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T. J. S. Schubert
important issue for achieving good results is to purify all starting materials before
the quaternization reaction is performed, as described in Sect. 8.2.1.
At lab scale (<5 kg), reactions are typically described in the literature as being
carried out in glass flasks equipped with a reflux condenser. To achieve the best
results, it is beneficial to use the Schlenk technique to exclude oxygen and moisture
as much as possible because N-heterocycles have the tendency to form colored side
products in the presence of oxygen.
Less often, quaternization reactions are performed in autoclaves, though the
advantages of this type of technique are generally underestimated. The reaction rates
and purity are typically much higher because there is a reduced tendency for side
reactions to occur.
At commercial scale (>5 kg), three different reaction setups are feasible.
The first setup uses larger reflux reactors (up to 100 L reaction volume), operated
at atmospheric pressure for reactions having a sufficient reaction rate. Consider the
alkylation of 1-methylimidazole with 1-bromobutane. It takes approximately 10 h
at 40 °C for completion of the reaction, while it takes three weeks at 55 °C for the
higher homologue 1-chlorobutane. Because of this long reaction time, the latter case
is better performed under pressure using an autoclave, leading to higher reaction
rates.
The second setup uses larger autoclaves. While lab autoclaves can typically be
operated up to pressures of 200 bar, at a larger scale of 1 metric ton, 10 bar is the
upper pressure limit. The scale-up of reactions performed in autoclaves is not trivial.
Since some alkylation reactions often have a strong tendency to show an autocatalytic
acceleration of the reaction rate, important reaction parameters must be determined,
such as the temperature dependence of the reaction rate, the reaction enthalpy, and
the activation energy. By monitoring these important parameters on a smaller scale,
it is possible to scale up to a higher reaction volume.
The third setup, which so far is not well-established in organic synthesis and
generally underestimated, is the use of continuous-flow microreaction technology.
For example, an amine (including nitrogen-containing heterocycles) and an alkylating agent are continuously taken from separate reservoirs, and each is pumped at
elevated pressures (approximately 5–10 bar) into a microreactor. To achieve these
pressures, high-performance liquid chromatography (HPLC) pumps can provide the
best results. Both starting materials are mixed within a mixer having a reactionspecific, tailor-made geometry. After the mixing process, the reaction mixture has
to remain at a specific reaction temperature until the reaction is complete. In some
cases, product and starting materials may form a 2-phase system, leading to deceleration of the reaction rate. If such a 2-phase system occurs, the use of a so-called
split-and-recombine mixer often leads to good results. Take for instance, the synthesis of 1-butyl-3-methylimidazolium bromide, the use of this technique leads to
superior results if operated at elevated temperature and pressure (Fig. 8.1).
T. J. S. Schubert
important issue for achieving good results is to purify all starting materials before
the quaternization reaction is performed, as described in Sect. 8.2.1.
At lab scale (<5 kg), reactions are typically described in the literature as being
carried out in glass flasks equipped with a reflux condenser. To achieve the best
results, it is beneficial to use the Schlenk technique to exclude oxygen and moisture
as much as possible because N-heterocycles have the tendency to form colored side
products in the presence of oxygen.
Less often, quaternization reactions are performed in autoclaves, though the
advantages of this type of technique are generally underestimated. The reaction rates
and purity are typically much higher because there is a reduced tendency for side
reactions to occur.
At commercial scale (>5 kg), three different reaction setups are feasible.
The first setup uses larger reflux reactors (up to 100 L reaction volume), operated
at atmospheric pressure for reactions having a sufficient reaction rate. Consider the
alkylation of 1-methylimidazole with 1-bromobutane. It takes approximately 10 h
at 40 °C for completion of the reaction, while it takes three weeks at 55 °C for the
higher homologue 1-chlorobutane. Because of this long reaction time, the latter case
is better performed under pressure using an autoclave, leading to higher reaction
rates.
The second setup uses larger autoclaves. While lab autoclaves can typically be
operated up to pressures of 200 bar, at a larger scale of 1 metric ton, 10 bar is the
upper pressure limit. The scale-up of reactions performed in autoclaves is not trivial.
Since some alkylation reactions often have a strong tendency to show an autocatalytic
acceleration of the reaction rate, important reaction parameters must be determined,
such as the temperature dependence of the reaction rate, the reaction enthalpy, and
the activation energy. By monitoring these important parameters on a smaller scale,
it is possible to scale up to a higher reaction volume.
The third setup, which so far is not well-established in organic synthesis and
generally underestimated, is the use of continuous-flow microreaction technology.
For example, an amine (including nitrogen-containing heterocycles) and an alkylating agent are continuously taken from separate reservoirs, and each is pumped at
elevated pressures (approximately 5–10 bar) into a microreactor. To achieve these
pressures, high-performance liquid chromatography (HPLC) pumps can provide the
best results. Both starting materials are mixed within a mixer having a reactionspecific, tailor-made geometry. After the mixing process, the reaction mixture has
to remain at a specific reaction temperature until the reaction is complete. In some
cases, product and starting materials may form a 2-phase system, leading to deceleration of the reaction rate. If such a 2-phase system occurs, the use of a so-called
split-and-recombine mixer often leads to good results. Take for instance, the synthesis of 1-butyl-3-methylimidazolium bromide, the use of this technique leads to
superior results if operated at elevated temperature and pressure (Fig. 8.1).