1. Catalyddion Aml-Ochrog mewn Hylyfoedd Uwchradd Martyn Poliakoff martyn.poliakoff@nottingham.ac.uk

2. Supercritical Fluids Gases e.g. CO 2, C 2 H 4, H 2 O compressed until they are nearly as dense as liquids SCFs can dissolve solids solubility increases with density (applied pressure)

3. Critical Points PcPc TcTc o C HC 38 H2OH2O 35 65 95 360 390 CO 2 2 C 3 H 8 22 7.4 MPa 4.3 H2OH2O

4. Supercritical Catalysis Catalysis in scCO 2 :- Hydrogenation, Hydroformylation Supercritical Water Biocatalysis

5. Miscibility of H 2 /scCO 2 Howdle, S. M., Healy, M. A., Poliakoff, M. J. Am. Chem. Soc. 1990 112, 4804. Jessop, Ph. G., Ikariya, T., Noyori, R. Nature 1994, 368, 231. T > T c T < T c Liquid H 2 Higher Concentration of “Dissolved” H 2 in scCO 2

6. Continuous Supercritical Hydrogenation scCO 2 CO 2 Product Substrate + H 2 Catalyst

7. Other Hydrogenations successfully carried out in scCO 2 and scPropane

8. continuous multipurpose 1000 ton p.a. scCO 2 Chemical Plant opened July,2002 Thomas Swan & Co

9. Hydrogenation of Isophorone O Pd Deloxan® 100 bar, scCO 2 40-170°C + H 2 O scCO 2 - quantitative, no by-products The product & by-products have similar boiling points Conventional process requires an expensive downstream separation

12. scCO 2 and Ionic Liquids scCO 2 very soluble in ILs (~ 0.6 mole fraction) ILs are insoluble in scCO 2 L.A. Blanchard, D. Hancu, E.J. Beckman and J.F. Brennecke, Nature, 1999, 399, 28 scCO 2 can extract many organics from ILs L. A. Blanchard and J. F. Brennecke, Ind. Eng. Chem. Res., 2001, 40, 287

13. Bi-phasic Catalysis: Cole-Hamilton P. B. Webb, M. F. Sellin, et al. J. Am. Chem. Soc.,2003, 125, 15577

14. Green Chemistry 12 Principles - Prevent wastes - Renewable materials - Omit derivatization steps - Degradable chemical products - Use safe synthetic methods - Catalytic reagents - Temperature, Pressure ambient - In-Process Monitoring - Very few auxiliary substances - E-factor, maximize feed in product - Low toxicity of chemical products - Yes it’s safe PRODUCTIVELYPRODUCTIVELY - Prevent wastes - Renewable materials - Omit derivatization steps - Degradable chemical products - Use safe synthetic methods - Catalytic reagents - Temperature, Pressure ambient - In-Process Monitoring - Very few auxiliary substances - E-factor, maximize feed in product - Low toxicity of chemical products - Yes it’s safe

15. Gas-Expanded Liquids Increasing Pressure Liquid +CO 2 Liquid +CO 2

16. Hydrogenation of α-pinene A. Serbanovic, V. Najdanovic-Visak, A. Paiva, G. Brunner, M. Nunes da Ponte 8th ISSF, Kyoto

17. Gas-Expanded liquids (GExLs) 1. Autoxidation … by O 2 in GExLs, DH Busch, B Subramaniam & co-workers, Green Chem., 2004, 6, 387. 2. Enhanced Solubility of gases in GExLs, JF Brennecke & coworkers, Ind. Eng. Chem. Res., 2006, 45, 5351. 3.CO 2 -Protected Amine Formation in GExLs X. Xie, C. L. Liotta & C. A. Eckert, Ind. Eng. Chem. Res., 2004, 43, 7907.

18. Hydrogenation of Isophorone O Pd Deloxan® 100 bar, scCO 2 40-170°C + H 2 O Reaction has a high space-time yield How is this influenced by the phase behaviour of the system?

19. Isophorone /CO 2 /H 2 phase boundaries OO H2H2 Two phase Operational window Two phase Operational window M. Sokolova Ke Jie

20. CO 2 - expansion & Hydrogenation Increases solubility of H 2 (B. Subramaniam, J. Brennecke) Increases diffusion  faster transport across phase boundary (EJ Beckman) Reduces viscosity All of these accelerate reaction

21. Hydrogenation of sertraline imine in CO 2 –expanded THF

22. Commercial Route to Zoloft ® Batch Process

23. Continuous hydrogenation of rac-sertraline in scCO 2 /THF Investigate both chemoselectivity & diastereoselectivity Aims: (1) < 1.5 % dechlorination (2) > 92:8 de P. Clark

24. Hydrogenation of rac-sertraline imine in scCO 2 /THF Catalystde (%) from NMR cis-trans- 5% Pt/ C5644 2% Pd/ C8713 5% Pd/ CaCO 3 973 System pressure (125-175 bar) has little effect on selectivity (Conditions: 175 bar; 3x excess H 2 ; 0.4 ml/ min org flow; 0.1 M soln in THF; 0.5 g catalyst; 1.0 ml/ min CO 2 flow)

25. Summary Switch from Batch to Continuous Dechlorination is reduced in scCO 2 – why? One of the first examples of diastereoselective hydrogenation in scCO 2 First example of hydrogenation of final stage pharmaceutical in scCO 2

26. Supercritical Catalysis Catalysis in scCO 2 Supercritical Water:- Selective Oxidation, Formation of Caprolactam Biocatalysis

27. Total Oxidation in scH 2 O T c 374 o C; p c 218 atm. At 300 o C, H 2 O is similar to acetone O 2 is miscible with H 2 O above T c Already in commercial use

28. Johnson Matthey + Chematur AquaCat Process for Catalyst Recovery opened Oct 10 th 2003

29. BeforeAfter Heterogeneous Catalyst Recovery

30. Partial oxidation in scH 2 O? Nottingham: P.A. Hamley, E.G. Verdugo, J. Fraga-Dubreuil, C. Yan, E. Venardou, R. Auerbach, R.J. Pulham,T. Ilkenhans, M.J. Clarke, J.M. Webster, M. Thomas, A. Johal. INVISTA Performance Technologies, UK: W.B. Thomas, G.R. Aird, I. Pearson, S.D. Housley, A.S. Coote, K. Whiston, L.M. Dudd, J. Fraga-Dubreuil (ICI D.A. Graham, P. Saxton)

31. 0.7 Mton p.a. per plant TA insoluble in CH 3 COOH 18% of world production of CH 3 COOH lost in the process Oxidation of p-Xylene CH 3 COOH 190 o C CH 3 COOH solvent Mn 2+ /Co 2+, CH 3 COO - /Br - catalysts

33. CH 3 COOH + 3 O 2 + 2 H 2 O TA

34. Oxidation of p-Xylene / scH 2 O p-Xyl Products MnBr 2 catalyst in cold H 2 O scH 2 O + O 2 PA Hamley, et al. Green Chem. (2002) 4, 235; (2005) 7, 294

35. Oxidation of p-Xylene in scH 2 O > 80% yield of TA > 90% selectivity for TA

36. Selective Oxidation in scH 2 O If our results are scalable, total elimination of CH 3 COOH increased energy recovery compared to existing process significant reduction in cost of manufacturing TA

37. EXAFS & Molecular Dynamics Results with 0.4 m MnBr 2 W. Partenheimer, Y. Chen, J. L. Fulton J. Am. Chem. Soc. 127, 14086, (2005)

38. IR spectroscopy in scH 2 O First achieved 1967 (Franck + Roth) Much work by T. B. Brill et al. J. Phys. Chem. (1996) 100, 7455 Recent work by Y. Ikushima et al., Achema, (2003)

39. 4000.0 36003200280024002000180016001400 1200.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.62 cm -1 A FTIR of Water 25 µm pathlength

40. High T & P IR Cell; Yu. E. Gorbaty Changes pathlength Windows Cell body Driving Mechanism 500 o C 1000 bar Inlet

41. Hydrolysis of MeCN 4000.0 3600 3200 2800 2400 0.01 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.13 cm -1 A CNCN N-H O-H 500bar 300ºC H2OH2O

42. High pressure Sample Loop CO 2 Product Reactants Catalyst CO 2 GC Analysis H2H2

43. Raman Spectroscopy Eleni Venardou; Appl. Spectrosc., (2003) 57

44. Raman Spectra of CH 3 CN in ncH 2 O 1000150020002500 2268 938 866 Time 0 30 min CNCN Raman shift / cm -1 no added acid 300 °C, 300 bar

45. CH 3 COOH in water CH 3 CONH 2 in water 50010001500200025003000 Raman shift / cm -1 1680 1140 2268 938 866 Time 0 30 min CNCN Raman Spectra of CH 3 CN in ncH 2 O

46. autocatalysis Hydrolysis of MeCN Effect of Concentration

47. Caprolactam Industrial synthetic route Problem 5 kg (NH 4 ) 2 SO 4 are made per kg CPL (NH 2 OH) 2 SO 4 Oleum Ammoximation Beckmann rearrangement N HO

48. Alternative Synthesis Cheaper feedstock, No cyclohexane oxidation No ammonium sulphate Yan Chong H2OH2O

50. H. Vogel et al. Chem. Eng. Technol. (1999) 22, 494 70% conv. ACN but only 45% yield CPL 400 o C, 4 min. residence time Strategy Study effects of T and p Concentration of feedstock H2OH2O ACN CPL

51. Caprolactam Summary Single-step green process Hydrolysis, SCW Cyclization, SCW 6-Aminocapronitrile, ACN6-Aminocaproic acid amide, ACA CPL  >60% yield of CPL within <2 min  No organic solvent  No additional catalysts C. Yan et al. WO2006078403

52. Supercritical Catalysis Catalysis in scCO 2 Supercritical Water Multiphasic Biocatalysis Helen Hobbs, Neil Thomas

53. Enzymes in Fluorous Biphase Hexane + substrate PFMC + Enzyme 25 ºC Substrate Hexane + Product PFMC + Enzyme 0 ºC Product Enzyme + substrate 40 ºC Enzyme Recycle PFMC Perfluoro- Methyl Cyclohexane

54. How can one dissolve an enzyme in a fluorous solvent (or even scCO 2 )?

55. Hydrophobic Ion Pairing + + + + + + + + Protein - - - - -- --

56. Fluorinated Anionic Surfactant Krytox NH 4 + n ~ 14/2500 KDP NH 4 + n ~ 7/1400 Soluble in Fluorous phase and scCO 2

57. Cytochrome c in aqueous buffer

58. Fluorous Phase added Fluorous + Krytox

59. HIP extraction into the Fluorous Phase But is the enzyme really dissolved?

60. + + ++ + + + + Expected Diameter: 6.8 nm Dynamic Light Scattering Candida rugosa lipase

61. KDP surfactant mw~1400 Expected length: 1.4 nm

62. + + ++ + + + + CRL - - - - - - - - Expected diameter: 9.6 nm (CRL-KDP)

63. Native CRL: 10.1 nm CRL-KDP: 6.5 nm CRL-Krytox: 10.1 nm Diameter (nm) Volume (%) 0 5 10 15 20 0.1110100100010000 CRL Size Distribution By Volume

64. Biocatalysis in Fluorous Biphase

65. CMT-KDP Recycling (FBS)

66. Dissolving Biomolecules Precipitation from aqueous buffer Dissolve in scCO 2

67. Biological Molecules in scCO 2 Cytochrome C

68. Supercritical Catalysis Continuous Reactions: Key aspect of supercritical fluids New Developments: “Green” technologies are not in competition Partnership between Chemists & Chemical Engineers

69. DICE: Driving Innovation in Chemistry & Chemical Engineering EPSRC initiative led by Nottingham to stimulate research at the interface of Chemistry/Chem.Eng 6 new faculty posts in Chem. & Chem. Eng. including 3 joint posts Big opportunities for collaboration particularly with POC at Cardiff

70. P. Clark E Venardou EG Verdugo J Fraga Dubreuil Chong Yan HR Hobbs P. Fields, R. Wilson, M. Guyler INVISTA, Thomas Swan & Co, GSK, ICI EPRSC, Royal Society, EU Marie Curie All our Students, Postdocs and Collaborators P Licence NR Thomas PA Hamley

71. Impact Factor 3.26 www.rsc.org/ Greenchem martyn.poliakoff@ nottingham.ac.uk

72. GSC-3 3rd International Conference on Green & Sustainable Chemistry 1-5 July 2007, Delft, The Netherlands

73. GSC-3 3rd International Conference on Green & Sustainable Chemistry 1-5 July 2007, Delft, The Netherlands Professor Graham Hutchings RSC Green Chemistry Lecturer