Early Reactions in Scheme are the Best Targets
When attempting to improve the early reactions in a reaction sequence, it is more difficult to make changes that have a major effect on the overall cost. The reason for this is that improvements in yield only reduce the cost of inputs for the reaction you are working on and any others that precede it in the scheme. If few reactions precede the one you are working on, then there are few inputs whose costs can be caused to decline.
For throughput, it is a different story. The biggest improvements in throughput occur for reactions that are required to convert the most kilograms. These reactions occur at the beginning of the reaction scheme where the same reaction must be repeated more frequently to amass the required intermediate amounts. Therefore, for the initial reactions in a reaction scheme, the emphasis most beneficially go towards increasing throughput.
Increases in throughput for reactions closer to the final product do not improve cost by much. Furthermore, they increase risk by committing more expensive intermediates to every single run. They also build up expensive product in inventory increasing the company’s carrying costs.
Safest Targets
The safest way to increase throughput without any risk to yield is to operate at a scale where at the point of maximum volume in the procedure, the plant reactor you are provided is at its maximum volume. That is— use every litre of the reactor’s volume consistent with the procedure. Getting more substrate into a reactor can also be achieved by distilling reaction solvent after the reaction’s quench to reduce the total reactor volume at the point of maximum volume.
Other ways to increase throughput that would need to be tested to see if they might not appreciably reduce overall reaction yield are:
- Decrease the solvent/substrate ratio
- Drive the reaction to completion by distilling the reaction solvent to concentrate reactants
- Operate at a higher reaction temperature to decrease the reaction time
- Find a reaction catalyst to reduce the reaction time
Decreasing the Solvent/Substrate Ratio
First a word of caution. The ratio of solvent to substrate affects more than the environment of the transition state. Increasing the concentrations often increases the reaction rate and this very often brings with it increased exothermicity. The cooling capacity of the reactor must be able to handle the increase.
Decreasing the solvent/substrate ratio to increase throughput needs to be tested in aggressive steps in the laboratory. In the laboratory, the available ratios of flask surface area to flask volume are very much higher than in the pilot plant. Since the effectiveness of an external cooling bath is proportional to this ratio (because the cooling is delivered through the walls of the vessel) increasing the cooling to maintain the previously established internal reaction will be easier in the laboratory when lower solvent/substrate ratios are tested. Since a significant increase in throughput is being sought, a 20% reduction in the solvent seems like a good starting point for a reaction where the original solvent/substrate ratio is about 20/1. That would be a ratio of 16/1.
Driving the Reaction to Completion by Distilling the Reaction Solvent to concentrate Reactants
This is a strategy that I have never seen demonstrated yet it is theoretically sound. A bimolecular reaction proceeds rapidly at the beginning when the concentrations of both reactants are relatively high but then slows as these concentrations are reduced by consumption to give the product(s). The most reaction time is passed during this terminal stage while the experimentalists wait for the final portions of starting materials to react. If the reaction period is significantly longer compared with the overall processing time for the step it presents an opportunity to increase throughput meaningfully by reducing the reaction time.
If the reaction temperature is the reflux temperature of the reaction solvent, it makes the process easiest to manage. When the reaction slows down solvent is distilled out of the reactor at the reflux temperature which is also the desired reaction temperature. As the overall volume inside the reactor is reduced by the distillation, the reaction rate increases because of the effective concentrations in the reactor increase. The overall reaction time to completion is shortened and with it to some degree the overall cycle time.
When the reaction temperature is below the boiling point of the solvent the same thing can be achieved by reducing the pressure in the reactor with a vacuum pump to the point where the distillation point of the reaction solvent becomes the reaction temperature. Then distillation at this reduced pressure drives the reaction to more rapid completion as in the simpler previous situation.
Operating at a Higher Reaction Temperature to decrease the reaction time
Raising a reaction’s temperature by 20C degrees will increase the rate of reaction by a factor of 2 according to a rule of thumb used by chemists. The long drawn-out reaction time during which the last portions of the reactants are converted can be accelerated by ramping up the reactor temperature towards the end to consume the last bits of the reactants. This would improve the throughput by reducing the reaction phase. Raising the final temperature could cause problems, however. Utilizing a higher reaction temperature than necessary can often give rise to byproducts that will contaminate a desired product. If the reaction that the experimenter is trying to conduct is an equilibrium reaction, the higher temperature could even drive the reaction back towards more starting materials and less product. The actual outcome can only be determined by experiments. Nevertheless, increasing the reaction temperature to finish a reaction can work and if it is a long reaction time that is being shortened, it can significantly improve cycle time.
Find a Reaction Catalyst to reduce the reaction time
This last idea is the most radical and the least specific. Still, it is often overlooked. Using topic searching in a chemical database, a modern chemist can quickly determine whether there is any catalyst known for widely-used name reactions. This literature searching is properly done at the stage of route scouting but it might be overlooked and can be reconsidered here. A catalyst by definition is used non-stoichiometric amounts because it is recycled back into the transition state. It should accelerate a reaction without any further change of conditions. So long as the catalyst is reasonably priced it should not add appreciably to the costs.
KiloMentor has written elsewhere about methods to decrease cycle time by making changes in the non-reaction portions of the reaction process step.
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