ChiralIonic Liquids. An Adolescent Technology. Jeremy Henle 1/24/12

Transcription

1 ChiralIonic Liquids An Adolescent Technology Jeremy Henle 1/24/12

2 Strategies in Asymmetric Synthesis Chiral Induction Starting Materials Chiral Catalysts Chiral Solvents Enantioenriched Chiral Auxillaries ChiralIonic Liquids

3 ChiralSolvents What does the actual solvent look like? What role do solvents play in the course of asymmetric reactions? Can solvents convey chiral information?

4 Molecular ChiralSolvents Advantages Hypothesized generality Potential for asymmetric unimolecular reactions Disadvantages Cost Complicated synthesis Reusibilityissues with molecular solvents Separation of products nly example: 10-20% ee, 40% in fortuitous cases Asymmetric Grignard Solvent Seebach, D., et al.,rganic Syntheses, Coll. Vol. 7, p.41 (1990); Vol. 61, p.24 (1983). Ionic liquids minimize these disadvantages!

5 Ionic Liquids Molten Salts NaCl, KCl, etc. High melting points When liquid, very viscous Corrosive Rarely useful to use 800 C molten salt in organic synthesis Ionic Liquids Low melting points (< 100 C) Manyliquid at room temperature Variable viscosities Designed solvent Reactivity also controlled

6 Ionic Liquids Known since the 1920s MP: 8 C Sugden, S.; Wilkins, H. JCS. (1929) Chloroalluminate ILs discovered in the late 1940s MP: 40 C Hurley, F. H.; Wier, Jr., T. P. J. Electrochem. Soc. (1951), 98, 207. Did not become widely useful in organic until the 1990s: neutral ILs MP: 15 C Wilkes, J. S.;Zaworotko, M.J.JCSCC. (1992), 965.

7 Ionic Liquids Common cations Common anions Cl -, Br -, BF 4-, PF 6-, SbF 6-, N 3-, CH 3 C 2-, CF 3 C 2 -

8 Ionic Liquids as rganic Solvents Substitute for polar/aqueous solvent systems But can be used with water sensitive substrates Stabilize charged intermediates Wide liquid phase temperature range Non-volatile Designer solvents Ease of product separation More expensive, but recyclable

9 Ionic Liquids in rganic Synthesis Hydrogenation C-C Coupling Chauvin, Y., et. al. ACIEE. (1995), 34, Mathew, C. J.; Smith, P. J.; Welton, T. Chem. Comm. 2000, 1249

10 Ionic Liquids in rganic Synthesis Baylis-Hillman Increased rate explained by association of IL with zwitterionic intermediate

11 Ionic Liquids in rganic Synthesis Diels-Alder Reactions Increased endo:exo selectivity (favoring endo) ILs act as lewisacids Can be used in conjunction with lewis acid Can be used in conjunction with lewis acid additives

12 Ionic Liquids in rganic Synthesis Diels-Alder Selectivity Endo:exo ratio similar to polar organic solvents MeH: 6.7, Acetone: 4.2 Aggarwal, A., et al. Green Chem. 2002, 4,

13 ChiralIonic Liquids Ideal candidates for chiral solvent system Easily synthesized, usually using members of the chiral pool of natural products More polymeric/highly ordered than molecular solvents Requires interaction for transmission of chiral information Consist of at least one chiral ion Chiral Cations Chiral Anion Doubly Chiral CILs

14 ChiralCations Ammonium Cations Imidazolium cations Pyridinium cations Gaumont, A-C., et al. Catalytic Methods in Asymmetric Synthesis: Advanced Materials, Techniques, and Applications

15 ChiralAnions Lactate based Amino acid based anions Tartrates, Sugars, Etc. Gaumont, A-C., et al. Catalytic Methods in Asymmetric Synthesis: Advanced Materials, Techniques, and Applications

16 Doubly ChiralIonic Liquids

17 Current Development Strategies with CILs As chiral solvents Achiral catalysts, stoichiometric reactions Chiral co-solvents and additives pockets of chirality rganocatalysts Attach organocatalytic moeities to ILs IL supported transition metal ligands

18 CIL as ChiralSolvent Initial Examples Asymmetric Baylis-Hillman First to achieve higher than 25% ee using chiral solvent 44% ee, 60% yield Demonstrated that H necessary for induction Hydrogen bonding

19 CIL as ChiralSolvent Initial Examples Asymmetric Aza-Baylis-Hillman Utilizing chiral anions, achieving up to 84% ee Comparable to contemporary catalysts H + [MtA + ] H Br Ts N + Me B PPh 3,rt,24h Br Ts HN Me 39%yield,84%ee Leitner,etal.Angew.Chem.Int.Ed.2006,45,2689

20 CIL as ChiralSolvent rigin of Stereoselectivity in Baylis-Hillman Close association of the chiralionic liquid with the zwitterionic intermediate

21 CIL as ChiralCo-solvent First Michael addition with CIL Further work begins to couple CILs with transition metal catalysis

22 CIL as ChiralSolvent Transition Metal Catalysis Utilizing close ion pairing

23 Extending hydrogenation CIL as ChiralSolvent Transition Metal Catalysis N H C 2 Me H 2,[Rh(cod) 2 ]BF 4 ligand,cil,tea(20eq) N H C 2 Me 99% yield 69%ee K 3 S PPh 2 PPh 2 C 2 Me N H 2 (CF 3 S 2 ) 2 N - K 3 S ligand Reused up to 5 times without reloading catalyst/solvent Pro-atropoisomericligandconveys chiralinformation from CIL to active complex CIL Leitner, W., et al. Chem. Commun. 2007, 4012

24 CIL as ChiralSolvent Transition Metal Catalysis Sharpless Dihydroxylation R nhex NHnHex N N nhex Ph nhex H C K 2 s 2 (H) 4 (0.5mol%),NM rt,24h Industrial Scalability R H H R=n-Bu,yield95%,85%ee R=Ph,yield92%,72%ee L.C.Branco,P.M.P.Gois,N.M.T.Lourenço,V.B.Kurteva, C.A.M.Afonso.Chem.Commun.2006, Reuse s/cil solution multiple times without purification

25 rganocatalysiswith CILs Proline derived CILs Initial results only on the model system

26 rganocatalysiswith CILs Asymmetric Aldol

27 rganocatalysiswith CILs CIL/IL solvent systems Extending 1,4 addition scope Innovation is using ionic liquid as solvent with CIL as the catalyst Broad range of ketones and nitroalkenes(15 examples)

28 Case Study: Diels-Alder Already known that ILs can enhance rate/selectivity of Diels-Alder reactions

29 Case Study: Diels-Alder First attempts yield poor enantioselectivity < 5% ee observed

30 Case Study: Diels-Alder Me + CIL C 2 Me HN N C10 H 21 90%yield,78:21dr,0%ee H Pernak, J., et al. Tetrahedron Lett. 2006, 47, Me CIL Ph N Ph TMS H N C 8H 17 Ph CF 3 S 3 60%de,0%ee H H H Ph N N Ph CF 3 S 3 68%de,0%ee N H Vo-Thanh,G.,etal.J.rg.Chem.2006,2,18. Vo-Thanh, G., et al. Tetrahedron. 2009, 65, 2260.

31 Case Study: Diels-Alder Combining technologies Combining ILs with chiral transition metal ligands

32 Case Study: Diels-Alder Aza-Diels-Alder Catalyst reusable up to 6 times before any loss of enantioselectivity

33 UnimolecularReactions Low enantioselectivity, but proof of concept Armstrong, D. W., et al. rg. Lett. 2005, 7, 335. Enantioselectivity observed when R = H Ion pairing required for chiral induction

34 Advantages of CIL as Chiral Source Can be used as a chiralsolvent source for certain transformations When paired with metal catalysts, decrease metal loading amounts Remove volatile solvents Ease of product separation/recyclability Industrial scalability Can use CIL within an IL system

35 Future Directions Asymmetric organocatalysis has become main focus However, chiral solvent systems still being investigated PTC solvents, homogenous cosolvents To date, no reasonable improvements over those reported Developing reusable CIL/IL systems Broadening the scope of known transformations Resolving techniques utilizing CIL systems

36 Conclusions ver the past decade, CILs have become more useful in organic synthesis As chiralsolvents, systems still require improvements in practicality However, CILs have been shown to be effective catalysts and However, CILs have been shown to be effective catalysts and additives, warranting consideration in industrial applications