of L-lactide over D-lactide by 14:1. The polymer had a Tm of 183.5 which is lower than that of the reported stereoblock complex reported by Spassky. The lower Tm could be attributed to lower stereoselectivity. Catalysts (R)-9 and (R, R)-10 could be used in the synthesis of neat L-lactide; if the polymer reaction were monitored carefully by CD, after polymerization of the reactive lactide (Dlactide is active with 9 and L-lactide is active with 10), the non-polymerized “left over” could be distilled off under reduced pressure. However no such study has yet been reported. H N O Al OiPr O N N Al But O tBu (R)-9 H N O tBu But (R, R)-10 Synthesis of Heterotactic PLA from rac-Lactide Achiral catalysts are easier to synthesize and generally less expensive than their chiral counterparts; consequently a research priority is to achieve stereocontrolled R R N Zn OR N R R polymerizations without chiral catalysts. In the polymerization of rac-lactide, the bulky nature of achiral catalyst 11 and the nature of the polymer chain-end stereocenter were used to influence the stereochemistry of the last inserted monomer, which determines the enantiomer enchained. If (R, R) configuration is enchained, then isotactic PLA is 11 formed, whereas if the chain end attacks (S, S), then heterotactic PLA forms. Complex R = iPr 28 11 was found to be highly active in the polymerization of rac-lactide with 90% of the linkages formed After 20 min at 20 oC, 11 polymerized rac-lactide to 95% between alternating L and D-lactide. conversion to PLA with a molecular weight of 37900 g/mol and a polydispersity index of 1.10. This material was also a non-crystalline, amorphous complex with a Tg of 49 oC; however since PLA is mostly used in low temperature environments, heterotactic PLA seems like a cheap alternative to the use of optically pure L or D-lactide.17-20 SYNTHESIS OF PLA FROM meso-LACTIDE Synthesis of Syndiotactic PLA Syndiotactic polymers often have better properties than their isotactic counterparts, such as increased crystallization rates and higher glass transition temperatures and melting points. Recent studies have thus targeted the synthesis of syndiotactic PLA with efficient seterochemical control and high yields.15 Previous results by Thakur21 and Kricheldork22 have demonstrated low conversion (up to 75 %) of meso-lactide to syndiotactic PLA. The two pathways for the stereoselectivity of this polymerization are shown in Figure 4. Consistent attack at the enantiotopic A or B acyl-O bond leads to syndiotactic PLA while alternating attack on B and A leads to heterotactic PLA. Coates and co-workers reported that (R)-9 exhibits a strong preference for opening of meso-lactide at the carbonyl group adjacent to the “R” stereogenic center, (Figure 5). Heterotactic R O O A O R O S O O O O kBA>>kBB O S R O n O O S B meso-lactide O R O S O O O O O R O S kB>>kA n Syndiotactic Figure 4. Different types of meso-lactide polymerization O LnAl O Rn R O S O O LnAl O Rn O O R S LnAl O O O ORn R O O S O O LnAl R O ORn O S O =AlLnORn+1 Figure 5. AlLn-catalyzed polymerization of meso-lactide 29 1 H NMR analysis of the polymer proved high syndiotactic content (96%). The polymer had a Tg and Tm of 50.7 and 149 oC, respectively, which were lower than the values of isotactic PLA at 60 and 180 oC. This deviation was attributed to a lower degree of crystallinity since 96% of monomer was converted to syndiotacic PLA. SYNTHESIS OF HETEROTACTIC PLA Coates and co-workers were interested in determining if syndiotactic PLA could be synthesized with an optically impure catalyst, rac-9. They found that the reaction gave amorphous heterotactic polymer with a Tg = 43.2 oC (Figure 6). The 1H NMR spectrum revealed heterotactic PLA. The authors have previously reported that (R)-9 prefers to attack the carbonyl closest to the “R” stereocenter. After initiation, the polymer chains switch enantiomeric aluminum catalyst before insertion into the next monomer site. Molecular modeling suggests that (R)-9 prefers the “R” center and (S)-9 prefers the “S” O O LRAl O O O O S O R LsAlOR OiPr Polymer exchange LrAlOR O O O LSAl O S R O OiPr A S L Al O O O R O S OiPr O O LRAl O R S O OiPr meso-lactide B LRAl O O S O R O O O O O R O S O R O O O O O R O S OiPr Repeat A, B S n LSAl O R O S O O O O O S O R OiPr Figure 6. Synthesis of heterotactic PLA from meso-lactide using rac-8 center. ORGANIC CATALYST FOR ROP OF LACTIDE An important consideration in the polymerization of lactide is the removal of metal contaminants, bound to the chain end before application in resorbable biomaterials.23 The application of organocatalysts to controlled lactide polymerization would be a highly viable alternative to 30 organometallic approaches. Several organic compounds have demonstrated high activity and enantioselectivity in a number of common organic transformations. Hedrick and co-workers were the first to report the use of first organic catalyst 4-(dimethylamino)pyridine (DMAP), 12, in the ROP of lactide.23 The catalytic cycle for 12 (Scheme 1a) and N-Heterocyclic carbene (NHC) 13 (Scheme 1b) are shown. Initiation occurs when an alcohol reacts with the lactide-organic catalyst complex, leaving a N N CF3 N terminal to act as a nucleophile to S N F3C N H 13 12 -hydroxyl group react with additional lactide N H N monomer. 14 High conversions of up to 99% in two hours were obtained with NHC 13. Thiourea-amine catalyst 14 has also been used but the ROP occurs by a different catalytic mechanism. Thiourea-amine 14 H-bonds to the carbonyl oxygen through the thiourea and the alcohol initiator is directed to attack the acyl-oxygen bond by the tertiary amine.25 Scheme 1. Proposed mechanism of ROP of Lactide with 12 and 13. N O (a) O O O O DMAP O O (b) O O OR OH O ROH DMAP O Mes N O N N Mes O O Mes N O O N Mes O O OR OH O ROH O O NHC O These organic catalysts are relatively inexpensive and highly active, and they yield PLA with low PDI because they are living polymerizations.23 Organocatalysts provide attractive substitutes for the ROP of lactide for biomedical and environmental applications.26 CONCLUSION AND FUTURE WORK PLA has recently attracted much attention as a biodegradable polymer for the replacement of oilbased material. Several different types of PLA have been synthesized with high stereoregularity and in high yield. More recent work has been devoted to the synthesis of organocatalysts because they are less 31 toxic than metal catalysts. Hedrick has prepared a series of organocatalysts that have been highly reactive for the ROP of lactide. However, so far they have not shown as high stereocontrol or high molecular weights as the metal catalysts have. 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