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Supporting Information

Mapping the pharmaceutical design space by amorphous ionic liquid strategies

Johannes Wiesta, Marco Saedtlera, Anja Balka, Benjamin Mergeta, Toni Widmerb, Heike Bruhnc, Marc Raccugliab, Elbast Walidb, Franck Picardb, Helga Stopperd, Wolfgang Dekantd, Tessa Lüh-manna, Christoph Sotriffera, Bruno Gallib, Ulrike Holzgrabea and Lorenz Meinel§a

a Institute for Pharmacy and Food Chemistry, Am Hubland, 97074 Würzburg, Germanyb Novartis Pharma AG, Lichtstraße 35, 4002 Basel, Switzerlandc Institute for Molecular Infection Biology (IMIB), Josef-Schneider-Straße 2, 97080 Würzburg, Germanyd Department of Toxicology, Institute for Pharmacology and Toxicology, Versbacher Straße 9, 97078 Würzburg, Germany

§To whom correspondence should be addressed:

Tel.: +49 931 318 54 71, Fax: +49 931 318 46 08; Email: [email protected]

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mailto:[email protected]

Table of Contents

Table of Contents.................................................................................................................................................................................................................................. 2Experimental Procedures...................................................................................................................................................................................................................... 3

General reaction control and purification.........................................................................................................................................................................................3Synthesis of counterions.................................................................................................................................................................................................................. 3

Synthesis of tributyl-(methyl)-phosphonium iodide.....................................................................................................................................................................3Synthesis of tributyl-(ethyl)-phosphonium iodide........................................................................................................................................................................3Synthesis of tributyl-(propyl)-phosphonium bromide..................................................................................................................................................................3Synthesis of tributyl-(pentyl)-phosphonium bromide..................................................................................................................................................................4Synthesis of tributyl-(hexyl)-phosphonium bromide...................................................................................................................................................................4Synthesis of benzyltributylphosphonium bromide......................................................................................................................................................................4Synthesis of N-benzyl-N,N-dibutylbutan-1-aminium bromide.....................................................................................................................................................4Synthesis of tributyl-(4-fluorobenzyl)-phosphonium bromide.....................................................................................................................................................4Synthesis of N,N-dibutyl-N-(4-fluorobenzyl)-butan-1-aminium bromide.....................................................................................................................................5Synthesis of tributyl-(4-chlorbenzyl)-phosphonium chloride.......................................................................................................................................................5Synthesis of tributyl-(4-iodobenzyl)-phosphonium bromide.......................................................................................................................................................5Synthesis of tributyl-(4-(trifluormethyl)-benzyl)-phosphonium bromide......................................................................................................................................5Synthesis of N-benzyl-N,N-dipropylpropan-1-aminium bromide................................................................................................................................................5Synthesis of tripropyl-(4-fluorobenzyl)-phosphonium bromide...................................................................................................................................................5Synthesis of 4-fluorobenzyl-N,N-dipropylpropan-1-aminium bromide........................................................................................................................................6Synthesis of tributyl-(2-hydroxyethyl)-phosphonium bromide....................................................................................................................................................6Synthesis of tributyl-(3-hydroxypropyl)-phosphonium chloride...................................................................................................................................................6Synthesis of tributyl-(2-hydroxypropyl)-phosphonium chloride...................................................................................................................................................6Synthesis of tributyl-(4-hydroxybutyl)-phosphonium bromide....................................................................................................................................................6Synthesis of ethan-1,3-diylbis-(tributylphosphonium) dibromide................................................................................................................................................7Synthesis of propan-1,3-diylbis-(tributylphosphonium) dibromide..............................................................................................................................................7Synthesis of butan-1,4-diylbis-(tributylphosphonium) dibromide................................................................................................................................................7Synthesis of N1,N1,N1,N4,N4,N4-Hexabutylbutan-1,4-diaminium dibromide............................................................................................................................7Synthesis of pentan-1,5-diylbis-(tributylphosphonium) dibromide..............................................................................................................................................7Synthesis of hexan-1,6-diylbis-(tributylphosphonium) dibromide...............................................................................................................................................8Synthesis of ethan-1,2-diylbis-(tripropylphosphonium) dibromide..............................................................................................................................................8Synthesis of propan-1,3-diylbis-(tripropylphosphonium) dibromide...........................................................................................................................................8Synthesis of butan-1,4-diylbis-(tripropylphosphonium) dibromide..............................................................................................................................................8Synthesis of N1,N1,N1,N4,N4,N4-hexapropylbutan-1,4-diaminium dibromide..........................................................................................................................8Synthesis of pentan-1,5-diylbis-(tripropylphosphonium) dibromide............................................................................................................................................8Synthesis of (benzen-1,3,5-triyltris(methylen))tris(tributylphosphonium) tribromide...................................................................................................................9Synthesis of (benzen-1,3,5-triyltris(methylen))tris-(tributylammonium) tribromide.....................................................................................................................9Synthesis of (benzen-1,3,5-triyltris(methylen))-tris-(tripropylphosphonium) tribromide..............................................................................................................9Synthesis of N,N',N''-(benzen-1,3,5-triyltris(methylene))-tris-(N,N-dipropylpropan-1-aminium) tribromide................................................................................9

Preparation of ionic liquids.............................................................................................................................................................................................................10Ionic liquids of the alkyl series (Xnnnn).......................................................................................................................................................................................12Ionic liquids of the benzyl series (XnnnΘY)..................................................................................................................................................................................15Ionic liquids of the hydroxyl series (XnnnnOH)..............................................................................................................................................................................20Ionic liquids of the dication series (Xnnn-m-Xnnn)..........................................................................................................................................................................22Ionic liquids of the trication series (triXnnn)................................................................................................................................................................................28

X-ray powder diffractograms of ionic liquids (XRPD).....................................................................................................................................................................31Dynamic vapor sorption data of ionic liquids (DVS).......................................................................................................................................................................32Flux, duration of supersaturation, water sorption and cytotoxicity.................................................................................................................................................50Molecular descriptors of the counterions.......................................................................................................................................................................................55Stability study of the ionic liquids used in animal study.................................................................................................................................................................57Pharmacokinetic studies................................................................................................................................................................................................................ 61

References.......................................................................................................................................................................................................................................... 62

Experimental Procedures

General reaction control and purification

Reaction control was done on TLC plates SIL G-25 pre-coated with fluorescent indicator 254 nm from Macherey-Nagel (Düren, Ger-many) with a mix of aqueous 0.2 M NH4NO3 solution and MeOH (2:3, v/v) and detection by iodine vapor. After reaction 50 mL dem-ineralized water was added and washed three times with 50 mL ethyl acetate. The product in the water phase was obtained by re-moval of water on a rotary evaporator and 24 h drying under vacuum over phosphorous pentoxide. For purification solid products were recrystallized in chloroform and ethyl acetate (3:1, v/v).

Synthesis of counterions

Scheme S1. Synthetic route for the counterions of the alkyl series

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Synthesis of tributyl-(methyl)-phosphonium iodide

0.82 g iodomethane (5.78 mmol) was dropwise added to 1.77 g tributylphosphine (8.8 mmol) under argon atmosphere and stirred for 30 min at RT. After purification 1.2 g white solid was obtained (58% yield, Rf = 0.84, m.p. = 149 °C (DSC), HPLC purity = 99%). IR (ATR) ~ν [cm-1]: 2958 (s), 2873 (s), 1462 (m), 1385 (m), 1099 (w), 944 (m), 717 (w). 1H NMR (DMSO-d6): δ 2.29 – 2.10 (m, 6H), 1.79 (d, J = 14.0, 3H), 1.53 – 1.34 (m, 12H), 0.92 (t, J = 7.1, 9H). 13C NMR (DMSO-d6): δ 23.3 (d, J= 15.9), 22.6 (d, J = 4.3), 18.9 (d, J = 49.3), 13.2, 3.2 (d, J = 51.5). The NMR data are consistent with the literature [1].

Synthesis of tributyl-(ethyl)-phosphonium iodide

0.87 g iodoethane (5.58 mmol) and 1.70 g tributylphosphine (8.4 mmol) were heated under argon atmosphere at 60 °C by microwave irradiation for 30 min. After purification 0.37 g white solid was obtained (18% yield, Rf = 0.87, m.p. = 141 °C, HPLC purity = > 99%). IR (ATR) ~ν [cm-1]: 2959 (s), 2932 (s), 2873 (s), 1463 (m), 1099 (w), 742 (w). 1H NMR (DMSO-d6): δ 2.29 – 2.10 (m, 8H), 1.53 – 1.34 (m, 12H), 1.13 (dt, J = 18.1, J = 7.9, 3H), 0.92 (t, J = 7.1, 9H). 13C NMR (DMSO-d6): δ 23.3 (d, J =15.6), 22.6 (d, J = 4.4), 16.9 (d, J = 47.6), 13.2, 11.3 (d, J = 48.8), 5.3 (d, J = 5.4). The NMR data are consistent with the literature [2].

Synthesis of tributyl-(propyl)-phosphonium bromide

0.76 g 1-bromopropane (6.15 mmol) and 1.87 g tributylphosphine (9.23 mmol) in 10 mL anhydrous acetonitrile were heated under ar-gon atmosphere at 70 °C for 5 h. After purification 1.3 g white solid was obtained (63% yield, m.p. = 80 °C, HPLC purity = > 99%). IR (ATR) ~ν [cm-1]: 2959 (s), 2932 (s), 2909 (s), 2872 (s), 1462 (m), 1377 (w), 1086 (m), 719 (w). 1H NMR (DMSO-d6): δ 2.29 – 2.14 (m, 8H), 1.60 – 1.32 (m, 14H), 1.01 (dt, J = 7.2, J = 1.4, 3H), 0.91 (t, J = 7.1, 9H). 13C NMR (DMSO-d6): δ 23.3 (d, J = 15.6), 22.6 (d, J = 4.5), 19.6 (d, J = 47.2), 17.4 (d, J = 47.6), 15.2 (d, J = 16.4), 14.7 (d, J = 4.3), 13.2. The NMR data are consistent with the literature [2].

Synthesis of tributyl-(pentyl)-phosphonium bromide

2.82 g 1-bromopentane (18.67 mmol) and 5.16 g tributylphosphine (25.5 mmol) were heated under argon atmosphere at 120 °C for 30 min under microwave irradiation. After purification 1.5 g colorless oil was obtained (25% yield, R f = 0.80, HPLC purity = 94%). IR (ATR) ~ν [cm-1]: 3292 (br, H2O), 2957 (s), 2930 (s), 2872 (s), 1624 (m), 1463 (m), 1231 (m), 1097 (m), 718 (w). 1H NMR (DMSO-d6): δ 2.29 – 2.10 (m, 8H), 1.60 – 1.28 (m, 18H), 0.92 (t, J = 7.1, 9H), 0.89 (t, J = 7.2, 3H). 13C NMR (DMSO-d6): δ 32.2 (d, J = 15.1), 23.3 (d, J =15.6), 22.6 (d, J = 4.4), 21.3, 20.2 (d, J = 4.3), 17.5 (d, J = 47.5), 17.4 (d, J = 47.6), 13.6, 13.2. The NMR data are consistent with the literature [2].

Synthesis of tributyl-(hexyl)-phosphonium bromide

2.7 g 1-bromohexane (16.36 mmol) and 4.94 g tributylphosphine (24.42 mmol) were heated under argon atmosphere at 120 °C for 30 min under microwave irradiation. After purification 1.2 g colorless oil was obtained (20% yield, R f = 0.82, HPLC purity = 97%). IR (ATR) ~ν [cm-1]: 2956 (s), 2928 (s), 2871 (s), 1464 (m), 1379 (w), 1097 (m), 719 (w). 1H NMR (DMSO-d6): δ 2.29 – 2.10 (m, 8H), 1.55 – 1.34 (m, 16H), 1.34 – 1.20 (m, 4H), 0.91 (t, J = 7.1, 9H), 0.88 (t, J = 6.5, 3H). 13C NMR (DMSO-d6): δ 30.4, 29.7 (d, J = 15.2), 23.3 (d, J = 15.6), 22.6 (d, J = 4.4), 21.8, 20.5 (d, J = 4.2), 17.6 (d, J = 47.4), 17.4 (d, J = 47.6), 13.8, 13.2. The NMR data are consistent with the literature [2].

Scheme S2. Synthetic route for the counterions of the benzyl series

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After reaction the obtained precipitates were filtered and washed four times with 30 mL ethyl acetate each (P444Ɵ/P444ƟF/P444ƟCl/N444Ɵ/N444ƟF/N333Ɵ/N333ƟF) and hexane (P444ƟI/P444ƟCF3), respectively. The precipitates were dried 24 h over phospho-rous pentoxide under vacuum.

Synthesis of benzyltributylphosphonium bromide

2.74 g benzyl bromide (16 mmol) was dropwise added to 4.86 g tributylphosphine (24 mmol) under argon atmosphere and stirred 10 min at RT. After purification 4.2 g white solid was obtained (70% yield, Rf = 0.74, m.p. 151 °C, HPLC purity = 98%). IR (ATR) ~ν [cm-1]: 2957 (m), 2930 (m), 2870 (m), 2797 (w), 1600 (w), 1495 (m), 1456 (m), 1096 (m), 1001 (w), 700 (s). 1H NMR (DMSO-d6): δ 7.50 – 7.30 (m, 5H), 3.84 (d, J = 15.5, 2H), 2.29 – 2.08 (m, 6H), 1.55 – 1.27 (m, 12H), 0.88 (t, J = 7.0, 9H). 13C NMR (DMSO-d6): δ 129.9 (d, J = 4.9), 129.3 (d, J = 8.6), 129.2 (d, J = 2.9), 128.0 (d, J = 3.4), 25.4 (d, J =44.4), 23.3 (d, J = 15.7), 22.5 (d, J = 4.6), 17.4 (d, J = 47.0), 13.2. The NMR data are consistent with the literature [3].

Synthesis of N-benzyl-N,N-dibutylbutan-1-aminium bromide

0.96 g benzyl bromide (5.61 mmol) and 2.88 g tributylamine (15.54 mmol) in 5 mL anhydrous acetonitrile were stirred under argon at-mosphere for 24 h at RT. After purification 1.2 g white solid was obtained (60% yield, Rf = 0.76, m.p. 184 °C (DSC), HPLC purity = > 99%). IR (ATR) ~ν [cm-1]: 2957 (s), 2872 (s), 1497 (w), 1476 (m), 1458 (m), 702 (m). 1H NMR (DMSO-d6): δ 7.60 - 7.45 (m, 5H), 4.57 (s, 2H), 3.20 – 3.00 (m, 6H), 1.85 – 1.60 (m, 6H), 1.31 (sext, J = 7.4, 6H), 0.94 (t, J = 7.4, 9H). 13C NMR (DMSO-d6): δ 132.5, 130.3, 129.0, 127.9, 61.3, 57.5, 23.3, 19.2, 13.5.

Synthesis of tributyl-(4-fluorobenzyl)-phosphonium bromide

1 g 4-fluorobenzyl bromide (5.29 mmol) was dropwise added to 1.55 g tributylphosphine (7.66 mmol) under argon atmosphere and stirred 10 min at RT. After purification 1.3 g white solid was obtained (64% yield, Rf = 0.74, m.p. 146-148 °C, HPLC purity = 99%). IR (ATR) ~ν [cm-1]: 2961 (m), 2916 (m), 2872 (m), 1603 (w), 1508 (s), 1460 (m), 1222 (s), 1160 (s), 1093 (m), 845 (s), 725 (w). 1H NMR (DMSO-d6): 7.48 – 7.37 (m, 2H), 7.33 – 7.22 (m, 2H), 3.87 (d, J = 15.3, 2H), 2.29 – 2.08 (m, 6H), 1.55 – 1.27 (m, 12H), 0.89 (t, J = 7.0, 9H). 13C NMR (DMSO-d6): δ 161.8 (dd, J = 244.4, J = 3.7), 132.0 (dd, J = 8.3, J = 4.9), 125.5 (dd, J = 8.5, J = 3.2), 116.1 (dd, J = 21.6, J = 2.9), 24.6 (d, J = 44.9), 23.3 (d, J = 15.7), 22.5 (d, J = 4.6), 17.3 (d, J = 46.9), 13.2.

Synthesis of N,N-dibutyl-N-(4-fluorobenzyl)-butan-1-aminium bromide

0.51 g 4-fluoro-benzyl bromide (2.70 mmol) and 0.74 g tributylamine (3.98 mmol) in 5 mL anhydrous acetonitrile were stirred under argon atmosphere for 4 d at 55 °C. After purification 0.7 g brown solid was obtained (66% yield, R f = 0.76, m.p. 179 °C (DSC), HPLC purity = > 99%). IR (ATR) ~ν [cm-1]: 2961 (s), 2874 (s), 1604 (m), 1511 (s), 1472 (s), 1225 (s), 1166 (m), 703 (w). 1H NMR (DMSO-d6): δ 7.67 – 7.47 (m, 2H), 7.47 – 7.30 (m, 2H), 4.57 (s, 2H), 3.20 – 3.00 (m, 6H), 1.85 – 1.60 (m, 6H), 1.31 (sext, J = 7.4, 6H), 0.94 (t, J = 7.3, 9H). 13C NMR (DMSO-d6): δ 163.1 (d, J = 248.0), 135.0 (d, J = 8.8), 124.3 (d, J = 3.2), 116.1 (d, J = 21.7), 60.4, 57.4, 23.3, 19.2, 13.5.

Synthesis of tributyl-(4-chlorbenzyl)-phosphonium chloride

1 g 4-chlorobenzyl chloride (6.21 mmol) was dropwise added to 1.67 g tributylphosphine (8.25 mmol) under argon atmosphere and stirred 120 h at RT. After purification 1.1 g white solid was obtained (55% yield, Rf = 0.76, m.p. 162-164 °C, HPLC purity = > 99%). IR (ATR) ~ν [cm-1]: 2959 (s), 2919 (s), 2872 (s), 1493 (s), 1463 (s), 1092 (s), 1019 (s), 845 (s), 727 (m), 718 (m), 635 (m). 1H NMR (DMSO-d6): δ 7.56 – 7.45 (m, 2H), 7.45 – 7.34 (m, 2H), 3.90 (d, J = 15.6, 2H), 2.29 – 2.08 (m, 6H), 1.55 – 1.27 (m, 12H), 0.89 (t, J = 6.9, 9H). 13C NMR (DMSO-d6): δ 132.8 (d, J = 4.2), 131.8 (d, J = 4.9), 129.1 (d, J = 2.8), 128.5 (d, J = 8.6), 24.8 (d, J = 44.9), 23.3 (d, J = 15.8), 22.5 (d, J = 4.6), 17.3 (d, J = 46.8), 13.2.

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Synthesis of tributyl-(4-iodobenzyl)-phosphonium bromide

1.19 g 4-iodobenzyl bromide (4 mmol) was dissolved in 5 mL anhydrous hexane and dropwise added to 1.23 g tributylphosphine (6.08 mmol), dissolved in 5 mL anhydrous hexane, under argon atmosphere and stirred 24 h at RT. After purification 0.6 g white solid was obtained (31% yield, Rf = 0.79, m.p. 203 °C (DSC), HPLC purity = 99%). IR (ATR) ~ν [cm-1]: 2959 (s), 2929 (s), 2871 (s), 1486 (m), 1462 (m), 1094 (m), 1009 (m), 839 (s), 717 (w). 1H NMR (DMSO-d6): δ 8.04 – 7.56 (m, 2H), 7.34 – 6.90 (m, 2H), 3.79 (d, J = 15.5, 2H), 2.29 – 2.01 (m, 6H), 1.55 – 1.22 (m, 12H), 0.89 (t, J = 6.9, 9H). 13C NMR (DMSO-d6): δ 137.9 (d, J = 2.9), 132.2 (d, J = 4.8), 129.0 (d, J = 8.5), 94.4 (d, J = 4.6), 24.8 (d, J = 44.9), 23.3 (d, J = 15.8), 22.5 (d, J = 4.5), 17.3 (d, J = 46.9), 13.2.

Synthesis of tributyl-(4-(trifluormethyl)-benzyl)-phosphonium bromide

1.08 g 4-trifluoro-benzyl bromide (4.52 mmol) was dissolved in 5 mL anhydrous hexane and dropwise added to 1.38 g tributylphos-phine (6.82 mmol), dissolved in 5 mL anhydrous hexane, under argon atmosphere and stirred 24 h at RT. After purification 1.9 g white solid was obtained (93% yield, Rf = 0.78, m.p. 157 °C (DSC), HPLC purity = 98%). IR (ATR) ~ν [cm-1]: 2961 (s), 2935 (s), 2918 (s), 2875 (s), 1618 (w), 1463 (m), 1324 (s), 1157 (s), 1123 (s), 1068 (s), 1023 (s), 857 (s), 728 (w). 1H NMR (DMSO-d6): δ 7.91 – 7.72 (m, 2H), 7.72 – 7.54 (m, 2H), 3.96 (d, J = 15.9, 2H), 2.29 – 2.08 (m, 6H), 1.55 – 1.27 (m, 12H), 0.89 (t, J = 7.0, 9H). 13C NMR (DMSO-d6): δ 134.6 (d, J = 7.4), 130.9 (d, J = 4.8), 128.5 (dq, J = 32.0, J = 3.5), 125.9 (m), 124.1 (dq, J = 273.2, J = 1.6), 25.4 (d, J = 44.1), 23.3 (d, J = 15.9), 22.5 (d, J = 4.6), 17.3 (d, J = 46.9), 13.2

Synthesis of N-benzyl-N,N-dipropylpropan-1-aminium bromide

1.09 g benzyl bromide (6.37 mmol) and 1.38 g tripropylamine (8.07 mmol) in 5 mL anhydrous acetonitrile were stirred under argon at-mosphere for 24 at RT. After purification 1.9 g white solid was obtained (93% yield, Rf = 0.68, m.p. 192 °C (DSC), HPLC purity = > 99%). IR (ATR) ~ν [cm-1]: 2973 (s), 2876 (s), 1474 (m), 1456 (m), 1385 (w), 1209 (w), 731 (s), 707 (m). 1H NMR (DMSO-d6): 7.64 – 7.38 (m, 5H), 4.54 (s, 2H), 3.18 – 2.92 (m, 6H), 1.87 – 1.65 (m, 6H), 0.90 (t, J = 7.3, 9H). 13C NMR (DMSO-d6): 132.5, 130.3, 129.1, 127.8, 61.3, 59.0, 15.0, 10.4. The NMR data are consistent with the literature [4].

Synthesis of tripropyl-(4-fluorobenzyl)-phosphonium bromide

1.08 g 4-fluorobenzyl bromide (5.71 mmol) and 1.0 g tripropylphosphine (6.24 mmol) in 5 mL anhydrous hexane were stirred under argon atmosphere for 24 h at RT. After purification 1.2 g white solid was obtained (95% yield, R f = 0.72, m.p. 184 °C (DSC), HPLC purity = > 99%). IR (ATR) ~ν [cm-1]: 2963 (s), 2932 (m), 2902 (m), 2873 (s), 1508 (s), 1456 (m), 1222 (s), 1162 (s), 1086 (s), 858 (s), 723 (m). 1H NMR (DMSO-d6): δ 7.44 – 7.36 (m, 2H), 7.32 – 7.23 (m, 2H), 3.83 (d, J = 15.3, 2H), 2.25 – 2.05 (m, 6H), 1.58 – 1.40 (m, 6H), 0.99 (dt, J = 7.3, J = 1.5, 9H). 13C NMR (DMSO-d6): δ 161.7 (dd, J = 244.6, J = 3.9), 132.0 (dd, J = 8.2, J = 4.9), 125.5 (dd, J = 8.5, J = 3.2), 116.1 (dd, J = 21.6, J = 2.9), 24.7 (d, J = 44.8), 19.6 (d, J = 46.4), 15.2 (d, J = 16.5), 14.6 (d, J = 4.4).

Synthesis of 4-fluorobenzyl-N,N-dipropylpropan-1-aminium bromide

1.14 g 4-fluoro-benzyl bromide (6.37 mmol) and 1.29 g tripropylamine (9.00 mmol) in 5 mL anhydrous acetonitrile were stirred under argon atmosphere for 24 h at RT. After purification 2.1 g white solid was obtained (94% yield, R f = 0.70, m.p. 165 °C (DSC), HPLC purity = > 99%). IR (ATR) ~ν [cm-1]: 2967 (s), 2879 (m), 1601 (m), 1512 (s), 1476 (m), 1225 (s), 1167 (m), 826 (m), 757 (m). 1H NMR (DMSO-d6): 7.64 – 7.50 (m, 2H), 7.42 – 7.31 (m, 2H), 4.55 (s, 2H), 3.18 – 2.92 (m, 6H), 1.87 – 1.65 (m, 6H), 0.90 (t, J = 7.3, 9H). 13C NMR (DMSO-d6): 163.1 (d, J = 247.9), 134.9 (d, J = 8.8), 124.2 (d, J = 3.2), 116.1 (d, J = 21.7), 60.4, 59.0, 15.0, 10.4.

Scheme S3. Synthetic route for the counterions of the hydroxyl series

S5

Synthesis of tributyl-(2-hydroxyethyl)-phosphonium bromide

0.75 g 2-bromoethanol (6 mmol) and 2.43 g tributylphosphine (12 mmol) were heated under argon atmosphere at 80 °C for 24 h. Af-ter purification 2.0 g colorless oil was obtained (99% yield, Rf = 0.76, HPLC purity = 95%). IR (ATR) ~ν [cm-1]: 3280 (br), 2958 (s), 2932 (s), 2873 (s), 1624 (H2O), 1465 (m), 1050 (m), 722 (w). 1H NMR (DMSO-d6): δ 5.26 (br, 1H), 3.77 (dt, J = 18.6, J = 6.2, 2H), 2.44 (dt, J = 12.6, J = 6.2, 2H), 2.29 – 2.10 (m, 6H), 1.58 – 1.30 (m, 12H), 0.91 (t, J = 7.2, 9H). 13C NMR (DMSO-d6): δ 54.3 (d, J = 6.1), 23.3 (d, J = 15.9), 22.7 (d, J = 4.5), 21.6 (d, J = 48.0), 18.2 (d, J = 47.5), 13.2.

Synthesis of tributyl-(3-hydroxypropyl)-phosphonium chloride

2.16 g 3-chloro-1-propanol (22.85 mmol) and 5.09 g tributylphosphine (25.16 mmol) were heated under argon atmosphere at 90 °C for 3.5 h under microwave irradiation. After purification 4.9 g colorless oil was obtained (82% yield, Rf = 0.72, HPLC purity = 94%). IR (ATR) ~ν [cm-1]: 3355 (br), 2958 (s), 2932 (s), 2872 (s), 1629 (H2O), 1464 (m), 1061 (m), 716 (w). 1H NMR (DMSO-d6): δ 4.86 (br, 1H), 3.46 (t, J = 5.9, 2H), 2.30 – 2.10 (m, 8H), 1.72 – 1.57 (m, 2H), 1.55 – 1.32 (m, 12H), 0.92 (t, J = 7.1, 9H). 13C NMR (DMSO-d6): δ 60.1 (d, J = 15.7), 23.8 (d, J = 4.3), 23.1 (d, J = 15.7), 22.4 (d, J = 4.4), 17.1 (d, J = 47.7), 14.5 (d, J = 49.1), 13.0.

Synthesis of tributyl-(2-hydroxypropyl)-phosphonium chloride

0.64 g 1-chloro-2-propanol (6.77 mmol) and 2.05 g tributylphosphine (10.13 mmol) were heated under argon atmosphere at 100 °C for 24 h. After purification 0.8 g colorless oil was obtained (42% yield, Rf = 0.76, HPLC purity = 70%). IR (ATR) ~ν [cm-1]: 3203 (s, br), 2958 (s), 2931 (s), 2873 (s), 1463 (m), 1123 (m), 1096 (m), 717 (w). 1H NMR (DMSO-d6): δ 5.51 (d, J = 4.9, 1H), 4.03 (br, 1H), 2.46 – 2.27 (m, 2H), 2.27 – 2.10 (m, 6H), 1.61 – 1.30 (m, 12H), 1.23 (dd, J = 6.0, J = 2.5, 3H), 0.92 (t, J = 7.2, 9H). 13C NMR (DMSO-d6): δ 61.4 (d, J = 6.2), 27.5 (d, J = 48.9), 25.6 (d, J = 14.3), 23.4 (d, J = 15.9), 22.7 (d, J = 4.5), 18.4 (d, J = 47.7), 13.2.

Synthesis of tributyl-(4-hydroxybutyl)-phosphonium bromide

1.01 g 85% 4-bromobutanol in THF (5.62 mmol) and 1.71 g tributylphosphine (8.45 mmol) were heated under argon atmosphere and protected from light at 80 °C for 24 h. After purification 1.5 g colorless oil was obtained (77% yield, Rf = 0.50, HPLC purity = 66%). IR (ATR) ~ν [cm-1]: 3343 (m, br), 2957 (s), 2929 (s), 2872 (s), 1463 (m), 1082 (m), 720 (w). 1H NMR (DMSO-d6): δ 4.02 (br, 1H), 3.44 (t, J = 5.7, 2H), 2.40 – 2.11 (m, 8H), 1.70 – 1.30 (m, 16H), 0.91 (t, J = 7.3, 9H). 13C NMR (DMSO-d6): δ 59.5, 23.3 (d, J = 15.6), 23.1 (d, J = 15.4), 22.6 (d, J = 4.3), 17.5 (d, J = 4.2), 17.4 (d, J = 47.3), 17.3 (d, J = 47.6), 13.3.

Scheme S4. Synthetic route for the counterions of the dication series

Synthesis of ethan-1,3-diylbis-(tributylphosphonium) dibromide

0.63 g 1,2-dibromoethane (3.38 mmol) and 1.9 g tributylphosphine (10.11 mmol) were heated under argon atmosphere at 100 °C for 24 h. After purification 2.0 g white solid was obtained (98% yield, Rf = 0.72, m.p. 77 °C (DSC), HPLC purity = 97%). IR (ATR) ~ν [cm-

1]: 2957 (s), 2930 (s), 2872 (s), 1464 (m), 1414 (m), 1383 (m), 1097 (m), 715 (w). 1H NMR (DMSO-d6): δ 2.82 – 2.67 (m, 4H), 2.45 – 2.28 (m, 12H), 1.60 – 1.31 (m, 24H), 0.93 (t, J = 7.2, 18H). 13C NMR (DMSO-d6): δ 23.5 – 23.1 (m), 22.8 – 22.4 (m), 17.9 – 16.6 (m), 13.3, 11.8 – 10.5 (m). The NMR data are consistent with the literature [5].

Synthesis of propan-1,3-diylbis-(tributylphosphonium) dibromide

S6

0.66 g 1,3-dibromopropane (3.29 mmol) and 2.0 g tributylphosphine (9.89 mmol) were heated under argon atmosphere at 100 °C for 24 h. After purification 1.4 g white solid was obtained (71% yield, Rf = 0.71, m.p. 90 °C (DSC), HPLC purity = 99%). IR (ATR) ~ν [cm-

1]: 3433 (m), 3376 (m), 2957 (s), 2930 (s), 2871 (s), 1464 (m), 1434 (m), 1418 (m), 1093 (m), 746 (w). 1H NMR (DMSO-d6): δ 2.48 – 2.38 (m, 4H), 2.37 – 2.20 (m, 12H), 1.86 – 1.66 (m, 2H), 1.61 – 1.31 (m, 24H), 0.92 (t, J = 7.2, 18H). 13C NMR (DMSO-d6): δ 23.3 (t, J = 10.2), 23.3 (d, J = 15.8), 22.8 – 22.5 (m), 18.6 (dd, J = 48.5, J = 16.6), 17.4 (d, J = 48.1), 13.3.

Synthesis of butan-1,4-diylbis-(tributylphosphonium) dibromide

0.70 g 1,4-dibromobutane (3.24 mmol) and 1.62 g tributylphosphine (8 mmol) were heated under argon atmosphere at 100 °C for 24 h. After purification 1.9 g colorless oil was obtained (94% yield, Rf = 0.70, HPLC purity = 89%). IR (ATR) ~ν [cm-1]: 3376 (br, H2O), 2958 (s), 2930 (s), 2872 (s), 1625 (w), 1463 (m), 1231 (w), 719 (w). 1H NMR (DMSO-d6): 2.40 – 2.28 (m, 4H), 2.28 – 2.10 (m, 12H), 1.72 – 1.56 (m, 4H), 1.55 – 1.33 (m, 24H), 0.92 (t, J = 7.1, 18H). 13C NMR (DMSO-d6): δ 23.4 (d, J = 15.8), 22.7 (d, J = 4.5), 21.9 (dd, J = 3.9, J = 16.7), 17.5 (d, J = 47.6), 17.2 (d, J = 47.6), 13.3.

Synthesis of N1,N1,N1,N4,N4,N4-Hexabutylbutan-1,4-diaminium dibromide

0.74 g 1,4-dibromobutane (3.43 mmol) and 1.90 g tributylamine (10.25 mmol) were heated under argon atmosphere for 24 h at 100 °C. After purification 0.9 g white solid was obtained (44% yield, Rf = 0.58, m.p. 159 °C (DSC), HPLC purity = 99%). IR (ATR) ~ν [cm-1]: 3449 (m), 2959 (s), 2872 (s), 1471 (m), 738 (w). 1H NMR (DMSO-d6): δ 3.29 – 3.22 (m, 4H), 3.22 – 3.11 (m, 12H), 1.75 – 1.48 (m, 16H), 1.33 (sext, J = 7.3, 12H), 0.95 (t, J = 7.3, 18H). 13C NMR (DMSO-d6): δ 57.8, 57.1, 23.1, 19.2, 18.5, 13.5.

Synthesis of pentan-1,5-diylbis-(tributylphosphonium) dibromide

0.72 g 1,5-dibromopentane (3.13 mmol) and 1.62 g tributylphosphine (8 mmol) were heated under argon atmosphere at 100 °C for 24 h. After purification 1.7 g colorless oil was obtained (83% yield, Rf = 0.70, HPLC purity = 90%). IR (ATR) ~ν [cm-1]: 3408 (br, H2O), 2956 (s), 2930 (s), 2871 (s), 1620 (w), 1463 (m), 1098 (m), 719 (w). 1H NMR (DMSO-d6): δ 2.37 – 2.13 (m, 16H), 1.62 – 1.33 (m, 30H), 0.92 (t, J = 7.1, 18H). 13C NMR (DMSO-d6): δ 31.1 (t, J = 15.4), 23.3 (d, J = 15.7), 22.7 (d, J = 4.5), 20.1 (d, J = 3.8), 17.5 (d, J = 47.5), 17.4 (d, J = 47.5), 13.2.

Synthesis of hexan-1,6-diylbis-(tributylphosphonium) dibromide

0.75 g 1,6-dibromohexane (3.07 mmol) and 1.87 g tributylphosphine (9.24 mmol) were heated under argon atmosphere at 100 °C for 24 h. After purification 1.7 g colorless oil was obtained (88% yield, Rf = 0.71, HPLC purity = 97%). IR (ATR) ~ν [cm-1]: 3403 (br, H2O), 2956 (s), 2930 (s), 2871 (s), 1620 (w), 1462 (m), 1098 (m), 718 (w). 1H NMR (DMSO-d6): δ 2.33 – 2.12 (m, 16H), 1.58 – 1.32 (m, 32H), 0.92 (t, J = 7.1, 18H). 13C NMR (DMSO-d6): δ 29.3 (d, J = 15.6), 23.3 (d, J = 15.6), 22.7 (d, J = 4.4), 20.5 (d, J = 4.2), 17.6 (d, J = 47.7), 17.4 (d, J = 47.5), 13.3.

Synthesis of ethan-1,2-diylbis-(tripropylphosphonium) dibromide

0.35 g 1,2-dibromoethane (1.86 mmol) and 0.9 g tripropylphosphine (5.61 mmol) in 5 mL anhydrous acetonitrile were heated under argon atmosphere at 100 °C for 24 h. After purification and recrystallization 0.9 g white solid was obtained (64% yield, Rf = 0.52, m.p., 126 °C (DSC), HPLC purity = 99%). IR (ATR) ~ν [cm-1]: 3435 (s), 3376 (s), 2963 (s), 2930 (s), 2909 (s), 2873 (s), 1633 (w), 1459 (m), 1077 (m), 721 (w). 1H NMR (DMSO-d6): δ 2.62 – 2.54 (m, 4H), 2.43 – 2.25 (m, 12H), 1.68 – 1.44 (m, 12H), 1.03 (dt, J = 7.2, J = 0.9, 18H). 13C NMR (DMSO-d6): δ 20.1 – 18.7 (m), 15.5 – 15.0 (m), 14.9 – 14.5 (m), 12.0 – 10.5 (m).

Synthesis of propan-1,3-diylbis-(tripropylphosphonium) dibromide

0.39 g 1,3-dibromo-propane (1.93 mmol) and 0.92 g tripropylphosphine (5.74 mmol) in 5 mL anhydrous acetonitrile were heated un-der argon atmosphere at 100 °C for 24 h. After purification and recrystallization 1.3 g white solid was obtained (95% yield, R f = 0.52, m.p. 315 °C (DSC), HPLC purity = > 99%). IR (ATR) ~ν [cm-1]: 2965 (s), 2935 (s), 2899 (s), 2874 (s), 1461 (m), 1076 (m), 728 (w). 1H NMR (DMSO-d6): δ 2.48 – 2.37 (m, 4H), 2.37 – 2.18 (m, 12H), 1.84 – 1.68 (m, 2H), 1.62 – 1.47 (m, 12H), 1.03 (dt, J = 7.1, J = 0.9, 18H). 13C NMR (DMSO-d6): δ 19.6 (d, J = 47.6), 18.8 (dd, J = 48.8, J = 16.4), 15.2 (t, J = 10.6), 15.2 (d, J = 16.4), 14.7 (m).

Synthesis of butan-1,4-diylbis-(tripropylphosphonium) dibromide

0.81 g 1,4-dibromobutane (3.75 mmol) and 1.79 g tripropylphosphine (11.17 mmol) in 5 mL anhydrous acetonitrile were heated under argon atmosphere at 100 °C for 24 h. After purification 2.0 g white solid was obtained (95% yield, Rf = 0.54, m.p. 99 °C (DSC), HPLC

S7

purity = 95%). IR (ATR) ~ν [cm-1]: 3447 (m), 2961 (s), 2920 (s), 2873 (s), 1456 (m), 1407 (m), 1079 (m), 850 (m), 719 (w). 1H NMR (DMSO-d6): δ 2.40 – 2.27 (m, 4H), 2.27 – 2.10 (m, 12H), 1.72 – 1.59 (m, 4H), 1.59 – 1.45 (m, 12H), 1.02 (dt, J = 7.2, J = 1.4, 18H). 13C NMR (DMSO-d6): δ 21.8 (dd, J = 17.1, J = 4.0), 19.7 (d, J = 47.1), 17.3 (d, J = 47.9), 15.3 (d, J = 16.6), 14.7 (d, J = 4.4).

Synthesis of N1,N1,N1,N4,N4,N4-hexapropylbutan-1,4-diaminium dibromide

0.67 g 1,4-dibromobutane (3.10 mmol) and 2.66 g tripropylamine (18.57 mmol) were heated under argon atmosphere for 24 h at 100 °C. After purification 0.5 g white solid was obtained (35% yield, Rf = 0.49, m.p. 229 °C (DSC), HPLC purity = 94%). IR (ATR) ~ν [cm-1]: 2964 (s), 2873 (s), 1474 (s), 1457 (m), 750 (m). 1H NMR (DMSO-d6): δ 3.29 – 3.20 (m, 4H), 3.20 – 3.05 (m, 12H), 1.82 – 1.44 (m, 16H), 0.91 (t, J = 7.2, 18H). 13C NMR (DMSO-d6): δ 59.5, 57.3, 18.5, 14.8, 10.6.

Synthesis of pentan-1,5-diylbis-(tripropylphosphonium) dibromide

0.42 g 1,5-dibromo-pentane (1.83 mmol) and 0.87 g tripropylphosphine (5.43 mmol) in 5 mL anhydrous acetonitrile were heated un-der argon atmosphere at 100 °C for 24 h. After purification and recrystallization 1.2 g white solid was obtained (99% yield, R f = 0.52, m.p. 169 °C (DSC), HPLC purity = > 99%). IR (ATR) ~ν [cm-1]: 2963 (s), 2933 (s), 2873 (s), 1457 (m), 1087 (m), 721 (w). 1H NMR (DMSO-d6): δ 2.37 – 2.12 (m, 16H), 1.65 – 1.42 (m, 18H), 1.02 (dt, J = 7.2, J = 0.9, 18H). 13C NMR (DMSO-d6): δ 31.1 (t, J = 15.7), 20.1 (d, J = 3.8), 19.7 (d, J = 47.1), 17.6 (d, J = 47.4), 15.3 (d, J = 16.5), 14.7 (d, J = 4.3).

S8

Scheme S5. Synthetic route for the counterions for the trication series

Synthesis of (benzen-1,3,5-triyltris(methylen))tris(tributylphosphonium) tribromide

0.75 g 1,3,5-tris-(bromomethyl)-benzene (2.1 mmol) and 1.91 g tributylphosphine (9.44 mmol) in 5 mL anhydrous acetonitrile were heated under argon atmosphere at 100 °C for 48 h. After purification 1.4 g brown solid was obtained (69% yield, R f = 0.69, m.p. 95 °C, HPLC purity = 96%). IR (ATR) ~ν [cm-1]: 3435 (m), 2956 (s), 2930 (s), 2871 (s), 1601 (w), 1459 (m), 1098 (w), 720 (w). 1H NMR (DMSO-d6): δ 7.44 (m, 3H), 3.98 (d, J = 15.9, 6H), 2.44 – 2.15 (m, 18H), 1.58 – 1.29 (m, 36H), 0.90 (t, J = 7.1, 27H). 13C NMR (DMSO-d6): δ 132.0 (m), 131.6 (m), 25.7 (d, J = 44.7), 23.9 (d, J = 16.0), 23.2 (m), 18.0 (d, J = 46.8), 13.9.

Synthesis of (benzen-1,3,5-triyltris(methylen))tris-(tributylammonium) tribromide

0.78 g 1,3,5-tris-(bromomethyl)-benzene (2.19 mmol) and 1.83 g tributylamine (9.87 mmol) in 5 mL anhydrous acetonitrile were heated under argon atmosphere at 100 °C for 48 h. After purification 1.3 g brown solid was obtained (65% yield, R f = 0.61, m.p. 218 °C (DSC), HPLC purity = 97%). IR (ATR) ~ν [cm-1]: 3444 (w), 2958 (s), 2873 (s), 1457 (m), 1380 (m), 739 (m). 1H NMR (DMSO-d6): δ 7.78 (s, 3H), 4.64 (s, 6H), 3.32 – 3.20 (m, 18H), 1.88 – 1.64 (m, 18H), 1.33 (sext, J = 7.3, 18H), 0.97 (t, J = 7.3 Hz, 27H). 13C NMR (DMSO-d6): δ 138.6, 129.7, 60.5, 57.7, 23.7, 19.5, 13.7.

Synthesis of (benzen-1,3,5-triyltris(methylen))-tris-(tripropylphosphonium) tribromide

0.43 g 1,3,5-tris-(bromomethyl)-benzene (1.2 mmol) and 0.86 g tripropylphosphine (5.37 mmol) in 5 mL anhydrous acetonitrile were heated under argon atmosphere at 100 °C for 48 h. After purification 1.0 g brown solid was obtained (98% yield, R f = 0.50, m.p. 251 °C (DSC), HPLC purity = 98%). IR (ATR) ~ν [cm-1]: 3454 (s), 3397 (s), 2963 (s), 2914 (s), 2873 (s), 1600 (w), 1457 (m), 1087 (m), 720 (m). 1H NMR (DMSO-d6): δ 7.36 (m, 3H), 3.95 (d, J = 15.9, 6H), 2.41 – 2.20 (m, 18H), 1.70 – 1.40 (m, 18H), 1.03 (dt, J = 7.2, J = 0.8, 27H). 13C NMR (DMSO-d6): δ 131.6 – 131.2 (m), 131.2 – 130.9 (m), 25.2 (d, J = 44.7), 19.6 (d, J = 46.3), 15.3 (d, J = 16.9), 14.9 – 14.6 (m). The NMR data are consistent with the literature [6].

Synthesis of N,N',N''-(benzen-1,3,5-triyltris(methylene))-tris-(N,N-dipropylpropan-1-aminium) tribromide

0.91 g 1,3,5-tris-(bromomethyl)-benzene (2.55 mmol) and 1.64 g tripropylamine (11.45 mmol) in 5 mL anhydrous acetonitrile were heated under argon atmosphere at 100 °C for 48 h. After purification 1.3 g brown solid was obtained (60% yield, Rf = 0.46, m.p. 231 °C (DSC), HPLC purity = > 95%). IR (ATR) ~ν [cm-1]: 3442 (w), 2968 (s), 2875 (w), 1459 (w), 1380 (w), 748 (w). 1H NMR (DMSO-d6): δ 7.81 (s, 3H), 4.65 (s, 6H), 3.33 – 3.20 (m, 18H), 1.82 (m, 18H), 0.97 (t, J = 7.1, 27H). 13C NMR (DMSO-d6): δ 138.6, 129.7, 60.4, 59.1, 15.3, 10.8.

S9

Preparation of ionic liquids

Aqueous tetrabutylphosphonium and tetrabutylammonium hydroxide solution (40%) were purchased from Sigma-Aldrich. The halide anions of the synthesized counterions were exchanged by hydroxide anions with exchange resin (Dowex 1x8), using approximately 400 mg substance, dissolved in 20 mL deionized water, eluted through 6 g resin with 12 drops/min at room temperature. The eluate was reduced to approximately 10 mL in vacuo and stored at 4 °C. The test of residual halogens was performed by silver nitrate in acidified solutions with nitric acid. The concentrations of the phosphonium and ammonium hydroxide solutions, respectively, were de-termined by quantitative 1H NMR spectroscopy. Reference standard was 2 mg maleic acid TraceCERT qNMR, dissolved in a solution of 0.55 mL DMSO-d6, and 0.05 mL sample solution was added. The 1H measurements were performed with a relaxation delay time of 60 s. The integrals of the 1H resonances of maleic acid — between the 13C satellites (δ = approx. 6.1 – 6.4 ppm) and the terminal methyl groups of the cations (δ = ca. 0.8 – 1.0 ppm) — were used to assess the content with Eq. (1):

msample=

I sampleI ref

∗N ref

N sample∗M sample

M ref∗mref∗Pref

P sample

[Eq. (1)]

(m = mass in mg, I = integrated area, P = purity, N = number of protons under the signal, M = molecular weight)For salt preparation the aqueous counterion hydroxide solution was added to the free acid, dissolved in methanol, and stirred until a clear solution was obtained. The ratio of the counterions of the alkyl, benzyl and hydroxyl series to API was 1:1, dication series 1:2 and trication series 1:3 as determined by 1H NMR spectroscopy, using the area under the signals of the 1H signal at 1.09 ppm (d, J = 6.8 Hz) of Selurampanel and of the methyl groups of the counterions approximately between 0.8 – 1.0 ppm. The salts were dried for 48 h at 55 °C in vacuo. The sulfonamide group of the drug was deprotonated in all ionic liquids as assessed by infrared spectroscopy (IR; data not shown). All Ionic liquids were white to slightly yellow, solid substances (data not shown) and exceeded 95% purity (ex-cept P4444OH (78%), P4443isoOH, N444Θ (91%)) as determined by high performance liquid chromatography with a charged aerosol detector (HPLC-CAD; data not shown).

Scheme S6. Preparation of Selurampanel salts with counterions of the alkyl series

Scheme S7. Preparation of Selurampanel salts with counterions of the benzyl series

S10

Scheme S8. Preparation of Selurampanel salts with counterions of the hydroxyl series

Scheme S9. Preparation of Selurampanel salts with counterions of the dication series

Scheme S10. Preparation of Selurampanel salts with counterions of the trication series

S11

Ionic liquids of the alkyl series (Xnnnn)

Figure S11. 1H NMR spectrum of P4441 in DMSO-d6.

Data of P4441: TG 63 °C (DSC), HPLC purity = 97%. IR (ATR) ~ν [cm-1]: 2958 (s), 2930 (s), 2871 (s), 1713 (m), 1659 (s), 1625 (m), 1463 (w), 1415 (m), 1243 (s), 1103 (s), 776 (w). 1H NMR (DMSO-d6): δ 10.85 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.08 (s, 1H), 6.25 (d, J = 1.8, 1H), 3.55 (s, 3H), 2.70 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.29 – 2.10 (m, 6H), 1.78 (d, J = 14.0, 3H), 1.53 – 1.34 (m, 12H), 1.09 (d, J = 6.8, 6H), 0.91 (t, J = 7.1, 9H). 13C NMR (DMSO-d6): δ 162.1, 153.3, 152.4, 142.8, 140.7, 137.9, 129.0, 121.4, 113.3, 113.3, 106.8, 43.7, 36.3, 29.9, 23.4, 23.3 (d, J = 15.9), 22.6 (d, J = 4.4), 18.9 (d, J = 49.2), 13.3, 3.1 (d, J = 51.5).


Data of P4442: TG 53 °C (DSC), HPLC purity = 98%. IR (ATR) ~ν [cm-1]: 2957 (s), 2930 (s), 2871 (s), 1713 (m), 1659 (s), 1625 (m), 1463 (w), 1415 (m), 1242 (s), 1104 (s), 775 (w). 1H NMR (DMSO-d6): δ 10.94 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.08 (s, 1H), 6.25 (d, J = 1.8, 1H), 3.55 (s, 3H), 2.70 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.29 – 2.10 (m, 8H), 1.53 – 1.34 (m, 12H), 1.12 (dt, J = 18.2, J = 7.6, 3H), 1.09 (d, J = 6.8, 6H), 0.91 (t, J = 7.1, 9H). 13C NMR (DMSO-d6): δ 162.1, 153.5, 151.9, 140.7, 139.4, 137.9, 129.0, 122.6,

S12

113.3, 111.1, 106.8, 43.7, 36.3, 30.0, 23.3, 23.3 (d, J = 15.9), 22.6 (d, J = 4.4), 16.9 (d, J = 47.6), 13.2, 11.3 (d, J = 48.8), 5.3 (d, J = 5.3).

S13


Data of P4443: TG 56 °C (DSC), HPLC purity = 98%. IR (ATR) ~ν [cm-1]: 2959 (s), 2930 (s), 2871 (s), 1714 (m), 1659 (s), 1625 (m), 1463 (w), 1415 (m), 1243 (m), 1104 (s), 776 (w). 1H NMR (DMSO-d6): δ 10.89 (s, 1H), 7.54 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.08 (s, 1H), 6.25 (d, J = 1.8, 1H), 3.55 (s, 3H), 2.70 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.29 – 2.10 (m, 8H), 1.60 – 1.32 (m, 14H), 1.09 (d, J = 6.8, 6H), 1.01 (dt, J = 7.2, J = 1.6, 3H), 0.91 (t, J = 7.1, 9H). 13C NMR (DMSO-d6): δ 162.2, 153.3, 152.6, 142.8, 140.8, 137.9, 129.0, 121.8, 113.4, 112.0, 106.8, 43.7, 36.3, 29.9, 23.3, 23.3 (d, J = 15.9), 22.6 (d, J = 3.9), 19.5 (d, J = 47.3), 17.3 (d, J = 47.6), 15.2 (d, J = 16.4), 14.7 (d, J = 4.1), 13.3.


Data of P4444: TG 57 °C (DSC), HPLC purity = 98%. IR (ATR) ~ν [cm-1]: 2958 (s), 2931 (s), 2872 (s), 1714 (m), 1660 (s), 1625 (m), 1461 (w), 1415 (m), 1243 (m), 1104 (s), 776 (w), 720 (w). 1H NMR (DMSO-d6): δ 10.61 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.09 (s, 1H), 6.25 (d, J = 1.8, 1H), 3.55 (s, 3H), 2.72 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.27 – 2.10 (m, 8H), 1.54 – 1.32 (m, 16H), 1.09 (d, J = 6.8, 6H), 0.91 (t, J = 7.1, 12H). 13C NMR (DMSO-d6): δ 162.1, 153.3, 152.4, 142.8, 140.7, 137.8, 128.9, 121.4, 113.3, 113.3, 106.7, 43.6, 36.2, 29.9, 23.4, 23.3 (d, J = 15.6), 22.6 (d, J = 4.5), 17.3 (d, J = 47.6), 13.2.

S14

Figure S15. 1H NMR spectrum of N4444 in DMSO-d6.

Data of N4444: TG 69 °C, HPLC purity = 99%. IR (ATR) ~ν [cm-1]: 2959 (s), 2931 (m), 2873 (m), 1714 (m), 1660 (s), 1625 (m), 1599 (m), 1458 (m), 1416 (m), 1244 (m), 1104 (m), 775 (w). 1H NMR (DMSO-d6): δ 10.58 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.10 (s, 1H), 6.25 (d, J = 1.8, 1H), 3.55 (s, 3H), 3.23 – 3.08 (m, 8H), 2.74 (s, 3H), 2.66 (sept, J = 6.8, 1H), 1.64 – 1.50 (m, 8H), 1.31 (sext, J = 7.4, 8H), 1.09 (d, J = 6.8, 6H), 0.93 (t, J = 7.1, 12H). 13C NMR (DMSO-d6): δ 162.0, 153.5, 152.3, 142.8, 140.7, 137.8, 129.0, 121.6, 113.2, 113.2, 106.8, 57.5, 43.6, 36.3, 30.0, 23.4, 23.0, 19.2, 13.5.


Data of P4445: TG 51 °C (DSC), HPLC purity = 95%. IR (ATR) ~ν [cm-1]: 2957 (m), 2928 (m), 2871 (m), 1714 (m), 1660 (s), 1625 (m), 1462 (w), 1416 (m), 1244 (m), 1104 (s), 776 (w). 1H NMR (DMSO-d6): δ 10.61 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.11 (s, 1H), 6.25 (d, J = 1.8, 1H), 3.55 (s, 3H), 2.75 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.27 – 2.10 (m, 8H), 1.55 – 1.26 (m, 18H), 1.09 (d, J = 6.8, 6H), 0.91 (t, J = 7.1, 9H), 0.87 (t, J = 7.2, 3H). 13C NMR (DMSO-d6): δ 162.0, 153.5, 152.3, 142.8, 140.7, 137.8, 129.0, 121.5, 113.2, 113.2, 106.8, 43.6, 36.3, 32.2 (d, J = 15.2), 30.0, 23.3 (d, J = 15.6), 23.2, 22.6 (d, J = 4.5), 21.3, 20.2 (d, J = 4.3), 17.5 (d, J = 47.5), 17.3 (d, J = 47.6), 13.6, 13.2

S15


Data of P4446: TG 41 °C (DSC), HPLC purity = 97%. IR (ATR) ~ν [cm-1]: 2957 (m), 2928 (m), 2871 (m), 1714 (m), 1660 (s), 1625 (m), 1463 (w), 1416 (m), 1245 (m), 1106 (s), 776 (w). 1H NMR (DMSO-d6): δ 10.61 (s, 1H), 7.58 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.14 (s, 1H), 6.26 (d, J = 1.8, 1H), 3.55 (s, 3H), 2.79 (s, 3H), 2.67 (sept, J = 6.8, 1H), 2.27 – 2.10 (m, 8H), 1.64 – 1.34 (m, 16H), 1.34 – 1.20 (m, 4H), 1.09 (d, J = 6.8, 6H), 0.90 (t, J = 7.1, 9H), 0.86 (t, J = 6.6, 3H). 13C NMR (DMSO-d6): δ 161.9, 153.9, 151.9, 142.5, 140.6, 137.9, 129.1, 122.0, 113.0, 113.0, 106.8, 43.6, 36.3, 30.4, 30.0, 29.7 (d, J = 15.1), 23.4, 23.3 (d, J = 15.6), 22.6 (d, J = 4.4), 21.8, 20.5 (d, J = 4.4), 17.5 (d, J = 47.4), 17.3 (d, J = 47.6), 13.8, 13.2.

Ionic liquids of the benzyl series (XnnnΘY)

Figure S18. 1H NMR spectrum of P444Θ in DMSO-d6.

Data of P444Ɵ: TG 64 °C (DSC), HPLC purity = 99%. IR (ATR) ~ν [cm-1]: 2958 (m), 2929 (m), 2871 (m), 1714 (m), 1658 (s), 1625 (m), 1455 (w), 1415 (m), 1242 (m), 1104 (s), 775 (w). 1H NMR (DMSO-d6): δ 10.56 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.46 – 7.32 (m, 5H), 7.11 (s, 1H), 6.25 (d, J = 1.8, 1H), 3.82 (d, J = 15.5, 2H), 3.55 (s, 3H), 2.75 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.26 – 2.03 (m, 6H), 1.60 – 1.20 (m, 12H), 1.09 (d, J = 6.8, 6H), 0.87 (t, J = 7.0, 9H). 13C NMR (DMSO-d6): δ 162.0, 153.6, 152.3, 142.8, 140.7, 137.9,

S16

130.0 (d, J = 8.6), 129.3 (d, J = 8.6), 129.2 (d, J = 2.9), 129.0, 128.0 (d, J = 3.4), 121.7, 113.2, 113.2, 106.8, 43.6, 36.3, 30.0, 25.4 (d, J = 44.6), 23.4, 23.3 (d, J = 15.8), 22.5 (d, J = 4.6), 17.3 (d, J = 47.0), 13.2.

S17

Figure S19. 1H NMR spectrum of N444Θ in DMSO-d6.

Data of N444Ɵ: TG 85 °C, HPLC purity = 91%. IR (ATR) ~ν [cm-1]: 2960 (s), 2931 (m), 2873 (m), 1713 (m), 1660 (s), 1625 (s), 1600 (s), 1458 (m), 1417 (m), 1244 (m), 1106 (s), 726 (w). 1H NMR (DMSO-d6): δ 10.64 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.60 – 7.45 (m, 5H), 7.10 (s, 1H), 6.25 (d, J = 1.8, 1H), 4.54 (s, 2H), 3.55 (s, 3H), 3.20 – 3.00 (m, 6H), 2.74 (s, 3H), 2.66 (sept, J = 6.8, 1H), 1.85 – 1.60 (m, 6H), 1.30 (sext, J = 7.3, 6H), 1.09 (d, J = 6.8, 6H), 0.94 (t, J = 7.3, 9H). 13C NMR (DMSO-d6): δ 162.1, 153.5, 152.3, 142.8, 140.7, 137.9, 132.5, 130.3, 129.1, 129.0, 127.9, 121.7, 113.2, 113.2, 106.8, 61.3, 57.5, 43.6, 36.3, 30.0, 23.4, 23.3, 19.2, 13.5.

Figure S20. 1H NMR spectrum of P444ΘF in DMSO-d6.

Data of P444ƟF: TG 51 °C (DSC), HPLC purity = 98%. IR (ATR) ~ν [cm-1]: 2959 (m), 2931 (m), 2872 (m), 1714 (m), 1660 (s), 1625 (m), 1509 (m), 1463 (w), 1416 (m), 1245 (m), 1104 (s), 776 (w). 1H NMR (DMSO-d6): δ 10.62 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.44 – 7.34 (m, 2H), 7.32 – 7.22 (m, 2H), 7.10 (s, 1H), 6.25 (d, J = 1.8, 1H), 3.81 (d, J = 15.2, 2H), 3.55 (s, 3H), 2.76 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.26 – 2.03 (m, 6H), 1.60 – 1.20 (m, 12H), 1.09 (d, J = 6.8, 6H), 0.89 (t, J = 7.0, 9H). 13C NMR (DMSO-d6): δ 162.0, 161.8 (dd, J = 244.4, J = 3.7), 153.5, 151.9, 142.8, 139.4, 137.9, 132.0 (dd, J = 8.3, J = 4.9), 129.0, 125.5 (dd, J = 8.5, J = 3.2), 122.6, 116.1 (dd, J = 21.6, J = 2.9), 113.2, 113.2, 106.8, 43.6, 36.3, 30.0, 24.6 (d, J = 44.9), 23.4, 23.3 (d, J = 15.7), 22.5 (d, J = 4.6), 17.3 (d, J = 47.0), 13.2.

S18

Figure S21. 1H NMR spectrum of N444ΘF in DMSO-d6.

Data of N444ƟF: TG 84 °C, HPLC purity = 98%. IR (ATR) ~ν [cm-1]: 2961 (s), 2931 (m), 2873 (m), 1714 (m), 1660 (s), 1625 (s), 1603 (s), 1513 (m), 1471 (m), 1417 (m), 1229 (s), 1104 (s), 726 (w). 1H NMR (DMSO-d6): δ 10.62 (s, 1H), 7.60 – 7.52 (m, 2H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.40 – 7.31 (m, 2H), 7.10 (s, 1H), 6.25 (d, J = 1.8, 1H), 4.54 (s, 2H), 3.55 (s, 3H), 3.20 – 3.00 (m, 6H), 2.73 (s, 3H), 2.66 (sept, J = 6.8, 1H), 1.87 – 1.65 (m, 6H), 1.30 (sext, J = 7.3, 6H), 1.09 (d, J = 6.8, 6H), 0.93 (t, J = 7.3, 9H). 13C NMR (DMSO-d6): δ 163.1 (d, J = 248.0), 162.0, 153.5, 152.3, 142.8, 140.7, 137.9, 135.0 (d, J = 8.7), 129.0, 124.3 (d, J = 3.2), 121.7, 116.1 (d, J = 21.7), 113.2, 113.2, 106.8, 60.4, 57.4, 43.6, 36.3, 29.9, 23.4, 23.3, 19.2, 13.5.

Figure S22. 1H NMR spectrum of P444ΘCl in DMSO-d6.

Data of P444ƟCl: TG 77 °C (DSC), HPLC purity = 98%. IR (ATR) ~ν [cm-1]: 2957 (m), 2930 (m), 2872 (m), 1713 (m), 1659 (s), 1625 (m), 1463 (w), 1413 (m), 1240 (m), 1101 (s), 775 (w). 1H NMR (DMSO-d6): δ 10.96 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.49 – 7.47 (m, 2H), 7.39 – 7.36 (m, 2H), 7.09 (s, 1H), 6.26 (d, J = 1.8, 1H), 3.83 (d, J = 15.5, 2H), 3.55 (s, 3H), 2.71 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.26 – 2.03 (m, 6H), 1.60 – 1.20 (m, 12H), 1.09 (d, J = 6.8, 6H), 0.88 (t, J = 7.1, 9H). 13C NMR (DMSO-d6): δ 162.1, 153.5, 152.2, 142.8, 140.7, 137.9, 132.8 (d, J = 4.1), 131.9 (d, J = 4.8), 129.2 (d, J = 2.8), 129.0, 128.4 (d, J = 8.6), 121.8, 113.3, 113.3, 106.8, 43.7, 36.3, 30.0, 24.8 (d, J = 44.5), 23.4, 23.3 (d, J = 15.9), 22.5 (d, J = 4.5), 17.3 (d, J = 46.9), 13.2.

S19

Figure S23. 1H NMR spectrum of P444ΘI in DMSO-d6.

Data of P444ƟI: TG 73 °C (DSC), HPLC purity = 98%. IR (ATR) ~ν [cm-1]: 2958 (m), 2930 (m), 2871 (m), 1713 (m), 1659 (s), 1625 (m), 1462 (w), 1415 (m), 1240 (m), 1103 (s), 775 (w). 1H NMR (DMSO-d6): δ 10.75 (s, 1H), 7.81 – 7.77 (m, 2H), 7.57 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.18 – 7.14 (m, 2H), 7.11 (s, 1H), 6.26 (d, J = 1.8, 1H), 3.79 (d, J = 15.5, 2H), 3.55 (s, 3H), 2.70 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.26 – 2.03 (m, 6H), 1.60 – 1.20 (m, 12H), 1.09 (d, J = 6.8, 6H), 0.88 (t, J = 6.9, 9H). 13C NMR (DMSO-d6): δ 161.9, 153.8, 152.0, 142.8, 140.6, 137.9, 137.9 (d, J = 3.0), 132.2 (d, J = 4.9), 129.1, 129.0 (d, J = 8.5), 121.9, 113.1, 113.1, 106.8, 94.4 (d, J = 4.6), 43.6, 36.3, 30.0, 25.0 (d, J = 44.4), 23.4, 23.3 (d, J = 15.8), 22.5 (d, J = 4.6), 17.3 (d, J = 46.8), 13.2.

Figure S24. 1H NMR spectrum of P444ΘCF3 in DMSO-d6.

Data of P444ƟCF3: TG 82 °C (DSC), HPLC purity = 99 %. IR (ATR) ~ν [cm-1]: 2959 (m), 2930 (m), 2873 (m), 1714 (m), 1660 (s), 1625 (m), 1464 (w), 1417 (m), 1323 (s), 1241 (m), 1106 (s), 1066 (m), 776 (w). 1H NMR (DMSO-d6): δ 10.72 (s, 1H), 7.82 – 7.78 (m, 2H), 7.62 – 7.58 (m, 2H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.10 (s, 1H), 6.26 (d, J = 1.8, 1H), 3.96 (d, J = 15.9, 2H), 3.55 (s, 3H), 2.70 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.26 – 2.03 (m, 6H), 1.60 – 1.20 (m, 12H), 1.09 (d, J = 6.8, 6H), 0.88 (t, J = 6.9, 9H). 13C NMR (DMSO-d6): δ 162.0, 153.7, 152.2, 142.8, 140.7, 137.9, 134.5 (dd, J = 8.4, J = 1.3), 131.0 (d, J = 4.8), 129.1, 128.5 (dq, J = 32.0, J = 3.5), 126.0 (m), 124.1 (dq, J = 272.1, J = 1.4), 121.8, 113.2, 113.2, 106.8, 43.7, 36.3, 30.0, 25.4 (d, J = 44.1), 23.4, 23.3 (d, J = 16.0), 22.5 (d, J = 4.6), 17.3 (d, J = 46.7), 13.2.

S20

Figure S25. 1H NMR spectrum of N333Ɵ in DMSO-d6.

Data of N333Ɵ: TG 86 °C, HPLC purity = 97%. IR (ATR) ~ν [cm-1]: 2967 (s), 2935 (m), 2875 (m), 1713 (m), 1659 (s), 1625 (s), 1596 (m), 1458 (m), 1416 (m), 1242 (s), 1103 (s), 727 (w). 1H NMR (DMSO-d6): δ 10.85 (s, 1H), 7.64 – 7.38 (m, 5H), 7.55 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.09 (s, 1H), 6.25 (d, J = 1.8, 1H), 4.54 (s, 2H), 3.55 (s, 3H), 3.18 – 2.92 (m, 6H), 2.72 (s, 3H), 2.66 (sept, J = 6.8, 1H), 1.87 – 1.65 (m, 6H), 1.09 (d, J = 6.8, 6H), 0.89 (t, J = 7.3, 9H). 13C NMR (DMSO-d6): δ 162.1, 153.4, 152.3, 142.8, 140.7, 137.9, 132.5, 130.3, 129.1, 129.0, 127.9, 121.8, 113.3, 113.3, 106.8, 61.3, 59.0, 43.7, 36.3, 29.9, 23.4, 15.0, 10.4.

Figure S26. 1H NMR spectrum of P333ƟF in DMSO-d6.

Data of P333ƟF: TG 81 °C, HPLC purity = 99%. IR (ATR) ~ν [cm-1]: 2965 (m), 2931 (m), 2875 (m), 1714 (m), 1656 (s), 1625 (m), 1509 (m), 1459 (w), 1415 (m), 1226 (s), 1104 (s), 776 (w). 1H NMR (DMSO-d6): δ 10.99 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.42 – 7.36 (m, 2H), 7.30 – 7.23 (m, 2H), 7.10 (s, 1H), 6.26 (d, J = 1.8, 1H), 3.81 (d, J = 15.3, 2H), 3.55 (s, 3H), 2.69 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.22 – 2.08 (m, 6H), 1.54 – 1.41 (m, 12H), 1.09 (d, J = 6.8, 6H), 0.98 (dt, J = 7.3, J = 1.6, 9H). 13C NMR (DMSO-d6): δ 162.1, 161.8 (dd, J = 244.6, J = 3.8), 153.5, 152.2, 142.5, 140.8, 137.9, 132.0 (dd, J = 8.3, J = 4.9), 129.0, 125.4 (dd, J = 8.5, J = 3.2), 122.4, 116.1 (dd, J = 21.6, J = 3.0), 113.3, 111.1, 106.8, 43.7, 36.3, 30.0, 24.7 (d, J = 44.8), 23.4, 19.5 (d, J = 46.4), 15.3 (d, J = 16.6), 14.6 (d, J = 4.4).

S21

Figure S27. 1H NMR spectrum of N333ƟF in DMSO-d6.

Data of N333ƟF: TG 78 °C, HPLC purity = 99%. IR (ATR) ~ν [cm-1]: 2966 (s), 2935 (m), 2875 (m), 1714 (m), 1660 (s), 1625 (s), 1603 (s), 1513 (m), 1473 (m), 1416 (m), 1229 (s), 1103 (s), 752 (w). 1H NMR (DMSO-d6): δ 10.75 (s, 1H), 7.60 – 7.51 (m, 2H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.42 – 7.33 (m, 2H), 7.10 (s, 1H), 6.25 (d, J = 1.8, 1H), 4.53 (s, 2H), 3.55 (s, 3H), 3.18 – 2.92 (m, 6H), 2.72 (s, 3H), 2.66 (sept, J = 6.8, 1H), 1.87 – 1.65 (m, 6H), 1.09 (d, J = 6.8, 6H), 0.89 (t, J = 7.3, 9H). 13C NMR (DMSO-d6): δ 163.1 (d, J = 248.0), 162.1, 153.4, 152.4, 142.1, 140.8, 137.9, 134.9 (d, J = 8.8), 129.0, 124.2 (d, J = 3.2), 121.7, 116.1 (d, J = 21.7), 113.3, 113.3, 106.8, 60.4, 58.9, 43.6, 36.3, 30.0, 23.4, 15.0, 10.4.

Ionic liquids of the hydroxyl series (XnnnnOH)

Figure S28. 1H NMR spectrum of P4442OH in DMSO-d6.

Data of P4442OH: TG 97 °C, HPLC purity = 97%. IR (ATR) ~ν [cm-1]: 3115 (br), 2957 (m), 2930 (m), 2871 (m), 1714 (m), 1660 (s), 1625 (m), 1463 (w), 1415 (m), 1251 (m), 1107 (m), 776 (w). 1H NMR (DMSO-d6): δ 10.53 (s, 1H), 7.57 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.13 (s, 1H), 6.25 (d, J = 1.8, 1H), 5.80 (br, 1H), 3.78 (dt, J = 18.8, J = 6.1, 2H), 3.55 (s, 3H), 2.75 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.44 (dt, J = 12.5, J = 6.1, 2H), 2.29 – 2.10 (m, 6H), 1.58 – 1.30 (m, 12H), 1.09 (d, J = 6.8, 6H), 0.89 (t, J = 7.2, 9H). 13C NMR (DMSO-d6): δ

S22

162.1, 153.7, 152.2, 142.8, 140.6, 137.9, 129.0, 121.9, 113.2, 113.1, 106.8, 54.3 (d, J = 6.1), 43.6, 36.3, 30.0, 23.4, 23.3 (d, J = 15.9), 22.7 (d, J = 4.5), 21.7 (d, J = 48.0), 18.2 (d, J = 47.5), 13.2.


Data of P4443OH: TG 77 °C, HPLC purity = 97%. IR (ATR) ~ν [cm-1]: 3108 (br), 2957 (m), 2930 (m), 2872 (m), 1715 (m), 1660 (s), 1625 (m), 1463 (w), 1414 (m), 1241 (m), 1104 (m), 776 (w). 1H NMR (DMSO-d6): δ 10.80 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.10 (s, 1H), 6.25 (d, J = 1.8, 1H), 4.89 (br, 1H), 3.55 (s, 3H), 3.47 (t, J = 5.9, 2H), 2.73 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.30 – 2.10 (m, 8H), 1.72 – 1.57 (m, 2H), 1.55 – 1.32 (m, 12H), 1.09 (d, J = 6.8, 6H), 0.91 (t, J = 7.2, 9H). 13C NMR (DMSO-d6): δ 162.0, 153.5, 152.3, 142.8, 140.7, 137.9, 129.0, 121.7, 113.2, 113.2, 106.8, 60.4 (d, J = 15.7), 43.6, 36.3, 30.0, 24.1 (d, J = 4.3), 23.4, 23.3 (d, J = 15.9), 22.6 (d, J = 4.5), 17.4 (d, J = 47.8), 14.7 (d, J = 49.3), 13.2.

Figure S30. 1H NMR spectrum of P4443isoOH in DMSO-d6.

Data of P4443isoOH: TG 58 °C, HPLC purity = 91%. IR (ATR) ~ν [cm-1]: 3114 (br), 2959 (m), 2931 (m), 2872 (m), 1715 (m), 1660 (s), 1625 (m), 1462 (w), 1414 (m), 1244 (m), 1105 (m), 776 (w). 1H NMR (DMSO-d6): δ 10.67 (s, 1H), 7.57 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.11 (s, 1H), 6.25 (d, J = 1.8, 1H), 5.57 (br, 1H), 4.04 (m, 1H), 3.55 (s, 3H), 2.75 (s, 3H), 2.66 (sept, J = 6.8, 1H), 2.46 – 2.27 (m, 2H), 2.26 – 2.10 (m, 6H), 1.61 – 1.30 (m, 2H), 1.23 (dd, J = 6.0, J = 2.4, 3H), 1.09 (d, J = 6.8, 6H), 0.90 (t, J = 7.2, 9H). 13C NMR (DMSO-d6): δ

S23

162.0, 153.5, 152.3, 142.1, 140.7, 137.9, 129.0, 121.7, 113.2, 113.2, 106.8, 61.5 (d, J = 6.3), 43.6, 36.3, 30.0, 27.5 (d, J = 48.8), 25.6 (d, J = 14.3), 23.4, 23.4 (d, J = 15.9), 22.7 (d, J = 4.5), 18.4 (d, J = 47.8), 13.2.


Data of P4444OH: TG 58 °C, HPLC purity = 78%. IR (ATR) ~ν [cm-1]: 3114 (br), 2957 (m), 2928 (m), 2867 (m), 1715 (m), 1659 (s), 1623 (m), 1454 (w), 1416 (m), 1242 (m), 1105 (m), 776 (w). 1H NMR (DMSO-d6): δ 10.62 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 1.8, 1H), 7.10 (s, 1H), 6.25 (d, J = 1.8, 1H), 4.52 (br, 1H), 3.55 (s, 3H), 3.44 (t, J = 5.6, 2H), 2.74 (s, 3H), 2.67 (sept, J = 6.8, 1H), 2.43 – 2.11 (m, 8H), 1.70 – 1.30 (m, 16H), 1.09 (d, J = 6.8, 6H), 0.91 (t, J = 7.1, 9H). 13C NMR (DMSO-d6): δ 162.0, 153.7, 152.1, 142.8, 140.6, 137.9, 129.0, 121.8, 113.1, 113.1, 106.8, 59.5, 43.6, 36.3, 30.0, 23.4, 23.3 (d, J = 15.6), 17.5 (d, J = 4.2), 17.4 (d, J = 47.3), 17.3 (d, J = 47.6), 13.2.

Ionic liquids of the dication series (Xnnn-m-Xnnn)

Figure S32. 1H NMR spectrum of P444-2-P444 in DMSO-d6.

Data of P444-2-P444: TG 106 °C, HPLC purity = 99%. IR (ATR) ~ν [cm-1]: 2958 (s), 2930 (s), 2871 (s), 1714 (m), 1657 (s), 1625 (m), 1463 (w), 1414 (m), 1239 (m), 1104 (m), 776 (w). 1H NMR (DMSO-d6): δ 10.92 (s, 2H), 7.57 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.12 (s, 2H), 6.25

S24

(d, J = 1.8, 2H), 3.54 (s, 6H), 2.71 (s, 6H), 2.66 (sept, J = 6.8, 2H), 2.82 – 2.58 (m, 4H), 2.40 – 2.25 (m, 12H), 1.60 – 1.30 (m, 24H), 1.09 (d, J = 6.8, 12H), 0.88 (t, J = 7.2, 18H). 13C NMR (DMSO-d6): δ 162.2, 153.7, 152.2, 142.8, 140.6, 137.9, 129.0, 121.7, 113.2, 113.2, 106.8, 43.7, 36.3, 30.0, 23.4, 23.5 – 23.1 (m), 22.8 – 22.4 (m), 17.8 – 16.4 (m), 11.5 – 10.3 (m), 13.3.


Data of P444-3-P444: TG 105 °C (DSC), HPLC purity = > 99%. IR (ATR) ~ν [cm-1]: 2958 (m), 2930 (m), 2872 (m), 1714 (m), 1660 (s), 1625 (s), 1458 (w), 1416 (m), 1241 (m), 1104 (s), 776 (w). 1H NMR (DMSO-d6): δ 10.77 (s, 2H), 7.58 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.14 (s, 2H), 6.25 (d, J = 1.8, 2H), 3.55 (s, 6H), 2.74 (s, 6H), 2.66 (sept, J = 6.8, 2H), 2.58 – 2.38 (m, 4H), 2.33 – 2.25 (m, 12H), 1.86 – 1.66 (m, 2H), 1.61 – 1.31 (m, 24H), 1.09 (d, J = 6.8, 12H), 0.92 (t, J = 7.2, 18H). 13C NMR (DMSO-d6): δ 162.0, 153.8, 152.0, 142.8, 140.5, 137.9, 129.0, 122.0, 113.2, 113.2, 106.8, 43.6, 36.3, 30.0, 23.4, 23.3 (t, J = 10.3), 23.3 (d, J = 15.8), 22.8 – 22.5 (m), 18.6 (dd, J = 48.5, J = 16.6), 17.3 (d, J = 47.9), 13.3.


Data of P444-4-P444: TG 89 °C (DSC), HPLC purity = 97%. IR (ATR) ~ν [cm-1]: 2958 (s), 2930 (s), 2872 (s), 1713 (m), 1659 (s), 1625 (s), 1458 (w), 1413 (m), 1240 (m), 1103 (s), 776 (w). 1H NMR (DMSO-d6): δ 10.85 (s, 2H), 7.56 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.11 (s, 2H), 6.25 (d, J = 1.8, 2H), 3.55 (s, 6H), 2.71 (s, 6H), 2.66 (sept, J = 6.8, 2H), 2.43 – 2.28 (m, 4H), 2.28 – 2.11 (m, 12H), 1.72 – 1.56 (m,

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4H), 1.56 – 1.30 (m, 24H), 1.09 (d, J = 6.8, 12H), 0.88 (t, J = 7.2, 18H). 13C NMR (DMSO-d6): δ 162.1, 153.5, 152.3, 142.8, 140.7, 137.9, 129.0, 121.8, 113.3, 113.3, 106.8, 43.7, 36.3, 30.0, 23.4, 23.4 (d, J = 15.8), 22.7 (d, J = 4.6), 21.8 (dd, J = 3.8, J = 16.8), 17.4 (d, J = 47.6), 17.1 (d, J = 48.1), 13.2.

Figure S35. 1H NMR spectrum of N444-4-N444 in DMSO-d6.

Data of N444-4-N444: TG 96 °C, HPLC purity = 99%, IR (ATR) ~ν [cm-1]: 2961 (s), 2931 (m), 2873 (m), 1714 (m), 1660 (s), 1625 (s), 1599 (s), 1467 (m), 1416 (m), 1240 (m), 1103 (m), 776 (w). 1H NMR (DMSO-d6): δ 10.66 (s, 2H), 7.56 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.11 (s, 2H), 6.24 (d, J = 1.8, 2H), 3.54 (s, 6H), 3.40 – 3.27 (m, 4H), 3.27 – 3.10 (m, 12H), 2.71 (s, 6H), 2.66 (sept, J = 6.8, 2H), 1.79 – 1.66 (m, 4H), 1.66 – 1.50 (m, 12H), 1.33 (sext, J = 7.3, 12H), 1.09 (d, J = 6.8, 12H), 0.90 (t, J = 7.3, 18H). 13C NMR (DMSO-d6): δ 162.2, 153.4, 152.5, 142.8, 140.7, 137.9, 129.0, 121.6, 113.3, 113.3, 106.7, 57.8, 57.3, 43.7, 36.3, 29.9, 23.4, 23.1, 19.2, 18.6, 13.5.


Data of P444-5-P444: TG 90 °C, HPLC purity = 96%. IR (ATR) ~ν [cm-1]: 2959 (s), 2931 (s), 2871 (s), 1715 (m), 1660 (s), 1626 (s), 1461 (w), 1416 (m), 1241 (m), 1105 (s), 775 (w). 1H NMR (DMSO-d6): δ 10.75 (s, 2H), 7.59 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.14 (s, 2H), 6.26 (d, J = 1.8, 2H), 3.55 (s, 6H), 2.80 (s, 6H), 2.67 (sept, J = 6.8, 2H), 2.31 – 2.10 (m, 16H), 1.62 – 1.30 (m, 30H), 1.09 (d, J = 6.8, 12H),

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0.89 (t, J = 7.1, 18H). 13C NMR (DMSO-d6): δ 161.8, 154.0, 151.8, 142.1, 140.5, 137.9, 129.1, 121.1, 113.1, 113.0, 106.8, 43.6, 36.3, 31.3 (t, J = 15.6), 30.0, 23.3, 23.3 (d, J = 15.7), 22.7 (d, J = 4.4), 20.1 (d, J = 3.8), 17.5 (d, J = 47.7), 17.3 (d, J = 47.6), 13.2.


Data of P444-6-P444: TG 81 °C, HPLC purity = > 99%. IR (ATR) ~ν [cm-1]: 2958 (s), 2929 (s), 2871 (s), 1714 (m), 1660 (s), 1625 (s), 1462 (w), 1415 (m), 1241 (m), 1104 (s), 775 (w). 1H NMR (DMSO-d6): δ 10.58 (s, 2H), 7.56 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.11 (s, 2H), 6.25 (d, J = 1.8, 2H), 3.55 (s, 6H), 2.74 (s, 6H), 2.66 (sept, J = 6.8, 2H), 2.31 – 2.10 (m, 16H), 1.62 – 1.30 (m, 32H), 1.09 (d, J = 6.8, 12H), 0.90 (t, J = 7.1, 18H). 13C NMR (DMSO-d6): δ 162.0, 153.7, 152.2, 142.8, 140.7, 137.9, 129.1, 121.8, 113.2, 113.2, 106.8, 43.7, 36.3, 30.0, 29.4 (d, J = 15.8), 23.4, 23.3 (d, J = 15.6), 22.6 (d, J = 4.4), 20.5 (d, J = 4.4), 17.5 (d, J = 47.4), 17.3 (d, J = 47.3), 13.2.


Data of P333-2-P333: TG 124 °C (DSC), HPLC purity = 99%. IR (ATR) ~ν [cm-1]: 2964 (s), 2931 (s), 2875 (s), 1713 (m), 1659 (s), 1625 (s), 1458 (w), 1414 (m), 1238 (m), 1104 (s), 775 (w). 1H NMR (DMSO-d6): δ 10.78 (s, 2H), 7.57 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.13 (s, 2H), 6.25 (d, J = 1.8, 2H), 3.55 (s, 6H), 2.71 (s, 6H), 2.67 (sept, J = 6.8, 2H), 2.79 – 2.62 (m, 4H), 2.43 – 2.25 (m, 12H), 1.68 – 1.44 (m, 12H), 1.09 (d, J = 6.8, 12H), 0.99 (dt, J = 7.1, J = 0.9, 18H). 13C NMR (DMSO-d6): δ 162.2, 153.7, 152.3, 142.8, 140.6, 137.9, 129.0, 121.7, 113.1, 113.1, 106.8, 43.7, 36.3, 30.0, 23.4, 20.0 – 18.5 (m), 15.4 – 15.0 (m), 14.8 – 14.6 (m), 12.0 – 10.5 (m).

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Data of P333-3-P333: TG 106 °C (DSC), HPLC purity = > 99%. IR (ATR) ~ν [cm-1]: 2964 (s), 2928 (s), 2875 (s), 1714 (m), 1656 (s), 1625 (s), 1457 (w), 1414 (m), 1239 (m), 1104 (s), 775 (w). 1H NMR (DMSO-d6): δ 10.77 (s, 2H), 7.56 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.12 (s, 2H), 6.25 (d, J = 1.8, 2H), 3.55 (s, 6H), 2.70 (s, 6H), 2.66 (sept, J = 6.8, 2H), 2.48 – 2.37 (m, 4H), 2.31 – 2.16 (m, 12H), 1.84 – 1.71 (m, 2H), 1.61 – 1.43 (m, 12H), 1.09 (d, J = 6.8, 12H), 0.99 (dt, J = 7.0, J = 1.0, 18H). 13C NMR (DMSO-d6): δ 162.2, 153.6, 152.3, 142.8, 140.6, 137.9, 129.0, 122.0, 113.2, 113.2, 106.8, 43.7, 36.3, 30.0, 23.4, 19.4 (d, J = 47.7), 18.8 (dd, J = 48.6, J = 16.9), 15.2 (t, J

= 10.8), 15.2 (d, J = 16.5), 14.7 (m).


Data of P333-4-P333: TG 107 °C (DSC), HPLC purity = 98%. IR (ATR) ~ν [cm-1]: 2963 (s), 2930 (s), 2873 (s), 1714 (m), 1658 (s), 1625 (s), 1459 (w), 1413 (m), 1239 (m), 1104 (s), 775 (w). 1H NMR (DMSO-d6): δ 10.67 (s, 2H), 7.56 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.12 (s, 2H), 6.25 (d, J = 1.8, 2H), 3.55 (s, 6H), 2.72 (s, 6H), 2.66 (sept, J = 6.8, 2H), 2.40 – 2.25 (m, 4H), 2.25 – 2.10 (m, 12H), 1.72 – 1.59 (m, 4H), 1.59 – 1.45 (m, 12H), 1.09 (d, J = 6.8, 12H), 1.00 (dt, J = 7.1, J = 1.4, 18H). 13C NMR (DMSO-d6): δ 162.1, 153.6, 152.2, 142.8,

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140.6, 137.9, 129.0, 121.8, 113.3, 113.3, 106.8, 43.7, 36.3, 30.0, 23.4, 21.8 (dd, J = 17.1, J = 4.0), 19.6 (d, J = 47.1), 17.2 (d, J = 48.1), 15.3 (d, J = 16.6), 14.7 (d, J = 4.3).

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Figure S41. 1H NMR spectrum of N333-4-N333 in DMSO-d6.

Data of N333-4-N333: TG 114 °C, HPLC purity = 97%. IR (ATR) ~ν [cm-1]: 2967 (s), 2935 (m), 2878 (m), 1713 (m), 1659 (s), 1624 (s), 1600 (s), 1463 (m), 1414 (m), 1240 (m), 1104 (m), 776 (w). 1H NMR (DMSO-d6): δ 10.72 (s, 2H), 7.56 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.12 (s, 2H), 6.25 (d, J = 1.8, 2H), 3.55 (s, 6H), 3.40 – 3.22 (m, 4H), 3.22 – 3.03 (m, 12H), 2.73 (s, 6H), 2.66 (sept, J = 6.8, 2H), 1.79 – 1.52 (m, 16H), 1.09 (d, J = 6.8, 12H), 0.88 (t, J = 7.2, 18H). 13C NMR (DMSO-d6): δ 162.1, 153.6, 152.2, 142.7, 140.6, 137.9, 129.0, 121.8, 113.2, 113.2, 106.8, 59.4, 57.4, 43.7, 36.3, 30.0, 23.4, 18.5, 14.8, 10.5.


Data of P333-5-P333: TG 101 °C (DSC), HPLC purity = > 99%. IR (ATR) ~ν [cm-1]: 2963 (s), 2930 (s), 2872 (s), 1714 (m), 1660 (s), 1625 (s), 1460 (w), 1413 (m), 1239 (m), 1104 (s), 775 (w). 1H NMR (DMSO-d6): δ 10.68 (s, 2H), 7.56 (s, 2H), 7.49 (d, J = 1.8, 2H), 7.11 (s, 2H), 6.25 (d, J = 1.8, 2H), 3.55 (s, 6H), 2.71 (s, 6H), 2.67 (sept, J = 6.8, 2H), 2.31 – 2.09 (m, 16H), 1.62 – 1.42 (m, 18H), 1.09 (d, J = 6.8, 12H), 0.99 (dt, J = 7.2, J = 1.4, 18H). 13C NMR (DMSO-d6): δ 161.1, 153.5, 152.5, 142.8, 140.7, 137.9, 129.0, 121.8, 113.3, 113.3, 106.8, 43.7, 36.3, 31.3 (t, J = 15.7), 30.0, 23.3, 20.1 (d, J = 3.5), 19.6 (d, J = 47.1), 17.6 (d, J = 47.4), 15.2 (d, J = 16.5), 14.7 (d, J = 4.3).

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Ionic liquids of the trication series (triXnnn)

Figure S43. 1H NMR spectrum of triP444 in DMSO-d6.

Data of triP444: TG 125 °C, HPLC purity = 97%. IR (ATR) ~ν [cm-1]: 2958 (s), 2927 (s), 2871 (s), 1714 (s), 1657 (s), 1625 (s), 1598 (s), 1462 (m), 1413 (m), 1240 (s), 1105 (s), 776 (w). 1H NMR (DMSO-d6): δ 10.95 (s, 3H), 7.64 (d, J = 1.8, 3H), 7.57 (s, 3H), 7.49 (d, J = 1.8, 3H), 7.13 (s, 3H), 6.24 (d, J = 1.8, 3H), 3.98 (d, J = 15.9, 6H), 3.54 (s, 9H), 2.71 (s, 9H), 2.67 (sept, J = 6.8, 3H), 2.31 – 2.13 (m, 18H), 1.49 – 1.25 (m, 36H), 1.09 (d, J = 6.8, 18H), 0.82 (t, J = 7.1, 27H). 13C NMR (DMSO-d6): δ 162.2, 153.7, 152.2, 142.8, 140.5, 137.9, 131.5, 129.0, 122.0, 113.1, 113.1, 106.8, 43.6, 36.3, 30.0, 25.1 (d, J = 45.3) 23.3 (d, J = 16.3), 23.4, 22.7 (m), 17.5 (d, J = 47.0), 13.2.

Figure S44. 1H NMR spectrum of triN444 in DMSO-d6.

Data of triN444: TG 146 °C, HPLC purity = 95%. IR (ATR) ~ν [cm-1]: 2960 (s), 2931 (s), 2873 (s), 1714 (s), 1658 (s), 1625 (s), 1599 (s), 1463 (m), 1415 (m), 1239 (s), 1104 (s), 879 (w), 774 (w). 1H NMR (DMSO-d6): δ 10.87 (s, 3H), 8.00 (s, 3H), 7.57 (s, 3H), 7.49 (d, J =

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1.8, 3H), 7.16 (s, 3H), 6.24 (d, J = 1.8, 3H), 4.77 (s, 6H), 3.54 (s, 9H), 3.35 – 3.18 (m, 18H), 2.71 (s, 9H), 2.66 (sept, J = 6.8, 3H), 1.82 – 1.56 (m, 18H), 1.28 (sext, J = 7.3, 18H), 1.09 (d, J = 6.8, 18H), 0.87 (t, J = 7.3, 27H). 13C NMR (DMSO-d6): δ 162.2, 153.7, 152.2, 142.8, 140.6, 138.8, 137.9, 129.9, 129.0, 122.0, 113.1, 112.9, 106.7, 60.8, 58.0, 43.6, 36.3, 30.0, 23.7, 23.4, 19.4. 13.6.

Figure S45. 1H NMR spectrum of triP333 in DMSO-d6.

Data of triP333: TG 140 °C, HPLC purity = 96%. IR (ATR) ~ν [cm-1]: 2962 (s), 2927 (s), 2875 (s), 1713 (s), 1656 (s), 1625 (s), 1596 (s), 1458 (m), 1412 (m), 1238 (s), 1104 (s), 774 (w). 1H NMR (DMSO-d6): δ 10.89 (s, 3H), 7.63 (d, J = 1.9, 3H), 7.58 (s, 3H), 7.49 (d, J = 1.8, 3H), 7.15 (s, 3H), 6.24 (d, J = 1.8, 3H), 3.99 (d, J = 15.9, 6H), 3.54 (s, 9H), 2.71 (s, 9H), 2.67 (sept, J = 6.8, 3H), 2.33 – 2.13 (m, 18H), 1.58 – 1.38 (m, 18H), 1.09 (d, J = 6.8, 18H), 0.94 (dt, J = 7.1, J = 0.9, 27H). 13C NMR (DMSO-d6): δ 162.3, 153.8, 152.2, 142.8, 140.5, 137.9, 131.4, 129.0, 122.0, 113.1, 113.1, 106.8, 43.6, 36.3, 30.0, 25.1 (d, J = 44.0) 23.4, 19.7 (d, J = 46.5), 15.2 (d, J = 17.0), 14.8 – 14.7 (m).

Figure S46. 1H NMR spectrum of triN333 in DMSO-d6.

Data of triN333: TG 148 °C, HPLC purity = too strong retention on column, therefore 1H NMR purity = > 95%, IR (ATR) ~ν [cm-1]: 2964 (s), 2878 (s), 1714 (s), 1659 (s), 1625 (s), 1599 (s), 1458 (m), 1415 (m), 1238 (s), 1104 (s), 751 (w). 1H NMR (DMSO-d6): δ 10.83 (s, 3H), 7.91 (s, 3H), 7.56 (s, 3H), 7.49 (d, J = 1.8, 3H), 7.14 (s, 3H), 6.25 (d, J = 1.8, 3H), 4.75 (s, 6H), 3.54 (s, 9H), 3.27 – 3.12 (m,

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18H), 2.70 (s, 9H), 2.66 (sept, J = 6.8, 3H), 1.89 – 1.62 (m, 18H), 1.09 (d, J = 6.8, 18H), 0.89 (t, J = 7.2, 27H). 13C NMR (DMSO-d6): δ 162.2, 153.6, 152.2, 142.8, 140.6, 138.6, 137.9, 129.9, 129.0, 121.9, 113.2, 113.2, 106.8, 60.5, 59.3, 43.6, 36.3, 30.0, 23.4, 15.3, 10.6.

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X-ray powder diffractograms of ionic liquids (XRPD)

Figure S47. XRPD diffractograms of the free acid and ionic liquids

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Dynamic vapor sorption data of ionic liquids (DVS)

Figure S48. DVS plot of P4441.


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S37



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Figure S55. DVS plot of P444Θ.

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Figure S56. DVS plot of N444Θ.

Figure S57. DVS plot of P444ΘF.

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Figure S58. DVS plot of N444ΘF.

Figure S59. DVS plot of P444ΘCl.

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Figure S60. DVS plot of P444ΘI.

Figure S61. DVS plot of P444ΘCF3.

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Figure S62. DVS plot of N333Θ.

Figure S63. DVS plot of P333ΘF.

S46

Figure S64. DVS plot of N333ΘF.

Figure S65. DVS plot of P4442OH.

S47


Figure S67. DVS plot of P4443isoOH.

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Figure S69. DVS plot of P444-2-P444.

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Figure S72. DVS plot of N444-4-N444.


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Figure S78. DVS plot of N333-4-N333.


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Figure S80. DVS plot of triP444.

Figure S81. DVS plot of triN444.

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Figure S82. DVS plot of triP333.

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Flux, duration of supersaturation, water sorption and cytotoxicity

Figure S83. Comparison of (A) flux [µmol min-1 cm-2] and (B) duration of supersaturation [min] of the free acid and the ionic liquids. Significant differences of the ionic liquids to the ionic liquid P4444 are indicated by asterisks (p ≤ 0.05).

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Figure S84. Comparison of (A) flux [µmol min-1 cm-2] of ammonium vs phosphonium analogs and (B) plotted against each other. Comparison of (C) duration of su-persaturation [min] of ammonium vs phosphonium analogs and (D) plotted against each other. Comparison of (E) water sorption [%] of ammonium vs phospho -nium analogs at 90% RH and (F) plotted against each other.

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Figure S85. Duration of supersaturation [min] of the ionic liquids plotted against S/S0

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Figure S86. Overview of the water sorption [%] of the ionic liquids at 90% RH.

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Figure S87. IC50 values [µM] of the counterions as bromide, chloride or iodide salts (see synthesis section) in (A) human hepatic cells HepG2, (B) human kidney cells HEK293T and (C) murine macrophages J774.1. Because of precipitation in the assay with murine macrophages the highest used concentration for N 333-4-N333

was 200 µM.

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Molecular descriptors of the counterions

Table S88. Molecular descriptors used for prediction of flux and water sorption.

substance code n_hydrophobic diameter n_charge

P4441 13 8 1

P4442 14 8 1

P4443 15 8 1

P4444 16 8 1

N4444 16 8 1

P4445 17 9 1

P4446 18 10 1

P444Ø 19 9 1

N444Ø 19 9 1

P444ØF 20 10 1

N444ØF 20 10 1

P444ØCl 20 10 1

P444ØI 20 10 1

P444ØCF3 23 11 1

N333Ø 16 8 1

P333ØF 17 9 1

N333ØF 17 9 1

P4442OH 14 8 1

P4443OH 15 8 1

P4443isoOH 15 8 1

P4444OH 16 9 1

P444-2-P444 26 11 2

P444-3-P444 27 12 2

P444-4-P444 28 13 2

N444-4-N444 28 13 2

P444-5-P444 29 14 2

P444-6-P444 30 15 2

P333-2-P333 20 9 2

P333-3-P333 21 10 2

P333-4-P333 22 11 2

N333-4-N333 22 11 2

P333-5-P333 23 12 2

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triP444 45 14 3

triN444 45 14 3

triP333 36 12 3

triN333 36 12 3

S64

Stability study of the ionic liquids used in animal study

Figure S89. DSC data of free acid.

Figure S90. DSC data of P4444.

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Figure S91. DSC data of P333-4-P333.

Figure S92. DSC data of triP444.

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Figure S93. XRPD data of free acid.

Figure S94. XRPD data of P4444.

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Figure S95. XRPD data of P333-4-P333.

Figure S96. XRPD data of triP444.

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Pharmacokinetic studies

Figure S97. Selurampanel plasma concentration [µg mL-1] of micronized free acid (A), P4444 (B), P333-4-P333 (C) and triP444 (D) orally administered as powder filled in capsules. Rat 96 and Rat 100 showed no exposure of Selurampanel in the P 4444 group (in red), these data were excluded. It should be noted that data is shown here and additionally in Figure 4 for the ease of understanding.

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References

[1] M. Selva, M. Fabris, V. Lucchini, A. Perosa, M. Noe, The reaction of primary aromatic amines with alkylene carbonates for the selective synthesis of bis-N-(2-hydroxy)alkylanilines: the catalytic effect of phosphonium-based ionic liquids, Org. Biomol. Chem., 8 (2010) 5187-5198.[2] G. Adamova, R.L. Gardas, M. Nieuwenhuyzen, A.V. Puga, L.P.N. Rebelo, A.J. Robertson, K.R. Seddon, Alkyltributylphosphonium chloride ionic liquids: synthesis, physicochemical properties and crystal structure, Dalton Trans., 41 (2012) 8316-8332.[3] J. Cvengros, S. Toma, S. Marque, A. Loupy, Synthesis of phosphonium salts under microwave acti-vation: Leaving group and phosphine substituents effects, Can. J. Chem., 82 (2004) 1365-1371.[4] B.F. Mentzen, A. Tuel, F. Bayard, Location of the tripropylbenzylammonium ion (P3BZY) in the as-synthesized zeolite ZSM-5: A study by solid-state NMR, computer simulations and X-ray synchrotron powder diffraction, Micropor. Mesopor. Mat., 93 (2006) 171-179.[5] M.Z. Ovakimyan, S.K. Barsegyan, N.M. Kikoyan, M.G. Indzhikyan, Properties of Onium Salts of Phosphorus and Nitrogen, Russ. J. Gen. Chem., 75 (2005) 1074-1076.[6] P.S. Sharma, T. Payagala, E. Wanigasekara, A.B. Wijeratne, J. Huang, D.W. Armstrong, Trigonal Tricationic Ionic Liquids: Molecular Engineering of Trications to Control Physiochemical Properties, Chem. Mater., 20 (2008) 4182-4184.

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