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

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1 ig peig Polymerizatio of Lactide for The sythesis of Poly (Lactic Acid) eported by Keith A. Porter Date 2 March 2006 ITDUCTI Poly (lactic acid) (PLA) shows promise as a valuable alterative to petroleum-based polymers for uses as plastics, fibers, ad coatigs. PLA is produced from reewable resources such as cor ad sugar beets, ad the material is biodegradable thus makig it ideal for idustrial use. 1,2 PLA is derived from lactic acid, which exists as two eatiomers: L- ad D-lactic acid, 1 ad 2. Lactic acid forms PLA C 3 1 C 3 2 upo polycodesatio; however, this is a equilibrium reactio ad difficulties completely removig water ca limit the maximum molecular weight attaied due to hydrolysis of the ester bods. A solutio to this problem is the use of the cyclic dimmer lactide. Lactide udergoes ig peig Polymerizatio (P) to give PLA. ice this is ot a codesatio polymerizatio, there is o eed for the removal of water. Cargill Dow LLC has capitalized o the P of lactide to produce about 300 x 10 6 lbs/year of PLA. 3 PLA belogs to a group of polymers kow as polyesters, which are amog the more versatile of orgaic polymers. The P of lactide is thermodyamically drive by the relief of agle strai ad switchig from (E) to (Z) ester coformatio upo rig opeig. 4 There are three stereoisomers of lactide, D-lactide (3), L-lactide (4), ad meso-lactide (5). This semiar will focus o the stereoselective sythesis of the differet PLA microstructures ad the properties that arise from stereohomogeeity BACKGUD IFMATI PLA is a aliphatic, hydrolyzable polyester (6). Upo exposure to heat ad water, the polymer breaks dow to low molecular weight oligomers. 5 Further degradatio ca occur by the actio of microorgaisms i the body ad i the eviromet to produce lactic acid i the C 3 former ad carbo dioxide ad water i the latter. PLA has may properties similar to its 6 petro-chemical based couterparts. PLA is glossy, trasparet, ad flavor-resistat, ad it ca be elastic or tough. The polymer has may uses ragig from bottles to high temperature plastic cookig dishes. 6 25

2 TEE-MGEEITY F PLA Four differet stereoisomers of PLA are show i Figure 1. Isotactic PLA is formed from either pure D- or L-lactide, ad the sequetial stereogeic carbos have the same absolute cofiguratio. I cotrast, Isotactic ydiotactic eterotactic Isotactic tereoblock m Figure 1. Differet microstructures of PLA sydiotactic PLA has alteratig cofiguratios of the sequetial stereoceters. Atactic PLA has a radom distributio of cofiguratios about the stereoceters while its heterotactic couterpart has regios of stereo-homogeeity. 7 Isotactic stereoblock PLA is similar to isotactic PLA but differs i that rac-lactide is used istead of pure L- or D-lactide. Thakur, Muso ad co-workers 8 showed that the tacticity ca be determied directly by 1 M aalysis of the methie hydroge. The most commo method for determiig the degree of crystalliity is by Differetial caig Calorimetry (DC). 9 As stereoregularity icreases, so does the overlap betwee PLA helices, thus icreasig the umber of stabilizig dipole-dipole iteractios. 10 The stroger the itermolecular forces, the greater the mechaical ad thermal properties of the polymer. 11 ice the properties arise from the stereochemistry 7, the developmet of ew types of stereocomplexes are vital to make stroger, more durable PLA. YTEI F PLA WIT PTICALLY ACTIVE LACTIDE Isotactic PLA is formed by the polymerizatio of either pure L or D-lactide. everal differet types of metal catalysts such as zic (II) ad titaium(iv) have bee evaluated, but ti (II) 2- ethylhexaoate ((ct) 2 ) (7) has bee most widely used because of high reactio rates, the solubility i the moomer melt, ad the ability to produce high molecular weights. 1,12 The coordiatio-isertio 26

3 mechaism is show i Figure 2. Molecular modelig suggests that two alcohols (these alcohols ca be iitiators such as Me or ipr or the propagatig hydrolyzed lactide) exchage with the octoate ligads (8a) followed by the coordiatio of lactide to the metal ceter (8b). Isertio of the alcohol (8c) followed by rig-opeig (8d) geerates a liear moomer (8e) ad starts propagatio. The P of eat lactide with (ct) 2 gives PLA havig molecular weights up to 10 6 g/mol at o C with catalyst cocetratio of ppm i 2-5 hours. 5 A major drawback of the ti catalyst is the icorporatio of the toxic metal o the polymer chai ed ad the resultig toxicity risk i biomedical applicatios. Aother is the broad polydispersity idex ragig from The large rage was attributed to the ti complex reactig with impurities i L-lactide to form ew iitiator species leadig to a iitiatio rate that is slower tha the propagatio rate equiv 8a Lactide 8b 8e Lactide 8d 8c Figure 2. Coordiatio-isertio mechaism of (ct) 2 catalyzed polymerizatio of L-lactide. YTEI F PLA WIT rac-lactide Kietic esolutio of rac-lactide ad the Formatio of Isotactic tereoblocks The kietic resolutio of rac-lactide was accomplished with two differet chiral alumium complexes passky ad co-workers 14a,b reported oe of the most importat discoveries i the stereocotrol of PLA; the use chiral Al(iPr)[()-(alBiap)] (()-9) catalyst promoted high selectivity i the kietic resolutio of rac-lactide. ()-9 showed a 20:1 preferece for the polymerizatio of D- 27

4 lactide over L-lactide (Figure 3). This was a major advace i the stereocotrolled polymerizatio of PLA because the separatio of rac-lactide to yield eatiopure lactide is expesive ad tedious. ()-9 D L 20:1 ratio L Figure 3. Kietic resolutio of rac-lactide. At 60 % coversio, the product was idetified by circular dichroism (CD) as poly(d-lactic acid) with a T m of 170 o C. At 100% coversio, the T m rose to 187 o C, idicatig that evetually, isotactic stereoblock PLA was sythesized. Feije ad co-worers 16 reported the first eat P of rac-lactide usig a chiral catalyst, (, ) sale-al catalyst (10) i the sythesis of isotactic stereoblock PLA. Alumium catalyst (, )-10 was prefered the P of L-lactide over D-lactide by 14:1. The polymer had a T m of which is lower tha that of the reported stereoblock complex reported by passky. The lower T m could be attributed to lower stereoselectivity. Catalysts ()-9 ad (, )-10 could be used i the sythesis of eat L-lactide; if the polymer reactio were moitored carefully by CD, after polymerizatio of the reactive lactide (Dlactide is active with 9 ad L-lactide is active with 10), the o-polymerized left over could be distilled off uder reduced pressure. owever o such study has yet bee reported. Al ipr But Al tbu ()-9 tbu But (, )-10 ythesis of eterotactic PLA from rac-lactide Achiral catalysts are easier to sythesize ad geerally less expesive tha their chiral couterparts; cosequetly a research priority is to achieve stereocotrolled Z polymerizatios without chiral catalysts. I the polymerizatio of rac-lactide, the bulky ature of achiral catalyst 11 ad the ature of the polymer chai-ed stereoceter were used to ifluece the stereochemistry of the last iserted moomer, which determies the eatiomer echaied. If (, ) cofiguratio is echaied, the isotactic PLA is 11 formed, whereas if the chai ed attacks (, ), the heterotactic PLA forms. Complex = ipr 28

5 11 was foud to be highly active i the polymerizatio of rac-lactide with 90% of the likages formed betwee alteratig L ad D-lactide. After 20 mi at 20 o C, 11 polymerized rac-lactide to 95% coversio to PLA with a molecular weight of g/mol ad a polydispersity idex of This material was also a o-crystallie, amorphous complex with a T g of 49 o C; however sice PLA is mostly used i low temperature eviromets, heterotactic PLA seems like a cheap alterative to the use of optically pure L or D-lactide YTEI F PLA FM meso-lactide ythesis of ydiotactic PLA ydiotactic polymers ofte have better properties tha their isotactic couterparts, such as icreased crystallizatio rates ad higher glass trasitio temperatures ad meltig poits. ecet studies have thus targeted the sythesis of sydiotactic PLA with efficiet seterochemical cotrol ad high yields. 15 Previous results by Thakur 21 ad Kricheldork 22 have demostrated low coversio (up to 75 %) of meso-lactide to sydiotactic PLA. The two pathways for the stereoselectivity of this polymerizatio are show i Figure 4. Cosistet attack at the eatiotopic A or B acyl- bod leads to sydiotactic PLA while alteratig attack o B ad A leads to heterotactic PLA. Coates ad co-workers reported that ()-9 exhibits a strog preferece for opeig of meso-lactide at the carboyl group adjacet to the stereogeic ceter, (Figure 5). eterotactic A k BA >>k BB B meso-lactide k B >>k A ydiotactic Figure 4. Differet types of meso-lactide polymerizatio L Al L Al L Al L Al =AlL +1 Figure 5. AlL -catalyzed polymerizatio of meso-lactide 29

6 1 M aalysis of the polymer proved high sydiotactic cotet (96%). The polymer had a T g ad T m of 50.7 ad 149 o C, respectively, which were lower tha the values of isotactic PLA at 60 ad 180 o C. This deviatio was attributed to a lower degree of crystalliity sice 96% of moomer was coverted to sydiotacic PLA. YTEI F ETETACTIC PLA Coates ad co-workers were iterested i determiig if sydiotactic PLA could be sythesized with a optically impure catalyst, rac-9. They foud that the reactio gave amorphous heterotactic polymer with a T g = 43.2 o C (Figure 6). The 1 M spectrum revealed heterotactic PLA. The authors have previously reported that ()-9 prefers to attack the carboyl closest to the stereoceter. After iitiatio, the polymer chais switch eatiomeric alumium catalyst before isertio ito the ext moomer site. Molecular modelig suggests that ()-9 prefers the ceter ad ()-9 prefers the L s Al L r Al L Al L Al ipr ipr Polymer exchage A L Al L Al ipr ipr meso-lactide B epeat A, B L Al L Al ipr ipr Figure 6. ythesis of heterotactic PLA from meso-lactide usig rac-8 ceter. GAIC CATALYT F P F LACTIDE A importat cosideratio i the polymerizatio of lactide is the removal of metal cotamiats, boud to the chai ed before applicatio i resorbable biomaterials. 23 The applicatio of orgaocatalysts to cotrolled lactide polymerizatio would be a highly viable alterative to 30

7 orgaometallic approaches. everal orgaic compouds have demostrated high activity ad eatioselectivity i a umber of commo orgaic trasformatios. edrick ad co-workers were the first to report the use of first orgaic catalyst 4-(dimethylamio)pyridie (DMAP), 12, i the P of lactide. 23 The catalytic cycle for 12 (cheme 1a) ad -eterocyclic carbee (C) 13 (cheme 1b) are show. Iitiatio occurs whe a alcohol reacts with the lactide-orgaic catalyst complex, leavig a CF 3 termial -hydroxyl group to act as a ucleophile to F 3 C react with additioal lactide moomer. igh coversios of up to 99% i two hours were obtaied with C 13. Thiourea-amie catalyst 14 has also bee used but the P occurs by a differet catalytic mechaism. Thiourea-amie 14 -bods to the carboyl oxyge through 25 the thiourea ad the alcohol iitiator is directed to attack the acyl-oxyge bod by the tertiary amie. cheme 1. Proposed mechaism of P of Lactide with 12 ad 13. (a) DMAP DMAP (b) Mes Mes Mes Mes C These orgaic catalysts are relatively iexpesive ad highly active, ad they yield PLA with low PDI because they are livig polymerizatios. 23 rgaocatalysts provide attractive substitutes for the P of lactide for biomedical ad evirometal applicatios. 26 CCLUI AD FUTUE WK PLA has recetly attracted much attetio as a biodegradable polymer for the replacemet of oilbased material. everal differet types of PLA have bee sythesized with high stereoregularity ad i high yield. More recet work has bee devoted to the sythesis of orgaocatalysts because they are less 31

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