Application of surface active amino acid ionic liquids as phase-transfer catalyst

Journal Pre-proof Application of surface active amino acid ionic liquids as phasetransfer catalyst

Emil Szepiński, Patrycja Smolarek, Maria J. Milewska, Justyna Łuczak PII:

S0167-7322(19)36628-0

DOI:

https://doi.org/10.1016/j.molliq.2020.112607

Reference:

MOLLIQ 112607

To appear in:

Journal of Molecular Liquids

Received date:

1 December 2019

Revised date:

27 January 2020

Accepted date:

28 January 2020

Please cite this article as: E. Szepiński, P. Smolarek, M.J. Milewska, et al., Application of surface active amino acid ionic liquids as phase-transfer catalyst, Journal of Molecular Liquids(2020), https://doi.org/10.1016/j.molliq.2020.112607

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© 2020 Published by Elsevier.

Journal Pre-proof Application of surface active amino acid ionic liquids as phase-transfer catalyst Emil Szepińskia, Patrycja Smolareka, Maria J. Milewskaa, Justyna Łuczakb a

Department of Organic Chemistry, Faculty of Chemistry Gdansk University of Technology, 80-233 Gdansk, Poland b Department of Process Engineering and Chemical Technology, Faculty of Chemistry Gdansk University of Technology, 80-233 Gdansk, Poland

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Abstract Five structurally related morpholinium derived ionic liquids containing N-acetyl-glycinate

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anion were synthesized and their thermal stability, surface properties and activity as phase

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transfer catalysts investigated. The thermal properties were studied by differential scanning calorimetry, while the adsorption at the air/water interface and micellization behavior was

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analyzed by surface tension measurements, conductometry and isothermal titration calorimetry. The catalytic activity was assessed in two model reactions that were N-alkylation

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of dibenzoazepine and C-alkylation reaction of fluorene derivatives. The effect of the chain length, thus surface activity of the newly synthetized ionic liquids on the yields of N- and C-

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alkylation reactions was discussed.

Introduction

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Key words ionic liquids, surface activity, micelles formation, phase transfer catalysis,

Ionic liquids (ILs) are not just solvents and may play multiple roles in chemical processes such as functional compounds or reacting species. According to the widely accepted definition, ILs are salts with melting temperature below 100oC, characterized by high enthalpies of vaporization (negligible volatility). The interest in this group of compounds is also related with the easiness to fine-tune their physical and chemical properties by modification/selection of ion moieties (“designer compounds”), thus adjusting the properties for specific application. Ionic liquids due to their amphiphilic structure (presence of charged hydrophilic headgroup and hydrophobic alkyl substituent) in these applications may be used in a manner analogous to conventional surfactants. In this regard, studies on the surface properties of ionic

Journal Pre-proof liquids have been developed intensively for many years with using various experimental and theoretical methods [1-10]. The relationship between alkyl chain length in the IL’s cation as well as an anion structure and ILs’ susceptibility to form micellar aggregates in solutions was described. This phenomenon was mainly observed for the long-chained IL’s derivatives, usually containing eight or more carbon atoms in the cation’s substituent. In that case, the micellar structures were formed by ILs composed of simple anions (Cl, Br, HSO4) [7-9], whereas the low solubility of ionic liquids containing hydrophobic ions such as [PF6] and [Tf2N] [11] resulted in phase separation prior to the formation of aggregates. Fewer studies were performed for ionic liquids with surface-active anions toward formation of anionic

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micelles [11,12].

The surface activity of ILs was used in some synthetic, catalytic and separation processes.

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Micellar aggregates in aqueous media provide an environment different from the bulk water,

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therefore they influence kinetics of the reactions and effectiveness of separation processes. For example, Bica et al. revealed that aqueous solutions of amphiphilic ionic liquids can be

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efficiently applied as micellar reaction media in Diels-Alder synthesis [13] (1,3cyclohexadiene with N-benzylmaleimide) and in nucleophilic substitution of the

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organophosphorus compounds [14]. It was found that the rate of Diels–Alder reaction occurring in micellar solutions can be enhanced compared to than in water [13]. In another

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example, the effect of the IL’s anion structure (halides and sulfonates), thus effectiveness of anion binding to the cationic micelle, on the acceleration of the nucleophilic substitution

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reaction rate was observed [14]. Moreover, the same group revealed also a correlation between extraction yield and the critical micelle concentration (CMC) of ILs in a micellar extraction of piperine from black pepper [15]. Ionic liquids with amphiphilic structures can be also used in organic synthesis to facilitate biphasic reactions as phase transfer catalysts (PTC). The PTC in the liquid/liquid system facilitates migration of anionic reagents between phases and thus accelerates the reaction. The tetraalkylammonium salts have been used as PTCs in liquid/liquid systems, starting from the pioneering works of Starks [16], Mąkosza [17] and Brändström.[18] Such salts when used as PTCs exhibit high catalytic activity and good selectivity. On the other hand, they are usually thermally unstable and often toxic. Moreover, catalyst separation and recovery is in their case an important challenge [19]. It is generally assumed that ILs used as PTCs alternative to tetraalkylammonium salts, can be easily recovered and are more environment-friendly [20]. Many ILs are highly thermostable [21]. In this regard, some conventional ILs were investigated as PTCs for different reactions, including nucleophilic substitution [22], alkylation [23], etherification [24],

Journal Pre-proof glycosidation [25], and epoxidation. An interest in this area has been mainly caused by the potential of ILs to be tailored for a particular application, since differences in cation type, alkyl chain length and anion structure have been shown to have a large impact on their effectiveness as PTCs. For example, Santiago et al. [26] compared 1-alkyl-3methylimidazolium tetrafluoroborate [AMIM][BF4] and heksafluorophosphte [AMIM][PF6] ILs as PTC in the oxidation of benzyl protected glycals, revealing that ILs with BF4 anion act more efficiently in the interchange of peracid (-HSO5) between organic and water phases. Moreover, elongation of the alkyl substituent in the imidazolium cation (higher surface activity) enhanced the formation and reactivity of dimethyldioxirane in the organic phase.

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Kumar et al. [25] analyzed a set of hydrophobic ILs in the O-glycosidation reactions under biphasic conditions using aqueous sodium hydroxide and chloroform. Generally, imidazolium

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and pyridinium salts revealed higher efficiency than ILs containing uronium, thiouronium,

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pyrrolidinium, morpholinium, piperidinium, and ammonium cations. Moreover, [PF6]-based ILs when used as PTC, provided glycosides in higher yields than the corresponding ILs

effectiveness

bistrifluoromethanesulfonylimide was

found

in

[Tf2N]

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containing

the

case

anions.

An

outstanding

PTC

1-hydroxyethyl-3-methylimidazolium

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hexafluorophosphate IL which significantly improved glycosidation rate and was easy to recycle via triphasic separation. Various liquid–liquid PTC reactions such as -elimination of

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alkyl halides, nucleophilic epoxidation of -unsaturated carbonyl compounds, alkylation of active methylenes, and nucleophilic substitution were chosen by Okamoto et al. [27] to

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investigate the behavior of dialkylimidazolium Ils as catalysts. In the case of nucleophilic epoxidation, elongation of the alkyl chains at the 1- and 3- positions of the heterocyclic ring increased catalytic activity, presumably due to enhanced solubility of (imidazolium) +X- pairs in the organic phase. Bender et al. [28], in turn, evaluated a series of imidazolium, pyridinium and pyrrolidinium ILs as PTC for the Williamson etherification of 1-octanol with 1chlorobutane. Reactivity was in this case determined by the structure of the IL’s cation. Pyrrolidinium salts were found to have high catalytic activity (analogously to classical quaternary ammonium salts) and conversion rate was related to the increase in alkyl chain length of the cation. However, yield of the reaction catalyzed by the imidazolium and pyridinium derivatives was on the same level as the blank reaction performed without catalyst. The effect of application of phosphonium-based ILs was evaluated in the model oalkylation reaction of 2-naphthol by Yadav et al.[29]. The reactivity of ILs was dependent on the anion forming IL and followed an order [Br] > [Cl] > [PF6]>decanoate.

Journal Pre-proof Although some progress in the studies of surface properties of ILs has been made by a number of authors (also form our group) [2,30], these investigations have been mainly restricted to conventional ILs, while the surface performance of so called biobased ILs remains almost unexplored [31,32]. Biobased ILs are designed to improve biocompatibility of ILs by using in their preparation nontoxic components. Moreover, according to our knowledge, application of surface active biobased ILs as PTC has also not been presented yet. In this work, we present preparation and characterization of physicochemical and surface properties of novel biobased ILs consisting of large N-alkylmorpholinium cations and a small, biocompatibile N-acetylglycinate anion and their application as PTCs in N- and C-alkylation

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reactions.

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Experimental 1. Materials

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All materials were purchased from commercial sources and used with further purification. 1H and 13C NMR spectra were recorded on a Varian Unity 500 plus (500 MHz and 125 MHz) or

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Bruker Advance III HD (400 MHz and 100 MHz, respectively) with TMS as standard. The

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mass spectra analyses were carried out using the Aqilent Technologies 6540 UHD Accurate – Mass Q-TOF LC/MS spectrum eter. Bromide content was measured via ion chromatography

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on Dionex ICS-3000 system with DionexIonPac® AS22 column, Dionex ASRS 300 suppressor, CD detection and eluted by 4.5 mmol/l Na2CO3, 1.4 mmol/l NaHCO3 buffer solution. Phase transitions temperatures was measured with Mettler-Toledo Refracto 30GS

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with heat rate 10K/min and N2 flow. Thermal transition temperatures of the morpholinium salts were determined by DSC, with a Mettler Toledo Refracto 30GS unit, under nitrogen. Samples between 5 and 15 mg were placed in aluminum pans and heated from 25 to 120C at a heating rate of 10C min-1 and cooled with an intracooler at a cooling rate of 10C min-1 to 30C and then heated again to 120C. Thermogravimetric analysis was performed using a Mettler Toledo Refracto TGA/DSC1 unit under nitrogen. Samples between 2 and 10 mg were placed in aluminium pans and heated from 30 to 350C at a heating rate of 10C min-1 . 2. Synthesis of ILs N-acetylglycine - AcGly was synthesized according to the procedure described by Herbst and Shemin [33], mp 205-208°C (lit. [21] 207-208°C). N-alkyl-N-methylmorpholinium bromide were synthesized according to our previously published procedure [34].

Journal Pre-proof N-alkyl-N-methylmorpholinium N-acetyl-glycinate – general procedure 5% w/v aqueous solution of 15 mmol Mor1,nBr was passed through Amberlite IRA400 [OH-] packed column to give [Mor1,n][OH]. Then, the solution was concentrated in vacuo at low temperature to avoid formation of by-products and added dropwise to the stirred solution of 18 mmol of AcGly in 50 ml of water. Reaction was carried out at room temperature for 24h, after which water was removed under reduced pressure. The remaining AcGly was precipitated by acetonitrile:methanol (9:1 v/v) mixture and filtered off. Evaporation of the solvent gave IL product as a colorless to yellowish oil which was dried at 50°C for 2h under 3Torr. All ILs were obtained in 90-95% yield and characterized by 1H NMR, 13C NMR, MS

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spectra and determination of bromide concentration. If Br- concentration was too high, the

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residual bromides were precipitated by dissolving IL in dry acetone.

N-n-butyl-N-methylmorpholinium N-acetyl-glycinate – [Mor1,4][AcGly] 1

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H NMR (500 MHz, D2O) δ [ppm]: 3.89 (m, 4H), 3.59 (d, 2H), 3.33 (m, 6H), 3.02 (s, 3H), 1.87 (s, 3H), 1.61 (m, 2H), 1.24 (m, 2H), 0.81 (t, J =7.4Hz, 3H) 13

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C NMR (125 MHz, D2O) δ [ppm]: 171.44, 169.06, 64.00, 60.29, 59.39, 46.47, 43.32, 23.19, 23.05, 19.67, 13.99

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HRMS-ESI: ES+ m/z: 158.1608 [M+]; calc. for C9H20NO 158.1539 ES- m/z: 116.0365 [M-]; calc. for C4H6NO3 116.0353

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Br- concentration = 0.0057%; nD20=1.4922

N-n-hexyl-N-methylmorpholinium N-acetyl-glycinate – [Mor1,6][AcGly] 1

13

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H NMR (500 MHz, CD3OD) δ [ppm]: 4.0 (m, 4H), 3.75 (s, 2H), 3.47 (m, 6H), 3.19 (s, 3H), 1.99 (s, 3H), 1.80 (m, 2H), 1.39 (m, 6H), 0.94 (t, 3H) C NMR (101 MHz, DMSO-d6) δ [ppm]: 170.05, 168.42, 64.19, 60.29, 59.36, 46.44, 44.80, 31.14, 25.89, 23.23, 22.34, 21.13, 14.30 HRMS-ESI: ES+ m/z: 186.1862; calc. for C11H24NO 186.1852 ES- m/z: 116.0367 [M-]; calc. for C4H6NO3 116.0353 Br- concentration = 0.0016%; nD20=1.4834 N-metyl-N-octylmorpholinium N-acetyl-glycinate – [Mor1,8][AcGly] 1

H NMR (500 MHz, CD3OD) δ [ppm]: 4.0 (m, 4H), 3.74 (s, 2H), 3.47 (m, 6H), 3.19 (s, 3H), 1.99 (s, 3H), 1.81 (m, 2H), 1.37 (m, 10H), 0.92 (t, J=7 Hz, 3H) 13

C NMR (101 MHz, DMSO-d6) δ [ppm]: 170.07, 168.42, 64.18, 60.29, 59.35, 46.43, 44.81, 31.64, 28.94, 26.25, 23.22, 22.52, 21.19, 14.43 HRMS-ESI: ES+ m/z: 214.2186 [M+]; calc. for C13H28NO 214.2165 ES- m/z: 116.0370 [M-]; calc. for C4H6NO3 116.0353

Journal Pre-proof Br- concentration = 0.0016%; nD20=1.4811 N-n-decyl-N-methylmorpholinium N-acetyl-glycinate – [Mor1,10][AcGly] 1

H NMR (500 MHz, CD3OD) δ [ppm]: 4.00 (m, 4H), 3.77 (s, 2H), 3.47 (m, 6H), 3.19 (s, 3H), 1.99 (s, 3H), 1.81 (m, 2H), 1.42 (m, 4H), 1.35 (m, 10H), 0.91 (t, 3H) 13

C NMR (101 MHz, DMSO-d6) δ [ppm]: 170.22, 168.48, 64.18, 60.29, 59.35, 46.43, 44.65, 31.75, 29.37, 29.29, 29.13, 28.99, 26.25, 23.21, 22.57, 21.19, 14.43 HRMS-ESI: ES+ m/z: 242.2301 [M+]; calc. for C15H32NO 242.2278 ES- m/z: 116.0361 [M-]; calc. for C4H6NO3 116.0353 Br- concentration = 0.001%; nD20=1.4828

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N-n-dodecyl-N-methylmorpholinium N-acetyl-glycinate – [Mor1,12][AcGly] 1

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H NMR (500 MHz, CD3OD) δ [ppm]: 4.00 (m, 4H), 3.76 (s, 2H), 3.47 (m, 6H), 3.19 (s, 3H), 1.99 (s, 3H), 1.81 (m, 2H), 1.42 (m, 4H), 1.33 (m, 14H), 0.91 (t, J=6.9Hz, 3H) 13

Br- concentration = 0,001%; nD20=1.4785

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C NMR (101 MHz, DMSO-d6) δ [ppm]: 171.11, 168.82, 64.18, 60.30, 59.34, 46.41, 43.89, 31.77, 29.49, 29.42, 29.30, 29.19, 29.01, 26.26, 23.10, 22.57, 21.20, 14.42 HRMS-ESI: ES+ m/z: 270.2905 [M+]; calc. for C17H36NO 270.2791 ES- m/z: 116.0359 [M-]; calc. for C4H6NO3 116.0353

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3. Surface activity characteristics

Surface tension isotherms of the IL aqueous solutions were determined at 25±0.1°C, using a

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video based optical contact angle meter (OCA 15, Dataphysics, Germany). The SCA 22 software module was used to analyze shape of the drop and calculate surface tension

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according to the pendant drop method. The temperature during measurements was controlled by a thermostatic water bath (AD07R-20, PolyScience, USA). The maximum surface excess concentration, Γmax, and the minimum area per IL molecule, Amin, at the air/water interface were calculated according to Gibbs adsorption equation: Γmax =-

1 dγ [ ] RT dlnc T,p

and: 𝐴𝑚𝑖𝑛 =

1016 𝑁𝐴 ∙ 𝛤𝑚𝑎𝑥

where R is the gas constant, T is the absolute temperature, γ is surface tension [mN/m], c is the concentration of IL in the solution [mmol/L], and NA is the Avogadro constant. The adsorption efficiency of the amphiphiles at the air/water interface (pC 20) was calculated as follows: 𝑝𝐶20 = −𝑙𝑜𝑔𝐶20

Journal Pre-proof where C20 is the amphiphile concentration required to reduce the surface tension of water by 20mN/m. The surface pressure (the surface tension reduction effectiveness) at the saturated air/solution interphase, Πcmc, was obtained from the surface tension curve by means of equation: 𝛱𝐶𝑀𝐶 = 𝛾𝑜 − 𝛾𝐶𝑀𝐶 where γo is the surface tension of the solvent and γCMC is the surface tension at CMC. The free energy of the micellization process was calculated from the following equation: Δ𝐺𝑚 = (2 − 𝛽)𝑅𝑇𝑙𝑛𝑋𝐶𝑀𝐶 where  is the degree of ionization taken from conductivity measurements and XCMC is the

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mole fraction of the IL monomers at CMC. The maximum surface excess concentration, the

energy of adsorption (ΔGads) calculation:

𝛱𝐶𝑀𝐶 𝛤𝑚𝑎𝑥

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∆𝐺𝑎𝑑 = ∆𝐺𝑚 −

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free energy of the micellization and the surface pressure were than further used for the free

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The conductivity measurements were performed at 25±0.1°C using a conductivity meter with an autotitrator (Cerko Lab System CLS/M/07/06, Poland) equipped with a microelectrode

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(Eurosensor, EPST-2ZA, Poland) and a thermostatic water bath (AD07R-20, PolyScience, USA). Based on the conductivity measurements the degree of ionization of the micelle ()

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was calculated as the ratio of the d/dc slopes of the two linear fragments of the conductivity curves.

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Nano-Isothermal Titration Calorimeter III (N-ITC III, CSC, USA) was used for determination of the thermodynamic parameters of the micellization process. In this experiment, the IL solution with a concentration about ten times higher than the expected CMC was titrated to the sample cell filled with water to detect the heat of the demicellization process. The titration experiment consisted of 48 injections of 5.15 L of IL aliquots. The enthalpograms created by Titration Bindworks software were used for determination the enthalpy of demicellization (Hdm) and confirm the CMC values. The entropy of micellization, Sm, was obtained from the relationship as given in equation: ∆𝑆𝑚 =

1 𝑇

(∆𝐻𝑚 − ∆𝐺𝑚 ).

4. Ionic liquids as phase transfer catalysts (PTC) N-n-butyl-dibenzazepine The reaction was carried out according to the modified procedure [35].

Journal Pre-proof 55 mmol PTC was added to the solution of 2.5 g (12.95 mmol) of dibenzoazepine, 5.52 g (31.67 mmol) of K2HPO4 and 4.99 g (36.4 mmol) of 1-bromobutane in 12.5 ml of toluene. The reaction mixture was refluxed for 5, 10 or 22 hours and then cooled to room temperature. The inorganic salts were filtered off. The filtrate was distilled under reduced pressure to remove the solvent. The residue was separated using column chromatography on silica gel with the mixture hexane: ethyl acetate 9.5 : 0.5 v/v as the eluent. The product was obtained as a yellow oil. The yields of the individual reactions are given in Table 3. 1

H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.29 (m, 2H), 7.08 (m, 4H), 6.99 (m, 2H), 6.74 (s,

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2H), 3.68 (t, J = 6.7 Hz, 2H), 1.43 (m, 2H), 1.30 (m, 2H), 0.80 (t, J = 7.2 Hz, 3H). 13

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C NMR (100 MHz, CDCl3) δ [ppm]: 151.22, 133.95, 132.17, 129.12, 128.72, 123.11,

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120.37, 50.33, 29.80, 20.19, 13.91.

2,7-dibromofluorene was synthesized according to the modified procedure described by Gu

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et al. [36] mp 161-163°C (lit. [24] mp 161-164°C).

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9,9-dibutyl-2,7-dibromofluorene

The reaction was carried out according to the modified procedure described in the literature

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[37].

To a solution of 1.0 g (3.1 mmol) of 2,7-dibromofluorene and 0.94 mmol of PTC in 10 mL of

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DMSO, 10 mL of a 50% solution of NaOH and 0.94 g (7.1 mmol) 1-bromobutane were added successively with stirring. The reaction mixture was heated to 80°C or 40°C for 1 or 2 h with stirring. The reaction mixture was then cooled to room temperature and poured into 10 ml of water. The resulting suspension was extracted with chloroform (3x10 ml). The organic layers were combined, washed with brine and dried with Mg2SO4. The solvent was evaporated and the residue was partitioned by silica gel column chromatography with hexane as the eluent. The product was obtained as the cream crystal mp 116-118°C (lit. [25b] 116,5-118,5°C). The yields of the individual reactions are given in Table 4. 1

H NMR (500 MHz, CDCl3) δ [ppm]: 7,52 (AB, 4H), 7,47 (s, 2H), 1.92–1.96 (m, 4H), 1,11 (sex, 4H), 0,71 (t, J = 7.5 Hz, 6H), 0,55 – 0,62 (m, 4H) 13

C NMR (100 MHz, CDCl3) δ [ppm]: 152.57, 139.09, 130.18, 125.19, 121.50, 120.59, 55.62, 40.03, 25.84, 22.96, 13.78 Results and Discussion

Synthesis of ionic liquids

Journal Pre-proof Preparation of ionic liquids containing glycine as an anion is a particular challenge. Such organic ionic liquids may be used for modification of biologically active fragile compounds under mild conditions, to raise their basicity and solubility. Five novel ionic liquids

of

general

formula:

N-alkyl-N-methylmorpholinium:

N-acetyl-glyciniate

[Mor1,n][AcGly] were prepared as shown in Scheme 1. A commercially available Nmethylmorpholine was used as a starting substrate which, upon treatment with 1bromobutane, 1-bromohexane, 1-bromooctane, 1-bromodecane or 1-bromododecane in acetonitrile, gave the respective quaternary morpholinium bromide salts [34]. These Mor1,nBr salts were converted into morpholinium hydroxides [Mor1,n][OH] by ion-exchange

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chromatography. N-acetyl-glycine was synthesized by the treatment of glycine with acetic anhydride [33]. In the final step, morpholinium hydroxides were treated with N-acetyl-glycine

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na

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re

-p

ro

in an anion exchange reaction.

Scheme 1

The chemical structure of the synthesized ILs was determined by 1H and

13

C NMR

spectroscopy and MS spectrometry. Moreover, a bromide content in ILs obtained was quantified. DSC differential scanning calorimeter with sealed aluminium pans was used to determine phase transitions temperatures and decomposition temperatures of obtained ionic liquids. All samples, weight 3-5 mg, were subjected in isothermal heating/cooling mode with 3 steps: heating to 200⁰ C, cooling to -30⁰ C and then heating to 300⁰ C. There was no thermal effect connected to phase transition observed under measurement conditions for none of the tested compounds. This suggests that melting, crystallization or glass transition temperatures are less than -30⁰ C. The thermal effect was only observed during the decomposition of the compounds and results are shown in Table 1. The obtained results

Journal Pre-proof show that the compounds whose decomposition begins at the lowest temperature are [Mor1,8][AcGly] < [Mor1,6][AcGly] < [Mor1,10][AcGly] and more thermally stable are ionic liquids with the longest and shortest alkyl chains [Mor1,12][AcGly] > [Mor1,4][AcGly]. Table 1. Decomposition temperatures of [Mor1,n][AcGly] ionic liquids. IL [Mor1,4][AcGly] [Mor1,6][AcGly] [Mor1,8][AcGly] [Mor1,10][AcGly] [Mor1,12][AcGly]

Tonset5% [⁰ C] 229 194 187 199 223

Tonset50% [⁰ C] 243 231 228 243 249

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Tonset5% [⁰ C] – glass transition temp. determined from onset to 5% mass loss Tonset50% [⁰ C] – decomposition temp. determined from onset to 50% mass loss

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Aggregation behavior of [Mor1,n][AcGly] derivatives

The surface activity and aggregation behavior of five N-acetyl-glycinate ILs containing

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different alkyl chain length in the N-alkyl-N-methylmorpholinium cation (from 4 up to 12 carbon atoms) were investigated by the surface tension and conductivity analysis. The

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positive charge and hydrophobic alkyl chain determined amphiphilic properties, thus ability of the morpholinium cation to adsorb at the air/water interface, to reduce the solution's surface

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tension, and to form micellar aggregates when critical micelle concentration (CMC) is reached. These phenomena are reflected by the surface tension changes of the solutions with

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increasing concentration of IL as presented Figure 1 (the Gibbs adsorption isotherms). Plateau region in the surface tension profiles represents presence of the micelles in the solutions, agglomerates which are not surface active.

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Journal Pre-proof

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Figure 1. Surface tension data (in mN/m) as a function of the logarithm of IL concentration (in mmol/dm3) measured at 25oC for aqueous solutions of [Mor1,12][AcGly] (), [Mor1,10][AcGly] (), [Mor1,8][AcGly] (), [Mor1,6][AcGly] (), [Mor1,4][AcGly] () The parameters characterizing adsorption of N-alkyl-N-methylmorpholinium N-acetyl-

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glyciniates at the air/water interface (Γmax, Amin, pC20, Πcmc and ΔGad) were calculated from the results of the Gibbs adsorption isotherm and presented in Table 2. As it was expected, the increasing hydrophobicity of the alkyl chain in the morpholinium cation enhanced the surface properties. These amphiphiles revealed higher adsorption efficiency (pC20), that is the concentration at which they reduce a surface tension by 20 mN/m. This parameter increased from 1.24 for [Mor1,6][AcGly] to 1.53 for the IL with twelve carbon atoms in the morpholinium cation, thus the latter more efficiently adsorbs at the air/water interface and has higher ability to reduce surface tension. The ionic liquid with the shortest alkyl chain [Mor1,4][AcGly] also revealed some surface activity, nevertheless, the ability to adsorb at the interface and depress surface tension was very low (surface tension was reduced by only 18 mN/m, thus pC20 could not be calculated). The maximum surface excess concentration, max, increased (from 2.24 to 3.22 mol/m2), and correspondingly Amin decreased (0.72-0.50 nm2) with lengthening the alkyl chain from C4 to C12. These observations indicated relatively

Journal Pre-proof more tight and more perpendicular arrangement of [Mor1,12][AcGly] at the air-water interface in comparison to homologues with shorter chain length. The higher adsorption efficiency of ILs with longer chains was also confirmed by more negative free energy of adsorption, ΔGads. The elongation of the alkyl substituent in the morpholinium cation appeared to have a small effect on the values of surface tension at CMC, CMC, which were close to 41–43 mN/m for all of the ILs and the surface pressure values, CMC, which were calculated to be in the range of 28-30 mN/m. This structural change, however, had a significant effect on the CMC values, and favored micelle formation, due to the higher hydrophobicity of the salt. The CMC values ranged from 905.11 up to 41.12 mM as determined by the surface tension experiments the

morpholinium

derivatives

containing

six

[Mor1,4][AcGly]

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for

and

twelve

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[Mor1,12][AcGly] carbon atoms in the alkyl substituent, respectively. The logarithmic relation between CMC and the number of carbon atoms in the alkyl chain can be presented in a form

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of the following relation:

log 𝐶𝑀𝐶 = 𝐴 − 𝐵𝑥

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where A, B are constants and x is the number of carbon atoms in the alkyl chain. For this

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homologous series of amino acid derived amphiphiles A was estimated to be 4.28, whereas B 0.22. The constant A characterizes series of compounds and varies with the nature and number of the hydrophilic groups. For N-alkyl-N-methylmorpholinium N-acetyl-glycinates this value

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was found to be in a range characteristic for other ionic liquids (from 3.8 to 4.7 [2]). The B constant, in turn, was found to be lower than for the simple alkyl chain substituted

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imidazolium and pyridinium derivatives [38,39] and for common ionic surfactants [40]. The B value represents the Gibbs free energy of a transfer a methylene unit from aqueous bulk solution to the micellar structure, and was calculated to be -1.61 kJ/mol. This value is similar, however less negative, than those reported for ionic liquids with simple halogen anions (also functionalysed) and n-alkyl ionic surfactants with a single ionic head [38-40]. This observation can be explained be the presence of more bulky amino acid anion. The above presented rule can be used for estimation the CMC data for the homologous with different chain length in the cation. Additionally, to confirm the CMC data, we performed the conductivity measurements (see Figure 2). The presented results reflects increasing number of IL’s ions in the solutions with higher concentration. The beginning of the micellization process, thus CMC of the salts, was identified based on the discontinuity in the presented dependences. Lower slopes after critical concentration reflects lower mobility of the micelles in comparison with IL monomers. The CMC values determined by these two methods were

Journal Pre-proof presented in Table 2, whereas the decreasing dependence of CMC on the hydrocarbon chain

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length presented in Figure 3.

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Figure 2. Exemplary results of specific conductivity (in mS/cm) variations as a function of IL’s concentration (in mmol/dm-3) determined for [Mor1,12][AcGly] () and [Mor1,10][AcGly] () at 25oC

Figure 3. Dependence of the CMC values determined for N-alkyl-N-methylmorpholinium Nacetyl-glycinates at 25oC on the number of carbon atoms in the alkyl chain

Journal Pre-proof Up to date, for biobased ILs, micellization behavior was only revealed in the case of salts derived from lipids, where ability to self-assembly is related with amphiphilic nature of the anion [31,32]. The CMC values of N-acetyl-glycinates being cationic surfactants were observed to be higher when compared to imidazolium analogous [41] as well as common surfactants [40] containing halogens as anions with simpler structure in comparison with amino acids. These results were reflected by the degree of ionization of the micelle, β, derived from the conductivity measurements (and presented in Table 2). The values of β are higher than those presented for salts containing simple chloride and bromide anions26 reflecting lower

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affinity of the amino acid anion to the cationic micelle due to the larger size and lower charge density. As a consequence, these anions are weaker in counterbalancing the electrostatic

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repulsion among the cationic headgroups of ILs in the micelle resulting in higher CMC.

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Table 2. Summary of the surface properties of [Mor1,n][AcGly] ionic liquids in aqueous solutions determined at 25oC Compound

[Mor1,4][AcGly] [Mor1,6][AcGly] [Mor1,8][AcGly] [Mor1,10][AcGly] [Mor1,12][AcGly] a

CMCa [mmol/L]

CMCb [mmol/L]

CMCc [mmol/L]

905.1±19 296.8±11 104.3±6 41.1±1.5

933.0±17 292.8±10 101.0±7 31.3±1.9

98.3±7 33.4±1.5

 0.47±0.03 0.54±0.02 0.67±0.02 0.72±0.02

CMC [mN/m] -

pC20

41.7 43.1 43.3 42.9

0.24 0.79 1.09 1.53

surface tension, b conductivity, c ITC

m x 106 [mol/m2]

Am [nm2]

cmc [mN/m]

2.24 2.49 2.91 3.13 3.22

0.72 0.65 0.55 0.51 0.50

30.21 28.56 28.32 29.16

e

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Gad [kJ/mol] -23.98 -28.49 -32.27 -40.44

Gm [kJ/mol] -15.69 -18.92 -20.69 -22.87

 is the degree of ionization, γcmc, the surface tension at the CMC; pC20, the surfactant concentration required to reduce the surface tension of the solvent by 20 mN/m; Γmax, the maximum surface excess concentration; Am, the minimum area per molecule at the interface; ΔGad, free energy of adsorption; ΔGm, free energy of micellization;

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Journal Pre-proof The  parameter increases with elongation of the length of the alkyl substituent due to increase in the van der Waals interactions between hydrocarbon chains and formation of the more highly ordered and compact micellar structures at lower CMC. These hydrophobic interactions governing micellization were also reflected in the standard Gibbs free energy of micelle formation which became more negative with lengthening the alkyl chain (from 15.69 to -22.87 kJ/mol for [Mor1,6][AcGly] and [Mor1,12][AcGly], respectively). The comparison of ΔGads with ΔGmic values demonstrated that adsorption of N-alkyl-N-methylmorpholinium Nacetyl-glycinates at the air-water interface is more favored than micellization in the bulk solution.

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The compound with the highest surface activity [Mor1,12][AcGly] was also analyzed

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taking into account thermodynamics of the micelles formation by isothermal tittration calorimentry (Figure 4). This technique enabled direct determination of the enthalpy of

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demicellisation (Hdem) due to titration of the concentrated IL solution (above CMC) to the reaction cell containing water. The peaks are that integrated and normalization with respect to

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the injected number of moles of IL providing the sigmoidal shaped enthalpograms

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representing three different concentration regions, thus three distinct phenomena occurring in the reaction cell. The first step (pre-micellar region) reflects heat of micelle dilution, demicellization and dilution of monomers in water. A sharp increase of the heat effect is

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achieved due to reaching CMC by IL (the first derivative of the integrated peaks versus the total concentration of IL, dQ/dc, provide CMC value). Finally, the thermal effect of the

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titration of the concentrated IL solution to the solution of aggregates is observed as a plateau. The difference between the two horizontal parts of the S-shaped curve representing the premicellar and postmicellar regions was used for calculation of Hdem. The micellization processes of [Mor1,12][AcGly] was found to be relatively highly endothermic (7.6 kJ/mol). This value was higher than noticed, for example, for imidazolium derivatives with analogous alkyl chain length but simpler anions [30,41]. The value of Hm is the sum of the energy required to release the solvent molecules from the hydration layer of the amphiphilic compound and the energy that is released when the hydrocarbons are transferred from the bulk solution to the micelle and the structure of the water around the micelle is recreated. In this regard, the effect of the formed phenomena probably dominates. Higher energy demands appear due to higher affinity of the compound to water. According to the Gibbs-Helmholz equation, Hm and Sm have an opposite effect on the free energy of micelles formation. For this compound, the influence of the Sm (TSm is equal to 31.1 kJ/mol) was higher than Hm

Journal Pre-proof indicating the entropy-driven micellization processes (an increase of the entropy change is a

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driving force of the micellization process).

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Figure 4. Enthalpogram of ITC titration of [Mor1,12][AcGly] aqueous solution at concentration of 314.2 mmol/L into water, first derivative indicates the CMC value N-alkylation reaction of dibenzoazepine in the presence of [Mor1,n][AcGly]) In this work, a possibility of application of novel ILs as phase transfer catalysts in Nalkylation of dibenzazepine, a well-known precursor of antidepressants, such as imipramine or carbamazepine [42], as the model substrate has been tested. In the patent literature, a selective N-alkylation of dibenzazepine with 1-bromo-3-chloropropane in the presence of benzyltrimethylammonium chloride (TEBAC) as a catalysts has been described [35]. That reaction was carried out until total disappearance of the substrate, i.e. for 18 h. In our studies, tetra-n-butylammonium bromide (TBAB) [43] was used instead of TEBAC as the reference PTC. The reactions in the presence of novel ILs or TBAB as PTCs were carried out for 5, 10 or 22 h in toluene at boiling temperature (Scheme 2). For comparative purposes, the reaction was also performed without PTC. The results are presented in Table 3.

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Scheme 3 Table 3. The yields of N-alkylation of dibenzazepine

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[Mor1,4][AcGly] [Mor1,6][AcGly] [Mor1,8][AcGly] [Mor1,10][AcGly] [Mor1,12][AcGly] TBAB [Mor1,12][AcGly] + H2O without PTC

22h 38 58 55 61 65 68 21 5

Yield (%) 10h 5h 15 6 25 14 31 14 28 14 28 14 31 21 -

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PTC

The yields of N-alkylation reaction run in the presence of ILs for 5h were generally

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low, at 14% level. The lowest conversion degree was noted for the [Mor1,4][AcGly] ionic liquid, with the shortest side chain of the cationic component. Difference in the reaction yields

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was observed, when the reaction was run for 22 hours. In that case, the higher yields were observed for ILs with the longer side chains and in reaction in the presence of

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[Mor1,12][AcGly] it reached 66%. This value is comparable to that found for the reaction, in which TBAB was used as a catalyst (68%). In the reaction run without any phase-transfer catalyst, the product was isolated with 5% yield, which confirms the need for using PTC in such reactions.

This reaction represents solid-liquid PTC conditions, in which the catalysts (onium salts) form hydrogen bonded complexes with amines [44]. In the case of the classical quaternary ammonium salts like e.g. TBAB, used in this work as the reference catalyst, this complex can be represented as [NR4+X-‧ ‧ ‧ HNAr’Ar”] with polarization toward the amide anion. Formation of analogous complexes can be expected for ionic liquids synthesized in this study, namely [Mor1,x][AcGly]. Here, we can assume formation of the hydrogen bonds between the oxygen atom in the morpholinium cation and the hydrogen atom in dibenzazepine. Moreover, interactions between the carboxylic group of N-acetylglycine and amine are also possible. In this regard, generally lower in comparison with TBAB catalytic activity of [Mor1,x][AcGly] may result from diminished negative charge density on the

Journal Pre-proof nitrogen atom. It is likely that the IL-amine complex promotes an increase of acidity of the hydrogen atom bonded with nitrogen in dibenzazepine, thereby facilitating de-protonation under PTC/OH conditions and formation of the N-anions. The longer hydrocarbon chain in IL the lower charge density on the cation, resulting in the weaker cation-anion interactions. As a consequence, one can expect that formation of IL-amine complex facilitates deprotonation of amine. The formed N-anion is nucleophilic enough to further participate in the alkylation reaction with 1-bromobutane. In this regard, ionic liquids with the longest alkyl substituent and the highest surface activity, [Mor1,12][AcGly], revealed the highest catalytic activity in the model N-alkylation reaction of the nitrogen containing heterocycle.

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C-alkylation reaction of fluorene derivatives in the presence of [Mor1,n][AcGly]

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The novel ILs were also tested as PTCs in C-alkylation. The dibromo derivative of fluorene was chosen as the model substrate. The disubstituted fluorenes are used as substrates

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in synthesis of mono- and dialkyl derivatives which are applied for preparation of conducting

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polymers [45], fluorogenic substances or materials for organic electroluminescence diodes [46].

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C-alkylation of 2,7-dibromofluorene was performed under conditions described in literature [37] (Scheme 3), i.e. the reaction mixtures were warmed at 80°C for 2h in the presence of

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TBAB or one of the novel ILs. Moreover, efficiency of novel ILs as PTC was also tested in shorter reaction period (1h/80°C) and at the lower temperature (1h/40°C). The results are

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presented in Table 4.

Scheme 3. Table 4. The yield of the C-alkylation reaction of 2,7-dibromofluorene PTC [Mor1,4][AcGly] [Mor1,6][AcGly] [Mor1,8][AcGly] [Mor1,10][AcGly] [Mor1,12][AcGly] TBAB without PTC

2h/80°C 43% 58% 60% 66% 67% 51% -

Yield (%) 1h/80°C 61% 64% 53% 76% 78% 81% -

1h/40°C 62% 70% 73% 77% 83% 69% -

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The C-alkylation reaction, if run in the presence of ILs at the lower temperature, i.e. 40⁰ C, the yields increased with side chain length of the IL cationic component, from 62% for [Mor1,4][AcGly] to 83% to [Mor1,12][AcGly]. The yield of reaction performed in the presence of TBAB was comparable to that observed for the reaction with [Mor1,6][AcGly] as the PTC. When the reaction was run at 80⁰ C, yields of the 1 h-long reaction were comparable, irrespective of the PTC used (76-81%). However, prolongation of the reaction time to 2 h, led to the notable yield decrease for the reactions run in the presence of TBAB and [Mor1,4][AcGly] (down to 51% and 41%, respectively). On the other hand, when the long

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side chain ILs were used as the PTC, the yield’s decrease was much smaller (down to 66% and 71%, respectively). A possible reason for the lowest yields observed at higher

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temperature, is the partial thermal disintegration of the products.

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In the case of this reaction, a term 'phase-transfer catalysis' is understood as a transport of the OH anions from concentrated aqueous sodium hydroxide solution to the organic phase

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by PTC in the form of morpholinium hydroxides. The C-alkylation reaction is possible to occur due to weakly acidic character of the bridged protons (C9-H sites) in 2,7-

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dibromofluorene. The pKa of the fluorene ring in DMSO was found to be 22.3 [47]. In this regard, 2,7-dibromofluorene can be deprotonated under PTC/OH conditions (probably at the

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phase boundary) providing the corresponding carbanions. These species migrate to the organic phase, in the form of ion-pairs with morpholinium cations, where further reaction

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occurs. The fluorenyl anions are nucleophilic enough to undergo C-alkylation reaction with varying degrees of difficulty, depending on the structure of ionic liquid. The longer alkyl substituent, the weaker interactions between IL’s anions, thus higher ability of IL to interact and transfer hydroxide anions to the phase boundary. Moreover, the longer substituent in the morpholinium cation means also the higher surface activity which probably facilitates the transfer of the reagents through the interface. Conclusions The amino acid derived N-alkyl-N-methylmorpholine N-acetylglycinates, having in their structure a cation with a chain length of 4 to 12 carbon atoms, can be classified as surface active agents based on the studies of the relationship between surface tension and molar concentration of the compound and critical concentration of micellization in aqueous solutions.

Journal Pre-proof The novel surface active ionic liquids were used as PTCss for the N-alkylation and Calkylation reactions. For the both alkylation reaction, one may observe the noticeable influence of structure of the cationic component of the IL on yield of the reactions run at higher temperature. For N-alkylation of iminostilbene, yields of the [Mor1,12][AcGly] ionic liquid-assisted reaction are comparable to those of the TBAB-assisted ones. For C-alkylation of 2,7-dibromofluorene, the advantage of this ionic liquid is clearly noticeable and allows the product to be obtained with over 15% higher yield than that for standard PTC. Taking into account the data, it can be concluded that they depend on the reaction conditions and the novel surfactant-type ILs may be successfully used as PTC, substituting the conventional ILs

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in this respect. Their biobased nature and good thermostability make them an interesting

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alternatives for conventional tetraalkylammonium salts as PTCs.

ODCIDs

Notes and references

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Emil Szepiński 0000-0002-8952-856X, Patrycja Smolarek 0000-0002-7141-4599, Maria J. Milewska 0000-0002-9740-0881, Justyna Łuczak 0000-0001-9939-7156

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[46] Q. Pei, Y. Yang, Efficient Photoluminescence and Electroluminescence from a Soluble Polyfluorene, J. Am. Chem. Soc., 118 (1998), 7416–7417. [47] F.G. Bordwell, Equilibrium Acidities in Dimethyl Sulfoxide Solution, Acc. Chem. Res., 21 (1988), 456-463.

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CRediT author statement Emil Szepiński – Investigation, Writing - Original Draft, Patrycja Smolarek – Investigation, Maria J. Milewska – Conceptualization, Resources, Writing - Original Draft, Writing Review & Editing, Visualization,

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Justyna Łuczak- Conceptualization, Investigation, Resources, Writing - Original Draft, Writing - Review & Editing, Visualization,

Journal Pre-proof Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Journal Pre-proof Graphical abstract

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Five novel N-alkyl-N-methylmorpholinium: N-acetylglycinate ILs were prepared The novel ILs exhibit surface activity determined by the alkyl chain length [Mor1,12][AcGly] afford similar or higher yields than TBAB in alkylation reactions Amino acid ionic liquids can serve as a good alternative for conventional PTCs

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