Separation as the Focus of Chemical Process Development

KiloMentor | revised 6th  January 2009 republished February 17/2017

This is a revision of one of the earliest articles from the KiloMentor archives. The original was written in 2007.  It restates for new readers the core idea of the KiloMentor process development philosophy and teaches an approach that KiloMentor thinks leads consistently to valuable ideas. for improving process throughput.

In synthesis, we talk about assembling, building, or constructing a molecular structure. This is a misleading metaphor because we are comparing an activity in the nano-world to an activity in the macro-world. Operating in the macroscopic world, as for example in building a house, we handle the pieces, we position the pieces, we join the pieces.

In chemical synthesis, we do none of these. The substructures we are endeavoring to unite are atomic in scale: to small to touch, to align, or even to see.

In chemical synthesis, the chemist adjusts macroscopic conditions: solvent ratios, stoichiometry, stirring, temperature, duration of exposure, etc. Then the chemist presents the proposed reaction partners, to each other under the orchestrated conditions and they interact, as their nature dictates; but, hopefully, this is also as we have planned.  How is this perspective different from the conventional one?  Chemical process development is simply making these parameter choices that cause nature’s choice to comply with what we want the outcome to be, efficient. Nature to be commanded must be obeyed.

According to the academic synthetic chemistry tradition, synthetic accomplishments are judged on the basis of the number of synthetic steps, the yield per step, and the overall yield for the combination of steps. High yields are good. A short sequence is good. The combination is elegant. According to this traditional perspective, the focus is on the reactants, the plan for reactant transformation, and the overall yield output from that plan. Separation of unreacted starting materials, by-products, co-products, catalysts, solvents, salts and other excipients and processing chemicals are in the background (the attitude is that work-up/purification can be done and will be done BUT these are not important criteria to evaluate the quality of the synthesis).  The give-away phrase of those who harbor this philosophy is “the product was isolated in the usual way.”

From the KiloMentor perspective, in this age of on-line substructure searching, coming up with creative transformations with strong literature analogies is no longer the domain of the synthetic genius but has come within the scope of good synthetic chemists. We do not have to depend upon our neuronal computer alone anymore. Now it is creative ideas for separation and purification that are not easy to search and have become the greater art in the project. The deconstruction of the chemical soup and the fishing out of the desired product in an adequate state of purity is paramount.

Is there any particular value in this way of looking at processes that surpasses the traditional way which focusing on the series of chemical reactions while taking the separation of intermediates as an obvious technical work? My perspective emphasizes:

• The work involved in setting up and controlling the necessary reaction conditions.
• The work involved in quenching the reaction condition/then working up the reaction and finally isolating and purifying the desired product.

The value in this perspective is that in chemical synthesis, the money, manpower and resources consumed during the reaction step phase, ie. while A & B are reacting with each other, is minuscule compared to the money, manpower and resources expended preparing for the reaction and recovering pure product from the reaction.

The clash of these perspectives leads to the question, “Which would I rather do- a four-step synthesis in which every conversion has many parameters that must be rigorously controlled and from which each intermediate must be isolated by gradient column chromatography and evaporated to a foam OR an eight-step synthesis which is rugged and forgiving of process deviations and from which each intermediate can be cleanly extracted in a separatory funnel or crystallized or distilled to give an adequate practical purity intermediate."

People have personal preferences and this is as it should be in a pluralistic society BUT I pick the second sequence and as the need for larger quantities and higher quality intensify, I increasingly prefer the second route.

Please note- I am not saying the number of chemical steps doesn’t matter. I am not saying that the overall yield does not matter. I am saying that elegance also encompasses simplicity, ruggedness, time economy and scalability.

OK so what. How does this insight change our behavior in the synthetic laboratory, office, or library? Based on an examination of what really goes on in a chemical process step a method of rating the difficulties of the separation is proposed as a quantitative tool to rank the challenges of a process scale-up.

We should evaluate or rate synthetic schemes using more criteria:

1. Number of Chemical Steps
2. Isolated overall Yield
3. Yields of the Individual Steps.
4. Difficulty Rating for Each Reaction Mixture Separation

How could we execute this new difficulty rating? We could classify work-ups:

A. The product can be separated practically pure by simply liquid-liquid extraction (ie acid-base pH or other phase switching)

B. Product can be separated by crystallization of precipitation as filterable solid.

C. Product can be separated by atmospheric or vacuum distillation based on a projected difference in boiling points (based on molecular weights)

D. Product can be separated based on chemical reactivity (formation of reversible simply separable derivative, or destruction of contaminant by reaction)

E. The product seems likely only to be separable in practical purity by chromatography.

Clearly, as process chemists, we want to face more A-C separations and fewer D-E type separations.

The Kilomentor blog will highlight methods to augment isolations and purifications so chemists can improve their ability to assign these ratings and take them Ito account when designing synthetic chemical processes that can be readily and ruggedly scaled up into the plant.