a comparative study of ultrasound-, microwave-, and microreactor-assisted imidazolium-based ionic...

DOI 10.1515/gps-2013-0086 Green Process Synth 2013; 2: 579–590

Marina Cvjetko Bubalo, Izidor Sabotin, Ivan Radoš, Joško Valentinčič, Tomislav Bosiljkov, Mladen Brnčić and Polona Žnidaršič-Plazl*

A comparative study of ultrasound-, microwave-, and microreactor-assisted imidazolium-based ionic liquid synthesis

Abstract: Synthesis of ionic liquid 1-heptyl-2,3-dimeth-ylimidazolium bromide was accomplished with the assistance of ultrasound, microwave irradiation, and a continuously operated microreactor and was compared with a conventional laboratory scale process applying magnetic stirring and water-bath heating. Results were compared with respect to process productivity, energy consumption, and product colourisation as an indica-tor of its purity. By using nonconventional technologies, volumetric productivity was 10- to 30-fold superior, while energy consumption was reduced by 45%–65%. Among the alternatives tested, ultrasound-assisted synthesis was shown as the most efficient one in terms of volumetric productivity (4.40 mol l-1 h-1) and specific power consump-tion (909.1 W h mol-1), while microwave-assisted process was the least favourable. However, only a microreactor system enabled the synthesis of a noncoloured product resulting from very efficient mixing and temperature con-trol. Due to significant process intensification along with high product quality and superior industrial perspectives, a continuous quaternisation within microchannels could be selected as the most promising green approach among the alternatives tested in this study. Integration of ultra-sound and microreactor technology including miniatur-ised heat exchanger is foreseen for process intensification.

Keywords: ionic liquids; microreactor; microwave irradia-tion; solvent-free synthesis; ultrasound.

*Corresponding author: Polona Žnidaršič-Plazl, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia, e-mail: polona.znidarsic@fkkt.uni-lj.siMarina Cvjetko Bubalo and Ivan Radoš: Faculty of Food Technology and Biotechnology, University of Zagreb, Pierottijeva 6, 10 000 Zagreb, Croatia; and Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, SloveniaIzidor Sabotin and Joško Valentinčič: Faculty of Mechanical Engineering, University of Ljubljana, Aškerčeva 6, 1000 Ljubljana, SloveniaTomislav Bosiljkov and Mladen Brnčić: Faculty of Food Technology and Biotechnology, University of Zagreb, Pierottijeva 6, 10 000 Zagreb, Croatia

1 Introduction

Application of ultrasound and microwaves, as well as micro-reactor technology, has received significant attention in the chemical and pharma industry during the last two decades [1–7]. Their common goal is to meet the needs of green chem-istry as an emerging approach to the design, manufacture, and use of chemical products in order to reduce or eliminate chemical hazards by choosing the safest and the most effi-cient way for their synthesis [8, 9]. Microwave irradiation induces dipolar polarisation and electrical conduction yield-ing rapid heating of polar materials. Among major advan-tages, reduced reaction times, effective heating, energy efficiency, ability to automate synthesis, solid-phase capabil-ity, and green chemistry could be exposed [1, 4]. On the other hand, the influence of ultrasound on a chemical reaction is attributed to the formation of cavitations, which are induced by the ultrasonic waves and whose collapse can release very high local temperatures and pressures. Enhancement in reaction rates and product yield in both heterogeneous and homogenous systems has been well documented [3, 5].

Microreactor technology exploiting microstructured devices for realisation of (bio)chemical processes was proved to enable excellent mass and heat transfer related to small dimensions and high surface-to-volume ratio facilitating more precise process control, as well as better reaction selectivity, kinetics and overall yields, minimal reagent and solvent consumption, and improved sustain-ability with reduced waste at low energy consumption as compared with conventional equipment [10, 11]. Numer-ous successful examples of implementation of this tech-nology in chemical and biochemical processes have been reported so far [2, 6, 7, 10, 11, and refs. therein]. All these new approaches are regarded as “enabling technologies” that drastically influence the way in which organic syn-thesis is being conducted [12].

During the last decade, ionic liquids (IL) were in the spotlight of the scientific and industrial community as a promising alternative to traditional organic solvents, from both environmental and technological aspects. The

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580 M. Cvjetko Bubalo et al.: Comparison of ultrasound-, microwave-, and microreactor-assisted IL synthesis

unique properties of ionic liquids, such as very low volatil-ity, nonflammability, and stability, make them suitable for use in a variety of different areas, such as organic synthe-sis and (bio)catalysis, electrochemistry, analytical chem-istry, separation technology, nanotechnology, renewable resource utilisation, and in use as functional fluids (e.g., lubricants, heat transfer fluids, corrosion inhibitors) [13].

Conventionally, the synthesis of ionic liquids via quat-ernisation of tertiary amine species is performed in stirred tanks using batch or semibatch processes. Although simple, these processes are excessively time- and energy-consuming [14]; therefore, sustainable nonconventional techniques for process intensification have been the subject of consider-able recent attention. At the beginning of this century, first reports on ionic liquids’ syntheses using microwave- and ultrasound-assisted processes were given by Namboodiri and Varma [15, 16], claiming a drastic decrease in the reac-tion time in both cases. Almost at the same time, a very effi-cient single-stage synthesis of several imidazolium-based ionic liquids with fluorinated anions using low-frequency ultrasound was described by Lévêque et al. [17]. Since then, a number of reports on successful microwave- and ultra-sound-assisted ionic liquids’ syntheses have confirmed the benefit of their application at the laboratory scale [18]. Similarly, the use of microfluidic devices for ionic liquid synthesis revealed that microreactor systems usually com-prising a micromixer and a hold-up section were advanta-geous as compared with conventional processes enabling high yields and high purity of product [14, 19–21]. This tech-nology was introduced in 2007 in industrial production of several ionic liquids (mostly halides) produced at that time in several kg/day quantities with ambitions to increase the capacity up to 1 t/a [22].

Herein, we compare various nonconventional processes for a solvent-free synthesis of ionic liquid 1-heptyl-2,3-di-methylimidazolium bromide [C7mmim][Br], which was used as a precursor for 1-heptyl-2,3-dimethylimidazolium bis(trifluoromethane)sulfonimide [C7mmim][Tf2N], recently shown to be a very promising solvent for lipase-catalysed isoamyl acetate synthesis using continuously operated min-iaturised enzymatic packed bed reactor [23]. Microwave- and ultrasound-assisted batch syntheses and processes within a continuously operated microreactor system were performed and results were compared with respect to process kinetics, energy consumption, and product colourisation as a purity indicator. To the best of our knowledge, a comparative study of the effectiveness of these alternative processes has not yet been conducted. Furthermore, the industrial scale-up perspectives for selected alternative technologies were discussed in order to evaluate the most promising green approach for ionic liquids’ synthesis.

2 Materials and methods2.1 Chemicals

All the reagents and solvents were purchased from com-mercial sources and used without further purification.

2.2 [C7mmim][Br] synthesis

2.2.1 Conventional batch process

Laboratory scale [C7mmim][Br] synthesis was performed in a round-bottom flask under reflux applying magnetic stir-ring. 1-bromoheptane (0.11 mol) was added to the stirred 1,2-dimethylimidazole (0.1 mol) and the reaction mixture of cca. 20 ml was stirred by a magnetic stirrer (RTC Basic, IKA Werke GmbH & Co. KG, Staufen, Germany) at 1000 rpm and thermostated by means of a water bath kept at 55 ± 2°C. The beginning of the reaction was set at the time the working temperature was reached, measured by a thermometer inserted through the neck of the flask. At selected time intervals, aliquots of the reaction mixture were removed from the reactor and analysed as described below.

2.2.2 Microwave-assisted batch process

A single-mode focused microwave reactor (Start S Micro-wave Labstation for Synthesis, MilestoneSrl., Sorisole, Italy) comprising a single magnetron system with rotat-ing diffuser for homogeneous microwave distribution in the cavity was used for microwave-assisted [C7mmim][Br] batch synthesis; 0.11 mol of 1-bromoheptane and 0.1 mol of 1,2-dimethylimidazole were added in a round-bottom flask under reflux, which was placed in a microwave reactor operated at 2450 MHz. Reaction conditions were as follows: time required to achieve working temperature, 2 min; bulk reaction temperature, 55 ± 1°C; average power input, 80 W; stirring by means of a magnetic stirrer at 200 min-1. Temperature measurements were performed at the reactor wall by IR sensor and a fully automated system has carried out temperature control by continuous adjust-ment of the microwave power output. At selected time intervals, the reaction was stopped and aliquots of the reaction mixture were analysed as described below.

2.2.3 Ultrasound-assisted batch process

Preliminary experiments aiming at the determination of optimal conditions for maintaining a reaction mixture

M. Cvjetko Bubalo et al.: Comparison of ultrasound-, microwave-, and microreactor-assisted IL synthesis 581

temperature at about 55°C were conducted as follows. Both reactants were placed in a glass beaker in amounts stated in the section on conventional batch synthesis. Treatment of the reaction mixture was conducted with an ultrasonic device UP 100 S with a constant frequency of 30 kHz or with UP 400 S (both Hielscher Ultrasonics GmbH, Teltow, Germany) with a constant frequency of 24 kHz, using cylindrical probe VS 70 T (dS7 = 7 mm) and by adjust-ing ultrasonic intensity in the range of 13.0–208.1 W cm-2. Reaction temperature was monitored by two digital ther-mometers set at diametrical sides of cylindrical probe at a distance of 1 cm. Reactions were conducted with or without cooling by water bath, set to 20°C.

After preliminary experiments, ultrasonic intensity of 82.0 W cm-2 and cooling with water bath set to 20°C were applied in further quaternisations. At selected time intervals, aliquots of reaction mixtures were analysed as described below.

2.2.4 Continuous process within a microreactor

Continuous synthesis was performed in a custom-made microreactor setup (Figure 1). 1,2-dimethylimidazole and 1-bromoheptane were placed in separate syringes thermo-stated at 55 ± 2°C by means of a custom-made heating system based on thermostated water circulation. High-pressure syringe pumps (Harvard Apparatus, Holliston, MA, USA) were used to continuously pump reactants in a stainless-steel, custom-designed slanted groove micromixer (SGM) [24] and further through a 1-m-long tube section made of fluorinated ethylene-propylene (FEP) with a diameter of 0.75 mm (Vici AG, Schenkon, Switzerland). Both the micro-mixer and the FEP tube section were embedded in a ther-mostated water bath, kept at 55°C. Variations in reaction time were achieved by adjusting the total flow rate of both reactants from 2.2 to 200 μl min-1, where the ratio of flow rates between 1,2-dimethylimidazole and 1-bromoheptane provided a 10% excess of the latter in the microreactor.

Reactants

Micromixer Reaction tube

Thermostatedwater bath

Product

Figure 1 Scheme of a custom-made microreactor-based setup used for [C7mmim][Br] synthesis.

After reaching a steady state, the outflow of the microflu-idic system was collected and analysed. The formation of the product was visually inspected by microscopic observa-tions of the FEP tube using an optical microscope (Reichert Inc., Depew, USA), while the micromixer was inspected by scanning electron microscopy (SEM, FEI Quanta 450 scan-ning electron microscope, Hillsboro, USA).

2.3 Fluid flow simulations and estimation of fluid properties

Fluid flow of both reactants in the SGM micromixer was described by Navier-Stokes equations in combination with a convection-diffusion model using a finite element method-based simulation program COMSOL 4.1 (COMSOL, Stockholm, Sweden). Meshing of simulated geometries was implemented by the software applying unstructured tetrahedral elements. Finer mesh adjustments were per-formed in order to obtain the required convergence at a reasonable time scale while maintaining the required accuracy. Mixing efficiency was quantified by calculat-ing the variance of the mixture in the micromixer. The viscosity and density of the reactants were measured at 55°C using thermostated Ostwald viscosimeter (The Emil Greiner Co., New York, USA) and pycnometer (Carl Stuart Co., Leek, UK), respectively. Diffusion coefficient for 1,2-dimethylimidazole in 1-bromoheptane was determined by the Wilke-Chang correlation [25].

2.4 Product analysis

The identity of the product was confirmed by 1H NMR recorded in DMSO-d6 on a Bruker AV300 (300 MHz) spec-trometer (Bruker, Rheinstetten, Germany) at Ruđer Bošković Institute (Zagreb, Croatia). Chemical shifts were expressed in ppm values using TMS as an internal standard; the chem-ical shifts of the product were as follows: δH 0.86–0.88 (t, 3

H, CH3), 1.29 (s, 6 H, CH2), 1.67–1.71 (m, 4 H, CH2), 2.54 (s, H, CH3), 3.74 (s, 3 H, N-CH3), 4.07–4.10 (t, 2 H, N-CH2), 7.62 (s, 1 H, H-5), 7.62 (s, 1 H, H-4), and 9.15 (s, 1 H, H-2).

Product concentration was determined by the Volhard titration method based on the determination of Br- concentration in the reaction mixture [26]. The reac-tion mixture was dissolved in ethanol, followed by the addition of aqueous solutions of 0.1 mol l-1 AgNO3, 0.2 mol l-1 NH4Fe(SO4)2, and 3.2 mol l-1 HNO3, giving a white suspen-sion. NH4SCN aqueous solution (0.035 mol l-1) was used to titrate the above suspension until red Fe(SCN)3 precipitate was formed. Product [C7mmim][Br] concentration was determined from the titration volume of NH4SCN. Volu-metric productivities for batch processes were calculated from the maximal product concentration and the time nec-essary to achieve it, while for a continuous process within a microreactor, volumetric productivity was calculated as the ratio of maximal product concentration at the outlet of the reactor and the corresponding residence time [27].

2.5 Electric energy consumption measurements

The electric energy consumption of the appliances used in the experiments (microwave reactor, ultrasonic reactor, syringe pumps, magnetic stirrers, and water baths) was measured by an electric energy consumption meter (REV Ritter GmbH, Hamburg, Germany) placed between the power source and the appliance. Specific energy con-sumption was calculated from the amount of electric energy (W h) consumed by all appliances used for the indi-vidual experiment setup during the synthesis of 1 mol of [C7mmim][Br].

3 Results and discussion

3.1 Determination of process parameters

Quaternisation of 1,2-dimethylimidazole with 1-bromohep-tane using conventional batch, microwave- and ultrasound-assisted processes, as well as a continuous process within a microreactor system was preformed in a solvent-free mode, which is more efficient and environmentally benign as compared with the reaction in organic solvent [20].

Although quaternisation reactions are usually carried out at higher temperatures, ranging from 70°C to 90°C [14, 28], a temperature of 55°C was used in our case in order to ensure process safety concerning the flash point of the

reactant 1-bromoheptane, which is 60°C [29]. Lower tem-peratures were not considered because previous studies confirmed that quaternisation is an endothermic reaction, strongly enhanced by an increase in temperature [30]. A constant reaction temperature of bulk liquid in quater-nisation performed by the assistance of microwave irra-diation was maintained by regulation based on real-time IR-based measurement and on software-based simultane-ous adjustment of irradiation power.

Within a microreactor system, a constant reaction temperature was ensured by embedding the system in a thermostated water bath. However, when the reaction was conducted by using ultrasound, we first had to evaluate the influence of ultrasonic intensity on the temperature of the reaction mixture with the aim to ensure a nearly con-stant operating temperature of 55°C. As expected, tem-perature was highly influenced by the applied ultrasonic intensity (Figure 2). When the mixture was not externally cooled by water bath, even at low ultrasonic intensities (13.0–45.5 W cm-2), it was not possible to maintain a con-stant reaction temperature at any value due to continuous delivery of the thermal energy (Figure 2A). When placing the ultrasound-treated reaction vessel in a cooling water bath (20°C), gradual temperature increase was observed until reaching a constant value, proportional to the ultrasonic intensity used (Figure 2B). During continuous ultrasound treatment providing an ultrasonic intensity of 182.0 W cm-2 and external cooling, the bulk liquid tem-perature of about 55°C could be maintained; thus, these conditions were used for further studies. A periodic ultra-sonic treatment with intercalated pauses (c = 30%–70%) was also tested (data not shown), where, during resting periods, product settling in the form of a very viscous liquid was observed, causing significant problems with mixing of the reaction mixture, so this approach was not considered for further investigation.

3.2 [C7mmim][Br] synthesis

A time course of batch quaternisation processes, per-formed either by conventional water bath heating (WB), microwave irradiation (MW), or ultrasound assistance (US), is shown in Figure 3A, while product yield based on its concentration at the exit of the microreactor system fed with reactants at various flow rates, yielding differ-ent residence times, is shown in Figure 3B. The maximal yield of about 66% was established in all tested systems, although some authors investigating the synthesis of ionic liquids suggested that chemical equilibrium of qua-ternisation reactions could be beneficially affected by the

application of microwave irradiation or ultrasound [15, 16, 30]. However, significant differences in reaction rate among the processes were noticed as a consequence of differences in mass and heat transfer efficiency. The time required to achieve maximum reaction yield was about 18 h for the conventional water bath heating system, while only 2 h was needed for microwave-assisted synthesis. This might be related to better heat transfer in a micro-wave-assisted reactor, where up to 85 times more efficient heating was reported when comparing various chemical transformations performed in sealed vessels applying microwaves with reactions in conventional batch reactors with reflux, resulting also in shorter reaction time [31].

However, the best performance was observed for ultrasound-assisted synthesis, where maximal yield was reached in 40 min (Figure 3A), which corresponds to the

00 5 10

208.1 W cm-2

156.0 W cm-2

45.5 W cm-2

182.5 W cm-2

104.0 W cm-2

26.0 W cm-2

65.0 W cm-2

15Time (min)

45.5 W cm-2

12.0 W cm-2

26.0 W cm-2

0 5 10 15

Time (min)

Figure 2 Temperature profiles of bulk reaction mixtures during synthesis of [C7mmim][Br] at various ultrasonic intensities stated in legends: (A) without external cooling and (B) with external cooling by means of a water bath set to 20°C. Initial conditions: 0.1 mol of 1,2-dimethylimidazole and 0.11 mol of 1-bromoheptane.

00 1 2 3 4 5

Residence time (h)

WBMWUS

0 5 10 15 20 25

Reaction time (h)

Figure 3 Synthesis of [C7mmim][Br]: (A) Time courses of batch processes using different heating systems: WB, thermostated water bath; MW, microwave irradiation; US, ultrasonication. (B) Product yield at the exit of the microchannel at total flow rates ranging from 2.2 to 220 μl min-1. Initial or inlet conditions: 1,2-dimethylimidazole and 10% excess of 1-bromoheptane; 55°C. Data are expressed as mean values with indicated standard deviations.

performance increase of a factor of 30 as compared with conventional water bath heating system. In the latter, heat transfer through the relatively low specific surface area between reactor walls and water bath, as well as mixing within the reactor by means of magnetic stirring, evi-dently limited the reaction rate. As reported by Hartman et al. [32], a comparison of the surface area per reactor volume for a typical microreactor and a round-bottom flask revealed at least two orders of magnitude greater surface area for microreactors, corresponding also to two orders of magnitude improvements in performance of mass transfer limited reactions.

In a continuously operated microreactor system, resi-dence time necessary to achieve maximum yield was about 2 h, as evident from Figure 3B. A huge increase in the reac-tion rate could be attributed to the very efficient mixing,

obtained within a custom-made micromixer, presented in Figure 4A. Numerical simulations of fluid flow dynam-ics of both reactants at the total flow rate of 7.36 μl min-1, presented in Figure 4B, revealed 87% of mixing efficiency after only six SGM grooves. The following fluid properties based on measurements at 55°C were used in the simula-tions: density of 1007.4 kg m-3 and viscosity of 1.92 mPas for 1,2-dimethylimidazole and density of 1113.6 kg m-3 and viscosity of 0.65 mPas for 1-bromoheptane. The diffusion coefficient for 1,2-dimethylimidazole in 1-bromoheptane, determined by Wilke-Chang correlation [25], was 2.7 × 10-9 m2 s-1. Along with evidently efficient mass transfer within a miniaturised mixer, a very efficient heat transfer in both sections of a microreactor system, namely, a micromixer and a FEP microtube, could be anticipated from previous studies on heat transport within microfluidic systems [10, 32, 33].

Conventional and microwave-assisted batch synthe-ses in laboratory scale reactors resulted in sedimentation of a more viscous hydrophobic product [C7mmim][Br], which formed a separate phase from hydrophilic reactant 1-bromoheptane, whereby amphiphilic imidazolium reac-tant was distributed between the two phases. The forma-tion of a viscous product lowered the mixing efficiency in batch reactors with magnetic stirring, namely, a microwave reactor and a round-bottom flask under reflux with con-ventional water bath heating, which negatively affected the reaction rate. However, the microwave-assisted process was evidently faster than the conventional one (Figure 3A), which was a consequence of far more efficient heating by ionic conduction mechanism.

In a microreactor system, the formation of hydro-phobic product, separated from the hydrophilic phase with 1-bromoheptane, was visually monitored in the FEP holding section. As shown in Figure 5, initially formed small droplets of [C7mmim][Br] tended to merge into larger

Figure 4 SGM used in the microreactor setup. (A) A SEM image of the micromixer and (B) a numerical simulation of mixing for the applied micromixer. Red and blue represent each of the reactants. A colour table defines mixing index values, where green corresponds to optimal mixing with a mass fraction of 0.5.

I=100 mm, τ=6 min

I=500 mm, τ=30 min

I=900 mm, τ=54 min

Figure 5 Slug flow behaviour of a two-phase system at various dis-tances (l) from the beginning of a FEP hold-up section and thereby at various residence times (τ) of a continuous [C7mmim][Br] synthe-sis within a microreactor system at a total flow rate of 7.36 μl min-1. Experimental conditions: 1,2-dimethylimidazole and 10% excess of 1-bromoheptane; 55°C.

ones, which were also much more viscous as compared with reactants. A significant increase in the amount of product within the FEP tube at increasing distances from the beginning of a holding section and, thereby, longer residence times were observed. Despite the internal mixing within Taylor droplets, the relatively low liquid-liquid interfacial area of the formed slug flow as compared with bubbly or droplet flow described in the literature [34] most likely prevent higher efficiency of this process.

On the other hand, the best efficiency of an ultrasound-assisted process might be attributed to the formation of an emulsion, presumably formed due to the disintegration of droplets of viscous product containing imidazolium reac-tant within the main phase of 1-bromoheptane, leading

to an extremely high interfacial area for the reaction and shorter diffusion paths. Furthermore, the formation of localised “hot spots” in an elastic liquid caused by cavi-tation in this process also increased reaction yield [14]. The very high efficiency of an ultrasound-assisted process compared with other techniques is evident also from the comparison of volumetric productivities of all processes, presented in Figure 6A.

3.3 Energy consumption

Besides productivity, low energy input in the process is another important issue to consider when estimat-ing the greenness of a certain synthetic procedure [8].

ity (m

WB MW US MR

WB MW US MR0

Figure 6 Comparison of [C7mmim][Br] synthesis performed by different techniques: (A) volumetric productivities and (B) specific power consumptions. Experimental conditions were the same as described in Figure 3. Abbreviations denominate processes performed by the application of: WB, conventional batch reactor with reflux thermostated by means of a water bath; MW, microwave irradiation; US, ultrasonication; MR, a microreactor.

In order to estimate the overall energy consumption of each technology tested in this study, the average electric power consumption of the appliances used in the experi-ments was monitored and corresponding specific power consumption values were calculated. As evident from Figure 6B, specific power consumption was reduced by approximately 45%–65% in nonconventional processes as compared with the conventional one. Furthermore, the application of ultrasound resulted in the most energy-efficient process among those tested. From a very sim-plistic standpoint, large energy savings in all alternative processes tested resulted from shorter processing times, as already demonstrated for laboratory-scale microwave-assisted ionic liquid syntheses [15, 35].

It should be mentioned that 90% of overall energy consumed within the microreactor system was used for heating of thermostated water bath, so its replacement with more efficient temperature control system would significantly reduce overall electric energy consumption. Reports on successful approach to energy savings in ionic liquids’ synthesis performed within microreactors include the study performed by Groβe Böwing and Jess [36], who proposed the use of a loop microreactor, where external recycle stream was cooled by a heat exchanger. Thereby, the runaway reactions were prevented, while tempera-ture could be simply regulated by varying recycle ratio. Furthermore, a microwave-assisted microreactor process-ing of 1-methyl-3-hexylimidazolium bromide synthesis was introduced by Minrath et al. [37], which resulted in very efficient temperature control and a huge process intensification.

3.4 Product colourisation

Although ionic liquid’s colour does not represent an infallible criterion of its purity, it is understandable that colourless products are more suitable for further use, especially for specific applications such as spectroscopy, electrochemistry, and catalysis [17]. The chemical entities of coloured matter have not yet been fully clarified, but several authors agreed that they are high-molecular and hydrophobic compounds present in ppb concentrations, formed as a result of decomposition or polymerisation of imidazolium species at temperatures above 100°C [20]. Löb et al. [38] have demonstrated that during quaterni-sation in the laboratory scale batch vessel, local mixture temperature could raise up to 150°C, forming so-called hot spots, resulting in product colourisation. On the con-trary, reactions performed within microfluidic devices enabling a temperature rise only in the range of 5°C–10°C

delivered an almost colourless product [38]. Furthermore, process intensification and very high throughput were accomplished by using microstructured heat exchanger [38]. The importance of removing heat released during ionic liquid synthesis in order to ensure isothermal con-ditions and, thus, high product purity was stated also in other studies [20, 39]. This is especially vital for quaterni-sations performed in a solvent-free mode, as was the case in this study, because “absorption” of excess energy by organic solvents is not possible. It should be noted that with our experimental setup, it was not possible to detect local overheating.

In all batch processes performed in this work, reac-tion mixtures slowly turned orange over the reaction time, while the product obtained in the microstructured device was almost colourless, as evident from Figure 7, which is in accordance with previously stated reports on microre-actor-based ionic liquid syntheses [37, 38]. This might be attributed to effective mixing and excellent heat transfer within the micromixer and the following reaction tube of a submillimeter diameter, demonstrated also in previous studies [24, 33].

On the other hand, colourisation of product observed in the microwave-assisted and conventional heated reac-tors is related to previously discussed insufficient mixing of a formed two-phase system, leading also to ineffec-tive heat removal. However, the most intense colourisa-tion of a product was observed with ultrasound-assisted [C7mmim][Br] synthesis, which might be attributed not only to localised high temperatures caused by exothermic reaction but also to high molecular kinetic energy gener-ated by transient cavitation. As reported in the literature, ultrasound can generate localised temperatures of up to 4500°C, related also to increased local pressures up to 50 MPa [35]. Strong colourisation of imidazolium ionic

Figure 7 Products of [C7mmim][Br] syntheses obtained by various processes after reaching equilibrium product concentration. Pro-cesses were performed and denominated as stated in Figures 3 and 6, respectively.

liquid prepared under ultrasound treatment was also reported by Oxley et al. [40], where a large number of by-products were detected by gas chromatography.

3.5 Industrial scale perspectives

In order to adequately compare technologies for the syn-thesis of the ionic liquids presented in this study, indus-trial application perspectives for each process should be considered. Generally, process productivity, product purity, savings in energy or raw material, capital invest-ment and operational costs, process safety, and environ-mental balance should be considered when designing an industrial process [14, 41].

One of the obstacles for industrial application of microwave- or ultrasound-assisted batch processes is related to by-product formation, which most likely occurred due to local overheating of the reaction mixture even in small reaction volumes (approx. 20 ml) used in this study. The spatial control over process parameters throughout enlarged reaction chambers would be even reduced, leading to less pure product. Although it seems that colourisation could not be the key parameter for esti-mating process efficiency, several authors reported that colour, once present in the ionic liquid, must be removed with unfavourable cost- and time-intensive procedures [42, 43]. It has been demonstrated that only application of distillation, a slow and energy-consuming process, yielded spectroscopically pure ionic liquid [44]. Another widely discussed cheaper decolourisation procedure uti-lises activated carbon or decolourising charcoal; however, Earle et al. [43] showed that this procedure was not com-pletely effective for the majority of synthesised ionic liquids.

Other disadvantages of the implementation of ultra-sound- or microwave- assisted technologies in large-scale syntheses in general include the lack of quantitative data on energy efficiency, apparatus costs, as well as inability to incorporate in situ reaction monitoring [14]. As for the ultrasound-assisted process, reactor design for large-scale industrial applications has not yet been demonstrated.

Scaling up the ultrasonic and microwave-assisted technology would also necessitate the implementation of bigger and costly energy sources, leading to a sig-nificant increase in energy consumption of the whole system. The energy efficiency of microwave-assisted technology was shown to severely drop upon increas-ing the scale and became much more comparable with conventional heating, so Sadler et al. [1] have concluded

that microwaves could be regarded as green form of heating only on the smaller scale. Morschhäuser et al. [4] have recently claimed that batch microwave tech-nology will not be able to deliver industrially relevant product quantities in an economically viable way. In addition, it was established that rapid heating and cooling profiles obtained on a small scale could not be transferred to a larger scale, so conditions responsible for the fast kinetics in typical small-scale microwave reactor can generally not be mimicked on scales leading to prolonged reaction and overall processing times [4]. Low penetration of microwaves in batch vessels above 3 l was declared to limit scale-up of microwave-assisted processes [12]. As a consequence of the apparent limita-tions of large-scale batch microwave processing, recent efforts have focused on performing microwave chemis-try under continuous flow conditions [4].

The strengths of the microreactor technology pre-sented also in this study (high productivity, low energy consumption, and production of colourless product), together with the possibility of process unit number-ing up, eliminating costly and problematic transfer from small-scale reactions to the full production scale, make this approach very interesting in terms of industrial appli-cation. A report on microreactor-assisted production of > 99% pure 1-butyl- 3-methylimidazolium bromide in a quantity of 9.3 kg/day definitely supports this statement [19]. Therefore, one of the aims of the presented microre-actor system design was to realise micromixer unit on a planar surface, which enables simple parallel (vertical) integration of monomer units. Besides, the planar nature of the micromixer simplified the production process chain especially regarding sealing, where precise positioning of the lid with respect to the functional microstructures was avoided. Microinjection moulding compatible with the micromixer design presented was identified as suitable manufacturing process for mass production. Furthermore, numbering up of low-cost microreactors within the same water bath with 20 l volume would severely reduce the specific energy consumption. A comparative estimation of capital and operating costs for several batch processes of pharma industry with potential microreactor-based continuous alternatives, performed by Roberge et al. [41], revealed that no significant difference could be expected regarding capital expenditure, while anticipated operat-ing costs would be severely reduced due to better pro-ductivity and product purity, reduced labour, and high automation.

Among perspective alternatives, the combination of the advantages of microreactor technology and ultrason-ics should be considered besides previously discussed

microwave-assisted microreactor processing. As already shown, ultrasonic energy could be introduced indi-rectly into microstructured devices through pressurised water as transfer medium [45]. We suppose that appli-cation of ultrasound-assisted microreactor processing in the process studied in this work would ensure a very high interfacial area for the reaction by disintegration of Taylor droplets of viscous product containing imidazo-lium reactant within the main phase of 1-bromoheptane. This approach was already successfully demonstrated by Hübner et al. [45] for hydrolysis of p-nitrophenylacetate. However, prevention of acoustic cavitation occurrence should be considered.

4 ConclusionsUltrasound-, microwave-, and microreactor-assisted labo-ratory scale [C7mmim][Br] syntheses were shown to be more rapid and energy efficient when compared with con-ventional process performed in round-bottom flask under reflux applying magnetic stirring and a thermostated water bath. Although ultrasound-assisted [C7mmim][Br] synthesis resulted in the fastest achievement of equilib-rium product concentration and the lowest specific energy consumption within the tested equipment, the product of high purity could be prepared only by the application of a microreactor system. This suggested that in all the other tested systems, it was not possible to avoid by-product for-mation, which resulted from overheating of reaction mix-tures despite the small reaction volumes used. Obviously, the application of microstructured devices enabled very efficient process control, based on very effective heat and mass transfer. Continuously operated process in a micro-reactor system also offers the possibility of numbering up without the need for process reoptimisation, so it was found to be the most promising technique among alter-natives tested in this study for large-scale ionic liquids’ production.

Acknowledgements: This work was supported through grants provided by the Ministry of Education, Science, and Sport of the Republic of Slovenia (Grant Nos. P2-0191, P2-0248, and 1000-08-310-126), the Ministry of Science, Education, and Sports of the Republic of Croatia (Grant No. 0582261-2256), and through Grant 03.01/66 from the Croatian Science Foundation. P. Žnidaršič-Plazl was partly financed through the BIOINTENSE project of the European Union 7th Framework Programme (Grant Agreement No. 312148) and I. Radoš was supported through an Erasmus

Mundus scholarship, provided by the European Commis-sion. The authors are thankful to Prof. J. Vorkapić-Furač from the University of Zagreb (FFTB) and to Prof. Junkar from the University of Ljubljana (FME) for their support. The authors thank Dr. A. Pohar, Dr. G. Stojkovič, and K.

Birtič from the University of Ljubljana (FCCT) for their gen-erous help during the experiment setup.

Received September 19, 2013; accepted November 1, 2013

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Marina Cvjetko Bubalo has been a teaching assistant at the Faculty of Food Technology and Biotechnology at the University of Zagreb since 2008. She received her diploma in biochemical engineering (2007) and her doctoral degree in biotechnology and bioprocess engineering (2012) from the same faculty. She finished a postgradu-ate training at the Faculty of Chemistry and Chemical Technology at the University of Ljubljana in the area of biochemical engineering, with emphasis on the synthesis of ionic liquids within microchan-nels and the use of these liquids as solvents for lipase-catalysed. Her current research interests are the preparation, application, and toxicity of ionic liquids and natural deep eutectic solvents.

Izidor Sabotin is a PhD student at the Faculty of Mechanical Engineering at the University of Ljubljana. He received his diploma degree in electrical engineering (2008) at the Faculty of Electri-cal Engineering at the University of Ljubljana. His main research interest is in microengineering technologies and development of microreactor systems for (bio)chemical synthesis.

Ivan Radoš received his master’s degree in bioprocess engineering from the Faculty of Food Technology and Biotechnology, University of Zagreb. He participated in this research through his graduate training in area of ionic liquid synthesis within microchannels under the supervision of Prof. Polona Žnidaršič-Plazl. Currently, he is working in the pharmaceutical industry as a Regulatory Affairs Specialist.

Joško Valentinčič obtained his PhD in 2003 at the University of Lju-bljana, Faculty of Mechanical Engineering. Since 2008, he has been working as an assistant professor and researcher at the Faculty of Mechanical Engineering. His current research is focused on micro-engineering technologies and development of microreactor systems for (bio)chemical synthesis.

Tomislav Bosiljkov defended his PhD (biotechnical sciences) at the Faculty of Food Technology and Biotechnology at the University of Zagreb. The main activity during and after his PhD, as well as postdoctoral investigation, is in the field of food technology (engi-neering). His research activities are in the field of high-intensity ultrasound with particular focus on preparation of emulsion and milk homogenisation processes. His current researches are based on high-pressure processing of food materials. He is also involved in the application of mathematical modelling and statistical tech-niques in good technology (e.g., mixing, drying, extraction, distilla-tion, filtration, extrusion).

Mladen Brnčić is an associate professor at the Faculty of Food Tech-nology and Biotechnology, Zagreb, Croatia. He received his PhD in food engineering at Zagreb’s University in 2006. He is working on novel food and environmental processing technologies, mostly ultrasound applications for enhanced extraction, drying, homog-enisation, and emulsification of raw materials and foodstuffs. He is a member of several European societies. Currently, Prof. Brnčić is holding positions of deputy head of the Department of Process Engi-neering and head of the Laboratory of Thermodynamics within the Faculty of Food Technology and Biotechnology. Prof. Brnčić is the coordinator of numerous projects in the area of ultrasound intensifi-cation processing and is also part of several international projects.

Polona Žnidaršič-Plazl graduated with a degree in chemical engi-neering at the University of Ljubljana, where she also obtained her master’s degree in biochemistry and her PhD in chemical engineering. Since 1989, she has been employed at the Faculty of Chemistry and Chemical Technology of the University of Ljubljana, Slovenia, where she currently works as an associate professor. Her major research interests are biotransformations, the application of microreactor technology in biotechnology, and microbial produc-tion of enzymes. She is a member of the Scientific Committee of the Section on Applied Biocatalysis of the European Federation of Biotechnology and of the Editorial Board of the journal Chemical and Biochemical Engineering Quarterly.

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