Catalyddion Aml-Ochrog mewn Hylyfoedd Uwchradd Martyn Poliakoff

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)

Critical Points PcPc TcTc o C HC 38 H2OH2O CO 2 2 C 3 H MPa 4.3 H2OH2O

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

Miscibility of H 2 /scCO 2 Howdle, S. M., Healy, M. A., Poliakoff, M. J. Am. Chem. Soc , 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

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

Other Hydrogenations successfully carried out in scCO 2 and scPropane

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

Hydrogenation of Isophorone O Pd Deloxan® 100 bar, scCO °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

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

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

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

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

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

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

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

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

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

Hydrogenation of sertraline imine in CO 2 –expanded THF

Commercial Route to Zoloft ® Batch Process

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

Hydrogenation of rac-sertraline imine in scCO 2 /THF Catalystde (%) from NMR cis-trans- 5% Pt/ C5644 2% Pd/ C8713 5% Pd/ CaCO System pressure ( 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)

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

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

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

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

BeforeAfter Heterogeneous Catalyst Recovery

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)

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

CH 3 COOH + 3 O H 2 O TA

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

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

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

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

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)

cm -1 A FTIR of Water 25 µm pathlength

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

Hydrolysis of MeCN cm -1 A CNCN N-H O-H 500bar 300ºC H2OH2O

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

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

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

CH 3 COOH in water CH 3 CONH 2 in water Raman shift / cm Time 0 30 min CNCN Raman Spectra of CH 3 CN in ncH 2 O

autocatalysis Hydrolysis of MeCN Effect of Concentration

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

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

H. Vogel et al. Chem. Eng. Technol. (1999) 22, % 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

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. WO

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

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

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

Hydrophobic Ion Pairing Protein

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

Cytochrome c in aqueous buffer

Fluorous Phase added Fluorous + Krytox

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

Expected Diameter: 6.8 nm Dynamic Light Scattering Candida rugosa lipase

KDP surfactant mw~1400 Expected length: 1.4 nm

CRL Expected diameter: 9.6 nm (CRL-KDP)

Native CRL: 10.1 nm CRL-KDP: 6.5 nm CRL-Krytox: 10.1 nm Diameter (nm) Volume (%) CRL Size Distribution By Volume

Biocatalysis in Fluorous Biphase

CMT-KDP Recycling (FBS)

Dissolving Biomolecules Precipitation from aqueous buffer Dissolve in scCO 2

Biological Molecules in scCO 2 Cytochrome C

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

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

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

Impact Factor Greenchem nottingham.ac.uk

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

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