\\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Title-R1d.png Petr Beňovský ENVIRONMENTAL ASPECTS \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png GREEN CHEMISTRY, SUSTAINABLE CHEMISTRY The design of chemical products and processes that reduce or eliminate the use or generation of hazardous substancese; Systematically pursued from the 90s of the 20th century; 1952 – Upjohn – the synthesis of cortisone – just 10 step synthesis of cortisone using fermentation for a key hydroxylation reaction at position 11 of progesterone \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png GREEN CHEMISTRY METRICS Atom Economy Trost, B. Science 254, 1471 (1991) Characterizes the “greeness“ of a synthetic process by calculating the number of atoms from all of the reactants that make it into the final product; Does not address the hazard, reaction yield, stoichiometry, the amount of solvent, … % Atom Economy = Molecular weight of the product / Molecular weight of all products x 100 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png GREEN CHEMISTRY METRICS Environmental Factor, E-Factor The ratio of waste over product It is usual to calculate E-factor without process water E-Factor = the amount of waste (kg) / the amount of the product (kg) Industry Segment Volume (t/y) E-Factor Oil Refining 106 - 108 < 0.1 Bulk Chemicals 104 - 106 < 1 - 5 Fine Chemicals 102 - 104 5 - 50 Pharmaceuticals 10 - 102 25 - 100 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png GREEN CHEMISTRY METRICS Reaction Mass Efficiency (RME) The idea is to keep the simplicity of the atom economy concept, but avoid the high impact of solvents which are found in the E-factor; RME takes into account reaction yield, stoichiometry and the use of catalysts or other reagents; % Reaction Mass Efficiency = Mass of desired product / Mass of all reactants x 100 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png GREEN CHEMISTRY METRICS Process Mass Intensity (PMI) PMI measures the mass of materials used to make 1 kg of the API % Process Mass Intensity = Mass of all material used to make the product (kg) / Mass of product (kg) x100 Allows companies to benchmark and quantify improvements to the efficiency and sustainability of their production Reasonable target of a single synthetic step is any value between 10 and 40 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png GREEN CHEMISTRY METRICS Process Mass Intensity (PMI) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png IBUPROFEN EXAMPLE Originator – Boots Group (1960s) Original name – Brufen (Aspro, Panadol, Nurofen) Generic names – Motrin, Advil, Nuprin, Ibalgin Sold as the racemate despite the fact that (S)-(+)-Ibuprofen is the active form; Fast epimerization in vivo \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png IBUPROFEN EXAMPLE Original synthesis – overall yield 40% Annual production in Great Britain 3000 tones \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png IBUPROFEN EXAMPLE New synthesis – BHC company (1990) Overall yield 77% Presidential Green Chemistry Challenge Greener Synthetic Pathways Award v roce 1997 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png BIOCATALYSIS Myths of biocatalysis: •Expensive •Unstable •Not readily available •Sensitive to reaction conditions •Not good enough or wrong selectivity •Give poor volumetric productivity •Difficult work-up Nowadays, all of them are mostly wrong \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png BIOCATALYSIS Hudlicky, T. et al J.Am.Chem.Soc. 116, 5108 (1994) Microbial oxidation using bacterial dioxygenase \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png BIOCATALYSIS 2018 – Nobel Prize for directed evolution of enzymes (Frances H. Arnold) Iterative change of amino acids in the enzyme until the desired property (acitivity, stability, selectivity) is achieved; Directed evolution mimics the processes of Darwinian evolution in a test tube \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png BIOCATALYSIS Bornscheuer, U.T. et al Angew.Chem.Int.Ed. 43, 6032 (2004) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png BIOCATALYSIS https://www.youtube.com/watch?v=up5QUdTLsBU&feature=youtu.be CODEXIS \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png BIOCATALYSIS CODEXIS \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png BIOCATALYSIS CODEXIS Atorvastatin (Lipitor®) 2006 – Presidential Green Chemistry Challenge Award Substantial waste reduction Overall yield > 90% Purity > 98% ee > 99.9% Low loading of enzymes Solvent recycling E-Factor is 5.8 (without used water) E-Factor is 18 (with used water) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png GREEN CHEMISTRY, SUSTAINABLE CHEMISTRY Ryoji Noyori “Green chemistry is not just a mere catch phrase; it is the key to the survival of mankind“