Quinine based ionic liquids: A tonic for base instability

Journal Pre-proof Quinine based ionic liquids: A tonic for base instability Peter McNeice, Federico M.F. Vallana, Simon J. Coles, Peter N. Horton, Patricia C. Marr, Kenneth R. Seddon, Andrew C. Marr PII:

S0167-7322(19)33430-0

DOI:

https://doi.org/10.1016/j.molliq.2019.111773

Reference:

MOLLIQ 111773

To appear in:

Journal of Molecular Liquids

Received Date: 18 June 2019 Revised Date:

17 September 2019

Accepted Date: 18 September 2019

Please cite this article as: P. McNeice, F.M.F. Vallana, S.J. Coles, P.N. Horton, P.C. Marr, K.R. Seddon, A.C. Marr, Quinine based ionic liquids: A tonic for base instability, Journal of Molecular Liquids (2019), doi: https://doi.org/10.1016/j.molliq.2019.111773. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Graphical Abstract

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Quinine Based Ionic Liquids: A Tonic for Base Instability

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Author names and affiliations

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Peter McNeice , Federico M. F. Vallana , Simon J Coles , Peter N. Horton , Patricia C. Marr , Kenneth R. a, a, Seddon † and Andrew C. Marr *

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a

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Stranmillis Road, Belfast, BT9 5AG, United Kingdom.

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b

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United Kingdom.

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Footnotes

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a

b

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School of Chemistry and Chemical Engineering, The Queen’s University of Belfast, The David Keir Building,

National Crystallography Service, School of Chemistry, University of Southampton, Southampton, SO17 1BJ,

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* Corresponding author. Email: [email protected]

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† Deceased

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Abstract

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Six basic ionic liquids were synthesised from the natural molecule quinine, including one room temperature ionic liquid. The thermal properties were studied and the basicity analysed by Hammett measurements. The properties are discussed in relation to the crystal structure of one of the salts, [C4Qn][NTf2] (2c) and electron density models generated using Spartan. The ionic liquids were shown to catalyse the Knoevenagel condensation of Malononitrile and Benzaldehyde.

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Keywords: Basic ionic liquids, Base stable ionic liquids, Fluorescent ionic liquids, Chiral ionic liquids, Quinine, Base catalysis, Knoevenagel condensation.

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1. Introduction

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Ionic liquids are materials composed entirely of ions which form stable liquids at any temperature, 100 °C is frequently defined as the upper melting point limit [1]. Ionic liquids are well known to have favourable physical properties including high thermal stability, low flammability and negligible vapour pressure, and this has led to them being hailed as green solvents as they pose lower immediate hazard than conventional organic solvents [2]. Despite the apparent stability, the imidazolium cation, the most common cation reported for preparing ionic liquids, is extremely sensitive to base [3]. The heterocyclic ring is easily deprotonated at C2 to form an N-heterocyclic carbene. This limits the use of ionic liquids, as it prevents their successful recycle in base catalysed reactions. Basic ionic liquids can be prepared by locating the basicity on the anion. This can create strong basicity, but often leads to instability as the anion can attack the cation, causing the breakdown of the ionic liquid [4]. Basic ionic liquids of greater stability can be prepared by locating basicity on the cation [5], usually on free Lewis basic sites. Examples of this class includes ionic liquids synthesised from diaminoalkanes [6] and 4-dimethylaminopyridine (DMAP) [7,8]. Diaminoalkane ionic liquids suffer from a lack of selective alkylation which complicates their synthesis. A mixture of mono and dialkylated species can be formed which are difficult to separate [6]. DMAP ionic liquids have reduced basicity due to withdrawal of electron density from the Lewis base by the cation [7,8]. We have previously had some success stabilising basic ionic liquids by using binary ionic liquids containing small amounts of alkoxide anions [9], and by heterogenising phosphonium hydroxide ionic liquids within silica and titania gels via the sol-gel process [10,11]. This manuscript focusses on a third approach, the use of quinine derived cations.

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Quinine is a natural molecule which can be extracted from the bark of cinchona trees [12]. Quinine salts are well known as phase transfer catalysts, most famously in the Sharpless asymmetric dihydroxylation [13]. Quinine halides are often used in the presence of strong bases such as KOH [14] and sodium tert-butoxide [15]. This indicates that the cation is relatively stable under basic conditions. This stability, combined with the developments in synthesising ionic liquids from renewables [16,17,18,19] makes quinine an ideal starting material for base stable ionic liquids. Quinine has been tethered to an imidazolium cation [20], and recently high melting quinine ionic liquids were synthesised and tested for enantiomeric recognition [21]. To the best of our knowledge quinine ionic liquids melting below 100 °C are unknown.

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This work comprises the synthesis of six quinine ionic liquids, including one which is low melting and one room temperature ionic liquid. Quinine reacts preferentially at the non-aromatic nitrogen, rather than the quinoline nitrogen, eliminating problems of low selectivity seen in the synthesis of previous basic ionic liquids [6] and the low base stability of aromatic cations used in conventional ionic liquids [22,23]. The use of the bistriflimide anion, and ether groups in the alkyl chain of the cation, lowers the melting points by a reduction in hydrogen bonding and an increase in flexibility, disrupting ion packing. The quinine ionic liquids have a free nitrogen atom which can act as a base, allowing them to be applied as basic catalysts, this has been demonstrated for the Knoevenagel condensation between malononitrile and benzaldehyde.

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2. Materials and methods

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2.1 Materials

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Solvents were purchased from Sigma-Aldrich and used as supplied without further purification. Quinine (98 %) was purchased from Tokyo Chemical Industry UK, iodomethane (99 %), iodobutane (99 %), bromobutane (99 %), iodohexane (98 %), bromohexane (98 %), bromooctane (99 %), 2bromoethyl methyl ether and 1-bromo-2-(2-methoxyethoxy)ethane (95 %) were purchased from Sigma-Aldrich. Bis(trifluoromethane)sulfonimide lithium salt was purchased from 3M. Malononitrile (99 %) and benzaldehyde (99 %) were purchased from Alfa Aesar.

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2.2 NMR spectroscopy

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Proton nuclear magnetic resonance (1H NMR) spectra, carbon nuclear magnetic resonance (13C NMR) spectra (assigned by Distortionless Enhancement by Polarization Transfer, DEPT), fluorine nuclear magnetic resonance (19F NMR) spectra and phosphorus nuclear magnetic resonance (31P NMR) spectra were recorded at 300 MHz using a Bruker Ultrashield 300 MHz spectrometer. Twodimensional nuclear magnetic resonance (2-D NMR), 1H-1H correlation spectroscopy (COSY) and 1H13 C heteronuclear single quantum coherence (HSQC) were recorded at 400 MHz using a Bruker Ultrashield 400 MHz spectrometer. Spectra were assigned using 2D NMR and comparison with the literature.

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2.3 FTIR spectroscopy

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FTIR spectra were recorded on Thermo Nicolet Nexus 670 and Perkin Elmer Spectrum Two.

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2.4 Thermogravimetric analysis (TGA)

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TGA measurements were carried out using a TGA Q5000 IR thermogravimetric analysis from TA Instruments. The samples were heated in N2 gas with a balance purge flow of 25 mL/min and a sample purge flow of 10 mL/min, with a heating rate of 10 °C per minute within a temperature range of 30 °C to 400 °C. 2

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2.5 Differential scanning calorimetry (DSC)

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DSC measurements were made on a DSC Q2000 from TA Instruments. The samples were heated in an aluminium pan with gas 1 helium, gas 2 N2, both with flow 50 mL/min, temperature cycled between – 90 °C and 200 °C at 20 °C per minute.

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2.6 Spartan calculations

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Spartan calculations were performed using SPARTAN '14 Quantum Mechanics Driver: (Win/64b) Release 1.1.4. Method: RB3LYP. Basis set: 6-31G(D).

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2.7 Synthesis and characterisation of quinine ionic liquids

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The chemical structure and abbreviation of all quinine ionic liquids are given in Figure 1. The structure of all compounds was confirmed by 1H, 13C, 19F and where appropriate, by the 2D 1H-13C HSQC and 2D 1H-1H Cosy NMR sequences as well as by mass spectrometry and elemental analysis. Spectra are available in ESI section 3 and 4. Synthesis of halides were adapted from Berkessel et. al. [24].

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2.7.1. Synthesis of 1-N-methyl quininium iodide: [MeQn][I] (1a)

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Quinine (2.09 g, 6.44 mmol) was dissolved in methanol (MeOH, 60 mL) to form a colourless solution. To this was added methyl iodide (1.26 g, 8.90 mmol) and the solution was stirred overnight at room temperature. The solvent was removed via rotary evaporation and dried for 30 minutes to yield a golden yellow solid. The solid was recrystallized from boiling MeOH (~ 7 mL). The recrystallized solid was washed with diethyl ether and dried overnight under high vacuum to yield an off-white solid. [MeQn][I] (1a) yield = 2.98 g, 6.40 mmol, 99.4 %.

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Quinine (0.25 g, 0.774 mmol) was dissolved in Me-THF (10 mL). To this was added methyl iodide (0.082 g, 0.58 mmol). The flask was capped and stirred at room temperature overnight. During this time a white precipitate formed which was filtered by gravity and washed with Me-THF. The precipitate was recrystallized from boiling methanol (~0.6 mL), filtered and washed with a small amount of diethyl ether. The solid was dried overnight under high vacuum. [MeQn][I] (1a) yield = 0.10 g, 0.217 mmol, 37.6 %.

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ESI-MS m/z: Found 339. 1968 (M+), calcd. for C21H27N2O2: 339.2062. Found 805.3190 (M+ + M+ + M-), calcd. for (C21H27N2O2)2I: 805.3180.

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1

H-NMR (300 MHz, DMSO-d6): δ: 1.30-1.37 (m, H, H5endo), 1.89-1.97 (m, H, H7endo), 2.04-2.05 (m, H, H5exo), 2.10-2.16 (m, 2H, H6endo, H4), 2.79-2.87 (m, H, H3), 3.38 (s, 3H, HA), 3.46-3.52 (m, H, H7exo), 3.61-3.80 (m, 3H, H2, H6exo), 4.02 (s, 3H, OCH3), 4.08-4.16 (m, H, H8), 5.00-5.16 (m, 2H, H11, H11′), 5.69-5.81 (m, H, H10), 6.25 (d, 3.20 Hz, H, H9), 6.53 (d, 3.39 Hz, H, OH), 7.21-7.22 (m, H, H19), 7.47 (dd, 2.45 Hz, 9.23 Hz, H, H17), 7.71 (d, 4.52 Hz, H, H14), 8.00 (d, 9.23 Hz, H, H20), 8.79 (d, 4.52 Hz, H, H13). 13C-NMR (300 MHz, DMSO-d6): δ: 19.74 (C7), 24.99, (C5), 26.28 (C4), 37.92 (C3), 49.24 (CA), 54.59 (C6) 56.02 (OCH3), 64.21 (C2), 64.26 (C8), 67.24 (C9), 101.93 (C17), 116.93 (C11), 120.35 (C19), 122.01 (C14), 125.55 (C16), 131.84 (C20), 138.41 (C10), 144.02 (C21), 144.24 (C15), 147.86 (C13), 157.78 (C18).

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2.7.2. Synthesis of 1-N-methyl quininium bistriflimide: [MeQn][NTf2] (1c)

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To 1-N-methyl quininium iodide, [1-N-MeQn][I] (1a) (2.42 g, 6.40 mmol) dissolved in dichloromethane (DCM, 5 mL) was added lithium bistriflimide (Li(NTf2), 2.42g, 8.32 mmol) dissolved 3

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in deionised water (5 mL). More water (5 mL) was added and to aid solubility as was MeOH (5 mL). The two-phase mixture was heated to 60 °C with stirring and with a reflux condenser fitted. The solid dissolved and orange droplets were visible. After 19 hours the reaction was stopped and the layers allowed to settle. The aqueous layer was decanted off. Fresh deionised water (10 mL) was added and the solution heated at 60 °C with stirring for 30 minutes. The water was decanted off after this time. This was repeated twice more. Then DCM was added followed by deionised water (10 mL) and the mixture stirred for 30 minutes before decanting off the aqueous phase. The organic phases were combined and washed twice more in a separating funnel. The combined aqueous layers were extracted twice with DCM. All organic phases were combined and dried by rotary evaporation to yield a yellow solid. This was further dried under high vacuum overnight. [MeQn][NTf2] (1c) yield = 3.57 g, 5.77 mmol, 90.2 %.

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Found C 44.57, H 4.17, N 6.78, S10.08. Calcd for C23H27F6N2O6S2: C 44.58, H 4.39, N 6.78, S 10.35 %. ESI-MS m/z: Found 339.1877 (M+), calcd. for C21H27N2O2: 339.2062. Found 279.9173 (M-), calcd. for C2F6NO4S2: 279.9173. TGA = 263 °C. m.p. = 130 °C. Tg = 55 °C.

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1

H-NMR (300 MHz, DMSO-d6): δ: 1.31-1.39 (m, H, H5endo), 1.89-1.97 (m, H, H7endo), 2.04-2.05 (m, H, H5exo), 2.12-2.18 (m, 2H, H6endo, H4), 2.77-2.85 (m, H, H3), 3.36-3.47 (m, H, H7exo), 3.40 (s, 3H, HA), 3.63-3.70 (m, 3H, H2, H6exo), 4.01 (s, 3H, OCH3), 4.06-4.14 (m, H, H8), 5.00-5.16 (m, 2H, H11, H11'), 5.70-5.81 (m, H, H10), 6.24 (d, 2.64 Hz, H, OH), 6.57 (d, 3.20 Hz, H, H9), 7.21-7.22 (m, H, H19), 7.47 (dd, 2.45 Hz, 9.23 Hz, H, H17), 7.72 (d, 4.52 Hz, H, H14), 8.01 (d, 9.23 Hz, H, H20), 8.30 (d, 4.52 Hz, H, H13). 13C-NMR (300 MHz, DMSO-d6): δ: 19.71 (C7), 25.00 (C5), 26.30 (C4), 37.98 (C3), 49.14 (CA), 54.62 (C6), 55.87 (OCH3), 64.31 (C2, C8), 67.19 (C9), 101.93 (C17), 116.89 (C11), 119.88 (q, 326.44 Hz, CF3) 120.34 (C19), 122.01 (C14), 125.55 (C16), 131.86 (C20), 138.38 (C10), 144.03 (C21), 144.24 (C15), 147.84 (C13), 157.79 (C18). 19F-NMR (300 MHz, DMSO-d6): δ: - 79.18. IR (KBr Disc): ͞ν (cm-1) = 3094 (OH), 3001 (CH), 2958 (CH), 2838 (CH), 1625 (alkene C=C), 1592 (C=N), 1558, 1511 (aromatic C=C), 1476, 1433, 1419, 1243, 1195 (C-O), 1135, 1057, 831, 603, 571, 505.

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2.7.3. Synthesis of 1-N-butyl quininium iodide: [C4Qn][I] (2a)

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Quinine (1.99 g, 6.15 mmol), was dissolved in MeOH (55 mL) to form a colourless solution. To this was added butyl iodide (1.49 g, 8.12 mmol). The solution was stirred at room temperature for 60 hours. TLC, eluting with 5:1 chloroform: methanol showed no reaction (Quinine only, Rf 0.45). The reaction was then heated to 40 °C with a reflux condenser for 24 hours and then 60 °C for 48 hours until TLC showed no further reaction progress. Product spot had Rf 0.07. Solvent was removed on rotary evaporator to yield a yellow solid. The solid was recrystallized twice with boiling MeOH to leave the pure product. The yellow solid was dried under high vacuum overnight. [C4Qn][I] (2a) yield = 0.52 g, 1.03 mmol, 16.7 %.

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Quinine (1.01 g, 3.10 mmol) was suspended in Me-THF (15 mL). To this was added butyl iodide (0.55 g, 2.98 mmol). A condenser was fitted and the mixture was stirred under reflux for 20 hours. During this time a pink precipitate formed in the purple solution. The precipitate was filtered by gravity and washed with Me-THF so that it became white. The solid was dried by rotary evaporation. [C4Qn][I] (2a) yield = 0.79 g, 1.56 mmol, 50.4 %.

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ESI-MS m/z: Found 381.2276 (M+), calcd. for C24H33N2O2: 381.2531. Found 889.4129 (M+ + M+ + M-), calcd. for (C24H33N2O2)2I: 889.4118.

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H-NMR (300 MHz, CDCl3): δ: 0.95 (t, 7.35 Hz, 3H, HD), 1.24-1.33 (m, H, H5endo), 1.52 (sext, 7.35 Hz, 2H, HC), 1.79-1.86 (m, 2H, HB), 1.89-1.94 (m, 2H, H7endo, H5exo), 2.03-2.09 (m, 2H, H6endo, H4), 2.65 (br s, H, H3), 2.80 (br s, H, H7exo), 3.08-3.13 (m, H, H6exo), 3.38-3.44 (m, H, H2), 3.51-3.59 (m, H, H2′), 4

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3.76-3.97 (m, 2H, HA), 3.89 (s, 3H, OCH3), 4.31 (t, 10.47 Hz, H, H8), 4.91-5.02 (m, 2H, H11, H11'), 5.42-5.43 (m, 2H, H9, H10), 6.37 (s, H, OH), 7.00 (d, 2.26 Hz, H, H19), 7.30 (dd, 2.45 Hz, 6.97 Hz, H, H17) 7.61 (d, 4.52 Hz, H, H14), 7.94 (d, 9.23 Hz, H, H20), 8.61 (d, 4.52 Hz, H, H13). 13C-NMR (300 MHz, CDCl3): δ: 12.86 (CD), 19.17 (C7), 20.36 (CC), 24.04 (CB, C5), 25.16 (C4), 36.45 (C3), 53.12 (C6), 55.23 (OCH3), 59.90 (C2), 60.57 (C8), 62.69 (CA) 65.60 (C9), 100.34 (C17), 116.70 (C11), 119.70 (C19), 120.14 (C14), 124.64 (C16), 131.01 (C20), 135.66 (C10), 142.25 (C21), 143.01 (C15), 146.52 (C13), 157.20 (C18).

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2.7.4. Synthesis of 1-N-butyl quininium bistriflimide: [C4Qn][NTf2] (2c)

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1-N-butyl quininium iodide, [1-N-C4Qn][I] (2a) (0.48 g, 0.945 mmol) was dissolved in MeOH (1 mL). To this was added Li(NTf2) (0.32 g, 1.14 mmol), dissolved in deionised water (0.5 mL). The two-phase mixture was stirred vigorously and heated to 70 °C for 18 hours. Water was decanted off and DCM added. Fresh water was added and the mixture heated with stirring for 20 minutes. The water was then decanted off. This was repeated twice more. The organic layer was washed twice more with water in a separating funnel. The combined aqueous layers were extracted twice with DCM. The organic layers were combined and solvent removed by rotary evaporation to yield a yellow glass. This was dried overnight under high vacuum. [C4Qn][NTf2] (2c) yield = 0.58 g, 0.861 mmol, 93.8 %.

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Found C 47.12, H 5.65, N 6.41, S 9.35. Calcd for C26H33F6N3O6S2: C 47.19, H 5.03, N 6.35, S 9.69. ESIMS m/z: Found 381.2511 (M+), calcd. for C24H33N2O2: 381.2531. Found 279.9173 (M-), calcd. for C2F6NO4S2: 279.9173. TGA = 224 °C. m.p. > 190 °C. Tg = 18 °C.

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H-NMR (300 MHz, CDCl3): δ: 0.92 (t, 7.16 Hz, 3H, HD), 1.20-1.30 (m, H, H5endo), 1.42 (sext, 6.97 Hz, 2H, HC), 1.79-1.83 (m, 2H, HB), 1.90-2.00 (m, 2H, H7endo, H5exo), 2.07-2.17 (m, 2H, H6endo, H4), 2.74 (br s, H, H3), 3.02-3.07 (m, H, H7exo), 3.35-3.66 (m, 5H, H2, H6exo, HA), 3.82 (s, 3H, OCH3), 4.26 (t, 11.30 Hz, H, H8), 4.92-5.01 (m, 2H, H11, H11'), 5.36-5.51 (m, 2H, H9, H10), 6.13 (s, H, OH), 6.91 (s, H, H19), 7.30 (d, 8.85 Hz, H, H17), 7.61 (d, 4.14 Hz, H, H14), 7.90 (d, 9.23 Hz, H, H20), 8.53 (d, 4.14 Hz, H, H13). 13 C-NMR (300 MHz, CDCl3): δ: 12.31 (CD), 18.83 (C7), 19.93 (CC), 23.71 (CB), 24.00 (C5), 25.01 (C4), 36.57 (C3), 53.16 (C6), 54.64 (OCH3), 59.87 (C2), 60.66 (C8), 64.09 (CA), 65.52 (C9), 99.57 (C17), 116.72 (C11), 118.65 (q, 321.84 Hz, CF3), 119.17 (C19), 120.45 (C14), 124.52 (C16), 130.75 (C20), 135.35 (C10), 141.95 (C21), 142.83 (C15), 146.31 (C13), 157.48 (C18). 19F-NMR (300 MHz, CDCl3): δ: 79.35. IR (KBr Disc): ͞ν (cm-1) = 3453 (OH), 2969 (CH), 2918 (CH), 2883 (CH), 2849 (CH), 1625 (alkene C=C), 1593 (C=N), 1558, 1512 (aromatic C=C), 1475, 1434, 1418, 1352, 1327, 1229, 1199 (C-O), 1137, 1056, 829, 739, 617, 570, 514.

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2.7.5. Synthesis of 1-N-hexyl quininium iodide: [C6Qn][I] (3a)

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Quinine (1.29 g, 3.99 mmol) was suspended in MeCN (8 mL). To this was added hexyl iodide (1.09 g 5.14 mmol). The suspension was stirred and heated to 80 °C so that the quinine dissolved. During the first 20 minutes the solution became orange. The total reaction time was 23 hours. Solvent was removed by rotary evaporation to leave a brown solid. This was stirred vigorously with cyclohexane (2 x 10 mL) for 20 minutes and then the solid filtered off each time. The solid was recrystallized from boiling methanol (~ 0.6 mL). The precipitate which formed at room temperature was washed with a small amount of cold methanol and then diethyl ether. The solid obtained was dried overnight on high vacuum. [C6Qn][I] (3a) yield = 1.37 g, 2.55 mmol, 64 %.

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Quinine (1.48 g, 4.57 mmol) was dissolved in Me-THF (45 mL). To this was added iodohexane (0.96 g, 4.50 mmol). The mixture was stirred and heated to reflux for 18 hours, during which time a white precipitate formed in a purple solution. The reaction was filtered under gravity and washed with a

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small amount of Me-THF. The solid was dried under high vacuum overnight. [C6Qn][I] (3a) yield = 0.713 g, 1.33 mmol, 29.5 %.

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ESI-MS m/z: Found 409.2697 (M+), calcd. for C26H37N2O2: 409.2844. Found 945.4755. (M+ + M+ + M-), calcd. for (C26H37N2O2)2I: 945.4744. 1

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H-NMR (300 MHz, CDCl3): δ: 0.85 (t, 7.16 Hz, 3H, HF), 1.25-1.41 (m, 5H, HE, HD, H5endo), 1.49-1.59 (m, 2H, HC), 1.80-2.00 (m, 4H, HB, H7endo, H5exo), 2.12-2.23 (m, 2H, H6endo, H4), 2.79-2.86 (m, H, H3), 2.97-3.04 (m, H, H7exo), 3.38-3.44 (m, H, H2), 3.59-3.68 (m, H, H2′), 3.86-3.94 (m, 2H, HA), 3.90 (s, 3H, OCH3), 4.04-4.14 (m, H, H6exo), 4.50-4.57 (m, H, H8), 4.98-5.05 (m, 2H, H11, H11′), 5.33 (d, 6.03 Hz, H, H9), 5.45-5.56 (m, H, H10), 6.43 (d, 6.22 Hz, H, OH), 7.06 (d, 2.45 Hz, H, H19), 7.35 (dd, 2.64 Hz, 9.23 Hz, H, H14), 7.65 (d, 4.33 Hz, H, H17), 8.00 (d, 9.23 Hz, H, H20), 8.69 (d, 4.52 Hz, H, H13). 13C-NMR (300 MHz, CDCl3): δ: 13.03 (CF), 20.27 (CE), 21.49 (C7), 22.16 (CD), 24.03 (CC), 25.19 (C5), 25.42 (C4), 30.48 (CB), 36.66 (C3), 53.18 (C6), 55.17 (OCH3), 60.17 (C2), 60.78 (C8), 62.40 (CA), 65.96 (C9), 100.72 (C17), 116.94 (C11), 119.69 (C19), 119.72 (C14), 124.67 (C16), 131.28 (C20), 135.46 (C10), 142.04 (C21), 143.21 (C15), 146.72 (C13), 157.22 (C18).

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2.7.6. Synthesis of 1-N-hexyl quininium bistriflimide: [C6Qn][NTf2] (3c)

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1-N-hexyl quininium iodide, [C6Qn][I] (3a) (0.43 g, 0.8 mmol) was dissolved in acetone (3 mL). To this was added Li(NTf2) (0.36 g, 1.25 mmol) in acetone (4 mL). The reaction was heated to 60 °C for 4 hours. The reaction was concentrated to half its volume and a further portion of Li(NTf2) (0.13 g, 0.45 mmol) was added. The reaction was stirred overnight. The solvent was removed by rotary evaporation to leave a red-brown oil which solidified on standing. The solid was heated to 60 °C and washed with deionised water (3 x 5 mL) with vigorous stirring. DCM (5 mL) was added and the layers were separated. The aqueous layers were combined and washed with DCM (2 x 5 mL) and the combined organic layers were removed by rotary evaporation to leave a dark purple solid liquid which became glassy when cooled. The material was dried overnight under high vacuum at 60 °C, during which time it was a liquid. The purple liquid again became a partially crystalline glass upon cooling. [C6Qn][NTf2] (3c) yield = 0.54 g, 0.788 mmol, 98.5 %.

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Found C 48.63, H 5.25, N 5.98 S 8.88. Calcd. For C28H37F6N3O6S2: C 48.76, H 5.41, N 6.09 S 9.30 %. ESIMS m/z: Found 409.2704 (M+), calcd. for C26H37N2O2: 409.2844. Found 279.9173 (M-), calcd. for C2F6NO4S2: 279.9173. TGA = 217 °C. m.p. < 45 °C.

30 31 32 33 34 35 36 37 38 39 40 41

1

H-NMR (300 MHz, CDCl3): δ: 0.83 (t, 7.15 Hz, 3H, HF), 1.24-1.33 (m, 5H, HE, HD, H5endo), 1.40-1.47 (m, 2H, HC), 1.78-1.95 (m, 3H, HB, H7endo), 2.01-2.02 (m, H, H5exo), 2.08-2.28 (m, 2H, H6endo, H4), 2.77 (br s, H, H3), 2.97-3.01 (m, H, H7exo), 3.29-3.50 (m, 2H, H2), 3.46-3.67 (m, 3H, H6exo, HA), 3.85 (s, 3H, OCH3), 4.24-4.31 (m, H, H8), 4.88 (d, 3.48 Hz, H, H9), 4.97-5.03 (m, 2H, H11, H11′), 5.41-5.52 (m, H, H10), 6.18 (s, H, OH), 6.93 (d, 2.57 Hz, H, H19), 7.34 (dd, 2.57 Hz, 9.35 Hz, H, H14), 7.62 (d, 4.77 Hz, H, H17), 7.96 (d, 9.35 Hz, H, H20), 8.63 (d, 4.59 Hz, H, H13). 13C-NMR (300 MHz, CDCl3): δ: 12.76 (CF), 19.82 (CE), 21.34 (C7), 21.94 (CD), 24.02 (CC), 25.06 (C5), 25.12 (C4), 30.19 (CB), 36.72 (C3), 53.13(C6), 54.67 (OCH3), 60.20 (C2), 60.73 (C8), 63.90 (CA), 65.88 (C9), 99.77 (C17), 117.00 (C11), 118.60 (q, 321.84 Hz, CF3), 119.10 (C19), 120.15 (C14), 124.44 (C16), 131.12 (C20), 135.21 (C10), 141.67 (C21), 143.05 (C15), 146.31 (C13), 157.44 (C18). 19F-NMR (300 MHz, CDCl3): δ: -78.78. IR (KBr Disc): ͞ν (cm-1) = 3493 (OH), 2961 (CH), 1627 (alkene C=C), 1593 (C=N), 1512 (aromatic C=C), 1475, 1435, 1351, 1195 (C-O), 1135, 1057, 827, 787, 741 617, 570, 513.

42

2.7.7. Synthesis of 1-N-octyl quininium bromide: [C8Qn][Br] (4b)

6

1 2 3 4 5 6

Quinine (1.00 g, 3.08 mmol) was suspended in Me-THF (9 mL). To this was added octyl bromide (0.60 g, 3.09 mmol) dissolved in Me-THF (6 mL). A condenser was fitted and the mixture heated to reflux so that a colourless solution formed. The reaction was continued overnight and an orange precipitate formed. The precipitate was separated by vacuum filtration and washed with Me-THF and diethyl ether to leave a white solid. The solid was dried by suction and then overnight under high vacuum. Yield [C8Qn][Br] (4b) = 0.92 g, 1.77 mmol, 57.3 %.

7 8

ESI-MS m/z: Found 437.2888 (M+), calcd. for C28H41N2O2: 437.3157. Found 955.5096 (M+ + M+ + M-), calcd. for (C28H41N2O2)2Br: 953.5508. 1

9 10 11 12 13 14 15 16 17

H-NMR (300 MHz, DMSO-d6): 0.88 (t, 6.24 Hz, 3H, HH), 1.29-1.38 (m, 11H, HG-HC, H5endo), 1.84-1.94 (m, 3H, HB, H7endo), 2.02 (br s, H, H5exo), 2.12-2.21 (m, 2H, H6endo, H4), 2.74-2.83 (m, H, H3), 3.41-3.65 (m, 3H, HA, H7exo), 3.73-3.79 (m, 3H, H2, H6exo), 3.90-4.00 (m, 4H, H8, OCH3), 5.00-5.16 (m, 2H, H11, H11′), 5.71-5.83 (m, H, H10), 6.26 (br s, H, OH), 6.52 (d, 3.30 Hz, H, H9), 7.26 (s, H, H19), 7.50 (d, 11.19 Hz, H, H17), 7.71 (d, 4.03 Hz, H, H14), 8.01 (d, 9.35 Hz, H, H20), 8.80 (d, 4.40 Hz, H, H13). 13CNMR (300 MHz, DMSO-d6): 14.37 (CH), 20.43 (CG), 22.35 (C7), 22.46 (CF), 25.00 (C5), 26.31 (C4), 26.60 (CE), 28.90 (CD), 28.93 (CC), 31.60 (CB), 37.91 (C3), 52.55 (C6), 55.84 (OCH3), 59.89 (C2), 60.29 (C8), 64.16 (CA), 66.60 (C9), 102.49 (C17), 116.96 (C11), 120.67 (C19), 121.72 (C14), 125.73 (C16), 131.87 (C20), 138.41 (C10), 144.08 (C21), 144.50 (C15), 147.89 (C13), 157.70 (C18).

18

2.7.8. Synthesis of 1-N-octyl quininium bistriflimide: [C8Qn][NTf2] (4c)

19 20 21 22 23 24 25

1-N-octyl quininium bromide, [C8Qn][I] (4b) (0.23 g, 0.444 mmol), was dissolved in acetone (7 mL). To this was added Li(NTf2) (0.26 g, 0.888 mmol). The reaction was stirred and heated to reflux for 17 hours. Solvent was removed by rotary evaporation to leave a white solid. The solid was dissolved in DCM (4 mL) and heated to reflux with deionised water (3 x 4 mL). The layers were separated and the aqueous layers were extracted with DCM (2 x 3 mL). The organic layers were combined and solvent removed by rotary evaporation. The white solid was dried under high vacuum overnight. Yield [C8Qn][NTf2] (4c) = 0.29 g, 0.406 mmol, 91.5 %.

26 27 28

Found C 50.20, H 6.13, N 5.96, S 8.93. Calcd. for C30H41F6N3O6S2: C 50.20, H 5.76, N, 5.85, S 8.93 %. ESI-MS m/z: Found 437.2823 (M+), calcd. for C28H41N2O2: 437.3157. Found 279.8977 (M-), calcd. for C2F6NO4S2: 279.9173. TGA = 240 °C. m.p. = 122.17 °C.

29 30 31 32 33 34 35 36 37 38 39 40

1

H-NMR (300 MHz, DMSO-d6): 0.94 (t, 7.02 Hz, 3H, HH), 1.34-1.44 (m, 11H, HG-HC, H5endo), 1.88-1.99 (m, 3H, HB, H7endo), 2.07 (br s, H, H5exo), 2.17-2.22 (m, 2H, H6endo, H4), 2.79-2.87 (m, H, H3), 3.45-3.67 (m, 3H, HA, H7exo), 3.76-3.83 (m, 3H, H2, H6exo), 3.96-3.99 (m, H, H8), 4.05 (s, 3H, OCH3), 5.06-5.22 (m, 2H, H11, H11'), 5.76-5.88 (m, H, H10), 6.30 (br s, H, OH), 6.56 (d, 3.22 Hz, H, H9), 7.31 (d, 2.34 Hz, H, H19), 7.55 (dd, 2.34 Hz, 9.06 Hz, H, H17), 7.77 (d, 4.38 Hz, H, H14), 8.07 (d, 9.35 Hz, H, H20), 8.76 (d, 4.38 Hz, H, H13). 13C-NMR (300 MHz, DMSO-d6): 14.33 (CH), 20.25 (CG), 22.35 (C7), 22.46 (CF), 25.00 (C5), 26.30 (C4), 26.60 (CE), 28.90 (CD), 28.93 (CC), 31.60 (CB), 37.92 (C3), 52.56 (C6), 55.78 (OCH3), 59.91 (C2), 60.30 (C8), 64.25 (CA), 66.64 (C9), 102.45 (C17), 116.96 (C11), 119.87 (d, 322.99 Hz, CF3), 120.66 (C19), 121.68 (C14), 125.70 (C16), 131.90 (C20), 138.38 (C10), 144.09 (C21), 144.47 (C15), 147.89 (C13), 157.70 (C18). 19F-NMR (300 MHz, DMSO-d6): -79.14. δ: IR (KBr Disc): ͞ν (cm-1) = 3476 (OH), 2960 (CH), 2930 (CH), 2860 (CH), 1622 (aromatic C=C), 1593 (C=N), 1510 (aromatic C=C), 1475, 1432, 1353, 1194 (C-O), 1139, 1052, 917, 827, 797, 741, 621, 570, 514.

41

2.7.9. Synthesis of 1-N-ethyl methylether quininium bromide: [C1OC2Qn][Br] (5b)

42 43

Quinine (1.30 g, 4.01 mmol) was dissolved in Me-THF (25 mL), 2-bromoethyl methyl ether (0.53 g, 3.79 mmol) was added to the stirred solution. The mixture was heated to 90 °C for 21 hours during 7

1 2 3 4 5 6

which time a purple solution formed. Upon cooling the reaction mixture gelled. The gel was broken up and stirred vigorously forming a solution and a precipitate. The precipitate was filtered and washed with a small amount of Me-THF to leave a pale pink solid that was dried by rotary evaporation. MeTHF remained in the product. This was carried through to the next step and then removed. Me-THF peaks from spectrum S9.1, S9.2 and S9.3 are underlined in analysis below. Crude yield [C1OC2Qn][Br] (5b) = 0.18 g, 0.399 mmol, 10.0 %.

7 8

ESI-MS m/z: Found 383.2256 (M+), calcd. for C23H31N2O3: 383.2324. Found 847.3843 (M+ + M+ + M-), calcd. for (C23H31N2O3)2Br: 846.3842. 1

9 10 11 12 13 14 15 16 17 18 19

H-NMR (300 MHz, CDCl3): δ: 1.38-1.47 (m, H, H5endo), 1.96-2.03 (m, H, H7endo), 2.05-2.08 (m, H, H5exo), 2.13-2.20 (m, H, H6endo), 2.25-2.35 (m, H, H4), 2.80-2.87 (m, H, H3), 3.23-3.29 (m, H, H7exo), 3.43 (s, 3H, HC), 3.66-3.70 (m, H, H6exo), 3.86-3.97 (m, 2H, HB), 3.99 (s, 3H, OCH3), 4.04-4.16 (m, 2H, HA), 4.29-4.37 (m, H, H2), 4.49-4.55 (m, H, H2′), 4.78-4.86 (m, H, H8) 5.07-5.13 (m, 2H, H11, H11'), 5.54-5.65 (m, H, H10), 6.19 (d, 6.42 Hz, H, OH), 6.45 (d, 5.69 Hz, H, H9), 7.33 (d, 2.57 Hz, H, H19), 7.40 (dd, 2.57 Hz, 9.17 Hz, H, H17), 7.70 (d, 4.40 Hz, H, H14), 8.06 (d, 9.17 Hz, H, H20), 8.76 (d, 4.58 Hz, H, H13). Me-THF = 1.23 (d, 6.05 Hz), 1.83-1.88 (m), 3.72-3.78 (m). 13C-NMR (300 MHz, DMSO-d6): δ: 20.61 (C7), 25.06 (C5), 26.28 (C4), 37.94 (C3), 53.51 (C6), 56.04 (OCH3), 58.54 (CC), 60.06 (CB), 60.82 (CA), 64.41 (C2), 65.41 (C8), 67.05 (C9), 102.79 (C17), 116.99 (C11), 120.63 (C19), 121.65 (C14), 125.87 (C16), 131.81 (C20), 138.44 (C10), 144.11 (C21), 144.37 (C15), 147.84 (C13), 157.74 (C18). Me-THF at 21.31, 25.50, 33.09, 67.39.

20

2.7.10. Synthesis of 1-N-ethyl methylether quininium bistriflimide: [C1OC2Qn][NTf2] (5c)

21 22 23 24 25 26 27

1-N-ethyl methylether quininium bromide, [C1OC2Qn][Br] (5b) (0.1726 g, 0.372 mmol) was dissolved in methanol (5 mL). To this was added Li(NTf2) (0.19 g, 0.651 mmol). The reaction was heated to 60 °C and stirred for 19 h. The solvent was removed by rotary evaporation to leave an orange solid. The solid was dissolved in DCM (3 mL) and heated to reflux with deionised water (3 x 3 mL) for 30 minutes, water was decanted after each reflux. The layers were separated in a funnel and organic solvent removed by rotary evaporation. The orange solid was dried overnight under high vacuum. Yield [C1OC2Qn][NTf2] (5c) = 0.20 g, 0.303 mmol, 81.5 %.

28 29 30

Found C 45.52, H 4.74, N 6.25, S 9.23. Calcd. for C25H31F6N3O7S2: C 45.24, H 4.71, N 6.33, S 9.23 %. ESI-MS m/z: 383.2367 (M+), calcd. for C23H31N2O3: 383.2324. Found 279.9173 (M-), calcd. for C2F6NO4S2: 279.9173. TGA = 207 °C. m.p. = 124 °C.

31 32 33 34 35 36 37 38 39 40 41

1

H-NMR (300 MHz, DMSO-d6): δ: 1.40-1.48 (m, H, H5endo), 1.94-2.01 (m, H, H7endo), 2.07 (m, H, H5exo), 2.15-2.26 (m, 2H, H6endo, H4), 2.82-2.90 (m, H, H3), 3.39 (s, 3H, HC) 3.52-3.69 (m, 3H, H7exo, H2), 3.853.95 (m, 3H, H6exo, HB), 4.02-4.04 (m, 3H, HA, H8), 4.07 (s, 3H, OCH3), 5.06-5.22 (m, 2H, H11, H11'), 5.77-5.89 (m, H, H10), 6.29 (d, 3.12 Hz, H, OH), 6.62 (d, 3.48 Hz, H, H9), 7.35 (d, 2.38 Hz, H, H19), 7.55 (dd, 2.38 Hz, 9.17 Hz, H, H17), 7.75 (d, 4.40 Hz, H, H14), 8.07 (d, 9.17 Hz, H, H20), 8.85 (d, 4.58 Hz, H, H13). 13C-NMR (300 MHz, DMSO-d6): δ: 20.67 (C7), 25.08 (C5), 26.27 (C4), 37.94 (C3), 53.52 (C6), 55.98 (OCH3), 58.52 (CC), 60.04 (CB), 60.82 (CA), 64.48 (C2), 65.39 (C8), 67.07 (C9), 102.75 (C17), 116.99 (C11), 120.63 (C19), 121.60 (C14), 125.82 (C16), 131.83 (C20), 138.39 (C10), 144.09 (C21), 144.34 (C15), 147.84 (C13), 157.74 (C18), CF3 not visible. 19F-NMR (300 MHz, DMSO-d6): δ: -78.72. IR (KBr Disc): ͞ν (cm-1) = 3066 (OH), 3003 (CH), 2962 (CH), 1625 (alkene C=C), 1511 (C=N), 1471 (aromatic C=C), 1345, 1320 1187 (C-O), 1139, 1059, 1032, 833, 601, 571.

42

2.7.11. Synthesis of 1-N-2-(2-methoxyethoxy)ethane quininium bromide: [C1OC2OC2Qn][Br] (6b)

8

1 2 3 4 5 6

Quinine (1.4767 g, 4.55 mmol), was dissolved in Me-THF (30 mL). To this was added 1-bromo-2-(2methoxyethoxy)ethane (0.7802 g, 4.26 mmol). The reaction was heated to 93 °C and stirred for 20 hours. A purple solution with some purple precipitate had formed. The precipitate was separated by filtration and washed with Me-THF and diethyl ether before drying overnight under high vacuum. The filtrate was concentrated by rotary evaporation and formed a gel on cooling. Yield [C1OC2OC2Qn][Br] (6b) = 0.44 g, 0.866 mmol, 19.0 %.

7 8

ESI-MS m/z: Found 427.2540 (M+), calcd. for C25H35N2O4: 427.2586. Found 935.4370 (M+ + M+ + M-), calcd. for (C25H35N2O4)2Br: 935.4366. 1

9 10 11 12 13 14 15 16 17

H-NMR (300 MHz, DMSO-d6): δ: 1.42-1.50 (m, H, H5endo), 1.89-1.97 (m, H, H7endo), 2.02-2.03 (m, H, H5exo), 2.13-2.18 (m, 2H, H6endo, H4), 2.79-2.86 (m, H, H3), 3.17 (s, 3H, HE), 3.35-3.37 (m, 2H, HD), 3.51-3.65 (m, 4H, HC, HB), 3.84-3.97 (m, 3H, H7exo, H2), 4.02-4.05 (m, 7H, OCH3, HA, H6exo, H8), 5.025.18 (m, 2H, H11, H11'), 5.75-5.86 (m, H, H10), 6.25 (d, 3.85 Hz, H, OH), 6.56 (d, 4.22 Hz, H, H9), 7.35 (d, 2.57 Hz, H, H19), 7.48 (dd, 2.57 Hz, 9.17 Hz, H, H17), 7.67 (d, 4.59 Hz, H, H14), 8.00 (d, 9.17 Hz, H, H20), 8.79 (d, 4.40 Hz, H, H13). 13C-NMR (400 MHz, DMSO-d6): δ: 20.66 (C7), 25.05 (C5), 26.31 (C4), 37.97 (C3), 53.40 (C6), 56.11 (OCH3), 58.38 (CE), 60.15 (CD), 60.84 (CC), 63.93 (C2), 64.39 (C8), 67.13 (C9), 69.77 (CB), 71.24 (CA), 102.80 (C17), 116.96 (C11), 120.54 (C19), 121.74 (C14), 126.02 (C16), 131.77 (C20), 138.44 (C10), 144.15 (C21), 144.37 (C15), 147.80 (C13), 157.74 (C18).

18 19

2.7.12. Synthesis of 1-N-2-(2-methoxyethoxy)ethane quininium bistriflimide: [C1OC2OC2Qn][NTf2] (6c)

20 21 22 23 24 25 26 27

1-N-2-(2-methoxyethoxy)ethane quininium bromide, [C1OC2OC2Qn][Br] (6b) (0.44 g, 0.866 mmol) was dissolved in acetone (3 mL). To this was added Li(NTf2) (0.41 g, 1.42 mmol). The brown solution was heated to 70 °C with stirring for 17 hours. Solvent was removed by rotary evaporation to leave a viscous brown liquid which solidified upon cooling. The solid was dissolved in DCM (3 mL) and refluxed three times with deionised water (3 x 5 mL) with water decanted after each reflux. Layers were separated in a funnel and the organic solvent was removed by rotary evaporation to leave a viscous liquid. The liquid was dried overnight under high vacuum. Yield [C1OC2OC2Qn][NTf2] (6c) = 0.56 g, 0.786 mmol), 90.7 %.

28 29 30

Found C 46.88, H 4.91, N 6.80, S 8.28. Calcd. for C27H35F6N3O6S2: C 45.82, H 4.98, N, 5.94, S 9.06 %. ESI-Ms m/z: Found 427.2278 (M+), calcd. for C25H35N2O4: 427.2586. Found 279.9173 (M-), calcd. for C25H35N2O4: 279.9173. TGA = 212 °C. Tg = -8 °C. Tm not observed.

31 32 33 34 35 36 37 38 39 40 41 42

1

H-NMR (300 MHz, DMSO-d6): δ: 1.44-1.52 (m, H, H5endo), 1.94-2.01 (m, H, H7endo), 2.08 (br s, H, H5exo), 2.18-2.34 (m, 2H, H6endo, H4), 2.83-2.90 (m, H, H3), 3.25 (s, 3H, HE), 3.44-3.46 (m, 2H, HD), 3.54-3.68 (m, 4H, HC, HB), 3.87-3.99 (m, 3H, H7exo, H2), 4.07-4.10 (m, 7H, OCH3, HA, H6exo, H8), 5.085.23 (m, 2H, H11, H11'), 5.79-5.90 (m, H, H10), 6.29 (br s, H, OH), 6.61 (d, 3.12 Hz, H, H9), 7.37 (br s, H, H19), 7.55 (d, 10.09 Hz, H, H17), 7.74 (d, 4.03 Hz, H, H14), 8.07 (d, 9.17 Hz, H, H20) 8.86 (d, 4.22 Hz, H, H13). 13C-NMR (400 MHz, DMSO-d6): δ: 20.55 (C7), 25.06 (C5), 26.27 (C4), 37.95 (C3), 53.43 (C6), 55.98 (OCH3), 58.40 (CE), 60.09 (CD), 60.82 (CC), 63.93 (C2), 64.47 (C8), 67.16 (C9), 69.78 (CB), 71.28 (CA), 102.74 (C17), 116.96 (C11), 119.87 (d, 321.84 Hz, CF3) 120.54 (C19), 121.66 (C14), 125.90 (C16), 131.81 (C20), 138.39 (C10), 144.12 (C21), 144.31 (C15), 147.81 (C13), 157.74 (C18). 19F-NMR (300 MHz, DMSO-d6): δ: -79.73. IR (Neat): ͞ν (cm-1) = 3192 (OH), 3082 (CH), 2937 (CH), 1622 (alkene C=C), 1560 (C=N), 1512 (aromatic C=C), 1462, 1433, 1357, 1232 (C-O), 1134, 1057, 934, 829, 790, 655, 571.

43

9

1

2.8. Knoevenagel condensation

2 3

2.8.1. General Procedure for Knoevenagel condensation demonstrated for [C4Qn][NTf2] (2c) (Table 3, entry 3). Adapted from Keithellakpam et al. [25].

4 5 6 7 8 9 10 11 12 13

Malononitrile (68.2 mg, 1.03 mmol) was added to a 10 mL round bottomed flask. To this was added benzaldehyde (0.10 g, 1.0 mmol) and DCM (0.18 g) and the flask capped and sealed. The mixture was briefly stirred to ensure it was homogeneous. Then [C4Qn][NTf2] (2c) (64.4 mg, 0.01 mmol, 0.1 mol eq.) was added, the total mass recorded, and the flask was capped, sealed and stirred at 500 RPM for 1 hour. After this time a reaction sample of known mass (0.3032 g) was taken. To this sample was added ethyl trifluoroacetate (0.3149g, 6.13 mmol, 1:1 wt/wt.). CDCl3 (0.4 mL) was added and a 1H NMR spectrum was recorded (ESI, Spectrum S13). The ethyl trifluoroacetate CH3 triplet at 1.26 ppm was monitored. Integration was set to 3 for 3H (ESI, Spectrum S13). The PhCH singlet of the product was monitored at 7.73 ppm. Integration was measured as 0.29 (ESI, Spectrum S13). The solution yield was calculated as detailed in section 2 of the ESI.

14

2.8.2. Recycle of [MeQn][NTf2] (1c)

15 16 17 18 19 20 21

Malononitrile (55.9 mg, 0.85 mmol, 1 eq.) was added to a 10 mL round bottomed flask. To this was added benzaldehyde (81.9 mg, 0.77 mmol, 1 eq.) and DCM (0.13 g) and the flask capped and sealed. The mixture was briefly stirred to ensure it was homogeneous. Then [MeQn][NTf2] (1c) (48.1 mg, 0.008 mmol, 0.1 eq.) was added, the total mass recorded, and the flask was capped, sealed and stirred at 500 RPM for 30 minutes. After this time a reaction sample of known mass (0.0242 g) was taken. To this sample was added ethyl trifluoroacetate (0.0111 g, 0.071 mmol). CDCl3 (0.4 mL) was added and a 1H NMR spectrum was recorded.

22 23 24 25 26 27 28

DCM was removed from the remaining reaction mixture via rotary evaporation to leave a yellow solid. The solid was suspended in diethyl ether (3 mL). This was filtered and the solid residue washed with diethyl ether (2 x 3 mL) to leave a white solid. This was dried via rotary evaporation to leave 39.5 mg of recovered [MeQn][NTf2] (1c). The recovered [MeQn][NTf2] (1c) was reused twice more, with the reaction procedure and recovery identical to that outlined above. 1H NMR of the recovered catalyst showed no reaction products (ESI Spectrum S14) and 1H NMR of the evaporated filtrate showed no [MeQn][NTf2] (ESI Spectrum S15).

29 30 31 32 33 34 35 36 37 38 39 10

1

3. Results and discussion

2

3.1. Synthesis of quinine ionic liquids

3 4 X-

5 6 7

RX

8

20 hours

[Li(NTf2)] -LiX X = [I]- (a), [Br]- (b), [NTf2]- (c)

9 10 11 12 13 14 15 16

[MeQn]+ (1)

[C4Qn]+ (2)

[C6Qn]+ (3)

[C8Qn]+ (4)

[C1OC2Qn]+ (5)

[C1OC2OC2Qn]+ (6)

17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

Figure 1: General for synthesis of quinine ionic liquids from quinine, structures of ionic liquids. A general reaction scheme for quinine ionic liquid synthesis and the structures of the cations is given in Figure 1. The synthesis follows the procedure of Berkessel et. al. [24]. Quinine was reacted with 1 molar equivalent of alkyl halide in either methanol or acetonitrile. Following this, an ion exchange using [Li(NTf2)] was performed. [MeQn][I] (1a) was synthesised in almost quantitative yield in methanol following recrystallisation in boiling methanol. This method was not successful for the other quinine halides, which were not readily recrystallised. Changing the solvent to 2methyltetrahydrofuran (Me-THF) caused precipitation of the quinine halide which could be obtained pure after filtration and washing with Me-THF and diethyl ether. This method was used to prepare the remaining quinine halides (2a, 3a, 4b, 5b, 6b) and has the added advantage that Me-THF is a ‘green’ solvent, which can be obtained from renewable sources [26]. This builds on the green 11

1 2 3

approach of using quinine as a starting material in order to synthesise green and sustainable basic ionic liquids. Synthesis of the halide salt was low yielding for the ether quinine ionic liquids [C1OC2Qn][NTf2] (5c) and [C1OC2Qn][NTf2] (6c). All ion exchange reactions yielded greater than 80 %.

4

3.2. Physical properties of quinine ionic liquids

5

Table 1: Thermal properties and Hammett basicity of quinine ionic liquids.

6 7 8 9

Entry Quinine Ionic Liquid Tmelting / °Ca Tdegradation / °Cb Hammett Basicity (H_)f 1 [MeQn][NTf2] (1c) 131 263 8.51 2 [C4Qn][NTf2] (2c) 107 224 8.65 3 [C6Qn][NTf2] (3c) < 45,c (11)d 217 9.40 4 [C8Qn][NTf2] (4c) 122 240 8.44 5 [C1OC2Qn][NTf2] (5c) 124 (10)d 207 8.72 6 [C1OC2OC2Qn][NTf2] (6c) < RT,e (- 8)d 213 9.95 a b Melting point measured by dye sensitised calorimetry. Degradation onset temperature measured by thermogravimetric analysis. c Visual observation. d Glass transition temperature. e No melting point observed by DSC. f Determined by monitoring UV absorbance at 595 nm of a 0.09 mM solution of IL in methanolic bromophenol blue.

10 11 12 13 14 15 16 17 18

The thermal properties and Hammett basicity functions of the quinine ionic liquids are shown in Table 1. The range of cation structures allows for assessment of the effect of the alkyl chain composition on physical properties and catalysis. Water is not influencing the properties as Karl Fischer titration showed <0.1 wt. % in all ionic liquids. The determination of the pH of an ionic liquid is not straightforward when it is insoluble or unstable in water. The Hammett function (H0) has been used as a measure of the acidity of non-aqueous Brønsted acid systems [27,28], and has more recently been used to determine basicity in non-aqueous systems [29,30]. The Hammett basicity (H_) of the quinine ionic liquids was measured by monitoring the UV absorbance of methanolic bromophenol blue at a fixed concentration of ionic liquid.

19 20 21 22 23 24 25 26

The melting point behaviour of the quinine salts was found to vary significantly as the additional functional group was changed (Table 1). The high melting points (above 100 °C), for several of the salts can be partly attributed to hydrogen bonding involving the hydroxyl group of the cation. SPARTAN calculations performed on [MeQn][NTf2] (1c) (ESI Section 8) [31] show hydrogen bonding interactions between this hydroxyl group and the anion. However, solving the structure of [C4Qn][NTf2] (2c) as a two-component twin by X-ray crystallography (Cambridge database CCDC = 1920034) shows, that in the solid crystalline state, hydrogen bonds form between the hydroxyl group and the free nitrogen atom of neighbouring cations (Figure 2, Figure 3, Table 2).

12

1 2

Figure 2: Crystal structure of [C4Qn][NTf2] (2c).

3 4 5

Figure 3: The following hydrogen bonding interactions with a maximum D-D distance of 2.9 Å and a minimum angle of 120 ° are present in [C4Qn][NTf2] (2c): O1–N32: 2.774 Å, O31–N2_1: 2.817 Å.

6 7 8 13

1

Table 2: Hydrogen bond information for [C4Qn][NTf2] (2c). D

H

A

O1 O31

H1 H31

N32 N21

2

---

3

Symmetry factor: -1+x,+y,+z

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

d(D-H)/Å

d(H-A)/Å

0.84 0.84

1.93 1.98

d(D-A)/Å 2.774(5) 2.817(5)

D-H-A/deg 176.6 171.5

The alkyl quinine ionic liquids (1c, 2c, 3c, 4c) (Table 1 entries 1-4) show decreasing melting point as the chain length increases from 1 to 6 carbon atoms before the trend reverses when the chain length is 8. Conventional wisdom suggests that initial increases in chain length will prevent stacking of the ions and lower the melting point [1]. The packing diagram obtained from X-ray crystallography supports this model (Figure 4). In [C4Qn][NTf2] (2c) crystals the butyl chain of one cation points towards the adjacent cation. As the chain length increases it is expected that the cations will be forced further apart, which will decrease interactions between them and decrease the melting point. Crystal structures of the long chain quinine ionic liquids were not obtained as these salts exhibited a glassy state and could not be crystallised. As the chain length continues to increase the van der Waals’ forces of attraction will increase, increasing the melting point. The ether quinine ionic liquids (5c, 6c) (Table 1 entries 5 and 6) were expected to have lower melting points than the alkyl equivalents due to the increased flexibility of the chains, discouraging regular stacking of the ions [32,33]. This is not the case for [C1OC2Qn][NTf2] (5c) (Table 1 entry 5), which contains one ether linkage, and has a higher melting point than the C4 alkyl analogue (2c) (Table 1 entry 2). The increased melting point of [C1OC2Qn][NTf2] (5c) may be due to weak interactions formed due to the electronegative oxygen atom. The longer chain [C1OC2OC2Qn][NTf2] (6c) (Table 1, entry 6), has a lower melting point. Presumably the increased flexibility [34] due to the inclusion of two ether groups, has overcome additional interactions and prevented long range ordering [35]. This disruption of ion packing is sufficient to allow [C1OC2OC2Qn][NTf2] (6c) to form a room temperature ionic liquid. We believe this to be the first room temperature ionic liquid reported based on the quinine backbone.

25 26

Figure 4: Packing diagram of [C4Qn][NTf2].

27 28 29 30 31

Decomposition temperature and Hammett basicity follow the same trend as melting point described above. Initially Hammett basicity increases with chain length. This may be due to disruption of the hydrogen bonding network discussed above. When the hydrogen bonding network is strong the quinoline nitrogen interacts with the hydroxyl group and is less available to deprotonate the indicator. When the hydrogen bonding network is weaker the quinoline is better able to 14

1 2 3 4 5 6 7 8 9 10

deprotonate the indicator and the Hammett basicity increases. This is supported by the relatively high basicity of the ether quinine ionic liquids (5c, 6c) (Table 1 entries 5 and 6). 5c and 6c are expected to have flexible chains which will disrupt the ion packing to a greater degree than the alkyl quinine ionic liquids (1c-4c). This will disrupt the hydrogen bonding network freeing the quinoline nitrogen to act as a base. [C8Qn][NTf2] (4c) has a lower Hammett basicity than expected (Table 1, entry 4). As discussed for melting point, decreased ion-ion interaction caused by the disruption in hydrogen bonding is possibly reversed by increase the van der Waals’ forces of attraction. This may prevent the quinoline nitrogen deprotonating the indicator molecule. Alternately, the long chain may hinder the deprotonation of the indicator molecule by preventing contact between the ionic liquid and the indicator.

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Trends in thermal stability are not clear and the behaviour exhibited is complex. Increasing chain length has been reported to reduce thermal decomposition temperatures in imidazolium ionic liquids [36,37]. Basicity can also affect thermal stability, as the basicity increases there is a greater potential for self-decomposition due to the nucleophilic attack of one cation on another. Neutral quinine begins to decompose around 200 °C (ESI Figure S7) and there is an important molecular component to decomposition. Ether quinine ionic liquids 5c and 6c (Table 1, entries 5 and 6) have reduced decomposition temperatures compared to the alkyl quinine ionic liquids (1c-4c) of similar chain length (Table 1 entries 1-4). This is to be expected as ether functionalities are prone to cleavage and ionic liquids with ether chains tend to have lower decomposition temperatures [38]. The decomposition temperatures compare favourably with traditional basic ionic liquids [BMIM][OH] (90 °C) [39] and [BMIM][OAc] (180 °C) [40]. DABCO based ionic liquids tend to decompose at temperatures above 300 °C [41,42] but are often over-alkylated leading to a mixture of mono and di-alkylated species which are difficult to separate. The quinine ionic liquids have the advantage of being derived from renewable sources, selective alkylation of one nitrogen atom, and cleaner synthesis by using Me-THF.

26 27 28 29 30 31 32

It has been discussed above that the cationic nitrogen can withdraw electron density from the basic nitrogen in ionic liquids [7]. In systems based on quinoline the two nitrogen atoms are distant, and Spartan calculations [31] carried out on [MeQn][NTf2] (1c) (Figure 5) suggest that the effect is small, as the electrostatic charge on the quinoline nitrogen was found to be similar before (-0.578) and after (-0.560) alkylation of the quinuclidine nitrogen, (the more negative value has greater electron density). Figure 5 displays the quinoline electron density in red. This is significant for the use of quinine ionic liquids as basic catalysts.

33 34 35 36 37 38 39

Figure 5: Electron density model of; Left) Quinine. Right) [MeQn][NTf2]. Quinoline nitrogen is boxed in each case.

40

3.3. Quinine ionic liquids as basic catalysts

41 42

The Knoevenagel condensation was introduced as a test reaction for base catalysed reactions in ionic liquids by Davis and co-workers [43]. In this work the Knoevenagel is used as a demonstration 15

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

of the catalytic ability of the quinine ionic liquids. The basicity of the ionic liquids was indicated by measuring their ability to act as catalysts for the Knoevenagel condensation of malononitrile and benzaldehyde (Figure 6), with yields ranging from 78-94 %. Control experiments showed that the product was not produced in the absence of a basic catalyst (Table 3, entry 1). The ether quinine ionic liquids (5c, 6c) exhibit higher yields than the analogous alkane chain ionic liquids (Table 3 entries 3, 5, 6, 7). This may be due to the disruption of the hydrogen bonding between the cation and quinoline, as discussed for melting point and / or due to interaction between the ether oxygens and the cation rather than the quinoline nitrogen, conserving basicity and enabling these catalysts to deprotonate the substrate more easily. The contained yield of Knoevenagel condensation (Table 3) does not follow the trend in Hammett basicity (Table 1). This could be due to a number of factors. For example steric hindrance of the longer chain ionic liquids may inhibit the catalyst access to the substrate, while the difference in van der Waals’ interactions may contribute to either a reduction or increase in the interaction between the catalyst and substrate. Additionally the conditions used to measure the Hammett basicity are different to those used in the reaction. The highest contained yield was observed for [C1OC2OC2Qn][NTf2] (6c), and this suggests that good liquid behaviour crossed with high Hammett basicity is a recipe for a good basic catalyst.

17 18 19 20 21 22 23 24 25

Recycling was tested for [MeQn][NTf2] (1c) (section 2.8.2.). A 30 minute reaction time was used to analyse recycling at yields lower than 90 %. Solvent was removed under vacuum and the product extracted into ether before filtering to recover the insoluble ionic liquid catalyst. The catalyst was dried under vacuum and reused. [MeQn][NTf2] (1c) was used for a total of four reactions with little change in activity (Figure 7). This is a facile recycling procedure compared to column chromatography used to recycle quinine from a reaction mixture [44]. The quinine ionic liquids demonstrated improved catalytic activity (Table 3 entries 2-8) and improved thermal stability compared to neutral quinine. Considering this alongside the ease of recycling, there are clear benefits to converting from quinine to quinine ionic liquids.

26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

The quinine ionic liquids produced higher yields than traditional bases (Table 3 entries 9, 10) and quinine itself (Table 3 entry 8). This suggests that the molecular functionality of the catalyst is important and it does not act solely as a base. Theoretical calculations have shown that the elimination of hydroxide to form the final product is the rate-limiting step in a similar Knoevenagel condensation in methanol [45]. The polar nature of the ionic liquid would favour this elimination, potentially hetero-functionality in the base could assist elimination of hydroxide from the substrate. The yields obtained are comparable to literature results. Keithellakpam et al. [25] used a basic cation based on hexamethylenetriamine (HMTA) in water to catalyse the same reaction. The isolated yields in Keithellakpam’s system ranged from 82 % to 100 %. The catalyst loading was 5-30 mole % (compared to 10 mole % ionic liquid concentration in this work). Xu et. al. [46] prepared a series of DABCO based ionic liquids and used 15 mole % catalyst in water, obtaining yields of 83-100 %. We have previously used a series of binary alkoxide ionic liquids, with general formula [Pyrr14][NTf2]x[OiPr]1-x, to catalyse this reaction. 1 mol % of the binary ionic liquids produced yields of 24-89 % [9]. Quinine ionic liquids are used here in a higher mole % and may be less basic than the binary ionic liquids. This could lead to the use of quinine ionic liquids to selective deprotonate a less acidic hydrogen atom on a complex molecule, leaving less reactive positions unchanged. We envisage them finding uses in other base catalysed reactions beyond the Knoevenagel condensation.

43

RT, 1 h, DCM

44 45

Basic catalyst (10 mole %) Figure 6: Knoevenagel condensation between benzaldehyde and malononitrile. 16

1

Table 3: Contained yield of Knoevenagel condensation catalysed by 10 mole % basic catalyst. Entry

2 3 4

Catalyst

Hammett Contained Benzaldehyde Malononitrile Basicity (H_) Yielda (±, SD) Conversion (±, SD) Conversion (±, SD) 1 None NA 0 <1 <1 2 [MeQn][NTf2] (1c) 8.51 79 (0.8) 95 (1.4) 86 (0.8) 3 [C4Qn][NTf2] (2c) 8.65 86 (4.9) 92 (3.7) 90 (2.1) 4 [C6Qn][NTf2] (3c) 9.40 78 (2.2) 92 (1.2) 86 (0.9) 5 [C8Qn][NTf2] (4c) 8.44 81 (1.4) 94 (2.2) 86 (0.5) 6 [C1OC2Qn][NTf2] (5c) 8.72 88 (3.3) 89 (2.1) 90 (1.7) 7 [C1OC2OC2Qn][NTf2] (6c) 9.95 94 (4.5) 97 (2.4) 92 (5.7) 8 Quinine 9.72 63 (3.7) 99 (0) 86 (2.1) 9 DABCO 9.80 62 (2.1) 99 (0) 99 (0) 10 DBU 10.17 74 (4.1) 99 (0) 89 (6.9) Conditions: Malononitrile (0.11 g, 1.72 mmol), benzaldehyde (0.18 g, 1.66 mmol), basic catalyst (10 mol %), DCM (0.31 g, 1:1 wt. % with reagents) (RT, stir rate 500 RPM and time 1 h). a Obtained from 1 H NMR against a known mass of ethyl trifluoroacetate, value is an average of three reactions.

Recycle of [MeQn][NTf2] (1c) for Knoevenagel Contained Yield (%)

100 90 80 70 60

58

57

56

58

1st run

2nd run

3rd run

4th run

50 40 30 20 10 0

5 6 7

Figure 7: Contained yield in recycling experiments of Knoevenagel condensation catalysed by [MeQn][NTf2] (1c).

8 9 10 11 12 13

[C6Qn][NTf2] (3c), [C1OC2Qn][NTf2] (5c) and [C1OC2OC2Qn][NTf2] (6c) were found to fluoresce under UV light (see the Graphical abstract). The higher melting point ionic liquids (1c, 2c, 4c) fluoresced when in solution. This could potentially allow for use in fluorescence-based applications. As well as acting as basic catalysts the quinine ionic liquids have a wide range of potential uses based on their fluorescence, their antimicrobial properties [47] and their potential for enantiomeric separations [21] or enantiomeric reactions [48].

14

4. Conclusions

15 16 17 18

Six quinine ionic liquids have been synthesised, including one which is low melting and one room temperature ionic liquid. The ionic liquids prepared exhibit high Hammett Basicity and have been used to successfully catalyse the Knoevenagel condensation of Malononitrile and Benzaldehyde. Recycle of [MeQn][NTf2] (1c) was possible for at least four reactions without loss of activity. These

17

1 2

new salts may be applied to other base catalysed reactions and find additional uses due to their fluorescence and the chiral properties of quinine.

3

Conflicts of interest

4

There are no conflicts of interest to declare.

5

Sources of funding

6

Queen’s University Ionic Liquid Laboratories

7

Acknowledgements

8 9

The industrial advisory board of Queens University Ionic Liquid Laboratories and Queen’s University Belfast, School of Chemistry and Chemical Engineering.

10

Appendix A. Supplementary Data

11

Electronic supplementary information (ESI) available: Hammett basicity, Knoevenagel condensation

12

yield calculation Spectra (NMR, FTIR, TGA, DSC), Crystallographic information, Spartan modelling.

13

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• • • • •

Six quinine ionic liquids have been prepared Solving the crystal structure gave information on hydrogen bonding and ion stacking The effect of intermolecular forces on stability and physical properties is discussed Hammett basicity of the ionic liquids was analysed Ionic liquids are efficient basic catalysts for a Knoevenagel condensation

Peter McNeice: https://orcid.org/0000-0002-6597-5437 Federico M. F. Vallana: https://orcid.org/0000-0002-1833-2308 Simon J. Coles: http://orcid.org/0000-0001-8414-9272 Patricia C. Marr: http://orcid.org/0000-0002-4964-1509 Andrew C. Marr: http://orcid.org/0000-0001-6798-0582

1

Quinine Based Ionic Liquids: A Tonic for Base Instability

2 3

Peter McNeice , Federico M. F. Vallana , Simon J Coles , Peter N. Horton , Patricia C. Marr , Kenneth R. a, a, Seddon † and Andrew C. Marr *

4

a

5

Stranmillis Road, Belfast, BT9 5AG, United Kingdom.

6

b

7

United Kingdom.

8

Footnotes

9

* Corresponding author. Email: [email protected]

a

a

b

b

a

School of Chemistry and Chemical Engineering, The Queen’s University of Belfast, The David Keir Building,

National Crystallography Service, School of Chemistry, University of Southampton, Southampton, SO17 1BJ,

10

† Deceased

11

1

12 13 14 15 16 17 18 19 20

All ionic liquids were first dried in a desiccator containing self-indicating silica gel under high vacuum (ca. 0.1 mbar) for 24 hours. A stock solution of the indicator was prepared by weighing out bromophenol blue (0.0247 g, 0.0369 mmol) into a 100 mL volumetric flask and diluting with methanol. The ionic liquid or base was weighed into a 2 mL screw top vial. After that, the bromophenol blue solution was injected into this vial with a micropipette in order to gain an ionic liquid concentration of 0.090 mmol/mL after the ionic liquid was completely dissolved in methanolic bromophenol blue. Then, the absorbance of the anionic indicator in the sample was measured using Ultraviolet-Visible (UV-Vis) analysis (Table S1). The Hammett Basicity value (H-) of each acidic ILs was calculated using the equations below:

21

H- = pKa(HI) + log([I-]/[HI])

22 23 24

Hammett Basicity (H_)

The pKa(HI) is the pKa value of the indicator, bromophenol blue in methanol, which is a constant value (8.90 for bromophenol blue) [1]. [I-] and [HI] are, respectively, the molar concentrations of anionic and neutral forms of the indicator.

25

[I-]/[HI] = ε/(ε1- - ε)

26 27 28 29 30

Where ε is the extinction co-efficient of the indicator at a given wavelength and ε1- is the extinction co-efficient at the same wavelength but with the indicator in fully anionic form. This point is determined by monitoring the neutral absorbance which completely disappears when the indicator is in the fully ionic state. Achieved by weighing 0.561 mg KOH into a 2 mL screw top vial and adding 1 mL indicator solution via syringe.

31

A = εLc

32 33 34

A is the absorbance, L is the distance the light travels through the solution and c is the concentration of the absorbing species. In each measurement, L and c are constant so the extinction co-efficient is proportional to the absorbance.

35 36

Table S1: Absorbance values of bromophenol blue in the presence of base and the corresponding Hammett basicity. -

[Bromophenol Blue] DBU

Max Absorbance at 595 nm 3.132 2.971 S1

[I-] / % 100 94.860

[HI] / % 0 5.140

H_ 10.17

DABCO Quinine [MeQn][NTf2] (1c) [C4Qn][NTf2] (2c) [C6Qn][NTf2] (3c) [C8Qn][NTf2] (4c) [C1OC2Qn][NTf2] (5c) [C1OC2OC2Qn][NTf2] (6c)

2.784 2.719 0.906 1.123 2.378 0.804 1.252 2.877

88.889 86.814 28.927 35.856 75.926 25.670 39.974 91.858

11.111 13.186 71.073 64.144 24.074 74.330 60.026 8.141

9.80 9.72 8.51 8.65 9.40 8.44 8.72 9.952

1 2

2

Knoevenagel condensation yield calculation

3 4 5

A Knoevenagel condensation catalysed by [C4Qn][NTf2] (2c) is described in manuscript section 2.8. The yield calculated below is one of three values which were averaged to give entry 3 in manuscript table 3.

6

Table S2: 1H NMR integration of product and internal standard signals. Compound Signal (ppm) Benzylidenemalononitrile PhCH (7.73) (Product) Ethyl trifluoroacetate OCH2CH3 (1.26) (Internal standard)

Integration 0.29 3

7 8

Moles internal standard = (mass added/RFM) = 0.3149/142.08 = 2.22 mmol

9 10

ratio(n Product/n Internal standard) = ((Product integration/number of hydrogens)/(Internal standard/number of hydrogens) = ((0.29/1)/3/3) = 0.29

11

n product in sample = (ratio x n Internal standard) = 0.29 x 2.22x10-3 = 6.44 mmol

12

n product total = n product in sample x (reaction mass/sample mass) = 6.44x10-3 x (0.4186/0.3032)

13

= 8.89 mmol

14

Yield = n product/n benzaldehyde = (8.89x10-3/9.66x10-3) x 100 = 92 %

15 16 17 18 19 20 21 22 23

S2

1

3

NMR Spectra

2

Spectrum S1.1: 1H NMR spectrum of [MeQn][I] (1a).

3 4 5 6

Spectrum S1.2: Expanded 1H NMR spectrum of [MeQn][I] (1a).

7 8 9 10 11 12 13 14 S3

1

Spectrum S1.3: 2D 1H-1H COSY of [MeQn][I] (1a).

2 4

6 8

9

2

8

7

6

5 4 F2 Chemical Shift (ppm)

3 4 5 6 7

Spectrum S1.4: 13C NMR spectrum of [MeQn][I] (1a).

8 9 10 11 12

S4

3

2

1

0

F1 Chemical Shift (ppm)

0

1

Spectrum S1.5: 2D 1H-13C HSQC of [MeQn][I] (1a).

50

100

10

2

9

8

7

6 5 4 F2 Chemical Shift (ppm)

3 4 5 6 7

Spectrum S2.1: 1H NMR spectrum of [MeQn][NTf2] (1c).

8 9 10 11 S5

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1 2 3

Spectrum S2.2: Expanded 1H NMR spectrum of [MeQn][NTf2] (1c).

4 5 6 7 8

Spectrum S2.3: 2D 1H-1H COSY of [MeQn][NTf2] (1c).

2 4 6 8

10

9

9

8

7

6

5 4 3 F2 Chemical Shift (ppm)

10 11 12 13 14 15 16

S6

2

1

0

-1

F1 Chemical Shift (ppm)

0

1

Spectrum S2.4: 13C NMR spectrum of [MeQn][NTf2] (1c).

2 3 4 5 6

Spectrum S2.5: 2D 1H-13C HSQC of [MeQn][NTf2] (1c).

50

100

10

7

9

8

7

6 5 4 F2 Chemical Shift (ppm)

8 9 10 11 S7

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1

Spectrum S2.6: 19F NMR spectrum of [MeQn][NTf2] (1c).

2 3 4 5

Spectrum S3.1: 1H NMR spectrum of [C4Qn][I] (2a).

6

7 S8

1 2

Spectrum S3.2: Expanded 1H NMR spectrum of [C4Qn][I] (2a).

3 4 5 6 7 8 9

Spectrum S3.3: 2D 1H-1H COSY of [C4Qn][I] (2a).

2 4 6 8

9

10

8

7

6

5 4 3 F2 Chemical Shift (ppm)

11 12 13 14 15 16 17 S9

2

1

0

F1 Chemical Shift (ppm)

0

1

Spectrum S3.4: 13C NMR spectra of [C4Qn][I] (2a).

2 3 4 5 6 7

Spectrum S3.5: 2D 1H-13C HSQC of [C4Qn][I] (2a).

50

100

10

8

9

8

7

6 5 4 F2 Chemical Shift (ppm)

9 10 11

S10

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1 2

Spectrum S4.1: 1H NMR spectrum of [C4Qn][NTf2] (2c).

3 4 5 6

Spectrum S4.2: Expanded 1H NMR spectrum of [C4Qn][NTf2] (2c).

7 8 9

S11

Spectrum S4.3: 2D 1H-1H COSY of [C4Qn][NTf2] (2c).

0 2 4 6 8 9

2

8

7

6

5 4 3 F2 Chemical Shift (ppm)

3 4 5 6 7 8

Spectrum S4.4: 13C NMR spectrum of [C4Qn][NTf2] (2c).

9 10 11 S12

2

1

0

-1

F1 Chemical Shift (ppm)

1

1 2 3

Spectrum S4.5: 2D 1H-13C HSQC of [C4Qn][NTf2] (2c).

50

100

10

4

9

8

7

6 5 4 F2 Chemical Shift (ppm)

5 6 7 8 9

Spectrum S4.6: 19F NMR spectrum of [C4Qn][NTf2] (2c).

10 11 12

S13

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1

Spectrum S5.1: 1H NMR spectrum of [C6Qn][I] (3a).

2 3 4 5 6

Spectrum S5.2: Expanded 1H NMR spectrum of [C6Qn][I] (3a).

7 8 9 10 11 S14

1

Spectrum S5.3: 2D 1H-1H COSY of [C6Qn][I] (3a).

6 8 10 12 14 14

2 3

13

12

11

10 9 8 F2 Chemical Shift (ppm)

4 5 6 7 8 9

Spectrum S5.4: 13C NMR spectrum of [C6Qn][I] (3a).

10 11 12

S15

7

6

5

4

F1 Chemical Shift (ppm)

4

1 2 3 4

Spectrum S5.5: 2D 1H-13C HSQC of [C6Qn][I] (3a).

50

100

10

5 6

9

8

7

6 5 4 F2 Chemical Shift (ppm)

7 8 9 10 11 12

Spectrum S6.1: 1H NMR spectrum of [C6Qn][NTf2] (3c).

S16

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1 2 3 4

Spectrum S6.2: Expanded 1H NMR spectrum of [C6Qn][NTf2] (3c).

5 6 7 8

Spectrum S6.3: 2D 1H-1H COSY of [C6Qn][NTf2] (3c).

S17

2 4 6 8

9

1

8

7

6

5 4 3 F2 Chemical Shift (ppm)

2 3 4 5 6 7 8 9 10

Spectrum S6.4: 13C NMR spectrum of [C6Qn][NTf2] (3c).

11 12 S18

2

1

0

F1 Chemical Shift (ppm)

0

1 2 3

Spectrum S6.5: 2D 1H-13C HSQC of [C6Qn][NTf2] (3c).

50

100

10

4

9

8

7

6 5 4 F2 Chemical Shift (ppm)

5 6 7 8 9 10

Spectrum S6.6: 19F NMR spectrum of [C6Qn][NTf2] (3c).

11 12

S19

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1 2

Spectrum S7.1: 1H NMR spectrum of [C8Qn][Br] (4b).

3

4 5 6

Spectrum S7.2: Expanded 1H NMR spectrum of [C8Qn][Br] (4b).

7 8 9

S20

1 2

Spectrum S7.3: 2D 1H-1H COSY of [C8Qn][Br] (4b).

2

4

6

8

9

3

8

7

6

5 4 F2 Chemical Shift (ppm)

4 5 6 7 8 9 10 11

Spectrum S7.4: 13C NMR spectrum of [C8Qn][Br] (4b).

12 S21

3

2

1

0

F1 Chemical Shift (ppm)

0

1 2 3 4

Spectrum S7.5: 2D 1H-13C HSQC of [C8Qn][Br] (4b).

50

100

10

5

9

8

7

6 5 4 F2 Chemical Shift (ppm)

6 7 8 9 10 11

Spectrum S8.1: 1H NMR spectrum of [C8Qn][NTf2] (4c).

12

S22

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1 2 3 4 5

Spectrum S8.2: Expanded 1H NMR spectrum of [C8Qn][NTf2] (4c).

6 7 8 9

Spectrum S8.3: 2D 1H-1H COSY of [C8Qn][NTf2] (4c).

2 4 6 8

9

10

8

7

6

5 4 F2 Chemical Shift (ppm)

11 12 13 14 15 S23

3

2

1

0

F1 Chemical Shift (ppm)

0

1 2 3 4

Spectrum S8.4: 13C NMR spectrum of [C8Qn][NTf2] (4c).

5 6 7 8 9 10

Spectrum S8.5: 2D 1H-13C HSQC of [C8Qn][NTf2] (4c).

50

100

10

11

9

8

7

6 5 4 F2 Chemical Shift (ppm)

12

S24

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1 2 3 4

Spectrum S8.6: 19F NMR spectrum of [C8Qn][NTf2] (4c).

5 6 7 8 9

Spectrum S9.1: 1H NMR spectrum of [C1OC2Qn][Br] (5b).

S25

1 2 3

Spectrum S9.2: Expanded 1H NMR spectrum of [C1OC2Qn][Br] (5b).

4 5 6 7 8 9 10

Spectrum S9.3: 2D 1H-1H COSY of [C1OC2Qn][Br] (5b).

S26

4

6

8

9

1

8

7

6 5 4 F2 Chemical Shift (ppm)

2 3 4 5 6 7 8 9

Spectrum S9.4: 13C NMR spectrum of [C1OC2Qn][Br] (5b).

10 11 12 S27

3

2

1

F1 Chemical Shift (ppm)

2

1 2

Spectrum S9.5: 2D 1H-13C HSQC of [C1OC2Qn][Br] (5b).

50

100

10

3

9

8

7

6 5 4 F2 Chemical Shift (ppm)

4 5 6 7

Spectrum S10.1: 1H NMR spectrum of [C1OC2Qn][NTf2] (5c).

8

9 10 11

S28

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1 2

Spectrum S10.2: Expanded 1H NMR spectrum of [C1OC2Qn][NTf2] (5c).

3 4 5 6 Spectrum S10.3: 2D 1H-1H COSY of [C1OC2Qn][NTf2] (5c).

2

4

6

8

9

8

8

7

6

5 4 F2 Chemical Shift (ppm)

9 10 11 12 13 14 15

Spectrum S10.4: 13C NMR spectrum of [C1OC2Qn][NTf2] (5c).

S29

3

2

1

F1 Chemical Shift (ppm)

7

1 2 3 4 5

Spectrum S10.5: 2D 1H-13C HSQC of [C1OC2Qn][NTf2] (5c).

50

100

10

6

9

8

7

6 5 4 F2 Chemical Shift (ppm)

7 8 9 10 11 12

S30

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1

Spectrum S10.6: 19F NMR spectrum of [C1OC2Qn][NTf2] (5c).

2 3 4 5 6

Spectrum S11.1: 1H NMR spectrum of [C1OC2OC2Qn][Br] (6b).

7 8 S31

1 2

Spectrum 11.2: Expanded 1H NMR spectrum of [C1OC2OC2Qn][Br] (6b).

3 4 5 6 7 Spectrum S11.3: 2D 1H-1H COSY of [C1OC2OC2Qn][Br] (6b).

2

4

6

8

9

9

8

7

6

5 4 F2 Chemical Shift (ppm)

10 11 12 13 14 15 16

Spectrum 11.4: 13C NMR spectrum of [C1OC2OC2Qn][Br] (6b). S32

3

2

1

F1 Chemical Shift (ppm)

8

1 2 3 4 5 6 Spectrum S11.5: 2D 1H-13C HSQC of [C1OC2OC2Qn][Br] (6b).

2

4

6

8

9

8

8

7

6

5 4 F2 Chemical Shift (ppm)

9 10 11 12 13

Spectrum S12.1: 1H NMR spectrum [C1OC2OC2Qn][NTf2] (6c). S33

3

2

1

F1 Chemical Shift (ppm)

7

1 2 3 4 5 6

Spectrum S12.2: Expanded 1H NMR spectrum of [C1OC2OC2Qn][NTf2] (6c).

7 8 9 10 11 S34

1 2

Spectrum S12.3: 2D 1H-1H COSY of [C1OC2OC2Qn][NTf2] (6c).

2

4

6

8

9

3

8

7

6

5 4 F2 Chemical Shift (ppm)

4 5 6 7 8 9

Spectrum S12.4: 13C NMR spectrum of [C1OC2OC2Qn][NTf2] (6c).

10 11 12 S35

3

2

1

0

F1 Chemical Shift (ppm)

0

1 2 3 4 5

Spectrum S12.5: 2D 1H-13C HSQC of [C1OC2OC2Qn][NTf2] (6c).

50

100

10

6

9

8

7

6 5 4 F2 Chemical Shift (ppm)

7 8 9

Spectrum S12.6: 19F NMR spectrum of [C1OC2OC2Qn][NTf2] (6c).

10 11 12 13 S36

3

2

1

0

-1

F1 Chemical Shift (ppm)

0

1 2

Spectrum S13: 1H NMR spectrum of Knoevenagel Condensation reaction mixture described in manuscript section 2.8. Yield calculation in ESI section 2.

3 4 5

Spectrum S14: 1H NMR spectrum of recovered [MeQn][NTf2] (1c).

6 7 8 9

Spectrum S15: 1H NMR spectrum of filtrate from Knoevenagel recycle reaction. S37

1 2

4

FTIR Spectra

3 4

Spectrum S16: FTIR spectrum of [MeQn][NTf2] (1c). 65

CH2

60

55

HO

%Transmittance

50

N H3C

O

45

+

H3C 40

N 35

F

F 30

S F

25

F

O O

F

S

-

N

F O

O

20 4000

3500

3000

2500

2000

1500

Wavenumbers (cm-1)

5 6 7 8 9

Spectrum S17: FTIR spectrum of [C4Qn][NTf2] (2c). S38

1000

500

110 105 100

CH2 95

%Transmittance

90

HO

85

N

+

O

80

H3C

75

N

70

F

F S

-

F

60

F

O O

F

65

CH3

S

N

F O

O 55 50 4000

3500

3000

2500

2000

1500

1000

500

1500

1000

500

Wavenumbers (cm-1)

1 2 3

Spectrum S18: FTIR spectrum of [C6Qn][NTf2] (3c). 165 160 155 150 145

%Transmittance

140 135 130 125 120 115

105

90

F

O O

F

100 95

F

F

110

S F

-

S

N

F O

O

85 4000

4

3500

3000

2500

2000

Wavenumbers (cm-1)

5 6 7 8 9

S39

1

Spectrum S19: FTIR spectrum of [C8Qn][NTf2] (4c).

2 3 4 5 6

Spectrum S20: FTIR spectrum of [C1OC2Qn][NTf2] (5c).

7 160

150

140

%Transmittance

130

120

CH2

110

100

HO

O 90

80

F F

N S

F

S

+

O H3C

O O F

N

O

-

O

F

F

N

CH3

70

4000

3500

3000

2500

2000

1500

Wavenumbers (cm-1)

8 9 10

S40

1000

500

1

Spectrum S21: FTIR spectrum of [C1OC2OC2Qn][NTf2] (6c).

2 92 90 88 86

CH2 %Transmittance

84 82

HO

80

+

N

O

78

H3C O

76

O F

74 72 70 4000

F

O

-

N S

F

S O O

F 3500

N

O

F

F 3000

H3C 2500

2000

1500

Wavenumbers (cm-1)

3 4

5

Thermogravimetric analysis (TGA)

5 6

Figure S1: TGA of [MeQn][NTf2] (1c).

7

S41

1000

500

Sample: PMN-2-014-DRY Size: 10.1630 mg

File: C:...\PETER McNEICE\PMN-2-014-DRY.001 Operator: SUZI Run Date: 21-Nov-2016 10:23 Instrument: TGA Q5000 V3.17 Build 265

TGA

120

100 18.38% (1.868mg) 223.92°C 97.92%

W eight (% )

80

52.35% (5.320mg)

60

40

20 0

1 2

100

200

300

400

Figure S2: TGA of [C4Qn][NTf2] (2c).

3 4

5 6

500 Universal V4.5A TA Instruments

Temperature (°C)

Figure S3: TGA of [C6Qn][NTf2] (3c). S42

1 2

3 4

Figure S4: TGA of [C8Qn][NTf2] (4c).

5 6 Sample: PMN-2-0151 Size: 4.0780 mg

File: C:...\TGA\JUNE-2017\Peter\PMN-2-0151.001 Operator: SUZI Run Date: 29-Jun-2017 18:32 Instrument: TGA Q5000 V3.17 Build 265

TGA

100

207.60°C 98.89%

80

74.47% (3.037mg)

Weight (%)

60

40

20 24.49% (0.9986mg)

0 0

7 8

200

400

600

800

1000 Universal V4.5A TA Instruments

Temperature (°C)

Figure S5: TGA of [C1OC2Qn][NTf2] (5c). S43

1 Sample: PMN 2 0137 Size: 5.0070 mg

File: C:...\TGA\JUNE-2017\Peter\PMN 2 0137.001 Operator: SUZI Run Date: 05-Jun-2017 12:07 Instrument: TGA Q5000 V3.17 Build 265

TGA

120

212.69°C 96.33%

Weight (%)

100

80

60

40 0

50

100

200

250

Figure S6: TGA of [C1OC2OC2Qn][NTf2] (6c).

4

5 6

300

350

400

Universal V4.5A TA Instruments

Temperature (°C)

2 3

150

Figure S7: TGA of quinine.

S44

1

6

Differential scanning calorimetry (DSC)

2 3

Figure S8: DSC of [MeQn][NTf2] (1c).

4 5

6 7

Figure S9: DSC of [C4Qn][NTf2] (2c).

S45

1 2

Figure S10: DSC of [C6Qn][NTf2] (3c).

3

4 5

Figure S11: DSC of [C8Qn][NTf2] (4c).

S46

1 2

Figure S12: DSC of [C1OC2Qn][NTf2] (5c).

3

4 5

Figure S13: DSC of [C1OC2OC2Qn][NTf2] (6c).

S47

1

7

X-ray crystallography

2 3

Crystallographic information was obtained at The UK National Crystallography Service (NCS) at Southampton [2].

4 5 6 7 8 9 10 11

Single colourless cut block-shaped crystals of [C4Qn][NTf2] (2c) were recrystallised from a mixture of methanol and ether. A suitable crystal (0.230 × 0.160 × 0.070) mm3 was selected and mounted on a MITIGEN holder in perfluoroether oil on a Rigaku FRE+ equipped with HF Varimax confocal mirrors and an AFC12 goniometer and HG Saturn 724+ detector diffractometer. The crystal was kept at T = 100(2) K during data collection. Using Olex2 [3], the structure was solved with the ShelXT [4] structure solution program, using the Intrinsic Phasing solution method. The model was refined with version 2014/7 of ShelXL [5] using Least Squares minimisation. Crystal and refinement data are given in Table S3.

12

Table S3: Crystal data and structure refinement for [C4Qn][NTf2] (2c). Compound Formula Dcalc./ g cm-3 μ/mm-1 Formula Weight Colour Shape Size/mm3 T/K Crystal System Flack Parameter Hooft Parameter Space Group a/Å b/Å c/Å α/° β/° γ/° V/Å3 Z Z' Wavelength/Å Radiation type ° Θmin/ ° Θmax/ Measured Refl. Independent Refl. Reflections Used Rint Parameters Restraints Largest Peak Deepest Hole GooF

[C4Qn][NTf2] (2c) C28H37.5F6N3O6.5S2 1.462 0.251 698.23 colourless cut block 0.230×0.160×0.070 100(2) monoclinic -0.04(4) 0.013(15) P21 8.6556(2) 33.5862(9) 11.0850(4) 90 100.162(3) 90 3171.95(16) 4 2 0.71075 MoKα 2.226 27.560 24329 24329 20536 . 829 6 0.467 -0.322 0.995 S48

wR2 (all data) wR2 R1 (all data) R1

0.1122 0.1077 0.0628 0.0509

1 2 3 4 5

Crystal Data. C28H37.5F6N3O6.5S2, Mr = 698.23, monoclinic, P21 (No. 4), a = 8.6556(2) Å, b = 33.5862(9) Å, c = 11.0850(4) Å, Β = 100.162(3)°, α = γ = 90°, V = 3171.95(16) Å3, T = 100(2) K, Z = 4, Z' = 2, μ(MoKα) = 0.251, 24329 reflections measured, 24329 unique (Rint = .) which were used in all calculations. The final wR2 was 0.1122 (all data) and R1 was 0.0509 (I > 2(I)).

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Data were measured using profile data from ω-scans scans of 1.0 ° per frame for 2.0 s using MoKα radiation (Rotating Anode, 45.0 kV, 55.0 mA). The total number of runs and images was based on the strategy calculation from the program CrysAlisPro [6] The maximum resolution achieved was Θ = 27.560°.

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Cell parameters were retrieved using the CrysAlisPro [6] software and refined using CrysAlisPro [6] on 17436 reflections, 72 % of the observed reflections. Data reduction was performed using the CrysAlisPro [6] software which corrects for Lorentz polarisation. The final completeness is 99.90 % out to 27.560° in Θ.

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A multi-scan absorption correction was performed using CrysAlisPro [6]. Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. The absorption coefficient μ of this material is 0.251 mm-1 at this wavelength (λ = 0.71075Å) and the minimum and maximum transmissions are 0.10023 and 1.00000.

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The structure was solved in the space group P21 (# 4) by Intrinsic Phasing using the ShelXT [4] structure solution program and refined by Least Squares using version 2014/7 of ShelXL [5]. All nonhydrogen atoms were refined anisotropically. Hydrogen atom positions were calculated geometrically and refined using the riding model.

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_refine_special_details: Refined as a 2-component twin.

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_exptl_absorpt_process_details: CrysAlisPro 1.171.39.34b [6] Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.

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_twin_special_details: Component 2 rotated by -179.9092° around [0.98 0.00 -0.22] (reciprocal) or [1.00 0.00 0.00] (direct)

27

The value of Z' is 2. This means that there are two independent molecules in the asymmetric unit.

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The Flack parameter was refined to -0.04(4). Determination of absolute structure using Bayesian statistics on Bijvoet differences using the Olex2 [3] results in 0.013(15). Note: The Flack parameter is used to determine chirality of the crystal studied, the value should be near 0, a value of 1 means that the stereochemistry is wrong and the model should be inverted. A value of 0.5 means that the crystal consists of a racemic mixture of the two enantiomers.

33

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8

Spartan modelling

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Quinine

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Job type: Geometry optimization.

4

Method: RB3LYP

5

Basis set: 6-31G(D)

6

Number of shells: 144

7

Number of basis functions: 408

8

Multiplicity: 1

9

Job type: Frequency calculation.

10

Method: RB3LYP

11

Basis set: 6-31G(D)

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[MeQn][NTf2] (1c)

14

Job type: Geometry optimization.

15

Method: RB3LYP

16

Basis set: 6-31G(D)

17

Number of shells: 216

18

Number of basis functions: 662

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Multiplicity: 1

20

Job type: Frequency calculation.

21

Method: RB3LYP

22

Basis set: 6-31G(D)

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Figure S14: Structure of quinine calculated by Spartan software.

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Figure S15: Structure of [MeQn][NTf2] (1c) calculated by Spartan software. The hydrogen of the OH group points towards the anion indicating hydrogen bonding.

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Figure S16: Structure and electron density of [MeQn][NTf2] (1c) calculated by Spartan software. S51

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Figure S17: Electron density model of [MeQn][NTf2] (1c) calculated by Spartan software.

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Figure S18: Electron density model of; Left) Quinine. Right) [MeQn][NTf2] (1c). Quinoline nitrogen is boxed in each case. Electrostatic charge of quinine (-0.578) is slightly greater than [MeQn][NTf2] (1c) (-0.560).

12 13

9

References

1

F. Rived, M. Rosés, E. Bosch, Dissociation constants of neutral and charged acids in methyl alcohol. The acid strength resolution, Anal. Chim. Acta. 374 (1998), 309-324. https://doi.org/10.1016/S00032670(98)00418-8.

2

S. J. Coles, P. A. Gale, Changing and challenging times for service crystallography, Chem. Sci. 3 (2012) 683-689. https://doi.org/10.1039/C2SC00955B.

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3

O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann, Olex2: A complete structure solution, refinement and analysis program, J. Appl. Cryst. 42 (2009) 339-341. https://doi.org/10.1107/S0021889808042726. 4

G.M. Sheldrick, ShelXT-Integrated space-group and crystal-structure determination, Acta Cryst. Sect A. 71 (2015) 3-8. https://doi.org/10.1107/S2053273314026370. 5

G.M. Sheldrick, Crytal structure refinement with ShelXL, Acta Cryst. Sect C. 27 (2015) 3-8. https://doi.org/10.1107/S2053229614024218

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Rikagu Oxford Diffraction, CrysAlisPro Software System (V1.171.39.34b), 2017.

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The authors have no conflicts of interest to declare