Use of Organic Superbases and Temperature Effects for the Development of Reversible Protic Amino Acid Salts

Abstract

Novel reversible organic salts based on amino acids in the presence of organic superbases [1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and tetramethylguanidine (TMG)] have been prepared. An optimized acid–base reaction methodology allowed the preparation of novel protic amino acid salts with improved water-solubility profiles and unexpected phase behavior. Complementary differential scanning calorimetry (DSC) and thermal ¹H NMR analysis indicated that a phase separation between water and amino acid salt occurs and that the process is reversible, depending upon temperature and the selected organic superbase. These studies open the possibility for tuning miscibility and ionicity of organic salts as well as development of reversible protic chiral ionic liquids or molten salts.

Key words

amino acids - green chemistry - ionic liquids - cations - protonation

• References and Notes

• 1 Miran MS, Kinoshita H, Yasuda T, Susan MdA. B. H, Watanabe M. Chem Commun. 2011; 47: 12676
• 2 Greaves TL, Drummond CJ. Chem. Rev. 2008; 108: 206
• 3 Ishikawa T. Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and Related Organocatalysts. Wiley; Wiltshire: 2009
• 4 Miran MS, Kinoshita H, Yasuda T, Susan MdA. B. H, Watanabe M. Phys. Chem. Chem. Phys. 2012; 14: 5178
• 5 Akbari J, Heydari A, Ma’mani L, Hosseini SH. C. R. Chimie 2010; 13: 544
• 6 Vitorino J, Leal JP, Minas da Piedade ME, Canongia Lopes JN, Esperança JM. S. S, Rebelo LP. N. J. Phys. Chem. B 2010; 114: 8905
• 7 Jessop PG, Heldebrandt DJ, Li X, Eckert CA, Liotta CL. Nature (London) 2005; 436: 1102
• 8 Carrera GV. S. M, Nunes da Ponte M, Branco LC. Tetrahedron 2012; 68: 7408
• 9 Fukumoto K, Yoshizawa M, Ohno H. J. Am. Chem. Soc. 2005; 127: 2398
• 10 Tao G.-H, He L, Sun N, Kou Y. Chem. Commun. 2005; 3562
• 11 Gonzáles L, Altava B, Bolte M, Burguete MI, García-Verdugo E, Luis SV. Eur. J. Org. Chem. 2012; 4996
• 12 Ohno H, Fukumoto K. Acc. Chem. Res. 2007; 40: 1122
• 13 Muhammad N, Man ZB, Bustam MA, Mutalib MI. A, Wilfred CD, Rafiq S. J. Chem. Eng. Data 2011; 56: 3157
• 14 Schreiter K, Spange S. J. Phys. Org. Chem. 2008; 21: 242
• 15 Ren C, Nap RJ, Szleifer I. J. Phys. Chem. B 2008; 112: 16238
• 16 Balevicius V, Aidas K. Appl. Magn. Reson. 2007; 32: 363
• 17 Angell CA, Byrne N, Belieres J.-P. Acc. Chem. Res. 2007; 40: 1228
• 18 Ueno K, Tokuda H, Watanabe M. Phys. Chem. Chem. Phys. 2010; 12: 1649
• 19 Gund P. J. Chem. Educ. 1972; 49: 100
• 20 Stoimenovski J, Izgorodina EI, MacFarlane DR. Phys. Chem. Chem. Phys. 2010; 12: 10341
• 21 http://sdbs.riodb.aist.go.jp/sdbs/cgi-bin/cre_index.cgi, last check at 28/7/2013.
• 22 ChemBioDraw Ultra 11.0, Cambridge Soft.
• 23 www.iapws.org/relguide/ionization.pdf. Last checked at 28/07/2013; The International Association for the Properties of Water and Steam – Release on the Ionization Constant of H₂O, August 2007.
• 24 Chaplin, M. Water’s Hydrogen Bond Strength; http://arxiv.org/ftp/arxiv/papers/0706/0706.1355.pdf.
• 25 Reagents and Solvents Commercial reagents were used as supplied: Glycine was supplied by BDH with a purity of 99%, l-alanine with a purity of 99% was provided by Alfa Aesar, l-phenylalanine purchased from Merck with a purity of >99%, (d,l)-tryptophan was supplied by Merck with a purity >99%, 1,1,3,3-tetramethylguanidine (TMG), 99%, was supplied by Sigma-Aldrich and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) ≥99%, was provided by Fluka. Solvents were also used as supplied: CH₂Cl₂ was supplied by Sigma-Aldrich, p.a. grade, MeOH was supplied by Sigma-Aldrich HPLC grade, distilled H₂O was processed by Diwer Technologies water max w2 equipment.
• 26 General Procedure for the Preparation of Amino Acid Based PIL and Ionic Mixtures The organic superbase (1 equiv) diluted in an organic solvent (1.5–2 mL) was added slowly to a suspension of an amino acid (1 equiv in 1.5–2 mL of solvent). The resultant mixture was stirred during a variable period of time at r.t. For workup, the solvent was evaporated using a rotary evaporator, and the resultant product was left under high vacuum for a period of 8–16 h. All the compounds prepared following this procedure were stored at 7 °C.
• 27 Solubility in Water To a weighed sample of a salt was added distilled H₂O, dropwise, until homogeneity. The mixture was weighed, and the proportion of compound to minimum quantity of H₂O was thus obtained.
• 28 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium 2-Aminoacetate {[DBUH][Gly]} Prepared using the general procedure for the preparation of amino acid based PIL and ionic mixtures. For the preparation of this specific compound, the reaction proceeds over 6 h using MeOH (3 mL) as solvent. After workup the product was obtained as a heterogeneous white liquid and solid mixture; yield 89%. ¹H NMR (400 MHz, D₂O): δ = 1.57–1.62 (m, 6 H), 1.90 (quint, J = 6 Hz, 2 H), 2.50–2.52 (m, 2 H), 3.14 (s, 2 H), 3.21 (t, J = 6 Hz, 2 H), 3.42 (t, J = 6 Hz, 2 H), 3.44–3.46 (m, 2 H) ppm. ¹³C NMR (100 MHz, D₂O): δ = 18.87, 23.25, 25.81, 28.40, 32.75, 37.91, 43.87, 48.16, 54.10, 165.91, 179.2 ppm. IR (KBr): 3422, 3250, 3119, 2935, 2862, 2623, 2231, 2169, 1647, 1586, 1560, 1476, 1437, 1401, 1366, 1324, 1302, 1270, 1207, 1156, 1126, 1107, 1089, 1043, 1009, 996, 984, 966, 929, 888, 829, 687, 666, 635, 609 cm^–1. Anal. Calcd for C₁₁H₂₁N₃O₂·2H₂O): C, 50.17; H, 9.57; N, 15.96. Found: C, 49.58; H, 9.27; N, 16.97.
• 29 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium (l)-2-Aminopropanoate {[DBUH][ (l)-Ala]} The reaction proceeded during 24 h at r.t. using MeOH (4 mL) as solvent. After workup the product was obtained as a white solid; yield 97%. ¹H NMR (400 MHz, D₂O): δ = 1.12 (d, J = 8 Hz, 3 H), 1.56–1.60 (m, 6 H), 1.88 (quint, J = 4 Hz, 2 H), 2.48–2.51 (m, 2 H), 3.19 (t, J = 6 Hz, 2 H), 3.23 (m, 1 H), 3.40 (t, J = 6 Hz, 2 H), 3.43–3.45 (m, 2 H) ppm. ¹³C NMR (100 MHz, D₂O): δ = 18.86, 19.88, 23.25, 25.80, 28.39, 32.73, 37.90, 48.14, 51.29, 54.08, 165.89, 183.65 ppm. IR (KBr): 3397, 3251, 3088, 3000, 2989, 2937, 2863, 2814, 2605, 2505, 2469, 2417, 2294, 2248, 2113, 1653, 1648, 1600, 1521, 1506, 1456, 1413, 1385, 1363, 1320, 1310, 1271, 1237, 1208, 1153, 1115, 1014, 997, 985, 967, 919, 888, 851, 773, 721, 648, 620 cm^–1.
• 30 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium (l)-2-Amino-3-phenylpropanoate {[DBUH][ (l)-Phe]} The reaction proceeded during 75 h at r.t. using CH₂Cl₂ (4 mL) as solvent. After workup procedure the product was obtained as an orange paste; yield 98%. ¹H NMR (400 MHz, D₂O): δ = 1.53–1.58 (m, 6 H), 1.85 (quint, J = 6 Hz, 2 H), 2.46–2.47 (m, 2 H), 2.94 (dd, J ₁ = 12 Hz, J ₂ = 8 Hz, 1 H), 3.10 (dd, J ₁ = 16 Hz, J ₂ = 6 Hz, 1 H), 3.16 (t, J = 4 Hz, 2 H), 3.36 (t, J = 6 Hz, 2 H), 3.40–3.42 (m, 2 H) ppm. ¹³C NMR (100 MHz, D₂O): δ = 18.85, 23.24, 25.80, 28.39, 32.74, 36.96, 37.90, 48.14, 54.08, 56.20, 127.49, 128.99, 129.33, 135.52, 175.16, 177.49 ppm. IR (KBr): 3426, 3107, 2935, 3258, 3033, 2908, 2883, 2123, 1646, 1560, 1496, 1457, 1410, 1323, 1307, 1207, 1162, 1107, 1075, 984, 913, 848, 746, 699 cm^–1. Anal. Calcd for C₁₈H₂₇N₃O₂·2.6H₂O): C, 59.35; H, 8.91; N, 11.54. Found: C, 59.13; H, 8.37; N, 11.11.
• 31 Bis(dimethylamino)methaniminium (l)-2-Amino-3-phenylpropanoate {[TMGH][ (l)-Phe]} The reaction proceeded during 75 h at r.t. using CH₂Cl₂ (4 mL) as solvent. After workup procedure the product was obtained as a beige paste; yield 100%. ¹H NMR (400 MHz, D₂O): δ = 2.80 (s, 12 H), 2.85 (m, 1 H), 3.00 (dd, J ₁ = 12 Hz, J ₂ = 4 Hz, 1 H), 3.62 (t, J = 6 Hz, 1 H), 7.15–7.27 (m, 5 H) ppm. ¹³C NMR (100 MHz, D₂O): δ = 38.32, 38.77, 56.63, 127.15, 128.81, 129.34, 136.51, 161.31, 177.81 ppm. IR (KBr): 3419, 3208, 2964, 2853, 2130, 1609, 1565, 1495, 1456, 1436, 1410, 1340, 1335, 1320, 1307, 1293, 1227, 1163, 1154, 1091, 1073, 1037, 1004, 949, 913, 876, 848, 779, 746, 699, 682, 605 cm^–1.
• 32 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium (d,l)-2-Amino-3-(1H-indol-3-yl)propanoate {[DBUH][(d,l)-Trp]} The reaction proceeded during 20 h at r.t. using CH₂Cl₂ (4 mL) as solvent. After workup procedure the product was obtained as a yellow solid; yield 100%. ¹H NMR (400 MHz, DMSO): δ = 1.56–1.63 (m, 6 H), 1.85 (quint, J = 6 Hz, 2 H), 2.67–2.70 (m, 2 H), 2.88 (dd, J ₁ = 16 H, J ₂ = 8 Hz, 1 H), 3.19 (t, J = 6 Hz, 2 H), 3.25 (m, 1 H), 3.42 (t, J = 6 Hz, 2 H), 3.48–3.50 (m, 2 H), 6.92 (t, J = 8 Hz, 1 H), 7.03 (t, J = 8 Hz, 1 H), 7.20 (s, 1 H), 7.32 (d, J = 8 Hz, 1 H), 7.53 (d, J = 8 Hz, 1 H), 10.80–11.00 (m, 1 H) ppm. ¹³C NMR (100 MHz, DMSO): δ = 18.97, 23.49, 26.04, 28.31, 28.51, 31.22, 37.50, 47.79, 53.18, 54.94, 55.25, 110.46, 111.26, 118.08, 118.43, 120.71, 123.83, 127.45, 136.28, 165.25, 172.47, 172.51 ppm. IR (KBr): 3403, 3242, 3106, 3053, 2934, 2861, 2555, 2097, 1719, 1703, 1647, 1608, 1487, 1456, 1404, 1358, 1341, 1320, 1312, 1278, 1229, 1207, 1160, 1106, 1068, 1055, 1008, 995, 984, 965, 914, 900, 877, 864, 845, 834, 766, 746, 738, 720, 691, 660, 625 cm^–1. Analysis Calcd for C₂₀H₂₈N₄O₂·2.4H₂O: C, 60.10; H, 8.27; N, 14.02. Found: C, 59.88; H, 7.95; N, 14.28.
• 33 Bis(dimethylamino)methaniminium (d,l)-2-Amino-3-(1H-indol-3-yl)propanoate {[TMGH][(d,l)-Trp]} The reaction proceeded during 23 h at r.t. using CH₂Cl₂ (4 mL) as solvent. After workup procedure the product was obtained as a brown solid; yield 100%. ¹H NMR (400 MHz, DMSO): δ = 2.76 (dd, J ₁ = 16 Hz, J ₂ = 8 Hz), 2.84 (s, 12 H), 3.21 (dd, J ₁ = 16 Hz, J ₂ = 4 Hz, 1 H), 3.29–3.30 (m, 1 H) 6.93 (t, J = 8 Hz, 1 H), 7.02 (t, J = 8 Hz, 1 H), 7.18 (s, 1 H), 7.32 (d, J = 8 Hz, 1 H), 7.52 (d, J = 8 Hz, 1 H), 11.01 (s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO): δ = 29.78, 29.80, 55.79, 111.25, 111.37, 117.38, 118.44, 120.62, 123.61, 127.56, 136.29, 161.65, 173.86 ppm. IR (KBr): 3404, 3088, 3056, 2965, 2816, 2742, 2546, 2099, 1718, 1703, 1653, 1608, 1506, 1487, 1456, 1412, 1359, 1341, 1312, 1279, 1232, 1167, 1098, 1068, 1039, 1008, 988, 964, 929, 877, 865, 846, 836, 773, 747, 738, 721, 660, 625 cm^–1. Anal. Calcd for C₁₆H₂₅N₅O₂·2.2H₂O: C, 53.52; H, 8.25; N, 19.51. Found: C, 53.94; H, 7.56; N, 18.83.