MICROWAVE CHEMISTRY OUT OF THE LAB AND INTO PRODUCTION

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1 SYMPSIUM SERIES N. 157 EPIC 211 # 211 IChemE MICRWAVE CHEMISTRY UT F THE LAB AND INT PRDUCTIN Yvonne Wharton C-Tech Innovation Ltd, Capenhurst Technology Park, Capenhurst, Chester, CHI 6EH, UK; vvonne.wharton@ctechinnovation.com C-Tech Innovation has developed a large scale continuous flow microwave reactor that is capable of producing.1 kg of product per working day. The reactor has been trialled using a wide range of reactions that are applicable to a variety of industrial sectors and has demonstrated a significant reduction in reaction times and increase in reaction yields. Some examples of the work carried out include the reduction in reaction time of a Suzuki coupling from 2 h to 1 min with no loss of yield, and a dihydropyrimidine synthesis which gave a 2-fold increase in yield and a reduction in reaction time from 8 h to 4 min. We have also successfully carried out the synthesis of an ionic liquid which gave a reduced reaction time from 4 h to 2 min and are hoping to establish this as an easy, more economical and more environmentally friendly route into a variety of commonly used ionic liquids that can be synthesised in a similar way. The shorter reaction times and reduced downstream work up as a result of the higher yields and purity achieved have demonstrated a considerable energy saving and reduction in C 2 emissions. The microwave flow reactor allows chemistry to be scaled up directly from lab scale to plant scale without the need for time consuming and costly process development. Using a continuous flow system lowers the inventory of hazardous or unstable products and intermediates, making scale up inherently safer than using a batch process. C-Tech Innovation has demonstrated that large-scale microwave-assisted synthesis is no longer in the future; it is here today. KEYWRDS: Microwave chemistry, scale up, continuous flow, energy savings INTRDUCTIN Microwave chemistry has been known since the 198s and is now widely used in academia and industry, particularly for the synthesis of small quantities of large numbers of new compounds e.g. in the pharmaceutical industry. A review for the RSC in 25 1 summarises a number of advantages that have been found for microwave chemical synthesis:. Faster reactions - reaction rates have been observed to be 1-1 times faster than when using conventional heating. Increased yield/selectivity many reactions show an increase in yield of the desired product e.g. the esterification of stearic acid has a yield of 97% compared to 83% using conventional heating and the oxidation of cyclohexene has a yield of 26% compared to just 12% using conventional heating. Energy efficiency as microwave heating is direct, i.e. the reactants and solvent are heated directly, and the energy normally used to raise the temperature of vessels, heat exchangers etc is not required. More recent work by liver Kappe at the University of Graz 2 has shown the additional energy efficiency savings possible due to the much shorter reaction times. This initial work has shown large energy efficiency savings of up to 9%. The energy/c 2 savings gained from the increase in chemical selectivity observed in many reactions has not been quantified to date, however any improvement in yield would give at least an equivalent reduction in energy usage. The total energy saving from this source is difficult to quantify but the effect on up and downstream processes and the reduction in waste disposal is likely to be significant. CHALLENGES F SCALE UP To date microwave chemistry has been restricted in scale to the laboratory, with equipment capable of producing milligrammes or a few grammes of material. Scale up has been prevented by two major problems; size limitations of the cavity and reactor (because of using single mode cavities or because of the limited penetration depth of microwaves in most media), and finding suitable materials to cope with the required pressure and temperature while being chemically compatible with the reaction mixture and transparent to the chosen microwave frequency. Scale-up by the laboratory instrument manufacturers has reached the limits of their designs at throughputs of grammes a day. E.g. Biotage s Advancer kilobatch system uses a batch vessel of 35 ml in a multi-mode cavity; it is not possible to scale this system significantly further as the penetration depth of microwaves will not allow uniform heating of larger batch vessels. CEM s voyager system uses microbore tubing in a single mode cavity, the potential for further scale-up of this system in limited by the size of the single mode cavity and the limitations of the tubing material. C-Tech s design overcomes these two stumbling blocks. The design is a continuous flow through system using a traveling wave microwave applicator (Figure 1). 117

2 SYMPSIUM SERIES N. 157 EPIC 211 # 211 IChemE Table 1. Summary of results comparing microwave heating to conventional heating Reaction Time Temperature Yield Quartz process tube Travelling wave applicator Pressure and microwave containment Suzuki coupling 2 h 128C 92% 2 min (MW) 168C 99% 1 min (MW) 1558C 98% Dihydropyrimidine 8 h 128C 35% 4 min (MW) 1458C 71% Ionic liquid 4 h 138C 95% 1 min (MW) 28C 95% Microwave source Figure 1. Design of microwave cavity This allows the use of relatively large bore process pipework and large amounts of power can be coupled to the load using this design, allowing the use of high flow rates and hence high throughputs. Investigation by C-Tech into materials and components found that large bore (up to 4 mm ID) quartz glass tubing is inert to most chemicals, transparent to microwaves and can be obtained in grades rated to.2 bar and.258c. A unique patented design for sealing the reactor tube and containing the microwave field was developed. The use of the quartz material and the ability to connect it to the rest of the system while containing the pressure and the microwave field overcomes the second stumbling block outlined above. Microwave specification. Up to 258C. Up to 2 bar. Flow rate up to 1 L /min (equivalent to 3 sec residence time). Can process up to 1 tonne/day. Chemically resistant construction RESULTS Three reactions were initially chosen for detailed study. A Suzuki reaction, a dihydropyrimidine cyclisation and an ionic liquid synthesis.the reactions were first carried out using conventional heating methods and their yields and reaction times noted. The reaction conditions were then transferred directly to the microwave flow reactor so a direct comparison between reaction times and yields could be made. All the reactions that were trialled showed significant decreases in reaction times when carried out in the microwave flow reactor and most showed increases in yield also. The results are summarised in Table 1. The energy consumption of the reactions carried out in the flow reactor was also logged throughout the reactions and used to make comparisons with a figure supplied by Croda 3 (see Table 2) for their average energy consumption of all their batch reactions. A selection of the reactions were also carried out in a conventionally heated flow reactor and the yields, reaction times and energy consumption of these reactions was noted in order to make comparisons between conventional and microwave heating in flow reactors. The same reaction mixtures were used as above and some validation was done in order to find the optimum reaction times. The reactions carried out in this way all showed significant improvements in the microwave flow reactor over the conventionally heated flow reactor. The results are summarised in Table 3 better. The differences in energy consumption between the microwave and conventionally heated flow reactors were compared and showed the microwave to be significantly more efficient (see Table 4). These increases in energy efficiency will arise from the shorter reaction times possible in the microwave reactor because of the rapid heating that is possible and also as microwave heating is a direct heating method there are no energy losses in heating the reactor walls rather than the reaction mixture. Table 2. Comparison of energy use in microwave reactor and batch reactor Reaction Energy/kg in MW Energy efficiency Energy/kg in batch (Croda) % energy saving in MW Suzuki.381 kwh/kg 57% 3.6 kwh/kg 89% Cyclisation 3.84 kwh/kg 42% 3.6 kwh/kg Ionic liquid.382 kwh/kg 39% 3.6 kwh/kg 89% 118

3 SYMPSIUM SERIES N. 157 EPIC 211 # 211 IChemE Table 3. Summary of results comparing microwave flow reactor to conventional flow reactor Reaction Time Temperature Yield Suzuki coupling 2 min 158C 9% 2 min (MW) 168C 99% Dihydropyrimidine 24 min 138C 11% 4 min (MW) 1458C 71% Table 4. Comparison of energy use in microwave flow reactor and conventionally heated flow reactor Reaction Energy/kg in MW Energy/kg in Coflore % energy saving in MW Suzuki.381 kwh/kg kwh/kg 98% Cyclisation 3.84 kwh/kg kwh/kg 86% heating resulted in significant reductions in reaction times compared to the conventional batch process and also led to significant increases in yields. The reduced reaction times also gave a considerable reduction in energy consumption (up to 9% in some cases) and C 2 emissions. These sizable increases in yield observed when using the reactor also gave a downstream energy saving as it reduced the amount of purification required (reducing solvents required) and also decreased the amount of starting materials necessary for the reaction. Using the continuous flow approach is also much safer than the batch approach on large scale as there is a much lower inventory of hazardous materials and, as microwave heating is a direct heating method, switching the power off immediately stops the energy input into the reaction in the event of an accident. This innovation should enable the transfer of technology directly from the lab to plant without the need for a time consuming and costly process development step and will also result in considerable energy savings if implemented. DISCUSSIN We have shown it is possible to transfer reactions directly from batch reactions to continuous flow microwave reactor without any process development and obtain superior results. The Suzuki and ionic liquid synthesis reactions gave significant reductions in energy use when run in the continuous flow microwave reactor. The dihydropyrimidine cyclisation gave a comparable energy requirement to the batch reaction figure (provided by Croda) but it did give 1% increase in yield when run in the microwave reactor rather than being done in batch. This increase in yield would lead to a reduction in energy and solvents required downstream for the work up and purification and also a 1% reduction in the volume of starting materials required for the synthesis. Calculating the energy saving that would be given by this increase in yield would involve a large amount of LCA work but it seems apparent that increasing the yield of a reaction by this magnitude will lead to energy savings elsewhere in the process. So all the reactions carried out so far in the microwave flow reactor have shown significant improvement over their batch processes either in yield, reaction times or energy consumption. Making the comparison between the microwave flow reactor and the conventional flow reactor showed that the microwave heating led to much faster reaction times and better yields, probably due to the rapid heating possible with the microwave. It was also shown to be much more energy efficient as it is a direct heating method so doesn t require heating of the reactor walls. CNCLUSIN C-Tech Innovation has demonstrated that microwave chemistry can be scaled up beyond laboratory scale and has developed a continuous flow microwave reactor capable of processing up to 1 tonne per day. A range of reactions were used to test the reactor and the use of microwave EXPERIMENTAL SYNTHESIS F 4-PHENYLBENZALDEHYDE Br + B Pd/C, KAc DMF/H 2 BATCH REACTIN 4-bromobenzaldehyde (1 eq.), phenylboronic acid (1.5 eq.) and potassium acetate (2.1 eq.) were added together in N,Ndimethylformamide (3 vol) and water (1.3 vol) and degassed with nitrogen. Palladium on carbon (.4 eq.) was then added and the reaction heated to 158C. After 2 h the reaction gave a 92% conversion to product. CNTINUUS FLW MICRWAVE REACTIN The 4-bromobenzaldehyde (1 eq.), phenylboronic acid (1.5 eq.) and potassium acetate (2.1 eq.) in N,N- dimethylformamide (3 vol) and water (1.3 vol) was added to the feed vessel and heated above 48C with stirring. nce complete dissolution had occurred the palladium on carbon (.4 eq.) was added to the mixture. The reaction mixture was then pumped through the reactor at a rate of 165 ml/min (which equates to approximately 2 min residence time) and irradiated at 2.5 kw. Samples were taken every 2 minutes for analysis and showed that at temperatures above 168C the reaction had gone to 99% completion. As the reaction was run using a flow rate of 165 ml/min this equates to.29 moles/min of 4-bromobenzaldehyde. Assuming a complete conversion to product this would give 38.2 g/min of product or 2.28 kg/h. The reaction was then repeated as before but using a flow rate of 295 ml/min (which equates to approximately 1 min residence time). Analysis of the samples taken again showed.98% conversion to product. Assuming a complete conversion 119

4 SYMPSIUM SERIES N. 157 EPIC 211 # 211 IChemE power (W) temp (C) Power (W) Tem p (C) Total Power Reflected power Incident power Temperature Total Power Reflected power Incident power Temp psens Graph 1. Suzuki reaction Graph 2. Dihydropyrimidine reaction to product this would give g/min of product or 4.8 kg/h (see Graph 1). can be calculated as.381 kwh/kg based on the total power or.219 kwh/kg based on the incident power. SYNTHESIS F 3,4-DIHYDR-5-(ETHXY CARBNYL)-6-METHYL-4-PHENYL-3,4-1H- PYRIMIDIN-2-NE + + N N Yb(Tf) 3 EtH, AcH N N BATCH REACTIN Ethylacetoacetate (1 eq.), urea (1.5 eq.), benzaldehyde (1 eq.) and ytterbium(iii) trifluoromethane sulfonate (.1 eq.) were added together in acetic acid (16 vol) and IMS (5 vol). The reaction mixture was heated to 118C and after 8 h showed 35% conversion to product. CNTINUUS FLW MICRWAVE REACTIN Ethylacetoacetate (1 eq.), urea (1.5 eq.), benzaldehyde (1 eq.) and ytterbium(iii) trifluoromethane sulfonate (.1 eq.) in acetic acid (16 vol) and IMS (5 vol) were added to the feed vessel and agitated with the stirrer. The reaction mixture was then pumped through the reactor at a rate of 75 ml/min (which equates to approximately 4 min residence time) and irradiated at between 5 W and 8 W to heat the reaction mixture above 128C; samples were taken every 2 min. Analysis of the samples showed 71% conversion to product. As the reaction was run using a flow rate of 72 ml/min this equates to.28 moles/min of ethylacetoacetate. Assuming 71% conversion to product this would give 5.12 g/min of product or 37 g/h. The reaction was tried again using longer residence times and higher temperatures, but did not offer any improvement on yield (see Graph 2). can be calculated as 3.84 kwh/kg based on the total power or 1.63 kwh/kg based on the incident power. SYNTHESIS F 1-BUTYL-3-METHYLIMIDAZLIUM BRMIDE + N N Br N N + BATCH REACTIN 1-bromobutane (1 eq.) and 1-methylimidazole (1eq.) were added together and heated to 138C, after 4 h the reaction showed complete conversion to product. Power (W) Total Power Incident power Reflected power Temp psens Graph 3. Ionic liquid reaction Br Temp (C) 12

5 SYMPSIUM SERIES N. 157 EPIC 211 # 211 IChemE CNTINUUS FLW MICRWAVE REACTIN 1-bromobutane (1 eq.) and 1-methylimidazole (1 eq.) were added to the 2 feed vessels and then pumped through the reactor. The pump speeds were set to 1 ml/min for the 1-bromobutane and 74 ml/min for the 1-methylimidazole, samples were taken for analysis every 2 min. The reaction was irradiated at 1 W in order to heat the reaction to 98C, at this point the temperature climbed rapidly and the power was reduced to 3 W. With this power input the temperature climbed to 1758C, at which point the microwave power was reduced to W and the temperature climbed to 28C and remained steady for about 5 min. Analysis showed a 95% conversion to product (see Graph 3). can be calculated as.382 kwh/kg based on the total power or.149 kwh/kg based on the incident power REFERENCES 1. Developments in Microwave Chemistry, Chemistry World, April n the Energy Efficiency of Microwave-Assisted rganic Reactions, Tahseen Razzaq and C. liver Kappe, Chem- SusChem, 28, 1, Accurate figures on industrial energy usage for chemical processing are difficult to obtain, however Croda estimate that their energy use is 13 GJ/tonne or 36 kwh/tonne published figure from Croda environmental report 121