\\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Title-R1d.png Petr Beňovský SOLVENT SELECTION \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png IMPORTANCE OF SOLVENTS •Reaction medium (transport, combine, separate) •Dissolution •(In)solubility •Kinetics •Health •Safety •Environmental aspects •Course of the reaction •Cost (purchase, recycle, dispose) • \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png PERSPECTIVE ON SOLVENT SELECTION ASPECT COMMENT Safety Avoid solvents that are toxic or highly flammable Promote high-yielding reactions Compatible with desired chemistry; Can isolate product in good yield? Convenient (minimize processing operations) Isolate product from reaction solvent? Operate at high concentrations? Water miscibility Azeotroping ability Control amount of water Cost of bulk and recoverability More important at the end of development cycle Environmental Ethics, and cost of recovery and non-compliance Long-term availability Acceptability for human use Water as solvent But, recovery of product from aqueous layer can be costly, plus cost of disposal Neat reactions Ionic liquids \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT SELECTION GUIDES Almost every company created specific solvent guide SmithKline Beecham – Curzons, A.D. et al Clean Products and Processes 1, 82 (1999) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT SELECTION GUIDES Sanofi – Prat D. et al Org.Process Res. Dev. 17, 1517 (2013) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT SELECTION GUIDES GlaxoSmithKline – Henderson, R.K. et al Green Chemistry 13, 854 (2011) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT SELECTION GUIDES ACS Green Chemistry Institute® Roundtable Solvent Selection Guide, March 2011 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Watch out hydrocarbon solvents with even number of carbons (toxicity, electrostatic buildup); Classification of solvents – ICH Harmonised Guideline Q3C – Impurities: Guideline for Residual Solvents Class 1 – solvents to be avoided (known human carcinogens, strongly suspected human carcinogens, and/or environmental hazards, e.g. carbon tetrachloride (concentration limit 4 ppm), 1,2-dichloroethane (5 ppm), 1,1,1-trichloroethane (1500 ppm), benzene (2 ppm)) Class 2 – solvents to be limited (non-genotoxic animal carcinogens, agents of irreversible toxicity, e.g. acetonitrile (410 ppm), chlorobenzene (360 ppm), chloroform (60 ppm), N,N-dimethylformamide (880 ppm), hexane (290 ppm), methanol (3000 ppm), N-methylpyrrolidone (530 ppm), toluene (890 ppm)) Class 3 – solvents with low toxic potential (permissible daily exposure 50 mg or more per day, e.g. acetic acid, acetone, ethyl acetate, heptane, 2-propanol, triethylamine) Solvents for which no adequate toxicological data was found – a manufacturer is asked to supply justification for residual levels of these solvents (e.g. diisopropyl ether, petroleum ether, trifluoroacetic acid) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS The best reaction solvent is the one that crystallizes the product directly from the reaction; Novartis – the Dimroth rearrangement – temperature and solubility turned out to be the most important – the product simply precipitated from the reaction mixture; Fischer, R.W. Org.Process Res. Dev.5, 581 (2001) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Dyson, P.J.; Jessop, P.G. Catal.Sci.Technol.6, 3302 (2016) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Homogeneous vs. Heterogeneous Reactions using gases Insolubility is sometimes advantageous (the Schotten-Baumann reaction, the Finkelstein reaction) Menshutkin (1890) The reaction rate of the reaction rate of triethylamine with alkyl halides providing quaternary ammonium salts strongly depends on a solvent (hexane 1, acetone 338, benzyl alcohol 739) Solvents commonly used in academia are not often welcomed for industrial applications Safety first ! \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS The Finkelstein reaction The reaction driven to completion by exploiting the different solubility of used and formed halides \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS The Halex reaction \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png MIXING OF HETEROGENEOUS MIXTURES Anderson, N.G. Practical Process Research and Development, A guide for organic chemists, 2nd Edition, Elsevier 2000 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Solvent TWA (ppm) Acetone 500 EtOAc 400 MeOH 200 t-BuOH 100 MTBE 50 MeCN 20 DMF 10 Pyridine 1 2-Methoxyethanol 0.1 TWA = Time-Weighted Average shift for five days for nearly safe exposure over an 8 h shift for five days for nearly all workers \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Also, always consider physical-chemical properties like •Flash point •Flammability •Boiling point •Melting point •Electrostatic charge accumulation •Recycling potential •Cost of solvent •Environmental aspects •Cost of disposal •Polarity \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Solvents rarely used in the pharmaceutical industry Solvent Disadvantage Alternative replacement Diethylether Flammable MTBE Diisopropylether Peroxide formation MTBE Hexane Electrostatic charge Neurological toxicity Heptanes, i-octane Chloroform Mutagenicity, environmental aspects, toxicity Dichloromethane, 2-MeTHF, toluene Benzene Toxicity Toluene Ethylene glycol Toxicity 1,2-Propandiol Acetonitrile Animal teratogen, potential acetamide generation (genotoxic) 2-propanol, acetone - water \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Solvents preferred for process development (Pfizer) Preferred Usable Undesirable Water Cyclohexane Pentane Acetone Heptane Hexanes Ethanol Toluene Diisopropyl ether 2-Propanol Methyl cyclohexane Diethyl ether Ethyl acetate MTBE Dichloroethane i-Propyl acetate i-Octane Dichloromethane Methanol 2-MeTHF Chloroform Methyl ethyl ketone DMSO DMF n-Butanol AcOH NMP t-Butanol Ethylene glycol 1,4-Dioxane Benzene Carbon tetrachloride \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Polarity of solvents Hughes-Ingold rules ((de)stabilization of transition state) Aliphatic nucleophilic substitution and elimination reactions; Considering pure electrostatic interactions between ions or dipolar molecules amd solvent molecules in initial and transition states; \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Hughes-Ingold rules \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Hughes-Ingold rules •An increase in solvent polarity results in an increase in the rates of those reactions in which the charge density is greater in the activated complex than in the initial reactant molecules; • •An increase in solvent polarity results in a decrease in the rates of those reactions in which the charge density is lower than in the initial reactant molecules; • •A change in solvent polarity will have negligible effect on the rates of those reactions that involve little or no change in the charge density from reactants to the activated complex. \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Polarity of solvents Reichardt, C. Pure Appl.Chem 76, 1903 (2004) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry, 3 rd Ed., Wiley-VCH, 2003 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Polarity of solvents ET(30) = h . c . NA . nmax [kcal . mol-1] Could be used even in solid rare gas matrices to establish polarity of rare gases (Xe ® Kr ® Ar ® Ne decreasing polarizability) ET(30) recommended and used for monitoring of a quality of desinfection solutions of alcohol/water in order to prevent SARS-CoV 2 infections \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Polarity of solvents ETN parameter – the negative solvatochromism of the p ® p* shifts of solutions of the betaine dye – more polar solvents stabilize the ground energy of the polar dye, producing thus greater shift in the position of p ® p* absorption relative to that found for solutions of the dye in tetramethylsilane. Colors of this dye in a solvent are indicative of the polarities of the solvent and solvent combination used to dissolve it. \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Reichardt, C. J.Org.Chem 87, 1616 (2022) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Reichardt, C. Pure Appl. Chem.76, 1903 (2004) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Polarity of solvents Solvent Polarity ETN Solubility in water (wt%) Bp of water-solvent azeotrope wt% of water removed by azeotrope ICH solvent class Water 1.000 - None None EtOH 0.654 ¥ 78 °C 4.0 3 AcOH 0.648 ¥ 77 °C 97 3 DMF 0.404 ¥ None None 2 Acetone 0.355 ¥ None None 3 CH2Cl2 0.309 1.3 38 °C 1.5 2 Toluene 0.099 0.06 84 °C 13.5 2 Et3N 0.043 5.5 75 °C 10 3 Heptane(s) 0.012 0.0004 79 °C 12.9 3 Cyclohexane 0.006 0.006 69 °C 9 2 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Polarity of solvent mixtures Solvent Polarity ETN Solvent mixture Calculated ETN MeOH 0.762 EtOH:H2O = 6.9:3.1 0.762 EtOH 0.654 Acetone:H2O = 4.6:5.4 0.654 H2O:CH2Cl2 = 0.2:99.8 0.310 H2O:MIBK = 1.9:98.1 0.283 H2O:CH2Cl2 = 0.2:99.8 0.310 H2O:EtOAc = 3.3:96.7 0.253 H2O:CH2Cl2 = 0.2:99.8 0.310 H2O:2-MeTHF = 5.3:94.7 0.223 i-PrOAc 0.210 Heptanes:EtOAc = 0.8:9.2 0.210 MeOH:H2O = 7:1 0.792 EtOH:H2O = 5:3 0.783 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLVENT CONSIDERATIONS Tendency of solvents to form azeotropes with water is considered advantageous (it is not practical and economical to dry solvents using drying agents on large scale); Be careful – dependence on pressure (breaking the azeotrope) Pressure (mm) Bp (°C) Water in azeotrope (wt%) 760 70.4 8.5 250 42.6 6.3 25 1.9 3.6 Effect of reducing distillation pressure on EtOAc – water: \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png IMPURITIES IN SOLVENTS Absolute solvents are rather expensive, common solvents contains some amount of water, for certain operations they should be dried (azeotropic distillation, molecular sieves, use of an excess of cheap reagent); Denatured solvents (ethanol) Stabilizers (e.g. BHT in THF) Tendency to form (hydrogen)peroxides (diisopropyl ether, butadiene, acetaldehyde, 1,4-dioxane, styrene, acrylonitrile, 2-butanol, benzyl alcohol, THF, MIBK, 2-propyl alcohol) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png IMPURITIES IN SOLVENTS Degradation of solvents (ethyl acetate, DMF) Side reactions (reesterifications, reaction with dichloromethane) Avoid unwanted formation of esters of sulfonic acids (potentially mutagenic) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SACRIFICIAL SOLVENTS Harrington, P.J. et al Org. Process Res. Dev. 10, 1157 (2006) About 50 eq. of 98% H2SO4 at 50 oC for 3 h followed by an aqueous quench provided ring sulfonation in the product; 5-6 eq. of 98% H2SO4 in toluene at 70 oC for 2 h – sulfonation of the product was significantly diminished. \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png IONIC LIQUIDS Ionic liquids are ionic compounds (salts) which are liquids below 100 oC. More commonly, ionic liquids have melting points below room temperature. \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png IONIC LIQUIDS \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SUPERCRITICAL FLUIDS Jessop, P.G.; Leitner, W. Chemical Synthesis Using Supercritical Fluids, Wiley-VCH 1999 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SUPERCRITICAL CARBON DIOXIDE Peach, J.; Eastoe, J. Beilstein J.Org.Chem. 10, 1878 (2014) Beckman, E.J. J.Supercritical Fluids 28, 121 (2004) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SUPERCRITICAL CARBON DIOXIDE FOOD INDUSTRY Coffee decaffeination Tea decaffeination Fatty acids from spent barley Vitamin E, hops, spices extraction Nicotine extraction Natural insecticide/pesticide extraction \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SUPERCRITICAL CARBON DIOXIDE Thomas Swan & Co., Ltd. Licence, P. et al Green Chem. 5, 99 (2003) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png GAS EXPANDED LIQUIDS (GXLs) Combination of a classical solvent and supercritical solvent (usually scCO2) – adjustable polarity;