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  1. Afscheidsrede prof.dr. R.A. Sheldonhoogleraar Biokatalyse en Organische ChemieDecember 7, 2007‘E Factors, Green Chemistry and Catalysis:Records of the Travelling Chemist’ 7 december 2007 R. A. Sheldon, Rec. Trav. Chem. 2007, 1, 1

  2. Green Chemistry Green chemistry efficiently utilises (preferably renewable) raw materials, eliminates waste and avoids the use of toxic and/or hazardous solvents and reagents in the manufacture and application of chemical products. Anastas and Warner, Eds, Green Chemistry. Theory & Practice, Oxford U. Press, 1998

  3. Sustainability Meeting the needs of the present generation without compromising the needs of future generations to meet their own needs is the goal “What we need is more imagination not more knowledge” Albert Einstein

  4. Do politicians understand the issues? It’s not pollution that is the problem it’s the impurities in our air and water. Dan Quayle

  5. + Cr2 (SO4)3 + 2KHSO4 + 9FeCl2 + 3NH4Cl + CO2 +8H2O 392 272 1143 160 44 144 byproducts Phloroglucinol Synthesis CH3 COOH O2N NO2 O2N NO2 H2N NH2 HO OH K2Cr2O7 Fe/HCl aq.HCl D - CO2 T H2SO4 / SO3 NO2 NO2 NH2 O H TNT phloroglucinol Ca. 40kg of solid waste per kg phloroglucinol HO OH O H MW = 126 Atom Utilisation = 126/2282 = ca. 5% E Factor = ca. 40 product “ To measure is to know ” Lord Kelvin

  6. Oxygen utilisation (1990) Syn gas utilisation (1983) Oxidant % Active O Byproduct H2O2 47 H2O t-BuOOH 18 t-BuOH CH3COOOH 22 CH3COOH NaOCl 22 NaCl KIO4 KIO3 2 CO + 3 H2 HOCH2CH2OH 100% 2 CO + 4 H2 H2C=CH2 + 2H2O 44% CH3 HC=CH2 + Cl2 + H2O CH3CH(OH)CH2Cl + HCl O Ca(OH)2 25% atom utilisation + CaCl2 + H2O CH3HC CH2 2. PO : Catalytic Oxidation O CH3HC=CH2 + H2O2 76% atom utilisation + H2O CH3HC CH2 “Atom for Atom” Atom utilisation (1991) 1. PO : Chlorohydrin process See Chem. Eng. Progr. 1991, 87(12), 11 See also Trost, Science, 1991, 254, 1471

  7. E Factors E Factor = kg waste/kg product Tonnage E Factor Bulk Chemicals 104-106 <1 - 5 Fine chemical Industry 102-104 5 - >50 Pharmaceutical Industry 10-103 25 - >10 [i] “Another aspect of process development mentioned by all pharmaceutical process chemists who spoke with C&EN, is the need for determining an E Factor”. A. N. Thayer, C&EN, August 6, 2007, pp.11-19. R.A.Sheldon, Chem &Ind, 1992, 903 ; 1997, 12

  8. I Factor = 4.19 R. A. Sheldon, Green Chem, 2007, 9, 1273-1283

  9. The E Factor • Is the actual amount of all waste formed in • the process, including solvent losses and waste • from energy production • (c.f. atom utilisation is a theoretical nr.) • E = [raw materials-product]/[product] • A good way to quickly show (e.g. to students) the • enormity of the waste problem • Undergraduate Course : “Green Chemistry & • Sustainable Technology”

  10. Major Sources of Waste • STOICHIOMETRIC ACIDS & BASES • STOICHIOMETRIC OXIDANTS & REDUCTANTS • - Na2Cr2O7, KMnO4, MnO2 • - LiAlH4, NaBH4, Zn, Fe/HCl • SOLVENT LOSSES • - Air emissions & aqueous effluent

  11. The Solution is Catalytic • Substitution of conventional Bronsted & Lewis acids • by recyclable,non-corrosive solid acids e.g zeolites • Atom efficient catalytic processes: • -hydration (H2O)reduction (H2),oxidation (O2 ,H2O2) • -carbonylation (CO),hydroformylation (CO/H2) • -amination (NH3), reductive amination (NH3 /H2) • with olefins and (alkyl)aromatics as raw materials • Alternative reaction media / biphasic catalysis • Biocatalysis, naturally

  12. Novel Media O2 H2O2 CO H2 H2O Enzymes Renewables Cascades Chirotechnology Research Themes Catalysis & Green Chemistry Sheldon, Arends and Hanefeld , Green Chemistry And Catalysis, Wiley, New York, 2007

  13. Heterogeneous Catalysis

  14. Peroxometal mechanism 1973 Shell SMPO process 1973 O H O H M O M O + O T i ( I V ) / S i O2 O O + R O H + R O O H R R Sheldon, Rec.Trav.Chim.Pays-Bas, 92, 253, 1973 Sheldon and van Doorn, J.Catal. 31, 427, 1973 Mimoun, Sharpless Pd/Pt (4nm) H2 + O2 H2O2 TS-1 O H2O2 + + H2O MeOH TS-1 O H2O2 + + H2O MeOH Enichem 1985 Headwaters/Evonik 2006 Ti-beta, Ti-MCM41, Ti-ITQ, etc van Bekkum, Corma Dakka, Sato, LeBars Redox Molecular Sieves (Zeozymes) Metal Catalyzed Epoxidation

  15. A m m o x i m a t i o n B e c k m a n n r e a r r a n g e m e n t Green Caprolactam Process : Sumitomo v a p o u r O NOH H2O2 / NH3 NH p h a s e O T S - 1 H i g h S i MFI C6H10O + H2O2 + NH3 C6H11NO + 2H2O Atom efficiency = 75% ; E = 0.32 (<0.1) O NOH (NH3OH)2SO4 NH H2SO4 O Atom efficiency =29% ; E = 4.5 Ichihashi and Kitamura,Catal.Today, 73, 23, 2002

  16. Redox Molecular Sieves :Philosophers’ Stones or Trojan horses ? Filtration Test for Heterogeneity: 60 50 40 30 conversion (%) 20 hot cold 10 0 0 30 60 90 120 150 180 Time (min) Lempers (1998) Chen (1995), Elings (1997), Plyuto, Schuchardt Sheldon, Wallau, Arends and Schuchardt, Acc. Chem. Res., 31 (1998) 485-493.

  17. Homogeneous Catalysis

  18. Catalysis in Non-conventional Reaction Media Two challenges : • Toxicity and/or hazards of atmospheric and • ground water pollution by conventional solvents • Separation/recycling of homogeneous catalysts • (Biphasic) catalysis in non-conventional media • - water • - supercritical carbon dioxide (Martyn Poliakoff) • - ionic liquids (Ken Seddon) • - fluorous biphasic (Istvan Horvath) “The best solvent is no solvent”

  19. OH Pd / tppts /H+ CO COOH Ibuprofen Aqueous Biphasic Cataysis 2. Aerobic Oxidation 1. Carbonylation R2 H + 0 . 5 O2 R1 O H Pd2+/ L air OH O R R 2 R Pd2+ L water + H2O O 1 R NaO3S S O3 N a P NaO3S S O3Na tppts S O3Na N N Papadogianakis, Verspui (2001) Moiseev ten Brink (2001) ten Brink, Arends, Sheldon, Science 287 (2000) 1636

  20. Catalysis in Ionic Liquids • Negligible vapour pressure • Designer solvents • Catalytic hydroformylation, • carbonylation, hydrogenation • and biocatalysis R2 OH + + + + N N OH N N N OH R3 R R1 R N + R4 OH R Anions : B F4 , P F6 , R C O , H2 P O4 , N O3 , H O C H2 C O2 2 O O O OH O OH + + OH NH2 O O CaLB in [bmim][BF4] and [bmim][PF6] O Madeira Lau (2003) Seddon RCOOOH RCOOH Product recovery? H2O2 H2O Madeira Lau, van Rantwijk, Seddon, Sheldon, Org.Lett. 2, 4189, 2000 Sheldon, Chem. Comm. 2001, 2399-2407

  21. OAc In situ product removal with scCO2 scCO2 phase OH OAc lipase IL phase scCO2 as mobile phase in batch or continuous operation Reetz et al,Chem.Comm.,2002, 992 Lozano et al,Chem.Comm.,2002, 692

  22. The Miscibility Switch Reactant Carbon dioxide CO2 + Product IL + Catalyst + Reactant + CO2 P  P  P  CO2 CO2 IL + Catalyst + Product + IL IL Ionic liquid + catalyst Product High pCO2 one phase Low pCO2 two phases Reaction Separation Peters & Witkamp

  23. Organocatalysis

  24. O. O. • No solvent • No Br- • NaOCl • Recyclable • Cheap raw • material • Chimassorb 944 N N N R1 . R1 OH O + “O” N N N O + H2O (CH2)6 H CH2Cl2/ H2O R2 R2 N N 5 “O” = NaOCl, m-CPBA, oxone (+ Br -) NH(tert-octyl) PIPO van Bekkum et al , Synthesis, 1996, 1153 Cu(II) / PIPO / O2 Dijksman (2001) N . O TEMPO Laccase : a multicopper oxidase O TEMPO (5m%) OH H l a c c a s e O RCH2OH + 0 . 5 O 2 2 N . Cu(II) / bipy (5m%) Base / MeCN / H2O O + RCHO H O N l a c c a s e 2 o x Gamez O Li (2004), Matijosyte de Vries/Hagen Organocatalytic Oxidations

  25. subtilisin phytase CaLB CPO laccase HNlase Biocatalysis Inventing New Enzymes & Enzymatic Reactions

  26. Why Biocatalysis? • Mild conditions: ambient temperature & • pressure in water • Enzymes are derived from renewable sources • and are biodegradable • High rates & highly specific : substrate, • chemo-, regio-, and enantiospecific • Higher quality product • Green Chemistry (environmental footprint)

  27. BASF Process NH2 NH2 Lipase O O O ee > 99% (S) + O NH2 O NH NaOH glycol-water (2:1), 150oC ee > 99% (S) ee > 99% (R) > 3000 tpa Enzymatic Ammoniolysis R O O R Nu NuH Ser O Nu = OH, OR, NH2 , RNH, OOH, etc O O NH3/t-BuOH R R OEt NH2 lipase, 40oC • Green amide synthesis • Enantioselective with • amino acid esters Steverink(1995), Hacking (1999) Wegman(2001) If you want to find something new you have to DO something new Edward De Bono

  28. O O 100 NH2 90 H N O 80 70 60 % yield (amide) CaLB, 50oC, 96h 50 40 Kinetic resolution 30 Nano Pd 20 Dynamic kinetic NH2 10 resolution - 88 % yield (4 days) - ee product 98 % . 0 0 20 40 60 80 100 120 time (h) H.Ismail(2007) Easy-on-easy-off resolution NHCOCH2Ar NH2 H2O NH2 P h ArCH2COX P h p e n a c y l a s e + P h p H 7 e e > 9 9 % p e n a c y l a s e NH2 p H 1 0 - 1 1 e e > 9 9 % P h V.Svedas L.van Langen(2001), R.Madeira Lau(2003), H.Ismail(2007) Dynamic Kinetic Resolution Pd –catalyzed racemization of 1-phenethylamine : Murahashi (1983) ; Reetz , DKR (1996).

  29. O A sp O H H N N H A r g O 2 A r g H N N O H H N 65% ee V N H O O H i s N N H 2 H N L y s H i s van de Velde Aksu-Kanbak Correia vanadate phytase H2O X H2O2 O Linker S e O O O H O X X Se Se OH OOH X = N O , C F 2 3 X = N O , C F Ser 2 3 O O subtilisin van der Toorn R2 R1 R2 R1 O ten Brink (2001) O C P O ArSCH3 H2O2 H2O + S + A r C H3 N N 99% yield >99% ee FeIII N N S C y s van Deurzen (1996) van de Velde (2000) Heme Low stability Inventing New Enzymes : Chemomimetic Biocatalysis

  30. Historically: Adapt Process to fit Catalyst Available Catalyst Dream Process

  31. Future: Adapt Catalyst to fit Ideal Process EVOLVE Catalyst Adapted Catalyst Dream Process Nightmare Process Compromise process to accommodate catalyst Adapt catalyst to optimum process Directed Evolution BOC HTS (directed evolution lab.) L.Otten

  32. gene A Genes From Nature gene B gene C gene D DNA ShufflingTM Library of Novel Genes Repeat HTP Screening DNA Shuffling : Evolution in the Fast Lane Novel Genes Stemmer,Nature,370, 389-391, 1994; Huisman et al (Codexis) See also Reetz, Advan. Catal. 2006, 1-69.

  33. O O OH O KRED Cl Cl OEt OEt 9 9 % ee > NADP+ NADPH g l u c o n a t e g l u c o s e GDH OH O OH O a q . NaCN , pH 7 Cl NC OEt OEt HHDH (>99.9% ee) Green Synthesis of Lipitor Intermediate (Codexis) Presidential Green Chemistry Challenge Award 2006 KRED = keto reductase ; GDH = glucose dehydrogenase HHDH = halohydrin dehalogenase (non-natural nucleophile) Nature Biotechnol. 2007, 25, 338-334 Huisman, Grate, Lalonde et al (Codexis)

  34. 1. KRED + GDH Parameter Process Design Initial Performance Final Performance Substrate loading 160 g/L 80 g/L 180 g/L Reaction time <16 hrs 24 hrs 8 hrs Enzyme loading <1 g/L 10 g/L 0.7 g/L Isolated yield >90% ~80% 97% Phase separation time >1 hr ~1 min. Volumetric Productivity >240 g/L.day 80 g/L.day 540 g/L.day 2. HHDH Parameter Process Design Initial Performance Final Performance Substrate loading 120 g/L 20 g/L 140 g/L Reaction time <16 hrs 72 hrs 5 hrs Enzyme loading <1.2 g/L 130 g/L 1.2 g/L Isolated yield >90% ~60% 92% Volumetric Productivity >180 g/L.day 7 g/L.day 670 g/L.day Improving Performance by Directed Evolution: test tube to commercial process with gene shuffling

  35. Disadvantages of Enzymes • Low operational stability & shelf-life • Cumbersome recovery & re-use • (batch vs continuous operation) • Product contamination Solution : Immobilization

  36. Cross-Linked Enzyme Aggregates (CLEAs) X-linker precipitant aggregate CLEA - Enzyme in solution glutaraldehyde or dextran polyaldehyde as X-linker • Enables recycling via filtration • Higher productivity • No need for highly pure enzyme • Simple procedure / widely applicable • Stability towards denaturation • CLEAS active in: • scCO2 (M. Poliakoff) • ILs (Sheldon) Sorgedrager (2006), Janssen (2006 ) (CLEA Technologies B.V.)

  37. Examples of Successful CLEAtion • Hydrolases • Pen. acylases (2) • Lipases (7) • Esterases (3) • Proteases (3) • Nitrilases (2) • Aminoacylase • Phytase • Galactosidase • Oxidoreductases • ADH • FDH • Glucose oxidase • Galactose oxidase • Laccase • Catalase • Chloroperoxidase • Lyases • R- & S- HnLases • PDC • DERA • Nitrile hydratase Cao, Lopez-Serrano, Mateo, Perez, van Langen, Sorgedrager Janssen, Bode, van Pelt, Chmura, Matijosyte, Aksu-Kanbak, Evolution vs Cleationism

  38. 5 a t m H2 amidase OCH3 OCH3 OH O N O N H N 0 , 4 % cat. 2 H H O O O Catalyst : Rh(monophos) on TUD-1 99% yield / 95% ee 97% yield / > 99% ee Simons (2007) PS- I H O RCO2OH H 2 2 O H lipase H O O RCOOH PS- I(O2CR)2 2 Kotlewska Catalytic Cascade Processes

  39. Trienzymatic Cascade with a Triple-Decker combi CLEA OH CONH2 OH H2O CN O Pen G amidase HCN /(S)-HnL NLase OH COOH Conv. 96% / ee >99% Chmura, Stolz

  40. Renewables & Green Chemistry : the Biorefinery Fuels CO2 + H2O photo- Biomass Polymers synthesis Bulk & Fine Chemicals Greener products Emons (1992), Arts(1996), Papadogianakis Metrics for renewables ?

  41. Carboxystarch : Safe & Natural Absorbing Polymer (SNAP) OH H H COOH Laccase CLEA TEMPO/O2 H [ H [ O O O O H HO H HO H H OH OH H O H O ] ] n n starch c a r b o x y s t a r c h • Non- toxic & biodegradable • Green (bio) catalytic process • Green raw materials Boumans (TNO) The plan is nothing, the planning is everything Mao Zedong

  42. Enantio- selectivity Environment Elegance Economy E The E Factor Think Green It’s better to travel one mile than to read a thousand books Confucius

  43. So it goes…………

  44. Collaboration & Funding EU IOP Katalyse IOP Koolhydraten Hoechst Celanese

  45. behind every successful man there is an astonished woman