Synthesis of Ionic Liquids Equipped with 2-Methoxyethoxymethyl

Article pubs.acs.org/OPRD

Synthesis of Ionic Liquids Equipped with 2‑Methoxyethoxymethyl/ Methoxymethyl Groups Using a Simple Microreactor System Toshiki Nokami,*,†,‡ Kuninobu Matsumoto,† Taka-aki Itoh,† Yukinobu Fukaya,†,‡ and Toshiyuki Itoh*,†,‡ †

Department of Chemistry and Biotechnology, ‡Center for Research on Green Sustainable Chemistry, Graduate School of Engineering, Tottori University, 4-101 Koyamacho-minami, Tottori City, 680-0909 Tottori, Japan S Supporting Information *

ABSTRACT: A simple microreactor system has been utilized for the continuous flow synthesis of novel ionic liquids having a (2-methoxyethoxy)methyl or methoxymethyl substituent. Conversion rates of N-bases and tributylphosphine in the microreactor system are faster than those in the batch system because of less diffusion distance in the tube reactor. This method allows us to prepare ionic liquids in efficient yields with high purity.

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INTRODUCTION Considerable attention has been devoted to ionic liquids (ILs) because of their contribution to the development of sustainable chemistry and engineering.1 Indeed, a variety of ILs has already been synthesized, and many of them are commercially available; however, novel ILs with new functions are still needed. Preparation of novel ILs in a preparative scale is the first and the key step of their investigation. In contrast to conventional organic molecules, ILs consist of organic cations and/or anions and are hard to purify, and their syntheses are always carried out on a large scale because they are produced as a solvent. Thus, it is particularly important to control the reactions in order to obtain ILs in high yields and purity without undesired byproducts and unreacted starting materials. Recently, we have developed a novel type of IL having the (2-methoxyethoxy)methyl substituent on a heteroatom such as diethyl((2-methoxyethoxy)methyl)methylammonium bistrifluoromethanesulfonylamide [N221MEM][Tf2N]2 and tributyl((2-methoxyethoxy)methyl)phosphonium bistrifluoromethanesulfonylamide [P444MEM][Tf2N]3 (Figure 1). These ILs have

preparation of a variety of organic molecules including ILs on a preparative scale.7 The devices and reaction conditions required for the synthesis of ILs depend on the requirement for heat exchange during their formation (Figure 2). For example, 1,3-

Figure 2. Synthesis of imidazolium salts using a microreactor.

dimethylimidazolium triflate [C1mim][TfO] was prepared by the highly exothermic reaction of 1-methylimidazole with methyl triflate (MeOTf) which was carried out using a microstructured plate-type reactor equipped with a cooling device. On the other hand, slow reactions (e.g., reaction of 1methylimidazole with butyl bromide) which have high activation energies require more thermal energy in order to overcome the energy barrier. In these cases, microreactors have advantages over external heating because of their shorter heat transfer path. 2-Methoxyethoxymethyl chloride (MEMCl) and methoxymethyl chloride (MOMCl) are known as good electrophiles, and their reactions with a trialkylamine (R3N) are also exothermic; however, their reactivity as electrophiles is lower than that of MeOTf. Therefore, an appropriate device for

Figure 1. ILs equipped with a MEM group on the heteroatom.

already been used as solvents for conventional organic reactions,4 enzymatic reactions,5 and as electrolytes for batteries.3b Although the two-step process (chloride salt formation and the subsequent ion exchange) for preparation of these ILs seems to be easy, large-scale production in a conventional flask as a batch reactor is not practical because of the heat release and the increase of viscosity during formation of the chlorides [N221MEM]Cl and [P444MEM]Cl. Therefore, a practical and environmentally benign method for their synthesis on a preparative scale is highly desirable. Continuous flow synthesis6 is recognized as a space-, time-, and energy-saving method and has already been applied for the © XXXX American Chemical Society

Special Issue: Continuous Processes 14 Received: April 20, 2014

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dx.doi.org/10.1021/op500131u | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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the reactions of N-bases with MEMCl/MOMCl are fast enough to complete in the tube-type reactor within several minutes. A simple microreactor system for flow synthesis of ammonium chlorides was devised, and time course experiments were performed (Figure 4). Although a stainless tube is better for heat exchange, we chose a Teflon tube which is easy to treat. A single stainless micromixer was used, and the reaction mixture was collected and stirred in a flask filled with a CH2Cl2 solution of MeOTf because of the high reactivity of MeOTf as a quenching reagent.9 Both MEMCl and N-base solutions in CH2Cl2 were introduced into the microreactor by using a dual syringe pump equipped with two glass syringes. Precooling tubes T1 and T2 (Teflon tube, length: 50 cm, diameter: 1.0 mm) were introduced between the two syringes and the micromixer M1 (T-type mixer made from stainless steel, diameter: 0.25 mm), and the tube reactor T3 (Teflon tube, length: 50 cm, diameter: 1.0 mm) was connected to the micromixer M1. The reaction temperature was controlled using an ice bath at 0 °C, and the reaction time was controlled by changing the flow rate of both solutions (0.098 mL/min for 2 min, 0.3925 mL/min for 1 min, and 0.785 mL/min for 15 s). In order to determine the amount of unreacted N-base and phosphine, the reaction mixture was collected in the flask filled with CH2Cl2 solution of MeOTf. Although yields of the desired ammonium/phosphonium salts depend on the reactivity of Nbases/Bu3P, over 95% of these N-bases/Bu3P were converted to the corresponding ammonium/phosphonium salts within 2 min; the observed yields which were better than those observed in the cases using a batch system.10 The reaction of Bu3P and MEMCl was performed at 30 °C (Figure 3a), because tributyl((2-methoxyethoxy)methyl)phosphonium triflate [P444MEM][TfO] was not obtained at 0 °C. This result may be attributed to overcooling from use of the microreactor system. Further optimization of the reaction conditions using the microreactor system was carried out before we initiated preparative synthesis of ILs (Table 1). The reaction of 1methylimidazole with MEMCl at 0 °C for 1 min reaction time was chosen as a model reaction for the optimization of reaction conditions. Changes of the diameter of micromixer M1 (250 and 500 μm) and the material of the tube reactor T3 (Teflon and SUS) did not influence the yield of 1-methyl-3-((2methoxyethoxy)methyl)imidazolium triflate [MEMmim][TfO] (entries 1−3).11 Although a higher flow rate (from 0.196 mL/ min to 0.393 mL/min) was examined with a longer tube reactor T3 (from 50 to 100 cm) to maintain the same reaction time of 1 min, the yield of [MEMmim][TfO] was slightly decreased (entry 4). The higher concentration (from 1.0 to 3.0 M) of both 1-methylimidazole and MEMCl gave better yields (entries 5 and 6). The best result (98% yield) was obtained using 3.0 M solution of both starting materials within a 2 min reaction time (entry 7). Further improvements to productivity should be achievable by decreasing the length scale of the micromixer and the diameter of the tubes, although this is the flow synthesis of viscous ionic liquids.12 Synthesis of ILs on a preparative scale was demonstrated (Table 2). Although the reaction without solvent is the most ideal process, some chloride salts give a crystalline solid below room temperature. Therefore, the reactions were carried out using CH2Cl2 or DMF solution of both N-base and MEMCl, and thus-obtained reaction mixtures were collected in a flask filled with lithium bis(trifluoromethanesulfonyl)amide (LiNTf2). The chloride anion of the ammonium ions is

synthesis of ILs equipped with a MEM/MOM group should be designed on the basis of the reactivity of MEMCl/MOMCl towards nucleophiles. Here we report the continuous flow synthesis of ILs using a simple microreactor system based on the reactivity investigation of MEMCl/MOMCl using a small batch reactor.

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RESULTS AND DISCUSSION We initiated our study by comparing the reactivity of N-bases and tributylphosphine (Bu3P) based on small-scale reaction in a flask. We found that the reaction of 1-methylpyrrolidine with MEMCl was extremely fast; however, it was important to reveal how fast the reaction was in order to perform the reactions with a microreactor system. We, therefore, performed a couple of competitive reactions of 1-methylpyrrolidine with MEMCl and MeOTf by changing the order of the addition to confirm the reactivity of MeOTf as a quenching agent. In the first reaction, MEMCl was added 15 s faster than MeOTf, and both 1-((2methoxyethoxy)methyl)-1-methylpyrrolidinium trifluoromethanesulfonate [MEMmpyr][TfO] and 1,1-dimethylpyrrolidinium trifluoromethanesulfonate [C1mpyr][TfO] were obtained in 94% and 6% yields, respectively (eq 1).8 In the next reaction,

MeOTf was added 15 s ahead of MEMCl, and [C1mpyr][TfO] was obtained as the sole product (eq 2). These results suggest that the reaction of MeOTf with 1-methylpyrrolidine is much faster than that of MEMCl. Thus, MeOTf was revealed to be appropriate as a quenching reagent for the kinetic experiments of N-bases and Bu3P with MEMCl/MOMCl in a batch system. Time course experiments to determine the reactivity of MEMCl/MOMCl towards N-bases and Bu3P were performed (Figure 3). The reactions of MEMCl/MOMCl were carried out using a small batch reactor, and MeOTf was subsequently added to trap the remaining nucleophile after a certain period of time (15 s, 1 min, or 2 min). Then, the yields of the desired ammonium ions and phosphonium ions together with the products of the reaction with MeOTf were evaluated by 1H NMR. Although a very short reaction time such as 15 s is not long enough to complete the reactions with MEMCl/MOMCl, the yields were improved in all cases by lengthening the reaction time from 15 s to 2 min. High reactivity of MEMCl/ MOMCl as electrophiles was enough to complete the reaction of 1-methylpyrrolidine within 1 min. The much lower reactivity of Bu3P was obvious because of the incomplete reaction even at 30 °C for 2 min; however, more than 50% of N-bases were consumed in the cases of 1-methylpyrrolidine and diethylmethylamine (Et2NMe) within 15 s. These results encouraged us to use a microreactor system for the preparation of ILs, because B



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Figure 3. Time course experiments of the reactions of N-base/Bu3P with MEMCl (a) and MOMCl (b) using a Schlenk tube.

Figure 4. Time course experiments of the reactions of N-base/phosphine with MEMCl (a) and MOMCl (b) using a microreactor system.

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Table 2. Preparative synthesis of ILsa

Table 1. Optimization of reaction conditions for flow synthesis of [MEMmim][TfO] as a model reaction

entry

conc. (M)

mixer M1 (μm)

tube reactor T3 (cm)

flow rate (mL/min)

yielda [MEMmim]/ [C1mim]

1 2 3 4 5 6 7b

1.0 1.0 1.0 1.0 2.0 3.0 3.0

250 500 250 250 250 250 250

50 Teflon 50 Teflon 50 SUS 100 Teflon 50 Teflon 50 Teflon 100 Teflon

0.196 0.196 0.196 0.393 0.196 0.196 0.196

79%/18% 76%/16% 78%/22% 71%/29% 93%/7% 96%/4% 98%/2%

a

NMR yields. bReaction time 2 min.

entry 1

immediately exchanged with bis(trifluoromethanesulfonyl)amide anion (Tf2N−) to obtain the corresponding ILs having Tf2N anion and lithium chloride (LiCl). DMF is an alternative to CH2Cl2 which is a typical halogenated solvent, because starting materials, chloride intermediates, and ILs are well dissolved in DMF. Moreover, DMF can be easily removed by washing with water, and this step has already been included in the purification procedure to remove the resulting LiCl which is produced after the anion exchange. Preparation of ILs having an MOM substituent was also achieved using DMF as a solvent (entries 9−12, Table 2).

2 3 4 5 6 7 8

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9

CONCLUSION In conclusion, we have utilized a practical microreactor system for the continuous flow synthesis of novel ILs having an MEM or MOM substituent. Conversion rates of N-bases and PBu3 in the microreactor system are faster than those of the batch system because of less diffusion distance in the tube reactor. This method enables us to prepare ILs such as [MEMmpyr][Tf2N] in good yields with high purity. Further scope of this method and physical property analyses of thus-obtained ILs are in progress in our laboratory.

10 11 12

N-base 1-methylpyrrolidine 1-methylpyrrolidine Et2NMe Et2NMe 1-methylpiperidine 1-methylpiperidine 1-methylimidazole 1-methylimidazole 1-methylpyrrolidine Et2NMe 1-methylpiperidine 1-methylimidazole

chloride

solvent

product (yield)b

MEM

CH2Cl2

MEM

DMF

MEM MEM MEM

CH2Cl2 DMF CH2Cl2

MEM

DMF

MEM

CH2Cl2

MEM

DMF

MOM

DMF

MOM MOM

DMF DMF

MOM

DMF

[MEMmpyr][Tf2N] (86%) [MEMmpyr][Tf2N] (86%) [N221MEM][Tf2N] (87%) [N221MEM][Tf2N] (89%) [MEMmpip][Tf2N] (88%) [MEMmpip][Tf2N] (89%) [MEMmim][Tf2N] (90%) [MEMmim][Tf2N] (88%) [MOMmpyr][Tf2N] (90%) [N221MOM][Tf2N] (93%) [MOMmpip][Tf2N] (96%) [MOMmim][Tf2N] (94%)

a

Typical reaction conditions, length of tube reactor: 50 cm, diameter of micromixer: 0.25 mm, flow rate: 0.196 mL/min, bath temperature: 0 °C. reaction time: 1.0 min, concentration: 3.0 M. bIsolated yields based on LiNTf2 (18 mmol).

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EXPERIMENTAL SECTION General. 1H and 13C NMR spectra were recorded on JEOL JNM-ECP500 (1H 500 MHz, 13C 125 MHz, 19F 470 MHz), and Bruker AVANCE II 600 (1H 600 MHz, 13C 150 MHz, 19F 565 MHz). 1,1,2,2-Tetrachloroethane was used as an internal standard for NMR yield (1H NMR, 5.95 ppm, 2 H). Infrared spectra were recorded on PerkinElmer Spectrum 65 FTIR spectrometer. Syringe pump PHD-2000 Infusion equipped with Hamilton Gastight syringes was supplied by Harvard Apparatus. Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification.

Kinetic Studies in a Batch. In a small Schlenk tube (volume: 10 mL) equipped with a magnetic stirring bar (stirring speed: 300 rpm, length: 10 mm), MEMCl (1.0 mmol) was dissolved with dry CH2Cl2 (2.0 mL) at 0 °C. 1Methylpyrrolidine (1.0 mmol) was added in one portion and stirred for 1.0 min at 0 °C. After stirring, trifluoromethanesulfonate (MeOTf) (1.1 mmol) was added and stirred for an additional 15 min. The solvent and other volatile reagents were removed to obtain a crude product under reduced pressure. NMR yields of ILs were calculated on the basis of 1,1,2,2tetrachloroethane as an internal standard. D



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(6) (a) Yoshida, J. Flash Chemistry Fast Organic Synthesis in Microsystems; Wiley: Chichester, 2008. (b) Micro Reaction Technology in Organic Synthesis; Wiles, C.; Watts, P., Eds.; CRC Press: Boca Raton, 2011. (c) Yoshida, J.; Kim, H.; Nagaki, A. ChemSusChem 2011, 4, 331. (d) Wiles, C.; Watts, P. Green Chem. 2012, 14, 38. (e) McQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78, 6384. (7) Preparation of ionic liquids using a microreactor see: (a) Waterkamp, D. A.; Heiland, M.; Schlüter, M.; Sauvageau, J. C.; Beyersdorff, T.; Thöming, J. Green Chem. 2007, 9, 1084. (b) Renken, A.; Hessel, V.; Löb, P.; Miszczuk, R.; Uerdingen, M.; Kiwi-Minsker, L. Chem. Eng. Processing 2007, 46, 840. (c) Gonzalez, M. A.; Ciszewski, J. T. Org. Process Res. Dev. 2009, 13, 64. (d) Wilms, D.; Klos, J.; Kilbinger, A. F. M.; Löwe, H.; Frey, H. Org. Process Res. Dev. 2009, 13, 961. (e) Löwe, H.; Axinte, R. D.; Breuth, D.; Hofmann, C. Chem. Eng. J. 2009, 155, 548. (f) Iken, H.; Guillen, F.; Chaumat, H.; Mazières, M.-R.; Plaquevent, J.-C.; Tzedakis, T. Tetrahedron Lett. 2012, 53, 3474. (g) Snead, D. R.; Jamison, T. F. Chem. Sci. 2013, 4, 2822. (8) Although the reaction product of 1-methylpyrrolidine with MEMCl is [MEMmpyr]Cl, the chloride salt subsequently reacts with MeOTf, and [MEMmpyr][TfO] is obtained together with CH3Cl gas. (9) In-line quenching is an alternative for the conventional quenching in the batch reactor; however, the conventional quenching does not affect the reproducibility. (10) We set up the flow reactor system equipped with the second micromixer for the in-line quenching with an excess amount of MeOTf solution in CH2Cl2. Although the reaction of pyrrolidine with 2methoxyethoxymethyl chloride (MEMCl) in 15 s was performed with the system, the yields of ionic liquids [MEMmpyr][TfO] and [C1mpyr][TfO] were 77% and 2%, respectively (average of 3 runs), which were lower than those observed in the case of the conventional quenching (96% and 4%, average of 2 runs). (11) We used the precooling tubes T1 and T2 made of Teflon for all reactions, because flow rates are slow enough to have a long residence time in the precooling tubes T1 and T2. (12) Nagy, K. D.; Shen, B.; Jamison, T. F.; Jensen, K. F. Org. Process Res. Dev. 2012, 16, 976.

Kinetic Studies and Preparative Scale Synthesis in a Simplified Flow System. A flow system equipped with a Tshaped micromixer M1 and a microtube reactor [T3 (inner diameter = 1.0 mm)] were used. A solution of MEMCl and 1methylpyrrolidine were introduced into precooling tubes (T1 and T2) and then into M1 by a syringe pump. The resulting solution passed through T3 (reaction time: 1 min). After a steady state was reached, the solution produced was collected in a flask filled with LiNTf2. The reaction mixture was stirred an additional 60 min. The thus-obtained solution of the ionic liquid was washed with water two times and dried under vacuum. The ionic liquid was dissolved in methanol, and a portion of activated carbon was added. The resulting mixture was stirred at room temperature for 24 h and then filtered to remove the activated carbon. Thus-obtained ILs were freezedried to remove solvent and a trace amount of water.

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ASSOCIATED CONTENT

S Supporting Information *

FT-IR spectra and 1H, 13C, and 19F NMR spectra of products. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *Tel/Fax: +81-857-31-5259. E-mail: [email protected]. jp. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge financial support from the Center for Research on Green Sustainable Chemistry (GSC), Tottori University from the MEXT. T.N. thanks the Tottori Prefecture Promotion Program for the Environmental Study of Art and Science and the Kyoto Technoscience Center for financial support. The authors thank Professor Hiroki Sakaguchi and Professor Hiroyuki Usui of Tottori University for fruitful discussion.

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REFERENCES

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Synthesis of Ionic Liquids Equipped with 2-Methoxyethoxymethyl

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