Ionic liquids
Figure 4: Production of ionic liquids. (FIGURE COURTESY OF SAFC)
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Precise control of the reaction temperature.
The production of certain ionic liquids in high purity is a special challenge. The reaction between imidazole derivatives
and sulfonates is extremely exothermic (see Figure 4). Conventional batch-synthesis procedures fail to yield products with
purities higher than about 96%. Even with very slow dosing times and careful cooling, batch reactors are heated by the reaction.
Investigations at Sigma Aldrich (Buchs, St. Gallen, Switzerland) showed that severe brown impurities are formed if the temperature
rises above 20 °C in any part of the batch reactor, which leads to a miscolored product. Subsequent purification is troublesome
and can only be achieved with huge efforts. Microreactors provide an ideal way out of this dilemma. Their superior heat-exchange
capabilities make it possible to carry out the synthesis with neat reagents at an external cooling of only –3 °C. Under these
conditions, the temperature inside the microreactor in the reaction zone is kept at a constant value of 8 °C, thus allowing
ionic liquids to be produced with a purity exceeding 99% with only traces of undesired materials. Because neat reagents can
be used without any solvent, the output of this procedure is very high.
There is much discussion whether ionic liquids can generally be called "green." Although the answer to this question may be
debated, it is quite obvious that the production of ionic liquids in a microreactor is as green as chemical synthesis can
be. All reagents are quantitatively converted into the final product. No solvents are needed for the synthesis or purification.
Absolutely no waste is generated.
Ring closure in synthesizing exomethylenecyclopentane
Figure 5: Production of exomethylenecyclopentane in a microreactor. DIBAH is diisobutylaluminium hydride. (FIGURE COURTESY
OF SAFC)
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Complete suppression of side reactions.
The cyclization of 1,5-hexadiene to exomethylenecyclopentane poses multiple challenges. The batch reaction affords an inseparable
mixture of the endo- and exo- cyclization product (see Figure 5). The desired kinetically favored product isomerizes under reaction conditions
in the presence of the catalyst. Separation of the two isomers is difficult because both have virtually the same boiling point.
In addition, the transition-metal catalyst used for this transformation requires a minimum working temperature of 55 °C. At
this temperature, the starting material evaporates.
Microreactor technology solved all these problems. By inserting a simple pressure valve into the product channel, the reaction
was performed at an elevated pressure of 2 bar. This higher pressure raised the boiling point of the reactant sufficiently
to 58 °C, a perfect working temperature for the catalyst, and the reaction proceeded without gas formation. Isomerization
of the desired product was completely suppressed, and a highly pure product (> 99%) was formed at a multikilogram scale.
Staudinger hydration
Figure 6: Two-stage microreactor assembly for the safe production and immediate conversion of organic azides. (FIGURE COURTESY
OF SAFC)
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Efficient phase-transfer catalysis, safe and scale-independent handling of explosive intermediates in small hold-up volumes
with instant conversion.
Organic azides are high-energy compounds. Substrates with multiple azide moieties and low-carbon content are potentially explosive.
For example, the azide intermediate shown in Figure 6 has a potential energy of 3.8 kJ/g at 114 °C, as measured by differential
scanning calorimetry.
A two-stage microreactor with a continuous-flow system allows for the safe handling of organic azides in small hold-up volumes
with immediate conversion in the second microreactor. In the first microreactor, the azide intermediate is formed by nucleophilic
substitution. The azide intermediate undergoes Staudinger hydration with triphenylphosphine in a subsequent second microreactor.
Notably, it is possible to work with biphasic systems in microreactors. A phase-transfer catalyst moderates the initial reaction
with efficient mixing by the microreactor.
Production capacity of o-xylylenediamine in two subsequent glass microreactors exceeds 1 kg/day with an overall yield of 60%. The work-up and isolation
of the potentially hazardous intermediate is completely avoided between reaction steps, thereby saving time and money while
offering the utmost scale-independent safety level.
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