Synthesis, characterization and properties of amino acid ionic liquids derived from the triaminocyclopropenium cation

Abstract

Amino acid ionic liquids (AAILs) [C₃(NEt₂)₂(NHR)]X (X = MeSO₄ and NTf₂) based on the triaminocyclopropenium (TAC) cation were synthesized where NHR is derived from an amino acid. Reaction of the alkoxycyclopropenium salt [C₃(NEt₂)₂(OCH₃)]MeSO₄ with an amino acid in the presence of Et₃N gives the corresponding AAILs; the methylsulfate anion was readily exchanged for bistriflamide. Monocations were obtained with L-alanine, L-proline, L-valine, L-threonine, L-serine, L-methionine, L-leucine, L-isoleucine, L-tryptophan, L-tyrosine and L-phenylalanine, whereas dications were obtained with L-lysine (two TAC cations), L-histidine (one TAC and one imidazolium cation) and L-arginine (one TAC and one guanidinium cation). L-Cysteine generated a mixture of the monocationic IL as well as a dication containing one TAC cation and one thiodiaminocyclopropenium cation. L-Asparagine and L-glutamine appear to produce mixtures of amino-linked and amido-linked TAC cations. These materials were obtained as a mixture of the IL and its zwitterion which was initially indicated by the ¹H NMR giving a reduced integral for the methylsulfate anion. The ratios of these IL/zwitterion mixtures were determined by pH titration and microanalysis. The chloride contents, decomposition temperatures, DSC data, viscosity, specific rotations, and pK_a values were determined and solubility studies were also carried out.

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Introduction

The term ‘ionic liquid’ (IL) refers to ionic materials that are liquids below 100 °C. They consist almost exclusively of ions and consequently have almost no vapour pressure. Combined with low flammability, good conductivity, ease of recycling and tuneable properties, ILs have become attractive for a large variety of applications.¹ Chiral ionic liquids (CILs) are becoming an important sub-class of ILs. Whereas chiral molecular solvents are rare and generally expensive, a large variety of CILs can be readily prepared via asymmetric synthesis or by incorporation of naturally-occurring chiral substrates. The first CIL, 1-butyl-3-methylimidazolium lactate, was reported in 1999.² Since then, research on CILs has been increasing rapidly and CILs have been successfully used as chiral solvents and chiral catalysts in a variety of asymmetric syntheses.³

Amino acid ionic liquids (AAILs) are a subset of CILs that are derived from amino acids. Amino acids are effective and excellent starting materials for the preparation of functional CILs: they come from the “chiral pool”,⁴ can contain a variety of functional groups and, due to their resemblance to biochemical substrates, AA-derived ILs have excellent potential for biodegradability. This property of biochemical substrate resemblance may also result in beneficial pharmaceutical applications with either increased or decreased toxicity;⁵ it should be possible to tune the toxicity of these materials. AAILs have also been shown to have excellent CO₂ absorption and membrane transport properties.^6–10 These factors, along with their low volatility, relatively low cost, ready availability and promising recyclability and/or biodegradability, make them extremely interesting from a green chemistry viewpoint.¹¹

The simplest route to an AAIL is by protonation or deprotonation of the amino or carboxylic group with an acid or base, respectively, to give the corresponding cation or anion, respectively. The AAILs are thus constructed without modification of the amino acid, and the side chain of the amino acid moiety is preserved. For example, cationic AAILs were derived directly by Tao et al. and Mu et al. from the amino acid by treatment with HCl, HNO₃, HBF₄, HPF₆, CF₃COOH and H₂SO₄ (Scheme 1).^12,13 Similarly, amino acid ester hydrochlorides can be turned into AAILs by either anion metathesis or by reaction of the chloride with a Lewis acid such as AlCl₃ or FeCl₂ (Scheme 1).¹⁴ The neutralization of ammonium,^15–18 phosphonium^16,19 or imidazolium²⁰ hydroxide by amino acids form the corresponding salts with anionic AAs and without any by-products other than water (Scheme 2).

Scheme 1 Acidic syntheses of AAILs.^12–14

Scheme 2 Basic syntheses of AAILs.^15–20

Other routes to AAILs involve derivatization of some species using an amino acid.²¹ For example, amino acid-derived guanidiniums were synthesized by reaction of chloroamidinium salts with amino acid methyl esters (L-alanine, L-valine and L-leucine) (Scheme 3).²² These classes of AAILs will resemble the original AA to varying degrees.

Scheme 3 Synthesis of guanidinium-based AAILs.²²

We introduced the triaminocyclopropenium (TAC) cation as a new class of IL in 2011.²³ TAC salts have attracted much interest^24,25 since they were first reported in 1971 by Yoshida and Tawara.²⁶ Despite the steric strain of the three-membered ring, these cations are remarkably unreactive: they are stable in boiling water and we have reported that the [NTf₂]⁻ salts can have thermal decomposition onset temperatures above 400 °C.²³ A high-lying HOMO results in an unusually low oxidation potential^27,28 and is also responsible for particularly weak cation–anion interactions. Experimentally, it has been observed that halides preferentially coordinate to other compounds instead: chloride hydrates,^29,30 iodide–iodoacetylene³¹ and iodide–iodoarene³² adducts have all been isolated from tris(dialkylamino)cyclopropenium (TDAC) halide salts. We have even observed weak dicationic dimers in the solid state structures of unsolvated TDAC halide salts.³³

Bandar and Lambert synthesized the first chiral TAC-based salt by attaching phenylalaninol to the TAC cation (Scheme 4), however, this salt is not an IL due to its high melting point.³⁴ The salt was then converted to the corresponding cyclopropenimine which was used as an enantioselective Brønsted base catalyst.

Scheme 4 Synthesis of first TAC-based chiral salt.³⁴

In this paper, we will discuss the preparation and properties of amino acid derived TAC ILs. Some of this work has been communicated earlier.³⁵

Experimental

All operations were performed using standard Schlenk techniques with a dinitrogen atmosphere in order to reduce exposure to water. ¹H-, ¹³C{¹H}-NMR spectra were collected on an Agilent DD2-400MR operating at 400 and 100 MHz, respectively or on a Varian INOVA-500 operating at 500 and 126 MHz, respectively, in CDCl₃, referenced to residual solvent peaks. FTIR spectra were obtained on the neat liquids using a Bruker ALPHA ATR spectrometer. Viscosities were measured from 20 °C (or above if solid) to 90 °C on a Brookfield DV-II+ Pro cone and plate sealed viscometer under inert atmosphere. Thermal Gravimetric Analysis (TGA) was determined with a thermal analysis instrument TA Q600 SDT (DSC-TGA) by utilizing platinum pans with 5 to 10 mg of the dry sample. The heating rate for TGA was 1 °C min⁻¹ and 10 °C min⁻¹ under nitrogen from 25 to 600 °C. Differential scanning calorimetry (DSC) was carried out on a Perkin Elmer DSC 8000. Three heating and cooling cycles were carried out from −100 to 100 °C or −100 to 150 °C using a scan rate of 10 °C min⁻¹, using a sample size of 2–10 mg and data was taken from the second run. Specific rotation was measured on a Perkin Elmer Polarimeter 341 after dissolving the sample in CHCl₃ or CH₃CN. For all the synthesized CILs, pK_a was determined by acid-base titration with the help of a calibrated pH meter. For CILs having methylsulfate as the anion, a known amount (0.01–0.1 g) was added to a 10 mL measuring flask and the volume was made up with Milli-Q water. For NTf₂⁻ salts, a known amount of CIL (0.010–1 g) was dissolved in 12 mL of acetone and then the volume of 10 mL measuring flask was made with Milli-Q water. A standard 0.001 M solution of NaOH was used to titrate against the 10 mL solution of CIL. The pK_a was calculated as pH at half equivalence point.

Triethylamine, amino acids, dimethylsulfate and lithium bistriflamide were purchased from Sigma Aldrich or Merck. C₃Cl₅H was synthesized by a known procedure.³⁶

General procedures for the synthesis of [C₃(NEt₂)₂(NHR)]⁺ salts ([E₄AA]⁺)

Four general procedures were used that differ mostly in the isolation and purification steps.

Procedure A. [C₃(NEt₂)₂(OMe)]MeSO₄ was stirred with L-amino acid and NEt₃ in water (50 mL) for one hour. Water was removed in vacuo and the product was dissolved in acetone (20 mL) and filtered to remove unreacted amino acid. The mixture was dissolved in ice cold water and the product was extracted with chloroform : ethanol (2 : 1) (3 × 30 mL). The solvent was removed in vacuo to give the AAIL as the methylsulfate salt (1a, 1b, 1j and 1k). [E₄AA]MeSO₄ was stirred with LiNTf₂ in 10 mL of water. The product was extracted with chloroform (3 × 10 mL) to give [E₄AA]NTf₂ (2a, 2b, 2j and 2k).

Procedure B. [C₃(NEt₂)₂(OMe)]MeSO₄ was stirred with L-amino acid and NEt₃ in water (50 mL) for one hour. A cold solution of NaOH (8 g in 10 mL water) was added to the aqueous mixture and Et₃N was extracted with diethylether (6 × 50 mL). The solution was acidified with HCl to pH = 1–2 and water was removed in vacuo. The mixture was dissolved in ethanol and filtered to remove NaCl and L-amino acid. The solvent was removed in vacuo to give [E₄AA]MeSO₄. [E₄AA]MeSO₄ was stirred with LiNTf₂ in 50 mL of water for 30 minutes. Ethanol (1 mL) was added to induce formation of a separate layer. The product was washed with water (3 × 10 mL) and dried in vacuo to give a light yellow viscous oil of [E₄AA]NTf₂ (2c, 2d, 2e, 2g and 2l).

Procedure C. [C₃(NEt₂)₂(OMe)]MeSO₄ was stirred with L-amino acid and NEt₃ in water (50 mL) for one hour. A cold solution of NaOH (8 g in 10 mL water) was added to the aqueous mixture and Et₃N was extracted with diethylether (6 × 50 mL). The solution was acidified with HCl to pH = 1–2 and water was removed in vacuo. The mixture was dissolved in acetone and filter to remove NaCl and L-amino acid and solvent was removed in vacuo to give a yellow viscous oil of [E₄AA]MeSO₄. [E₄AA]MeSO₄ was stirred with LiNTf₂ in 50 mL of water for 30 minutes. The product was extracted with CHCl₃ (3 × 50 mL), washed with water (3 × 50 mL) and dried in vacuo to give 2f and 2i.

Procedure D. [C₃(NEt₂)₂(OMe)]MeSO₄ was stirred with L-amino acid and NEt₃ in water (50 mL) for one hour. A cold solution of NaOH (8 g in 10 mL water) was added to the aqueous mixture and Et₃N was extracted with diethylether (6 × 50 mL). The solution was acidified with HCl to pH = 1–2 and water was removed in vacuo. The mixture was dissolved in ethanol and filtered to remove NaCl and L-amino acid. The solvent was removed in vacuo to give a yellow viscous oil of [E₄AA]MeSO₄. [E₄AA]MeSO₄ was stirred with LiNTf₂ in 50 mL of water for 30 minutes. Ethanol (1 mL) was added to induce a separate layer. The product is washed with water (3 × 10 mL) and dried in vacuo to give a mixture of [E₄AA]NTf₂ with its methyl and ethyl esters. The mixture was heated to reflux overnight with conc. HCl (60 mL) to hydrolyze the esters and then dried in vacuo. The product was washed with water (3 × 50 mL) and dried in vacuo to give [E₄AA]NTf₂ (2h and 2m).

Bis(diethylamino)-S-(1-carboxyethylamino)cyclopropenium methylsulfate, [C₃(NEt₂)₂(NH(CHMeCOOH))]MeSO₄, [E₄Ala]MeSO₄ (1a). Using procedure A, [C₃(NEt₂)₂(OMe)]MeSO₄ (10 g, 31 mmol), L-alanine (3.59 g, 40 mmol) and NEt₃ (6.4 mL, 40 mmol) gave an orange viscous oil of 1a (10 g, 77%). ¹H NMR (500 MHz, CDCl₃): δ 8.36 (m, 1H, NH), 5.65 (br, 1H, COOH), 4.01 (m, 1H, CH), 3.71 (s, 1.68H, CH₃SO₄), 3.38 (m, 8H, NCH₂CH₃), 1.58 (d, ³J_HH = 7.0 Hz, 3H, Me), 1.24 (t, ³J_HH = 6.6 Hz, 12H, NCH₂CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 175.37 (COOH), 115.75 (unique ring C), 115.18 (equivalent ring C), 56.54 (CHMe), 54.74 (CH₃SO₄), 46.54 (NCH₂CH₃), 18.34 (CHCH₃), 14.22 (NCH₂CH₃). FT-IR (cm⁻¹): 3204 (w), 2975 (w), 2937 (w), 1721 (w), 1532 (s), 1447 (m), 1383 (mw), 1359 (mw), 1300 (mw), 1248 (m), 1213 (ms), 1192 (ms), 1167 (m), 1059 (m), 1008 (ms), 760 (m), 736 (ms). ES-MS: found m/z 268.2023 (M⁺); calcd: 268.2020 (M⁺). Anal. calcd for 0.62(C₁₅H₂₉N₃O₆S) : 0.38(C₁₄H₂₅N₃O₂) + 4% H₂O: C, 51.28; H, 8.46; N, 12.34. Found: C, 51.70; H, 8.34; N, 11.82.

Bis(diethylamino)-S-(1-carboxy-2-methylpropylamino)cyclopropenium methylsulfate, [C₃(NEt₂)₂(NH(C₄H₈COOH))]MeSO₄, [E₄Val]MeSO₄ (1b). Using procedure A, [C₃(NEt₂)₂(OMe)]MeSO₄ (15 g, 47 mmol), L-valine (7.09 g, 61 mmol) and NEt₃ (9.7 mL, 61 mmol) gave an orange viscous oil of 1b (10 g, 55%). ¹H NMR (400 MHz, CDCl₃): δ 8.44 (br, 1H, NH), 3.67 (s, 0.97H, CH₃SO₄), 3.62 (d, ³J_HH = 6.4 Hz, 1H, CH), 3.38 (m, 8H, NCH₂CH₃), 2.23 (m, 1H, CH), 1.22 (t, ³J_HH = 7.2 Hz, 12H, NCH₂CH₃), 1.03 (d, ³J_HH = 6.8 Hz, 3H, CH₃), 0.98 (d, ³J_HH = 7.0 Hz, 3H, CH₃). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 174.25 (COOH), 115.87 (equivalent ring C), 115.46 (unique ring C), 68.82 (CHNH), 54.27 (CH₃SO₄), 46.62 (NCH₂CH₃), 31.00 (CH(CH₃)₂), 19.28 (CH₃), 18.80 (CH₃), 14.27 (NCH₂CH₃). FT-IR (cm⁻¹): 3200 (w), 2969 (w), 2937 (w), 1532 (s), 1447 (m), 1383 (m), 1359 (mw), 1301 (mw), 1248 (m), 1216 (ms), 1193 (m), 1058 (m), 1010 (ms), 745 (m). ES-MS: found m/z 296.2335 (M⁺); calcd: 296.2333 (M⁺). Anal. calcd for 0.45(C₁₇H₃₃N₃O₆S) : 0.55(C₁₆H₂₉N₃O₂) + 0.9% H₂O: C, 57.74; H, 9.13; N, 12.34. Found: C, 57.10; H, 9.01; N, 12.08.

Bis(diethylamino)-S-(1-carboxy-2-hyroxylpropylamino)cyclopropenium methylsulfate, [C₃(NEt₂)₂(NH(C₃H₆OCOOH))]MeSO₄, [E₄Thr]MeSO₄ (1j). Using procedure A, [C₃(NEt₂)₂(OMe)]MeSO₄ (10 g, 31 mmol), L-threonine (4.8 g, 40 mmol) and NEt₃ (6.5 mL, 40 mmol) gave an orange viscous oil of 1j (9.3 g, 76%). ¹H NMR (500 MHz, CDCl₃): δ 8.04 (br, 1H, NH), 5.27 (br, 2H, OH + H₂O), 4.08 (m, 1H, NCH), 3.69 (m, 1H, CHOH), 3.67 (s, 0.6H, CH₃SO₄), 3.37 (q, ³J_HH = 7.16 Hz, 8H, NCH₂CH₃), 1.23 (d, ³J_HH = 7.5 Hz, 3H, CH₃), 1.21 (t, ³J_HH = 7.25 Hz, 12H, NCH₂CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 173.37 (COOH), 115.98 (equivalent ring C), 115.35 (unique ring C), 67.78 (CHCH₃), 67.20 (CHNH), 54.31 (CH₃SO₄), 46.49 (NCH₂CH₃), 19.42 (CH₃), 14.20 (NCH₂CH₃). FT-IR (cm⁻¹): 3216 (w, br), 2976 (w), 2937 (w), 1722 (w), 1534 (s), 1446 (m), 1384 (mw), 1350 (m), 1300 (mw), 1254 (m), 1217 (m), 1182 (s), 1137 (m), 1056 (ms), 1008 (ms), 740 (m). ES-MS: found m/z 298.2125 (M⁺); calcd: 298.2125 (M⁺). Anal. calcd for 0.45(C₁₆H₃₁N₃O₇S) : 0.55(C₁₅H₂₇N₃O₃) + 0.3% H₂O: C, 54.27; H, 8.47; N, 12.35. Found: C, 54.31; H, 8.78; N, 12.23.

Bis(diethylamino)-S-(2-carboxypyrrolidino)cyclopropenium methylsulfate, [C₃(NEt₂)₂(N(C₄H₇COOH))]MeSO₄, [E₄Pro]MeSO₄ (1k). Using procedure A, [C₃(NEt₂)₂(OMe)]MeSO₄ (5.65 g, 18 mmol), L-proline (2.62 g, 23 mmol) and NEt₃ (3.64 mL, 23 mmol) gave an orange oil of 1k (5.5 g, 78%). ¹H NMR (400 MHz, CDCl₃): δ 7.37 (br, 1H, COOH), 4.42 (dd, ³J_HH = 3.6 Hz, ³J_HH = 8 Hz, 1H, CH), 3.72 (m, 1H, NCH₂), 3.68 (s, 1.43H, CH₃SO₄), 3.60 (ddd, ³J_HH = 7.9 Hz, 1H, NCH₂), 3.34 (m, 8H, NCH₂CH₃), 2.31 (m, 2H, NCH₂CH₂CH₂), 2.01 (m, 2H, NCH₂CH₂), 1.21 (t, ³J_HH = 6.6 Hz, 12H, NCH₂CH₃). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 174.09 (COOH), 116.08 (equivalent ring C), 114.80 (unique ring C), 64.60 (NCH), 54.26 (CH₃SO₄), 51.89 (NCH₂), 46.77 (NCH₂CH₃), 31.13 (NCHCH₂), 24.32 (NCH₂CH₂CH₂), 13.94 (NCH₂CH₃). ES-MS: found m/z 294.2179 (M⁺); calcd: 294.2176 (M⁺). Anal. calcd for 0.65(C₁₇H₃₁N₃O₆S) : 0.35(C₁₆H₂₇N₃O₂) + 2.9% H₂O: C, 54.03; H, 8.33; N, 11.40. Found: C, 54.57; H, 8.89; N, 11.59.

Bis(diethylamino)-S-(1-carboxyethylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NH(CHMeCOOH))]NTf₂, [E₄Ala]NTf₂ (2a). Using procedure A, [E₄Ala]MeSO₄ (2.1 g, 5 mmol) was stirred with LiNTf₂ (4.8 g, 16 mmol) to give 2a (2.6 g, 81%). ¹H NMR (500 MHz, CDCl₃): δ 9.18 (br, 1H, COOH), 6.99 (d, ³J_HH = 7.0 Hz, 1H, NH), 4.03 (m, 1H, CH), 3.35 (q, ³J_HH = 7.5 Hz, 8H, NCH₂CH₃), 1.51 (d, ³J_HH = 7.0 Hz, 3H, CH₃), 1.22 (t, ³J_HH = 7.2 Hz, 12H, NCH₂CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 175.36 (COOH), 119.82 (q, ¹J_CF = 320 Hz, CF₃), 116.04 (equivalent ring C), 114.01 (unique ring C), 56.05 (CHMe), 46.65 (NCH₂CH₃), 18.65 (CH₃), 14.1 (NCH₂CH₃). FT-IR (cm⁻¹): 3338 (w), 2982 (w), 1733 (w), 1532 (m), 1450 (mw), 1386 (m), 1348 (m), 1177 (s), 1133 (ms), 1053 (ms), 788 (mw), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 268.2021 (M⁺); calcd: 268.2020 (M⁺). Anal. calcd for 0.93(C₁₆H₂₆N₄O₆S₂F₆) : 0.07(C₁₄H₂₅N₃O₂) + 0.9% H₂O: C, 36.61; H, 5.16; N, 10.49. Found: C, 36.14; H, 5.31; N, 10.40.

Bis(diethylamino)-S-(1-carboxy-2-methylpropylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NH(C₄H₈COOH))]NTf₂, [E₄Val]NTf₂ (2b). Using procedure A, [E₄Val]MeSO₄ (2 g, 5 mmol) was stirred with LiNTf₂ (4.2 g, 15 mmol) to give 2b (1.7 g, 60%). ¹H NMR (500 MHz, CDCl₃): δ 7.13 (d, ³J_HH = 8.5 Hz, 1H, NH), 3.66 (t, ³J_HH = 7.8 Hz, 1H, CH), 3.38 (q, ³J_HH = 7.16 Hz, 8H, NCH₂CH₃), 2.18 (m, 1H, CH), 1.23 (t, ³J_HH = 7.25 Hz, 12H, NCH₂CH₃), 1.02 (d, ³J_HH = 6.5 Hz, 3H, CH₃), 0.99 (d, ³J_HH = 7.0 Hz, 3H, CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 173.93 (COOH), 119.80 (q, ¹J_CF = 322 Hz, CF₃), 115.96 (equivalent ring C), 114.24 (unique ring C), 67.36 (CHNH), 46.73 (NCH₂CH₃), 31.07 (CH(CH₃)₂), 18.73 (CH₃), 18.36 (CH₃), 14.11 (NCH₂CH₃). FT-IR (cm⁻¹): 3338 (w), 2975 (w), 1720 (w), 1532 (ms), 1448 (mw), 1386 (m), 1348 (m), 1177 (s), 1135 (ms), 1054 (ms), 787 (mw), 652 (mw), 614 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 296.2331 (M⁺); calcd: 296.2333 (M⁺). Anal. calcd for 0.80(C₁₈H₃₀N₄O₆S₂F₆) : 0.20(C₁₆H₂₉N₃O₂) + 2.9% H₂O: C, 41.75; H, 6.31; N, 10.31. Found: C, 41.38; H, 6.46; N, 10.56.

Bis(diethylamino)-S-(1-carboxy-3,3-dimethylethylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCOOHC₃H₄(CH₃)₂)]NTf₂, [E₄Leu]NTf₂ (2c). Using procedure B, [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 19 mmol), L-leucine (2.4 g, 25 mmol) and NEt₃ (3.9 mL, 25 mmol) gave a yellow viscous oil of 1c (4 g, 54%). Salt 1c was stirred with LiNTf₂ (11 g, 39 mmol) to give 2c (2.5 g, 85%).¹H NMR (400 MHz, CDCl₃): δ 6.92 (d, ³J_HH = 9.0 Hz, 1H, NH), 3.95 (m, 1H, NHCH), 3.41 (m, ³J_HH = 8.0 Hz, 4H, NCH₂CH₃), 3.38 (q, ³J_HH = 7.0 Hz, 4H, NCH₂CH₃), 3.37 (q, ³J_HH = 7.0 Hz, 4H, NCH₂CH₃), 1.81 (m, 1H, CH(CH₃)₂), 1.74 (m, 2H, CH₂CH(CH₃)₂), 1.26 (t, ³J_HH = 7.0 Hz, 12H, NCH₂CH₃), 1.00 (d, ³J_HH = 6.0 Hz, 3H, CH(CH₃)), 0.96 (d, ³J_HH = 6.0 Hz, 3H, CH(CH₃)). ¹³C{H} NMR (100 MHz, CDCl₃) δ 175.07 (COOH), 119.79 (q, ¹J_CF = 319 Hz, CF₃), 116.17 (symmetric ring C), 114.81 (unique ring C), 58.49 (NCH), 46.29 (NCH₂CH₃), 40.63 (CH(CH₃)₂), 24.66 (CH₂CH), 21.89 (CH(CH₃)), 20.35 (CH(CH₃)), 13.13 (NCH₂CH₃). FT-IR (cm⁻¹): 3332 (w), 2962 (w), 1690 (w), 1533 (m), 1449 (mw), 1386 (m), 1347 (m), 1178 (s), 1134 (ms), 1055 (ms), 787 (mw), 653 (mw), 614 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 311.2528 (M + 1); calcd: 310.2489 (M⁺). Anal. calcd for 0.85(C₁₉H₃₂N₄O₆S₂F₆) : 0.15(C₁₇H₃₁N₃O₂) + 1.0% H₂O: C, 42.32; H, 6.21; N, 10.00. Found: C, 42.35; H, 6.09; N, 9.79.

Bis(diethylamino)-S-(1-carboxy-2-methylbutylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCOOHC₂H₂(CH₃)CH₂CH₃COOH)]NTf₂, [E₄Ile]NTf₂ (2d). Using procedure B, [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 16 mmol), L-isoleucine (2.6 g, 21 mmol) and NEt₃ (3.2 mL, 21 mmol) gave a yellow viscous oil of 1d (5.5 g, 85%). Salt 1d was stirred with LiNTf₂ (11 g, 39 mmol) to give 2d (6.6 g, 95%). ¹H NMR (400 MHz, CDCl₃): δ 6.64 (d, ³J_HH = 8.0 Hz, 1H, NH), 3.79 (dd, ³J_HH = 4.0 Hz, ³J_HH = 8.0 Hz, 1H, NHCH), 3.39 (q, ³J_HH = 8.0 Hz, 8H, NCH₂CH₃), 1.95 (m, 1H, NHCHCH), 1.59 (m, 1H, NHCHCHCH₂), 1.29 (m, 1H, NHCHCHCH₂), 1.25 (t, ³J_HH = 7.0 Hz, 12H, NCH₂CH₃), 0.99 (d, ³J_HH = 8.0 Hz, 12H, CHCH₃), 0.93 (t, ³J_HH = 6.0 Hz, 12H, CH₂CH₃). ¹³C{H} NMR (100 MHz, CDCl₃) δ 173.93 (COOH), 119.82 (q, ¹J_CF = 319 Hz, CF₃), 116.34 (symmetric ring C), 113.87 (unique ring C), 65.56 (NHCH), 46.81 (NCH₂CH₃), 37.55 (NHCHCH), 25.14 (CHCHCH₂), 15.05 (CH₂(CH₃)), 14.07 (NCH₂CH₃), 11.21 (CH(CH₃)). FT-IR (cm⁻¹): 3329 (w), 2974 (w), 1724 (w), 1529 (m), 1449 (mw), 1386 (m), 1348 (m), 1178 (s), 1134 (ms), 1055 (ms), 788 (mw), 652 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 310.2493 (M⁺); calcd: 310.2489 (M⁺). Anal. calcd for 0.9(C₁₉H₃₂N₄O₆S₂F₆) : 0.1(C₁₇H₃₁N₃O₂) + 1.0% H₂O: C, 40.96; H, 5.98; N, 9.80. Found: C, 41.01; H, 5.88; N, 9.60.

Bis(diethylamino)-S-(1-carboxy-3-methylthioproylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCOOHC₃H₅SCH₃)]NTf₂, [E₄Met]NTf₂ (2e). Using procedure B, [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 16 mmol), L-methionine (3 g, 21 mmol) and NEt₃ (3.2 mL, 21 mmol) gave a yellow viscous oil of 1e (5 g, 71%). Salt 1e was stirred with LiNTf₂ (14 g, 48 mmol) to give 2e (2.9 g, 72%). ¹H NMR (400 MHz, CD₃OD): δ 3.97 (dd, ³J_HH = 8.0 Hz, ³J_HH = 12.0 Hz, 1H, NCH), 3.43 (q, ³J_HH = 7.2 Hz, 8H, NCH₂CH₃), 2.67 (m, 1H, CH₃SCH₂), 2.62 (m, 1H, CH₃SCH₂), 2.26 (m, 1H, CH₃SCH₂CH₂), 2.1 (s, 3H, CH₃S), 1.96 (m, 1H, CH₃SCH₂CH₂), 1.26 (t, ³J_HH = 7.2 Hz, 12H, NCH₂CH₃). ¹³C{H} NMR (100 MHz, CD₃OD) δ 176.74 (COOH), 119.81 (q, ¹J_CF = 319 Hz, CF₃), 115.79 (symmetric ring C), 115.75 (unique ring C), 60.75 (NHCH), 46.21 (NCH₂CH₃), 31.56 (SCH₂), 30.29 (SCH₂CH₂), 13.19 (CH₃S), 13.02 (NCH₂CH₃). FT-IR (cm⁻¹): 3330 (w), 2978 (w), 1534 (m), 1446 (mw), 1386 (m), 1349 (m), 1178 (s), 1135 (ms), 1054 (ms), 787 (mw), 653 (mw), 614 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 328.2067 (M⁺); calcd: 328.2053 (M⁺). Anal. calcd for 0.72(C₁₈H₃₀N₄O₆S₃F₆) : 0.28(C₁₆H₂₉N₃O₂S₁) + 0.5% H₂O: C, 41.79; H, 6.10; N, 10.17. Found: C, 41.82; H, 5.96; N, 9.99.

Bis(diethylamino)-S-(1-carboxy-2-phenylethylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCOOHC₂H₃C₆H₅)]NTf₂, [E₄Phe]NTf₂ (2f). Using procedure C, [C₃(NEt₂)₂(OMe)]MeSO₄ (4 g, 12 mmol), L-phenylalanine (2.67 g, 16 mmol) and NEt₃ (2.6 mL, 16 mmol) gave a yellow viscous oil of 1f (3 g, 51%). Salt 1f was stirred with LiNTf₂ (6.5 g, 24 mmol) to give 2f (4 g, 85%).¹H NMR (400 MHz, CDCl₃): δ 7.96 (br, 1H, COOH), 7.29 (m, 5H, phenyl ring), 6.66 (d, ³J_HH = 9.2 Hz, 1H, NH), 4.1 (ddd, ³J_HH = 4.0 Hz, ³J_HH = 9.6 Hz, 1H, NHCH), 3.33 (dd, ³J_HH = 4.0 Hz, ³J_HH = 14.0 Hz, 1H, NHCHCH₂), 3.27 (q, ³J_HH = 7.0 Hz, 8H, NCH₂), 3.09 (dd, ³J_HH = 9.6 Hz, ³J_HH = 14.0 Hz, 1H, NHCHCH₂), 1.17 (t, ³J_HH = 7.0 Hz, 12H, NCH₂CH₃). ¹³C{H} NMR (100 MHz, CDCl₃): δ 173.86 (COOH), 136.32 (phenyl ring), 129.44 (phenyl ring), 128.76 (phenyl ring), 127.26 (phenyl ring), 119.82 (q, ¹J_CF = 319 Hz, CF₃), 116.15 (symmetric ring C), 113.93 (asymmetric ring C), 62.37 (NHCH), 46.75 (NCH₂), 38.28 (NHCHCH₂), 13.99 (NHCH₂CH₃). FT-IR (cm⁻¹): 3334 (w), 2982 (w), 1723 (m), 1530 (m), 1449 (mw), 1386 (m), 1348 (m), 1177 (s), 1133 (ms), 1054 (ms), 788 (mw), 739 (mw), 703 (mw), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 344.2344 (M⁺); calcd: 344.2333 (M⁺). Anal. calcd for 0.90(C₂₁H₂₈N₄O₆S₂F₆) : 0.10(C₁₉H₂₇N₃O₂): C, 44.38; H, 5.02; N, 9.57. Found: C, 44.41; H, 5.11; N, 9.17.

Bis(diethylamino)-S-(1-carboxy-2-(1H-indol-3-yl)ethylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCOOHC₂H₃C₈H₆N)]NTf₂, [E₄Try]NTf₂ (2g). Using procedure B, [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 16 mmol), L-tryptophan (4 g, 21 mmol) and NEt₃ (3.2 mL, 21 mmol) gave a yellow viscous oil of 1g (4 g, 52%). Salt 1g was stirred with LiNTf₂ (7 g, 24 mmol) to give 2g (3.6 g, 79%). ¹H NMR (400 MHz, CDCl₃): δ 10.42 (br, 1/2H, COOH), 7.61 (d, ³J_HH = 8.0 Hz, 1H, indol ring), 7.34 (d, 1H, ³J_HH = 8.0 Hz, 1H, indol ring), 7.15 (s, 1H, indol ring), 7.10 (dd, ³J_HH = 7.0 Hz, 1H, indol ring), 7.03 (dd, ³J_HH = 7.0 Hz, 1H, indol ring), 4.10 (dd, ³J_HH = 4.0 Hz, ³J_HH = 10.6 Hz, 1H, NHCH), 3.51 (dd, ³J_HH = 4.0 Hz, ³J_HH = 14.5 Hz, 1H, NHCHCH₂), 3.18 (q, ³J_HH = 7.0 Hz, 8H, NCH₂CH₃), 3.08 (dd, ³J_HH = 10.2 Hz, ³J_HH = 14.5 Hz, 1H, NHCHCH₂), 1.08 (t, ³J_HH = 7.0 Hz, 12H, NCH₂CH₃). ¹³C{H} NMR (100 MHz, CDCl₃): δ 173.94 (COOH), 136.70 (indol ring C9), 127.19 (indol ring C8), 123.58 (indol ring C2), 121.28 (indol ring C4), 119.82 (q, ¹J_CF = 319 Hz, CF₃), 118.73 (indol ring C5), 117.79 (indol ring C6), 115.07 (symmetric ring C), 114.93 (unique ring C), 111.23 (indol ring C7), 110.12 (indol ring C1), 62.82 (NHCH), 45.99 (NCH₂CH₃), 29.32 (NHCHCH₂), 13.01 (NCH₂CH₃). FT-IR (cm⁻¹): 3394 (w), 3334 (w), 2965 (w), 2924 (w), 1715 (w), 1538 (m), 1447 (mw), 1385 (m), 1347 (m), 1179 (s), 1132 (ms), 1053 (s), 788 (m), 741 (m), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 383.2445 (M⁺); calcd: 383.2442 (M⁺) (M⁺). Anal. calcd for 0.79(C₂₄H₃₁N₅O₆S₂F₆) : 0.21(C₂₂H₃₀N₄O₂): C, 48.82; H, 5.37; N, 11.41. Found: C, 49.25; H, 5.44; N, 11.33.

Bis(diethylamino)-S-(1-carboxy-2-hydroxyphenylethylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCOOHC₂H₃C₆H₅O)]NTf₂, [E₄Tyr]NTf₂ (2h). Using procedure D, [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 16 mmol), L-tyrosine (3.7 g, 21 mmol) and NEt₃ (3.2 mL, 21 mmol) gave a yellow viscous oil of 1h (5 g, 70%). Salt 1h was stirred with LiNTf₂ (9 g, 33 mmol) to give 2h (6.2 g, 91%). ¹H NMR (400 MHz, CD₃OD): δ 7.09 (d, ³J_HH = 8.4 Hz, 2H, benzyl ring), 6.72 (d, ³J_HH = 8.4 Hz, 2H, benzyl ring), 4.05 (dd, ³J_HH = 4.0 Hz, ³J_HH = 10.0 Hz, 1H, NHCH), 3.37 (q, ³J_HH = 7.0 Hz, 1H, NHCH₂), 3.25 (dd, ³J_HH = 4.0 Hz, ³J_HH = 14.0 Hz, 1H, NHCHCH₂), 2.83 (dd, ³J_HH = 4.0 Hz, ³J_HH = 14.0 Hz, 1H, NHCHCH₂), 1.19 (t, ³J_HH = 7.0 Hz, 1H, NHCH₂CH₃). ¹³C{H} NMR (100 MHz, (CD₃)₃SO₂): δ 172.91 (COOH), 156.66 (benzyl ring C with OH), 130.77 (benzyl ring C), 127.51 (benzyl ring C), 119.82 (q, ¹J_CF = 319 Hz, CF₃), 115.55 (symmetric ring C), 114.88 (asymmetric ring C), 62.61 (NHCH), 46.33 (NHCH₂CH₃), 37.67 (NHCHCH₂), 14.39 (NCH₂CH₃). FT-IR (cm⁻¹): 3400 (w), 3327 (w), 2982 (w), 1728 (w), 1532 (m), 1517 (m), 1447 (mw), 1386 (m), 1348 (m), 1180 (s), 1132 (ms), 1054 (ms), 788 (mw), 740 (mw), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 360.2290 (M⁺); calcd: 360.2282 (M⁺). Anal. calcd for 0.91(C₂₂H₃₀N₄O₇S₂F₆) : 0.09(C₂₀H₂₉N₃O₃) + 0.5% H₂O: C, 43.33; H, 5.06; N, 8.97. Found: C, 43.40; H, 4.99; N, 8.64.

Bis(diethylamino)-S-(1-carboxy-2-hydroxyethylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCOOHC₂H₃CH₂OH)]NTf₂, [E₄Ser]NTf₂ (2i). Using procedure C, [C₃(NEt₂)₂(OMe)]MeSO₄ (4 g, 12 mmol), L-serine (1.7 g, 16 mmol) and NEt₃ (2.6 mL, 16 mmol) gave a yellow viscous oil of 1i (4.7 g, 92%). Salt 1i was stirred with LiNTf₂ (10 g, 33 mmol) to give 2i (4 g, 68%). ¹H NMR (400 MHz, (CD₃)₃SO₂): δ 8.41 (d, ³J_HH = 8.0 Hz, 1H, NH), 4.03 (m, ³J_HH = 8.0 Hz, NHCH), 3.78 (dd, ³J_HH = 4.0 Hz, ³J_HH = 8.0 Hz, 1H, NHCHCH₂), 3.78 (dd, ³J_HH = 4.0 Hz, ³J_HH = 11.0 Hz, 1H, NHCHCH₂), 3.73 (dd, ³J_HH = 4.0 Hz, ³J_HH = 11.0 Hz, 1H, NHCHCH₂), 3.37 (q, ³J_HH = 7.0 Hz, 8H, NCH₂), 1.16 (t, ³J_HH = 7.0 Hz, 8H, NCH₂CH₃). ¹³C{H} NMR (100 MHz, (CD₃)₃SO₂): δ 171.94 (COOH), 119.82 (q, ¹J_CF = 319 Hz, CF₃), 115.84 (symmetric ring C), 115.47 (asymmetric ring C), 62.31 (NHCH), 62.13 (NHCHCH₂), 46.29 (NCH₂), 14.43 (NHCH₂CH₃). FT-IR (cm⁻¹): 3500 (w), 3337 (w), 2982 (w), 1736 (m), 1533 (m), 1449 (mw), 1386 (m), 1347 (m), 1178 (s), 1133 (ms), 1053 (ms), 788 (mw), 739 (mw), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 284.1973 (M⁺); calcd: 284.1969 (M⁺). Anal. calcd for 0.94(C₁₆H₂₆N₄O₇S₂F₆) : 0.06(C₁₄H₂₅N₃O₃): C, 35.56; H, 4.89; N, 10.21. Found: C, 35.95; H, 4.95; N, 10.11.

Bis(diethylamino)-S-(1-carboxy-2-hyroxylpropylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NH(C₃H₆OCOOH))]NTf₂, [E₄Thr]NTf₂ (2j). Using procedure A, [E₄Thr]MeSO₄ (2 g, 5 mmol) was stirred with LiNTf₂ (4.2 g, 15 mmol) to give 2j (1.4 g, 49%). ¹H NMR (500 MHz, CDCl₃): δ 7.18 (br, 1H, COOH), 6.75 (d, ³J_HH = 9.0 Hz, 1H, NH), 5.26 (br, 2H, OH + H₂O), 4.39 (dq, 1H, NCH), 3.76 (dd, ³J_HH = 2.5 Hz, ³J_HH = 6.5 Hz, 1H, CHOH), 3.36 (q, ³J_HH = 7.2 Hz, 8H, NCH₂CH₃), 1.29 (d, ³J_HH = 6.5 Hz, 3H, CH₃), 1.24 (t, ³J_HH = 7.3 Hz, 12H, NCH₂CH₃).¹³C{¹H} NMR (126 MHz, CDCl₃) δ 170.40 (COO), 117.38 (q, ¹J_CF = 291 Hz, CF₃), 116.28 (equivalent ring C), 114.74 (unique ring C), 72.64 (CHNH), 67.80 (CHCH₃), 46.78(NCH₂CH₃), 19.50 (CH₃), 14.02 (NCH₂CH₃). FT-IR (cm⁻¹): 3500 (w), 3342 (w), 2983 (w), 1722 (m), 1531 (m), 1448 (mw), 1387 (m), 1347 (m), 1180 (s), 1133 (ms), 1054 (ms), 788 (mw), 740 (mw), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 298.2130 (M⁺); calcd: 298.2125 (M⁺). Anal. calcd for 0.85(C₁₇H₂₈N₄O₇S₂F₆) : 0.15(C₁₅H₂₇N₃O₃) + 1.9% H₂O: C, 38.32; H, 5.74; N, 10.35. Found: C, 38.57; H, 5.51; N, 10.52.

Bis(diethylamino)-S-(2-carboxypyrrolidino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(N(C₄H₇COOH))]NTf₂, [E₄Pro]NTf₂ (2k). Using procedure A, [E₄Pro]MeSO₄ (2 g, 5 mmol) was stirred with LiNTf₂ (4.2 g, 15 mmol) to give 2k (1 g, 36%). ¹H NMR (500 MHz, CDCl₃): δ 7.55 (br, 1H, COOH), 4.44 (dd, ³J_HH = 3.5 Hz, ³J_H = 8.5 Hz, 1H, NCHCOOH), 3.70 (dt, ³J_HH = 6.5 Hz, ³J_HH = 8.3 Hz 1H, NCH), 3.64 (q, ³J_HH = 7.5 Hz, 1H, NCH), 3.34 (m, 8H, NCH₂CH₃), 2.38 (m, 1H, NCHCOOHCH), 2.23 (m, 1H, NCHCOOHCH), 2.05 (m, 2H, NCH₂CH₂), 1.25 (t, ³J_HH = 7.25 Hz, 12H, NCH₂CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 173.80 (COOH), 119.61 (q, ¹J_CF = 322 Hz, CF₃), 116.08 (equivalent ring C), 113.74 (unique ring C), 63.33 (NCH), 51.54 (NCH₂), 46.74 (NCH₂CH₃), 30.51 (NCHCH₂), 23.90 (NCH₂CH₂CH₂), 13.70 (NCH₂CH₃). FT-IR (cm⁻¹): 2981 (w), 1741 (m), 1528 (m), 1448 (mw), 1386 (m), 1349 (m), 1174 (s), 1134 (ms), 1052 (ms), 786 (mw), 652 (mw), 614 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 294.2170 (M⁺); calcd: 294.2176 (M⁺). Anal. calcd for 0.85(C₁₈H₂₈N₄O₆S₂F₆) : 0.15(C₁₆H₂₇N₃O₂) + 2.9% H₂O: C, 40.59; H, 5.73; N, 10.13. Found: C, 40.41; H, 5.69; N, 10.24.

Bis(diethylamino)-S-(1-carboxy-4-guanidiniumbutylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NH(COOH)(C₅H₁₂N₃))][NTf₂]₂ [E₄ArgH][NTf₂]₂ (2l). Using procedure B, [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 16 mmol), L-arginine (3.5 g, 21 mmol) and NEt₃ (3.2 mL, 21 mmol) gave a yellow viscous oil. The oil was stirred with LiNTf₂ (10 g, 34 mmol) to give 2l (2.2 g, 73%). ¹H NMR (400 MHz, CD₃OD): δ 3.88 (dd, ³J_HH = 5.0 Hz, ³J_HH = 7.0 Hz, 1H, NCH), 3.42 (q, ³J_HH = 7.0 Hz, 8H, NCH₂CH₃), 3.23 (dd, ³J_HH = 4.0 Hz, 2H, NHCHCH₂CH₂CH₂), 1.98 (m, 1H, NHCHCH₂CH₂), 1.82 (m, 1H, NHCHCH₂CH₂), 1.78 (m, 2H, NHCHCH₂), 1.25 (t, ³J_HH = 7 Hz, 12H, NCH₂CH₃). ¹³C{H} NMR (100 MHz, CD₃OD) δ 175.65 (COOH), 157.25 (guanidinium C), 119.93 (q, ¹J_CF = 320 Hz, CF₃), 116.07 (equivalent ring C), 115.02 (unique ring C), 60.73 (NHCH), 46.21 (NCH₂CH₃), 40.61 (CH₂CH₂CH₂), 29.38 (NHCHCH₂), 25.21 (NHCHCH₂CH₂), 13.18 (NCH₂CH₃). FT-IR (cm⁻¹): 3600 (vw), 3380 (w), 3365 (w), 3185 (w), 2983 (w), 1664 (mw), 1534 (m), 1449 (mw), 1386 (m), 1346 (m), 1180 (s), 1131 (ms), 1052 (ms), 788 (mw), 739 (mw), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 177.1366 (M²⁺), 353.2660 (M⁺); calcd: 177.1366 (M²⁺), 353.2660 (M⁺). Anal. calcd for 0.52(C₂₁H₃₄N₈O₁₄S₄F₁₂) : 0.27(C₁₉H₃₃N₇O₆S₂F₆): C, 30.69; H, 4.34; N, 13.38. Found: C, 30.67; H, 4.28; N, 13.45.

Bis(diethylamino)-S-(1-carboxy-2-imidazoliumethylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NH(COOH)C₂H₃C₃N₂H₄)][NTf₂]₂, [E₄HisH][NTf₂]₂ (2m). Using procedure C, [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 16 mmol), L-histidine (3 g, 21 mmol) and NEt₃ (3.2 mL, 21 mmol) gave a yellow viscous oil (5.8 g). The oil was stirred with LiNTf₂ (11 g, 39 mmol) to give 2m (7 g, 87%). ¹H NMR (400 MHz, CD₃OD): δ 8.74 (s, 1H, NCHNH), 7.41 (s, 1H, NCHNHCH), 4.29 (dd, 1H, ³J_HH = 4.0 Hz, ³J_HH = 10.0 Hz, NCH), 3.42 (q, ³J_HH = 7.0 Hz, 9H, NCH₂CH₃/CH₂), 3.22 (dd, = 8 Hz, ³J_HH = 12.0 Hz, 1H, CH₂), 1.24 (t, ³J_HH = 7.0 Hz, 12H, NCH₂CH₃). ¹³C{H} NMR (100 MHz, CD₃OD) δ 171.91 (COOH), 133.73 (imidazolium ring C), 129.24 (imidazolium ring C), 119.78 (q, ¹J_CF = 319 Hz, CF₃), 117.31 (symmetric ring C), 116.79 (unique ring C), 113.86 (imidazolium ring C), 58.45 (NHCH), 46.67 (NCH₂CH₃), 26.72 (NHCHCH₂), 13.02 (NCH₂CH₃). FT-IR (cm⁻¹): 3226 (w, br), 2985 (w), 1733 (m), 1555 (m), 1530 (m), 1450 (mw), 1387 (m), 1345 (m), 1177 (s), 1130 (ms), 1052 (ms), 788 (mw), 739 (mw), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 167.6167 (M²⁺), 334.2243 (M⁺); calcd: 167.6155 (M²⁺), 334.2238 (M⁺). Anal. calcd for 0.91(C₂₁H₂₉N₇O₁₀S₄F₁₂) : 0.09(C₁₉H₂₈N₆O₆S₂F₆): C, 29.06; H, 3.40; N, 11.22. Found: C, 29.28; H, 3.51; N, 10.90.

Tetrakis(diethylamino)-bis(bis(diethylamino)cyclopropenium)-S-(1-carboxy-5-aminopentylamine)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCOOHC₅H₉NH)C₃(NEt₂)₂][NTf₂]₂, [E₈Lys][NTf₂]₂ (4). [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 16 mmol) was stirred with L-lysine (1.12 g, 8 mmol) and NEt₃ (3.87 mL, 25 mmol) in water (50 mL) for an hour. A cold solution of NaOH (8 g in 10 mL water) was added to the aqueous mixture and the Et₃N was extracted with diethylether (6 × 50 mL). The solution was acidified with HCl to pH = 1–2 and water was removed in vacuo. The mixture was dissolved in ethanol and filtered to remove NaCl and L-lysine and the solvent was removed in vacuo to give a yellow viscous oil of mixture of [E₄Lys]MeSO₄ (1n) and [E₈Lys](MeSO₄)₂ (3.86 g). The mixture was stirred with LiNTf₂ (4.36 g, 15 mmol) in 50 mL of water for 30 minutes. The water was then removed in vacuo and the product was dissolved in CHCl₃ : CH₃CN 2 : 1 (50 mL) and washed with conc. HCl (3 × 50 mL) and dried in vacuo to give a light yellow viscous oil of 4 (1.32 g, 95%). ¹H NMR (400 MHz, CD₃CN): δ 6.41 (d, ³J_HH = 8.0 Hz, 1H, NH), 6.17 (t, ³J_HH = 8.0 Hz, 1H, NH), 4.00 (ddd, 1H, NHCH), 3.39 (m, ³J_HH = 8.0 Hz, 16H, NCH₂CH₃), 3.28 (q, ³J_HH = 8.0 Hz, 2H, NCHCH₂), 1.96 (m, 1H, CH₂), 1.82 (m, 1H, CH₂), 1.65 (m, 2H, CH₂), 1.52 (m, 2H, CH₂), 1.22 (t, ³J_HH = 8.0 Hz, 24H, CH₂CH₃). ¹³C{¹H} NMR (100 MHz, CD₃CN) δ 172.84 (COOH), 120.82 (q, ¹J_CF = 319 Hz, CF₃), 117.62 (symmetric ring C), 116.85 (symmetric ring C), 115.84 (unique ring C), 114.485 (unique ring C), 60.13 (NCH), 47.44 (NCH₂CH₃), 47.36 (NCH₂CH₃), 46.92 (NCH₂), 32.29 (NCHCH₂), 30.39 (NCH₂CH₂), 23.21 (CH₂), 14.42 (NCH₂CH₃), 14.36 (NCH₂CH₃). FT-IR (cm⁻¹): 3341 (w), 2982 (w), 1540 (m), 1449 (mw), 1386 (m), 1348 (m), 1177 (s), 1133 (ms), 1054 (ms), 788 (mw), 739 (mw), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 252.2080 (M²⁺); calcd: 252.2070 (M²⁺). Anal. calcd for 0.97(C₃₂H₅₂N₈O₁₀S₄F₁₂) : 0.03(C₃₀H₅₁N₇O₆S₂F₆) + 0.2% H₂O C, 36.27; H, 4.99; N, 10.55. Found: C, 36.36; H, 5.05; N, 10.45.

Treatment of [C₃(NEt₂)₂(OMe)]MeSO₄ with L-cysteine to generate [E₄Cys]⁺ (2o) and [E₈Cys]²⁺ (6). [C₃(NMe₂)₂(OMe)]MeSO₄ (4.12 g, 12 mmol), L-cysteine (1.95 g, 12 mmol) and NEt₃ (2.6 mL, 16 mmol) in water (50 mL) was stirred for one hour. A cold solution of NaOH (8 g in 10 mL water) was added and Et₃N was extracted with diethylether (6 × 50 mL). The solution was acidified with HCl to pH 1–2 and water was removed in vacuo. The mixture was dissolved in ethanol and filtered to remove NaCl and L-cysteine. The solvent was removed in vacuo to give a yellow viscous oil containing a mixture of [E₄Cys]⁺ and [E₈Cys]²⁺ (4.5 g). ES-MS: found m/z 300.1741; calcd for [E₄Cys]⁺ 300.1740; Found m/z 239.6648; calcd for [E₈Cys]²⁺ 239.6642.

Bis(diethylamino)-S-(1-carboxy-3-carbamoylpropylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCH(COOH)(CH₂CONH₂))]NTf₂, [E₄Asn]NTf₂ (2p). [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 16 mmol) was stirred with L-asparagine (2.77 g, 21 mmol) and NEt₃ (3.23 mL, 21 mmol) in water (50 mL) for an hour. A cold solution of NaOH (8 g in 10 mL water) was added to the aqueous mixture and Et₃N was extracted with diethylether (6 × 50 mL). The mixture was dissolved in acetone and filtered to remove NaCl and L-asparagine. The solvent was removed in vacuo to give a yellow viscous oil of [E₄Asn]MeSO₄ (5.1 g, 78%). [E₄Asn]MeSO₄ was stirred with LiNTf₂ (10.40 g, 36 mmol) in 50 mL of water and CHCl₃ (30 mL) mixture for 30 minutes. The organic layer was washed with water (3 × 10 mL). The product was dried in vacuo to give a light yellow viscous oil of 2p (5.54 g, 78%). ¹H NMR (400 MHz, CD₃OD): δ 7.87 (s, 1H, NH), 4.45 (dd, ³J_HH = 9.0 Hz, ³J_HH = 4.4 Hz, 1H, NHCH), 3.44 (q, ³J_HH = 7.2 Hz, 8H, CH₂CH₃), 2.94 (dd, ³J_HH = 16 Hz, ³J_HH = 4.4 Hz, 1H, CH₂), 2.71 (dd, ³J_HH = 16 Hz, ³J_HH = 9.0 Hz, 1H, CH₂), 1.29 (t, ³J_HH = 7.2 Hz, 12H, CH₂CH₃). ¹³C{¹H} NMR (100 MHz, CD₃OD): δ 172.59 (COOH), 172.54 (CONH₂), 119.79 (q, ¹J_CF = 319 Hz, CF₃), 116.11 (symmetric ring C), 114.67 (asymmetric ring C), 56.29 (NHCH), 46.56 (CH₂CH₃), 36.71 (CHCH₂), 13.09 (CH₂CH₃). ES-MS: found m/z 311.2084 (M⁺); calcd: 311.2078 (M⁺). Anal. calcd for C₁₇H₂₇N₅O₇S₂F₆ + 4.5% H₂O: C, 33.03; H, 4.88; N, 11.33. Found: C, 33.19; H, 4.48; N, 10.66.

Bis(diethylamino)-S-(1-carboxy-4-carbamoylbutylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCH(COOH)(CH₂CH₂CONH₂))]NTf₂, [E₄Gln]NTf₂ (2q). [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 16 mmol) was stirred with L-glutamine (3.07 g, 21 mmol) and NEt₃ (3.23 mL, 21 mmol) in water (50 mL) for an hour. A cold solution of NaOH (8 g in 10 mL water) was added to the aqueous mixture and Et₃N was extracted with diethylether (6 × 50 mL). The solution was acidified with HCl to pH 1–2 and water was removed in vacuo. The mixture was dissolved in ethanol and filtered to remove NaCl and L-glutamine. The solvent was removed in vacuo to give a yellow viscous oil of [E₄Gln]MeSO₄ (5.27 g, 80%). [E₄Gln]MeSO₄ was stirred with LiNTf₂ (10.33 g, 36 mmol) in 50 mL of water and CHCl₃ : CH₃CN 3 : 1 (30 mL) mixture for 30 minutes. The organic layer was washed with water (3 × 10 mL). The product was dried in vacuo to give a light yellow viscous oil of 2q (3 g, 62%). ¹H NMR (400 MHz, CD₃OD): minor product: δ 7.88 (s, 1H, NH), 4.15 (dd, ³J_HH = 5.2, 9.6 Hz, 1H, CH), 3.42 (m, 8H, CH₂CH₃), 2.52 (t, ³J_HH = 7.2 Hz, 2H, CH₂CO), 2.29 (m, 1H, CH₂CH₂CO), 2.02 (m, 1H, CH₂CH₂CO), 1.26 (m, 12H, CH₃). Major product: 4.11 (dd, ³J_HH = 4.8, 9.6 Hz, 1H, CH), 3.42 (m, 8H, CH₂CH₃), 2.44 (t, ³J_HH = 7.2 Hz, 2H, CH₂CO), 2.29 (m, 1H, CH₂CH₂CO), 2.02 (m, 1H, CH₂CH₂CO), 1.26 (m, 12H, CH₃). ¹³C{¹H} NMR (100 MHz, CD₃CN): minor product: δ 176.29 (C=O), 174.81 (COOH), 120.82 (q, ¹J_CF = 319 Hz, CF₃), 117.86 (equivalent ring C), 116.13 (unique ring C), 60.23 (NCH), 47.88 (NCH₂CH₃), 31.01 (CH₂), 28.32 (CH₂), 14.65 (NCH₂CH₃). Major product: δ 177.54 (C=O), 174.84 (COOH), 120.82 (q, ¹J_CF = 319 Hz, CF₃), 117.79 (equivalent ring C), 116.17 (unique ring C), 60.37 (NCH), 47.88 (NCH₂CH₃), 32.26 (CH₂), 28.77 (CH₂), 14.65 (NCH₂CH₃). FT-IR (cm⁻¹): 3327 (w), 2983 (w), 1709 (m), 1577 (m), 1550 (m), 1535 (m), 1494 (m), 1449 (m), 1387 (mw), 1347 (ms), 1178 (s), 1133 (ms), 1052 (ms), 788 (m), 739 (mw), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 325.2240 (M⁺); calcd: 325.2234 (M⁺). Anal. calcd for C₁₈H₂₉N₅O₇S₂F₆ + 1.2% H₂O: C, 35.28; H, 4.90; N, 11.43. Found: C, 35.67; H, 4.84; N, 10.30.

Bis(diethylamino)-S-(1,2-dicarboxyethylamino)cyclopropenium bistriflamide, [C₃(NEt₂)₂(NHCH(COOH)CH₂COOH)]NTf₂, [E₄Asp]NTf₂ (2r). [C₃(NEt₂)₂(OMe)]MeSO₄ (5 g, 16 mmol) was stirred with L-aspartic acid (2.68 g, 21 mmol) and NEt₃ (6.4 mL, 42 mmol) in water (50 mL) for one hour. A cold solution of NaOH (8 g in 10 mL water) was added to the aqueous mixture and Et₃N was extracted with diethylether (6 × 50 mL). The solution was acidified with HCl to pH 1–2 and water was removed in vacuo. The mixture was dissolved in ethanol and filtered to remove NaCl and L-asparatic acid. The solvent was removed in vacuo to give a yellow viscous oil of [E₄Asp]MeSO₄ (5.77 g, 88%). [E₄Asp]MeSO₄ was stirred with LiNTf₂ (11.9 g, 41 mmol) in 50 mL of water for 30 minutes. Ethanol (1 mL) was added to induce a separate layer, which was washed with water (3 × 10 mL). Ethanol results in a mixture with ethyl esters so these were hydrolyzed by heating to reflux with conc. HCl overnight (100 mL). The solution was dissolved in CH₃CN (50 mL) followed by water washes (3 × 50 mL). The product was dried in vacuo to give a light yellow viscous oil of 2r (3 g, 37%). ¹H NMR (400 MHz, CD₃OD): δ 7.89 (s, 1H, NH), 4.36 (dd, ³J_HH = 4.3, 9.2 Hz, 1H, CH), 3.45 (q, ³J_HH = 7.3 Hz, 8H, NCH₂CH₃), 3.03 (dd, ³J_HH = 4.3, 17.2 Hz, 1H, CH₂), 2.76 (dd, ³J_HH = 9.2, 17.2 Hz, 1H, CH₂) 1.27 (t, ³J_HH = 7.3 Hz, 12H, NCH₂CH₃). ¹³C{¹H} NMR (CD₃OD): δ 174.52 (COOH), 173.92 (COOH), 120.82 (q, ¹J_CF = 319 Hz, CF₃), 117.55 (equivalent ring C), 116.52 (unique ring C), 58.48 (CH), 47.90 (CH₂CH₃), 37.97 (CH₂), 14.66 (CH₃). FT-IR (cm⁻¹): 3250 (w, br), 2982 (w), 1721 (m), 1535 (m), 1449 (mw), 1387 (m), 1346 (m), 1177 (s), 1132 (ms), 1053 (ms), 788 (mw), 739 (mw), 653 (mw), 613 (m), 600 (m), 570 (m), 510 (m). ES-MS: found m/z 312.1923 (M⁺); calcd: 312.1918 (M⁺). Anal. calcd for 0.88(C₁₇H₂₆N₄O₈S₂F₆) : 0.12(C₁₅H₂₅N₃O₄) + 0.25% H₂O: C, 37.17; H, 4.88; N, 9.92. Found: C, 37.27; H, 5.03; N, 9.66 (IL : zwitterion 0.88 : 0.12).

Results and discussion

Synthesis

The general synthetic route we used to prepare TAC-based AAILs involved addition of the alkoxydiaminocyclopropenium salt [C₃(NEt₂)₂OMe]MeSO₄ to a mixture of amino acid, Et₃N and water (Table 1). The AAIL [E₄AA]MeSO₄ (1) forms rapidly and the solutions were stirred for just one hour at ambient temperature. Et₃N is added to keep the amino acid in the anionic form since ammonium groups are unable to react with the alkoxycyclopropenium cation.

Table 1 Syntheses of [E₄AA]MeSO₄ (1) and [E₄AA]NTf₂ (2)

Salt	Cation abbreviation	R	Amino acid
a Proline is a secondary amino acid, so there is no NH group on the TAC cations in 1k and 2k.
1a/2a	[E4Ala]^+	CH3	Alanine
1b/2b	[E4Val]^+	CH(CH3)2	Valine
1c/2c	[E4Leu]^+	CH2CH(CH3)2	Leucine
1d/2d	[E4Ile]^+	CH(CH3) (CH2CH3)	Isoleucine
1e/2e	[E4Met]^+	CH2CH2SMe	Methionine
1f/2f	[E4Phe]^+	CH2Ph	Phenylalanine
1g/2g	[E4Trp]^+	CH2C8H6N	Tryptophan
1h/2h	[E4Tyr]^+	CH2C6H4OH	Tyrosine
1i/2i	[E4Ser]^+	CH2OH	Serine
1j/2j	[E4Thr]^+	CH(OH)CH3	Threonine
1k/2k	[E4Pro]^+	C4H7	Proline^a
1l/2l	[E4ArgH]^2+	CH2C3H9N3	Arginine
1m/2m	[E4HisH]^2+	CH2C3N2H3	Histidine
1n/2n	[E4Lys]^+	CH2C3H6NH	Lysine
1o/2o	[E4Cys]^+	CH2SH	Cysteine
1p/2p	[E4Asn]^+	CH2CONH2	Asparagine
1q/2q	[E4Gln]^+	CH2CH2CONH2	Glutamine
1r/2r	[E4Asp]^+	CH2COOH	Aspartic acid

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In only some cases (1a, 1b, 1j and 1k) were the MeSO₄⁻ salts isolated and characterized, due to issues of purity. Exchange of MeSO₄⁻ for NTf₂⁻ to give the AAILs [E₄AA]NTf₂ (2) generally facilitated the purification process. The main impurities were [Et₃NH]⁺ and the excess amino acid. The various solubility properties of the amino acids and the products led to four general isolation and purification procedures, as described in the Experimental section. The differences sometimes appear minor but they are frequently critical (e.g. using ethanol rather than acetone to precipitate the amino acid, or adding a small amount of ethanol to induce a phase separation).

Although the reaction shown in Table 1 works as expected for non-polar aliphatic amino acids (alanine, valine, leucine, isoleucine and methionine), aromatic amino acids (phenylalanine, tryptophan and tyrosine) and polar uncharged amino acids (serine, threonine, proline and arginine), the ¹H-NMR integral for the MeSO₄⁻ peak was always low and the microanalysis results were very high in C, H and N. We concluded the presence of the neutral zwitterion 3 (Scheme 5). Several attempts to isolate either pure IL or pure zwitterion were all unsuccessful as any attempt to purify the resultant product from reagents or side-products resulted in IL/zwitterion mixtures.

Scheme 5 Equilibrium between an AAIL and its zwitterion.

Remarkably, we found (see later) that the IL/zwitterion ratio of the isolated product was essentially unaffected by changing the pH of the aqueous layer. The zwitterion content was found to be much higher in the MeSO₄⁻ ILs (30–65%) than in the NTf₂⁻ ILs (0–50%) (Table 2). Both these results were contrary to our expectations. Changing the IL/zwitterion ratios in the aqueous layer might be expected to change the ratio in the organic layer, and why would the zwitterion content be so highly anion dependent? Our hypothesis is based on consideration of the equilibria shown in Fig. 1.

Table 2 Zwitterion molar percentage from pH titration, NMR spectroscopy and microanalysis

	pH titration	^1H NMR	Microanalysis	Wt% water (microanalysis)
1a	47	44	38	4.0
1b	63	68	55	0.9
1j	36	80	55	0.3
1k	29	53	35	2.9
2a	9	—	7	0.9
2b	2	—	20	2.9
2c	19	—	15	1.0
2d	5	—	10	1.0
2e	46	—	28	0.5
2f	31	—	10	0.0
2g	45	—	21	0.0
2h	28	—	9	0.5
2i	6	—	6	0.0
2j	3	—	15	1.9
2k	7	—	15	2.9
2l	5	—	48% M^+	0.0
2m	30	—	9% M^+	0.0
4	10	—	3% M^+	0.2
2p	12	—	0	4.5
2q/7	28	—	0	1.2
2r	—	—	12	0.3

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Fig. 1 Equilibria of AAILs and zwitterion in aqueous and organic phases.

Addition of acid to an aqueous solution of the AAIL increases the amount of IL relative to the zwitterion. Extraction with an organic solvent then gives more of the IL in the organic layer. However, ILs increase the polarity of the organic layer. Consequently, K_Z (and K_HZ+) does not remain constant as the pH is changed in the aqueous layer; more zwitterion moves into the polar organic layer, and the IL/zwitterion ratio remains almost constant. The MeSO₄⁻ salts are more “polar” than NTf₂⁻ salts and so the zwitterion has greater solubility in the organic/MeSO₄⁻ salt mixture than in the organic/NTf₂⁻ salt mixture. Quantification of the IL : zwitterion ratios will be discussed later.

Although the presence of zwitterions makes the measurement and interpretation of physical properties problematic, in terms of their potential applications it is not considered to be a problem. Zwitterions are generally considered to be a sub-class of ILs; zwitterions are also polar materials with high boiling points.³⁷ Their presence may even be advantageous in some circumstances.

The reactions of L-arginine and L-histidine with the alkoxycyclopropenium cation gave interesting dications [E₄ArgH][NTf₂]₂ (2l) and [E₄HisH][NTf₂]₂ (2m), respectively, containing two different cationic centres. In 2l, guanidinium and cyclopropenium cationic centres are present, whereas in 2m, there are imidazolium and cyclopropenium cationic centres.

AAILs with dications have been previously reported with diammonium^38,39 and ammonium/imidazolium cationic centres in which amino acids acted as the counteranion.³⁹ Huang et al. synthesized chiral geminal dications with amino acids attached to a dicationic centre with two imidazolium units.⁴⁰ To our knowledge, the present work is the first time where dications have been obtained in which amino acids provide one of the cationic centres.

In the case of L-lysine, a 2 : 1 ratio of [E₄OMe]⁺ : L-lysine was utilized and a mixture of dicationic [E₈Lys][NTf₂]₂ (4) (containing two cyclopropenium cations) and monocationic [E₄Lys]NTf₂ (2n) was obtained following anion metathesis to the NTf₂⁻ salts. Washes with conc. HCl were carried out to remove the monocation (presumably as the highly water-soluble ammonium/cyclopropenium dicationic salt [E₄LysH]Cl₂ (5)) and to leave 4 in reasonably pure form; although pH titrations indicated the additional presence of the monocation containing two cyclopropenium groups and a carboxylate group. Attempts to isolate and purify 2n or 5 from the mixture were unsuccessful.

The amino acids L-cysteine, L-asparagine, L-glutamine and L-aspartic acid were also treated with the alkoxycyclopropenium cation to prepare the corresponding AAILs. With L-cysteine, a mixture of two products was indicated by a complex NMR spectrum and two prominent peaks in the ES-MS: a peak at m/z 300.1740 is consistent with [E₄Cys]⁺ while a peak at m/z 239.6648 is consistent with the dication [E₈Cys]²⁺. [E₄Cys]⁺ is likely to have the same structure as salt 2o whereas the dication [E₈Cys]²⁺ is likely to contain both an N-linked TAC cation and an S-linked diaminothiocyclopropenium cation (6). It is known that amino substituents on cyclopropenium rings are much more stable than thio substituents.⁴¹ Unfortunately, the separation of 2o and 6 proved to be difficult and was not completely achieved, allowing only MS characterisation.

L-Asparagine and L-glutamine each have an amide linkage in the amino acid side chain. The amide N atom is expected to be less nucleophilic than the amino N atom, so coupling at the amino end is expected to give [E₄Asn]NTf₂ (2p) and [E₄Gln]NTf₂ (2q), respectively. The presence of both a carboxylic group and an amide group significantly increases the water solubility of these salts. In the case of glutamine, microanalysis and ES-MS suggested the formation of the expected salts. However, in the ¹H- (Fig. 2) and ¹³C{¹H}-NMR spectra in CD₃OD of 2q there are two sets of peaks in an approximately 2 : 1 ratio. The ¹H NMR integrals are consistent with one cyclopropenium fragment and one glutamine fragment. We would not expect separate peaks for any IL/zwitterion pair due to rapid proton exchange; also, the integral ratios do not change significantly over time which probably rules out CD₃ ester formation. The addition of either DCl or NaOD to a solution of 2q in D₂O similarly does not significantly affect the ratios. There is only one NH peak and its integral is consistent with the minor product. The most likely explanation is formation of the amide-linked isomer 7 as the major product. It is likely that the NH proton in 7 is exchanged readily with CD₃OD due to additional resonance stabilisation of the neutral cyclopropenimine intermediate by the carbonyl group. With L-asparagine, the major product appears to be 2p, with perhaps some of the other isomer analogous to 7 (<10%). The NH proton of 2p is not exchanged in CD₃OD and the NMR chemical shifts are consistent with the minor product from the glutamine product mixture. Steric factors may be playing a significant role in this case. The amide is less sterically-crowded than the amino end in glutamine, but perhaps the difference is not as great in asparagine where the two ends are closer.

Fig. 2 ¹H NMR of [E₄Gln]TFSA (2q/7) in CD₃OD.

Aspartic acid gave the expected product 2r along with some zwitterion which, in this case, could arise from deprotonation of either of the two carboxylic acid groups.

Characterisation

The ILs were initially characterised by ¹H and ¹³C{¹H} NMR, ES-MS and microanalysis. Due to rapid rotation about the cyclopropenium exocyclic C–N bonds on the NMR timescale, all NMR spectra show only one set of signals for the four ethyl groups. The chemical shifts of the COOH and TAC NH protons are quite variable and highly dependent on concentration and solvent due to their various hydrogen bonding interactions. They are both exchanged rapidly in proton donor solvents such as CD₃OD. Otherwise, the NMR spectra are generally as expected. ES-MS always gives a strong parent ion peak and was also useful for identifying the formation of dications. As discussed above, microanalysis results, as well as the ¹H NMR integrals for the MeSO₄⁻ salts, indicated the presence of significant amounts of the corresponding zwitterion. We endeavoured to quantify the IL : zwitterion ratio by four separate methods: ¹H NMR integrals, microanalysis, pH titration and polarimetry. The results from microanalysis, pH titration and NMR spectroscopy (for the MeSO₄⁻ salts) are given in Table 2.

For the MeSO₄⁻ salts 1, microanalysis, pH titration and NMR integrals were found to be in broad agreement for 1a and 1b whereas for the proline and threonine-based ILs 1j and 1k, respectively, the agreement was remarkably abysmal. The NMR results were consistently lower in IL than was found for the microanalytical results. Sources in error for the microanalytical results can be due to inhomogeneity of the samples and uncertainly around the amount of water present. The measured molar percentage of IL for the three techniques varied from 21% to 71%, but were generally found to be in the range 35–65%. For the bistriflamide salts, the molar percentage of IL was generally found to be significantly higher: based on the microanalytical results they ranged 72–94% and based on the pH titrations they ranged 54–98%. Upon conversion from the methylsulfate salt to the bistriflamide salt, the molar % of IL increased by 20–61% with a mean increase of 35%. This is consistent with the less polar bistriflamide salt dissolving less zwitterion in the organic phase. Unfortunately, there are no obvious trends within the bistriflamide series.

Attempts were made to determine the IL : zwitterion ratio of the water-soluble AAILs 1a, 1b, 1j and 1k by polarimetry in acidic (pH 0 with added HCl), neutral and basic (pH 14 with added NaOH) aqueous media (Table 3), however, the optical rotations were found to vary unpredictably with pH. Wood has similarly shown that the addition of acid or base to an amino acid solution produces a marked and unpredictable change in the specific rotation.⁴² We suggest that the variation in optical rotation may be due to the formation of a variety of salt/zwitterion hydrogen-bonded aggregates with a variety of conformations and, consequently, different optical rotations.⁴³ Some possible aggregates are shown in Fig. 3. Notably, it is therefore also not possible to determine the optical purity of the samples using this technique.

Table 3 Optical rotation of selected water-soluble AAIL in acidic, neutral and basic water (concentrations in parentheses)

	Acidic	Neutral	Basic
1a	−29.05 (0.02)	−18.67 (0.1)	−9.47 (0.04)
1b	−3.23 (0.01)	−0.57 (0.03)	−1.69 (0.1)
1j	+13.63 (0.02)	+12.05 (0.1)	+4.00 (0.02)
1k	−58.33 (0.1)	−88.26 (0.01)	−84.76 (0.02)

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Fig. 3 Some possible H-bonded aggregates between IL and zwitterion: (a) IL/IL, (b) IL/zwitterion and (c) IL and two zwitterions.

Properties

The properties of AAILs were investigated by viscometry, polarimetry, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and pK_a measurements (Table 4). It is important to note that high chloride contents were found for CILs having methylsulfate as the anion. High chloride contents are known to decrease thermal stability and increase viscosity.

Table 4 Physical properties of TAC-based CILs

Salt	Chloride content (ppm)	Td (1) 1 °C min^−1	Td (10) 10 °C min^−1	Tg (°C)	Tm (°C)	Viscosity at 75 °C (mPa s)	[α]^20D	pKa (of COOH)
1a	2289	188	215	−36.5	—	562	− 26.46° (c 3.4, EtOH)	3.61
1b	41 369	190	215	−50.9	—	—	−0.57° (c 1.7, H2O)	4.01
1j	3229	151	188	—	40.4	—	−5.49° (c 2.7, H2O)	4.43
1k	9706	200	231	−15.7	−7.3	838	−88.26° (c 0.6, H2O)	3.36
2a	435	210	245	−26.0	—	329	−31.18° (c 2.0, EtOH)	3.46
2b	185	209	245	—		574	−16.54° (c 1.3, EtOH)	3.23
2c	93	214	244	—	—	—	−36.36° (c 1.4, CH3CN)	3.67
2d	109	227	260	−37.2	—	—	−20.95° (c 2.0, CH3CN)	3.73
2e	968	218	238	—	—	—	−28.63° (c 2.2, CH3CN)	3.28
2f	112	213	259	—	—	—	−14.28° (c 1.5, CH3CN)	3.61
2g	89	227	263	—	—	—	−29.9° (c 1.0, CH3CN)	3.88
2h	474	238	268	0.3	—	—	−11.5° (c 1.0, CH3CN)	3.56
2i	100	131	161	−20.9	—	—	−6.89° (c 2.03, CH3CN)	4.16
2j	38	145	178	−15.8	—	884	−18.1° (c 8.2, EtOH)	5.23
2k	174	230	272	−40.9	—	230	−42.47° (c 2.2, EtOH)	4.70
2l	475	220	254	—	—	—	+9.7° (c 1.9, CH3CN)	4.02
2m	161	215	244	−17.6	—	—	−1.39° (c 1.9, CH3CN)	3.51
4	182	223	252	−48.3	—	—	−4.31° (c 2.32, CH3CN)	4.41

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The T_d's of the TAC-based AAILs were low and ranged from 161 °C ([E₄Ser]NTf₂) to 272 °C ([E₄Pro]NTf₂) at 10 °C min⁻¹. The various functional groups of the amino acid side chain are thought to decrease the T_d compared to [C₃(NEt₂)₃]NTf₂ (393 °C at 10 °C min⁻¹).²³ Generally, it would be expected that AAILs having MeSO₄⁻ as the anion would show lower T_d compared to the corresponding NTf₂⁻ anions due to the greater nucleophilicity of the MeSO₄⁻ anion. However, the threonine derivative 2j (178 °C) was found to have a lower T_d than 1j (188 °C). Notably, along with the serine derivative 2i (161 °C), these have much lower T_d than the other salts (238–272 °C for the NTf₂⁻ salts), which suggests that decomposition does not primarily involve the anion in these cases; presumably a nucleophilic hydroxyl group is the cause of the low T_d in these materials. For comparison, the imidazolium-based AAILs [emim]AA are stable at temperatures of 170–250 °C.^20,44 These results are similar to our TAC-based AAILs. The T_ds of phosphonium-based AAILs are higher and are similar to the pure amino acids; they range from 200 to 320 °C.^16,44 On the other hand, ammonium-based AAILs have considerably lower T_d values of 150–220 °C.^8,16 Of course, unlike the TAC-based AAILs, these all contain anionic AAs. Tao et al. reported a variety of cationic AAs in which T_d ranges from 120–240 °C at 5 °C min⁻¹.¹² The most stable ones they reported contain the BF₄⁻ anion: ProBF₄ has a T_d of 236 °C (5 °C min⁻¹) compared to 1k at 231 °C and 2k at 272 °C (both at 10 °C min⁻¹) and AlaBF₄ has a T_d of 241 °C (5 °C min⁻¹) compared to 1a at 215 °C and 2a at 245 °C (both at 10 °C min⁻¹). Given that BF₄⁻ salts are generally 10–20 °C less stable than NTf₂⁻ salts,²³ these results suggest that there is not a big difference between the stability of [E₄AA]⁺ salts and [AA]⁺ salts.

DSC data were collected for the TAC-based AAILs (Table 4). As would be expected for such a wide range of functional groups, there are no discernible trends. Furthermore, given the significant amounts of zwitterion present in some of the samples, caution should be exercised when interpreting these results. In most cases, a glass transition was observed between −50 and 0 °C. Only two of the MeSO₄⁻ salts showed a melting point, though this could be for the zwitterion. Due to the presence of extensive hydrogen bonding in these systems, all samples are highly viscous and this limits the opportunity for crystallisation and the determination of a melting point. Consequently, only glass transitions were observed for most salts. TAC-based AAILs generally have higher glass transition temperatures (0 to −50 °C) than the imidazolium-based AAILs (−23 to −52 °C).²⁰

High viscosities for TAC-based AAILs (Table 4) result from intermolecular hydrogen bonding. Not all viscosities were measured due to instrument limitations (1b, 1j, 2c–2i, 2l, 2m and 4) and the highly-viscous nature of the AAILs. Viscosity measurements were only made at 75 °C on the small aliphatic AAILs 1a/2a, 2b and 1k/2k as well as the OH functionalised 2j. As would be expected for the MeSO₄⁻/NTf₂⁻ pairs 1a/2a and 1k/2k, the viscosity is higher for the MeSO₄⁻ salt. Salt 2j has the highest viscosity (884 mPa s) of those we measured and this is likely due to the additional hydrogen-bonding of the hydroxy group. Other classes of AAILs in which the amino acid is part of the cation have similarly high viscosities: Kou and coworkers reported a viscosity of 5140 cP at 30 °C for [Pro]NO₃.^12,45 They also reported a number of other similar AAILs containing protonated amino acids of the type [AA][anion] (with mostly NO₃⁻, BF₄⁻ and PF₆⁻ anions) without any viscosity measurements as they were either high melting solids or found to be highly viscous. Even the ester derivatives were found to have relatively high viscosities; from 186 cP for the methyl ester of [Pro]NO₃ at 30 °C to 2030 cP for the ethyl ester of [Ala]NO₃. In contrast to these AAILs, a number of AAILs in which the AA is in the anion ([cation][AA]) have been found to have remarkably low viscosities, the tetraalkylammonium salts in particular.^{6,20b,46–49} Wu, Zhang and coworkers have reported viscosities as low as 29 mPa s for [N₂₂₂₄][Ala].⁶ Weak cation–anion interactions as well as low molecular weights contribute to these low viscosities.

The pK_a of the AAILs were determined by potentiometric titration and the results are given in Table 4. He, Tao and coworkers determined the pK_a value for a number of nitrate AAILs, [AA]NO₃, and found the pK_a values to range 2.08–2.42.⁵⁰ This increase in acidity compared to acetic acid (pK_a = 4.76) can be attributed to the electron-withdrawing effect of the positive charge as well as the formation of an intramolecular hydrogen-bonded five-membered ring for the zwitterion. For the dications [Arg](NO₃)₂, [His](NO₃)₂ and [Lys](NO₃)₂, the pK_a values were found to be 2.29, 2.01 and 2.37, respectively, so additional charge in these compounds did not have a significant impact on the pK_a values. Dyson and coworkers have reported pK_a values for imidazolium carboxylic acids of the type [MeIm(CH₂COOH)]X (X = Cl, BF₄, SO₃CF₃) in which the pK_a ranges from 1.90 to 2.03.⁵¹ This increase in acidity may be due to the formation of a more favourable six-membered ring, albeit to a less acidic imidazolium C–H group. Extending the chain of the carboxylic acid group, [MeIM(CH₂CH₂CH₂COOH)]X, increases the pK_a values to 3.83–4.11 due to the unfavourable ring size and greater distance from the positive charge.⁵¹ We obtained pK_a values for the methylsulfate salts from 3.36 to 4.43. This is intermediate between acetic acid and the [AA]NO₃ series of salts. Although the ring-size in the zwitterion would be the same as for [AA]NO₃, the positive charge at the N atom is reduced in the cyclopropenium salt, giving a weaker proton donor group, and the bond angle is greater at N due to the sp² hybridisation, and this increases the steric strain on the already-strained five-membered ring.

The pK_a values for all the AAILs with hydrophobic NTf₂⁻ anions were determined in 20% acetone–water to increase the solubility. The pK_a value of acetic acid was also determined in 20% acetone–water and found to increase by 0.2 pK_a units, so the values given in Table 4 have been corrected by this amount to ease comparison with other acids. Most of the acids lie in the range 3.23–4.16 which is similar to the MeSO₄⁻ salts. At first glance, the threonine and proline salts 2j and 2k appear anonymously high at 5.23 and 4.70, respectively. However, the threonine salt has a hydroxyl group that is able to form a hydrogen-bonded ring before loss of a proton, thus reducing the acidity. Notably, the corresponding MeSO₄⁻ salt 1j also has a high pK_a (4.43) and the serine salt 2i, which also has a hydroxyl group in a similar position, has the highest pK_a (4.16) of the other salts. The proline salt 2k has no acidic NH group with which to form a hydrogen-bonded ring, thus reducing its acidity, however, it's not clear why the corresponding MeSO₄⁻ salt 1k is more acidic (pK_a = 3.36).

The dications 2l, 2m and 4 are no more acidic than the monocationic AAILs 2; similar to what was found by He, Tao and coworkers for the nitrate salts of the corresponding dicationic amino acids. In both cases, the histidine salt is most acidic, pK_a = 3.51 (this would have a 7-membered ring to the imidazolium group), whereas the lysine salt is least acidic, pK_a = 4.41 (this would have an unfavourable 9-membered ring to the other cyclopropenium or ammonium group). The arginine salt would have an intermediate-sized 8-membered ring to the guanidinium group, and its acidity (pK_a = 4.02) lies between the other dications.

Miscibility studies were carried out for the AAILs. The hydrophilic methylsulfate salts are completely miscible or soluble in water, whereas the hydrophobic NTf₂⁻ salts were not. Miscibility studies were not carried out in methanol or ethanol due to their tendency to form esters. All of the AAILs were found to be immiscible or insoluble in the non-polar solvents diethylether, toluene and hexane. On the other hand, the only solvent we investigated in which all of the AAILs are soluble or miscible is acetonitrile. Almost all are miscible or soluble in CH₂Cl₂, the notable exceptions being the dicationic salts 2l and 2m as well as, somewhat curiously, the amide-containing 2p. Chloroform was found to be quite discerning; its reduced polarity compared to CH₂Cl₂ reduces its ability to break up some of the AAILs. Like CH₂Cl₂, 2l, 2m and 2p are immiscible in CHCl₃, but so are 2g and 2h (containing both aromatic rings and proton donor groups), 2q/7 (containing an amide group) and 2i (a small AAIL with a proton donor group). Additionally, salt 2a is partially miscible in CHCl₃ (>50% IL); this was the smallest AAIL that we investigated.

Conclusions

AAILs based on the TAC cation were successfully prepared by treatment of an alkoxy salt with an amino acid. These salts are quite different from previous AAILs: other AAILs usually contain the amino acid in the anion whereas the cationic examples contain protic and hydrophilic ammonium functional groups as the cationic centre instead of the relatively unreactive and hydrophobic triaminocyclopropenium cation. Consequently, we expect both their physical and chemical properties to be significantly different from previously-reported AAILs. Most salts were isolated as the monocations [E₄AA]⁺ (1a/2a to 1k/2k and 1n/2n to 1r/2r) along with significant amounts of the corresponding zwitterion. AAs containing guanidine (Arg) (2l) and histidine (His) (2m) were isolated as the corresponding dications (TAC/guanidinium and TAC/imidazolium, respectively) and a related dication was also observed, but not isolated, with Lys (2n) (TAC/ammonium). Lys also formed a dication containing two TAC cations while Cys (2o) formed a dication due to the additional formation of a thio-cyclopropenium cationic centre. Asn (2p) and Gln (2q) appeared to give mixtures of amino and amido-linked TAC salts.

The percentage of zwitterion was determined by a combination of techniques: pH titration, NMR integrals and microanalysis were most consistent. Polarimetry was notably inconsistent, presumably due to the formation of various hydrogen-bonded species at different pH. T_d was found to be similar to other cationic-based AAILs and generally lower than anionic-based AAILs. High viscosities also seem to be more similar to other cationic-based AAILs rather than anionic based AAILs. pK_a values were found to be higher than other cationic AAILs and we attributed this, as well as variations within the series, to differences in the stability of intramolecular hydrogen-bonded rings in the acid versus the conjugate base. Unfortunately, pK_a calculations involving ions and zwitterions are known to be difficult and unreliable, so we have not attempted these. Miscibility studies showed that many of the NTf₂⁻ salts have narrow solubility ranges with some immiscible in CH₂Cl₂ and CHCl₃. Acetonitrile is the only solvent in which all are soluble.

Acknowledgements

Ruhamah Yunis thanks the University of Canterbury, Christchurch, New Zealand for a UC doctoral scholarship. Dr. Deborah Crittenden, University of Canterbury, is thanked for useful discussions.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra10171b

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