So I’ve been working out a process for the last few days. Among other things the compound is a ketal and it’s synthesis is pretty simple. Ketone and diol brew in a pot of refluxing hydrocarbon and through the magic of equilibration, the water and hydrocarbon vapors condense and phase separate in a Dean-Stark apparatus. The water phase drops to the bottom of a graduated collector and the progress of the reaction is monitored by watching the water volume accumulate. 

This reaction is straight forward enough that I can easily make up the procedure myself. So I calculated a favorite weight percentage for concentration and pitched in the reagents. I chose a few of my favorite acid catalysts as well for a series of trial runs. Everybody knows that these reactions run faster with an acid catalyst. Such mechanisms are used to torment sophomore organic students everywhere.

After satisfactory completion with a few catalysts, I decided to round out my table of data with a run without catalyst. What better way to show the critical nature of the catalyst than to run a blank?

As luck would have it, the reaction ran splendidly without added catalyst. In fact, there was precious little increase in yield over the test interval with added catalyst.  Even better, without the catalyst the color of the reaction mixture was lighter (the substrate is a little sensitive).

So I took the carbonyl reagent and shook it up with some water and plunged a pH probe into it. What I had assumed to be a neutral organic material was quite acidic on contact with water. Hmmm.

A dive into the literature (patents, actually) revealed that the history of the compound most likely involves exposure to HCl from a continuous acid hydrolysis and steam distillation. And the Aldrich bottle did say that ca 1 % water is present. A fact that I neglected in my haste to set up the reaction.

The upshot is that I didn’t anticipate that there was residual acid catalyst in the reagent itself.

This is good to know from the scale-up perspective. An acid catalyst probably won’t be needed and loading procedures and sourcing do not have to be done to use a separate catalyst.  

Now the trick is to determine if it is safe to combine all of the reagents in the reactor or if one needs to be fed in as the reaction proceeds. A run where all of the reagents are in the pot from the start is called a batch run.  A run where one or more reagents are fed into the vessel over the course of the reaction is called a semi-batch run.  The reaction rate is greatest if all of the reagents are present from the start, but it does represent an accumulation of energy in a low phi-factor vessel that could be a runaway hazard. I’ll have to noodle through this issue if this reaction gets scaled up.

Taking into account the phi factor, or the thermal inertia of the system, is one of the crucial details in scale-up. Eventually, you have to make a decision on whether to configure the run as a batch or a semi-batch process. The precautionary principle usually leads to semi-batch unless you can prove that a batch configuration is safe.

Running a process at reflux with a heated jacket relies on the overhead condenser to be the primary thermal safety device. This usually is very effective in knocking down condensable components in the gas phase. A good condenser has a huge effect on the heat balance of a reactor system.

Knocking down condensable components helps to regulate the pressure and temperature of the pot. The transition from liquid to gas phase carries heat away from the reaction mass quite effectively under ordinary conditions.

However, it is possible for a reaction to accelerate to a point where the condenser capacity is inadequate. At such a point the jacket may be filled with heating fluid and a switchover to chiller fluid may take a relatively long time. 

A reactor can behave as an adiabatic system if you pick a time interval that is short enough. So, a reaction mass that exotherms rapidly enough may find itself in an approximately adiabatic containment. In this condition, the reaction mass can accelerate with gusto as pressure and temperature ramp skyward, multiplying the reaction rate. Decomposition reactions kick in and non-condensable gases are evolved that further pressure the system. Hopefully, the rupture disk and vent were properly sized because there is going to be an administrative mess to clean up afterwards.

This scenario is one to be avoided. Reaction calorimetry and ARC testing give results that help tremendously with engineering around a runaway scenario. A parameter of particular interest in the adiabatic Time to Maximum Rate (TMRad).  TMR is extracted from the slope of a linear portion of an Antoine curve determined by ARC. A formula for the line can be substituted with a desired time and a temperature can be calculated.

A particularly useful value to come from this is the temperature affording a 24 hour TMR. Many companies will determine the 24 hr TMR and set a policy to operate at a set temperature margin below the 24 hr TMR temp:  a 60 C margin is not uncommon.