1. Imperial College London Lecture 8 Biorenewable Polymers 2: The Stereoselective Polymerisation of Lactide Dr. Ed Marshall Rm: M220, Mezzanine Floor, RCS 1 e.marshall@imperial.ac.uk www.ch.ic.ac.uk/marshall/4I11.html 4I-11 - Lecture 8 - Slide 1 4I-11 Case studies in Inorganic Chemistry

2. Every step is reversible. Coordinative-insertion Mechanism Imperial College London Recap of Lecture 7: Mechanism of propagation 4I-11 - 8 - 2

3. Imperial College London Last lecture 4I-11 - 8 - 3 (salen)Al(OR) and derivatives convert rac-lactide into isotactic poly(lactide) Product is believed to be a stereoblock copolymer, with short sequences of all R alternating with short sequences of all S (as opposed to a stereocomplex, formed from complete all R chains and all S chains) correct structure incorrect structure

4. Imperial College London Remaining learning outcomes Over these two lectures you should acquire the knowledge to allow you to: 1. Describe why the polymerisation of lactide is so intensely researched. 2. Explain how chiral and achiral (salen)-supported Al complexes may be used to prepare isotactic and syndiotactic polylactide. 3. Explain how  -diketiminate supported complexes of Zn and Mg may be used to prepare heterotactic polylactide. 4. Understand how computational chemistry may be used to investigate polymerisation mechanisms and to shed light onto the causes of stereoselectivity. 4I-11 - 8 - 4

5. Imperial College London  -Diketiminate ligands diketimine canonicals: Deprotonation results in a monoanionic bidentate ligand - known as NacNac or BDI. e.g. Ar = 2,6-diisopropylphenyl [(BDI)Mg i Pr] 4I-11 - 8 - 5 Dalton Trans. 2003, 3088 - WebCT Gibson2003.pdf

6. R = i Pr, P r = 0.90 R = n Pr, P r = 0.76 R = Et, P r = 0.79 Imperial College London First report of heterotactic PLA Coates rac-LA CH 2 Cl 2 25 °C (S) (R) Heterotactic PLA 100 equiv rac-LA consumed in 20 mins Highly stereoselective - P r = 0.90 (0.94 at 0 °C) steric bulk of i Pr groups is essential for stereocontrol 4I-11 - 8 - 6 J. Am. Chem. Soc. 2001, 123, 3229 - WebCT Coates2001.pdf

7. Under the same conditions - i.e. CH 2 Cl 2, 25 °C - [(BDI)Mg(  -O i Pr) 2 ] gives atactic PLA Imperial College London The Mg analogue rac-LA THF 25 °C Heterotactic PLA, P r = 0.90 Chisholm But the Mg initiator is heteroselective in coordinating solvents: 4I-11 - 8 - 7 Inorg. Chem. 2002, 41, 2785 - WebCT Chishiolm2002.pdf

8. Imperial College London However, magnesium BDI initiators can be heteroselective NMR studies reveal that in THF, the Mg-propagating species is mononuclear, but in CH 2 Cl 2 it is dimeric. The Zn analogue is monomeric even in CH 2 Cl 2 : Heterotactic PLA formed when the propagating species are mononuclear Propagating Mg species in THF Propagating Zn species in CH 2 Cl 2 4I-11 - 8 - 8 J. Am. Chem. Soc. 2005, 127, 6048 - WebCT Rzepa2005.pdf

9. Imperial College London Computational studies Goals of this project: to understand the mechanism of ring-opening better. to explain why the Mg and Zn initiators give heterotactic PLA. to explain why reduction in the N-aryl ortho substituents (e.g. from i Pr to Et) leads to a loss in stereoselectivity. Method employed: (i) Reaction coordinate mapped out for the insertion of two LA units (LA1 and LA2) using (BDI)Mg(OMe)(THF) as the initiator. (ii) Free energies of competing transition states (i.e. R,R or S,S-lactide insertion) calculated. All calculations performed at a very high level [B3-LYP 6-311G(3d)] - many of the calculated geometries took 7 - 10 days to converge. 4I-11 - 8 - 9

10. Imperial College London The Reaction Coordinate - calculated for LA1 = (R,R) & LA2 = (S,S) Two transition states, TS1 and TS2 TS2 is higher in energy than TS1 4I-11 - 8 - 10

11. Imperial College London Revised mechanism TS1: Formation of new M-O bond and cleavage of M-OR bond TS2: Formation of new M-O bond and cleavage of heterocycle Both transition states involve bond breaking / forming 4I-11 - 8 - 11

12. Imperial College London Computing the origin of stereocontrol Although initially calculated for LA1 = R,R-lactide and LA2 = S,S-lactide, we have to consider several other possible assemblies. Total number of assembly modes: LA1 = R,R or S,S; LA2 = R,R or S,S; LA2 may approach either face of the ring-opened LA1 8 possibilities However, the 8 possible assembly modes exist as 4 enantiomeric pairs: 4I-11 - 8 - 12

13. Imperial College London e.g. Consider the approach of S,S-LA2 to R,R-LA1 8 possible assembly modes = 4 enantiomeric pairs ∴ only 4 calculations required S S S S R R R R mirror image 4I-11 - 8 - 13

14. Imperial College London Curtis-Hammett Principle Since every stage of the ring-opening mechanism is reversible, the product distribution (i.e. whether R,R or S,S lactide is inserted) depends only on the competing geometries for the rate-determining step. Calculated transition state free energies (kcal mol -1 ): LA1LA2TS1TS2 RR 13.520.2 SS 6.725.4 RRSS10.518.9 SSRR12.528.1 In every case TS2 is rate-determining Therefore, the reason for heterotactic stereocontrol must lie within the four competing geometries for TS2 - RR,RR - SS,SS - RR,SS - and SS,RR. lowest barrier for heterotactic PLA 4I-11 - 8 - 14

15. Imperial College London Competing TS2 geometries - the origin of stereocontrol RR,SS: 18.9 kcalmol -1 4I-11 - 8 - 15

16. Imperial College London Competing TS2 geometries - the origin of stereocontrol RR,SS: 18.9 kcalmol -1 RR,RR: 20.2 kcalmol -1 4I-11 - 8 - 16

17. Imperial College London Competing TS2 geometries - the origin of stereocontrol SS,RR: 18.9 kcal mol -1 RR,RR: 20.2 kcal mol -1 SS,SS: 25.4 kcal mol -1 4I-11 - 8 - 17

18. Imperial College London Competing TS2 geometries - the origin of stereocontrol SS,RR: 18.9 kcal mol -1 RR,RR: 20.2 kcal mol -1 SS,SS: 25.4 kcal mol -1 SS,RR: 28.1 kcal mol -1 Heterotactic PLA formed via LA1= R,R and LA2 = S,S. Next R,R then inserts via the enantiomer of the SS,RR transition state 4I-11 - 8 - 18

19. Imperial College London Summary of the origin of stereocontrol 4I-11 - 8 - 19 Heterotactic PLA formed via LA1 = R,R and LA2 = S,S. R,R-LA3 then inserts via the enantiomer of the SS,RR transition state

20. Imperial College London Conclusions Heterotactic PLA may be prepared using  -diketiminate Zn and Mg alkoxides, but the Mg initiators must be used in THF. The propagating species responsible for heterotactic PLA formation is mononuclear. Computational analysis reveals that the rate determining step is TS2, i.e. the cleavage of the monomer heterocycle. Heterotactic PLA arises because of the minimisation of Me - Me steric clashes in the competing geometries of TS2. 4I-11 - 8 - 20