LYSINOL: A RENEWABLY RESOURCED ALTERNATIVE TO PETROCHEMICAL ETHYLENEAMINES AND AMINOALCOHOLS Kenneth G. Moloy, Pranit S. Metkar, & Mark A. Scialdone Dupont Central Research and Development, Experimental Station 200 Powder Mill Road, Wilmington, DE 19803, USA Lysine OH HO HO O OH OH also alcohols, acetate, etc. • • • • • • • Corynebacterium glutamicum H 2N CO2H NH2 L-Lysine Second largest production volume of any amino acid (glutamic acid/MSG #1). Essential amino acid, used almost exclusively as animal feed (swine, poultry). 50 Year old fermentation process from glucose: – Net 4 e- reduction, selectively break five C-OH bonds, selectively make two C-NH2 bonds. High yield: ~ 0.5 g lysine-HCl/g glucose vs. 0.56 g/g theoretical yield (90%). Commodity volumes: ca. 2x109 kg per year and continues to grow. Cheap “Lysine” = lysine monohydrochloride, 80 % lysine content – Lysine sulfate and lysine free base (50 % aq solution) are also available albeit in smaller production volume. 2 Lysine Economics Global Lysine Production US Lysine-HCl Price 3.0 2500 Estimate: $2/kg market price, $1.5/kg cost of manufacture. 2.5 2000 2.0 1500 $/kg 1.5 kt 1000 500 0 1960 China: ca. $2/kg average (2012) $0.85/kg April 2014 1.0 0.5 1980 2000 2020 0.0 1995 2000 2005 2010 2015 Ongoing capacity increases in the Asia, US, Brazil, and Russia despite price pressure. Capacity increases accompanied by significant R&D to further reduce cost. Ajinomoto multigenerational lysine R&D Lysine from non-food sources “cellulosic lysine” http://www.ajinomoto.com/csr/earth/climate.html 3 Lysine as a chemical intermediate: Polyamides H 2N NH2 1,5-pentanediamine CO2 H 2N NH + NH3 α -aminocaprolactam zwitterion structure limits reactivity Nylon 5,# copolymers Ajinomoto/Toray, Cathay, others O - H 2N Diacid H 2N CO2H 5-aminovaleric acid Nylon 6 (via caprolactam) Frost (Amyris), WO2005/123669A1 Wicks (Draths), WO2010/011967A1 Nylon 5 Pukin, et al., J. Mol. Catal. B: Enzym., 2010 ? H 2N OH NH2 Lysinol (2,6-diamino-1-hexanol) 4 Lysinol: Literature Only 23 unique citations refer to lysinol (S, R, or rac), derivatives, or salts. A single reference describes the synthesis, isolation, and characterization of lysinol free base. Literature examples are limited to multi-step, stoichiometric conversion of lysine. H 2N CO2H 1) CBz-Cl 2) BH3 NH2 CBzHN CH2OH NHCBz H2, Pd/C H 2N CH2OH NH2 Kihara, et al., J. Polym. Sci., Part A: Polym. Chem., 1996, 34, 2173. 5 Amino Acids to Amino Alcohols Carboxylic acids and esters are not easily hydrogenated: Ru/C RCO2R' + H2 RCH2OH + R'OH Catalyst Selection Guide, Johnson Matthey, 2007; 200-280 °C 200-300 bar Manyar, et al., Chem. Commun., 2010, 46, 6279 Amino acids are easier - at acidic pH: H + NH3 R + NH3 pH < 3 - CO2 pH 4-8 + R CO2H activated toward reduction + H2 Ru/C 100-180 °C 35-100 bar NH3 R CH2OH Examples for alanine, serine, valine, leucine, proline,… but not lysine. K. P. Pimparkar; D. J. Miller; J. E. Jackson, Ind. Eng. Chem. Res. 2008, 47, 7648 F. T. Jere; J. E. Jackson; D. J. Miller, D. Ind. Eng. Chem. Res. 2004, 43, 3297 Urtel, et al., WO2005077871 (BASF) Antons, et al., WO9938838 (Bayer) 6 Lysine Hydrogenation Conditions: • 5 % Ru/C • 100-120 °C • 50-70 bar • 20-30 wt% lysine in water • Initial pH ~ 1.8-2 (~1.1 eq H2SO4) NH2 H 2N lysine NH2 OH 2 H2 CO2H -H O H2N 2 lysinol crude product Results: • Quantitative lysine conversion • 90+ % lysinol selectivity • 50-70 % isolated yields of high purity lysinol 1) OH2) remove Na2SO4 3) distill Feed Grade lysine also works: Lys-HCl Lys-sulfate 50% aq base 7 Product Distribution NH2 + 2H H2 N CO2H lysine -H2O 2 H2 + 2H NH2 OH H2 N lysinol T > ~ 130 °C pHi < ~ 1.5 - H2 O + H2 - NH4 NH2 + H N H piperidine + - CO - H2 H2 N OH N H 2-hydroxymethylpiperidine 2,5-diaminohexane - NH4 - H2 O + H2 + NH3 - H2 O N H H 2H + NH2 + 2H H N H + H2 - NH3 H + + NH2 1-aminohexane 2-aminomethylpiperidine 8 Hydrogenation Kinetics 1st order in H2 1st order in catalyst 0 order in lysine Alanine hydrogenation kinetics: Jere, F. T.; Jackson, J. E.; Miller, D. J. Ind. Eng. Chem. Res., 2004, 43, 3297 NH2 H 2N CO2H H 2N pKa1= 2.2 pKa2 = 8.8 pKa3= 10.5 NH2 OH pKa1= 10.5 pKa2 = 12.8 Lysinol is a stronger base than lysine pH increases with increasing conversion Initial pH 1.3 2.2 Final pH 3.5 6.9 Conv >99% 75 % 9 Catalyst Recycle Hydrogenation rates are relatively low, large catalyst charges are used to reduce batch time. Catalyst is routinely recovered and reused. Filtrate [Ru] is below detection limits (< 1 ppm) 3 g lysine (10 % aq), 1.1 equiv H2SO4, pHi = 1.7; 1 g 5% Ru/C, 120 °C, 65 bar H2, 16 h. 10 Stereoretention: Mosher amide & 19F NMR H3CO NH2 CF3 Cl OH + 2 H2 N O S-Mosher's acid chloride S-lysinol iPr F 3C R H3CO Ph O S N H N H -71.39 F 3C R H3CO -71.40 R CF3 Ph OCH3 -71.45 HO O Ph N H RSR 2EtN HO O S-lysine product + S-Mosher chloride O R N H R CF3 Ph OCH3 -71.36 Result via peak deconvolution: 88-96 % ee, stereochemistry largely retained rac-lysine product + S-Mosher chloride 1:1 RSR:RRR R-lysine product + S-Mosher chloride RRR ppm 11 Lysinol Polyamides O O NH2 OH HO H 2N R OH HO O N H - H 2O O N H R n Lysinol:adipic acid (R= (CH2)4) copolymer is insoluble, cannot be melt processed. Example Mole % lysinol Mole % HMD Nylon 66 5% 0 5 100 95 22800 10% 15% 20% 10 15 20 90 85 80 6704 insol insol Mn Mz PDI 1st mp, °C 2nd mp, °C 70330 502000 2 3.1 264 253 250 1630 28450 2.4 244 231 215 236 222 206 Mw Conclusion: Cross-linking occurs via ester formation, therefore lysinol based thermoplastic polyamides are not accessible. 12 Polyfunctional Amines NH3 + O 1) reaction H2 N 2) distillation HN N OH 2 1) NH3/catalyst 2) distillation OH 3 Triamines Cl Ethanolamines OH Diamines NH3 + NH2 H2 N 2) caustic 3) distillation Tetraamines H2 N N H NH2 N N NH HN NH2 H N H2 N Lysinol HN H N 1) reaction Cl Complex product mixtures Hazardous raw materials Petrochemical-based NH2 Ethyleneamines NH2 N N H2 N HN 3 N NH2 N H N N NH2 NH2 H 2N OH Similar functionality, structure, and molecular weight H2 N H N Pentaamines N H H N NH2 N H2 N NH2 H2 N N N H NH2 HN N H N N H N NH2 NH2 N H 13 Ethanolamines, Ethyleneamines Pricing: Ethanolamines ~ $1.9/kg; Ethyleneamines ~ $ 4.5-5.5/kg • • • • • • • • • • • • • • Ethyleneamine Markets Global production: 2x109 kg/yr Chemical Intermediates Polyamide/Epoxy Chelants Fungicides Lube Oils Bleach Activator Paper Resins Piperazine Derivatives Oil Field Chemicals Urethanes Surfactants Fabric Softeners Asphalt Fuel Additives amine ‘hardener’ OH O O O O O O n BADGE NH2 OH + 2 H2 N OH N X N OH X O OH X OH N OH N OH X OH O X N OH N OH 14 Epoxy Thermosets: Lysinol vs. Ethyleneamine (DETA) Formulated at 1 NH per epoxy Tack-free after several hours @ RT Cured @ 60-100 °C Thermoset properties are nearly indistinguishable Lysinol Diethylenetriamine 4.6(1.1) 4.7(0.5) Compression Modulus, MPa 1678(133) 1489(69) Strain at Yield, % 11.6(0.5) 16.3(0.4) Stress at Yield, MPa 103(1) 104(1) Instrumented Hardness, MPa 228(48) 199(35) Reduced Modulus, MPa 3506(412) 3287(279) 50% aq NaOH 5.5(2.5) 5.0(1.1) 30% aq H2SO4 3.8(1.0) 4.4(0.5) H2O 2.4(0.2) 2.3(0.4) 3.5% aq NaCl 2.6(0.3) 1.9(1.5) acetone 6.9(2.3) 5.4(1.9) toluene 0.4(0.1) 0.2(0.4) Lap Shear Tensile Strength, MPa Compression Nanoindentation TGA DETA lysinol Chemical Resistance, % mass gain 15 Other polymers from lysinol Polyurea/polyurethane thermoset O R NH2 OCN OH H 2N R O NCO N H N H O O N H N H N H R n Polyimide (solution processible) NH2 OH H 2N O O O + O O OH N H O N H HO2C OH O N CO2H O O N O O O 16 Take home message Lysine and lysinol are worth our attention! Renewable, inexpensive, abundant and non-toxic raw materials Water solvent and co-product High selectivity catalysis Acknowledgments Mark Scialdone Pranit Metkar Ellen Baldassare Charlie Bellini Jan Hytrek Bryan Cheng Dupont CR&D Joe Bozell for 1) reading my paper and 2) inviting me to share my work at this conference 17
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