Wednesday, December 18, 2013

Process Wednesday: Stupid reactor cleaning solvents!

Bert Hulshof's* "Right First Time in Fine-Chemical Process Scale-up" has a rather wonderful chapter of "non-flyers", as he calls them. These are reactions/processes that worked well in the lab, but not in the plant. Here's one about a Grignard that I found hilariously funny:
- Pilot-plant scale 
9. The pilot plant results were identical to those in the lab.
10. However, on plant-scale, the Grignard reaction could not be initiated.  
 - Review 
11. Back in the lab, it was demonstrated that small quantities of acetone are the real cause of this Grignard initiation problem.
12. Acetone was a cleaning solvent, frequently used to dry reactors, condensers and piping. Usually final traces of this solvent could be removed by applying vacuum on various equipment sections.  
 - Solution 
13. After the make-up of magnesium and THF, a certain quantity of Grignard solution of the previous batch was added to destroy remaining acetone...
I can only imagine the irritation of the chemists upon learning of this stumbling block.

Grignard initiation on plant scale can be tricky and potentially quite dangerous (in terms of adding a bunch of halide and magnesium together that might react all-at-once and spray hot flammable solvent out of the rupture disk.) I've heard of SOPs where a verifiable initiation (as measured by exotherm or other in-process check) must take place before the full quantity of halide can be added.

*Sadly, Dr. Hulshof's passing was noted in OPRD recently. 


  1. An older and wiser colleague of mine experienced the same problem, 20 yrs ago, and came to a very similar solution. It was a good thing to know, the first time I followed a Grignard on a pilot plant. On the other side, the good part of running a pilot (or production) Grignard, as opposed to running a lab trial, is that the initiation is much more easy to detect.

  2. I am not sure why you found this funny as to me suggests chemists who are not thinking very comprehensively during scale-up transition. Since acetone is commonly used as final cleaning and "drying" steps in large fixed equipment, and total removal of all residues is extremely difficult without precise measures (e.g. prolonged vacuum), might anticipate impact on doing Grignards or any reactions that are moisture/ketone sensitive. Knowing as much as possible about what came before in a non-dedicated reactors is often important as all cleaning tends to be "relative" and depends on previous reactions/reagents/solvents, standardized wash procedures, equipment configurations and probably other details that must be considered. I have done a number of large scale Grignards and believe initially would perform pre-rinses with the intended solvent, i.e. THF, Glyme or MTBE, then found (or learned form older/wiser colleague) an effective means to clean/activate the magnesium turnings was to add to vessel and heat them for a short time in heptane (can't remember if went to reflux or only 50-60C) which had a dual role to drive out other residues such as acetone. I recall once had an fairly acid-sensitive raw material and since a particular reactor was cleaned periodically with acid solutions we did a precautionary rinse with bicarb solution as a preconditioning step. Most of my irritation at learning these type things would be more self-directed if it was something I should well have caught in a risks profile exercise however frequently enough seems unpredictable stuff still happens in process that either irritates or entertains to drive any fixed routine or boredom away.

  3. MTBE is not an effective solvent for Grignard fomartions. But you can use for example 10:1 mix of toluene and THF instead, or 2-MeTHF, or di-n-butyl ether

  4. I am not abiding why you begin this funny as to me suggests chemists who are not cerebration actual assiduously during scale-up transition. Back acetone is frequently acclimated as final charwoman and "drying" accomplish in ample anchored equipment, and absolute abatement of all residues is acutely difficult after absolute measures (e.g. abiding vacuum), ability ahead appulse on accomplishing Grignards or any reactions that are moisture/ketone sensitive. Knowing as abundant as accessible about what came afore in a non-dedicated reactors is generally important as all charwoman tends to be "relative" and depends on antecedent reactions/reagents/solvents, connected ablution procedures, accessories configurations and apparently added data that accept to be considered. I accept done a amount of ample calibration Grignards and accept initially would accomplish pre-rinses with the advised solvent, i.e. THF, Glyme or MTBE, again begin (or abstruse anatomy older/wiser colleague) an able agency to clean/activate the magnesium turnings was to add to barge and calefaction them for a abbreviate time in heptane (can't bethink if went to abatement or alone 50-60C) which had a bifold role to drive out added residues such as acetone. I anamnesis already had an adequately acid-sensitive raw actual and back a accurate reactor was bankrupt periodically with acerbic solutions we did a basic bathe with bicarb band-aid as a preconditioning step. Most of my affliction at acquirements these blazon things would be added self-directed if it was something I should able-bodied accept bent in a risks contour exercise about frequently abundant seems capricious being still happens in action that either irritates or entertains to drive any anchored accepted or apathy away.

    Cleaning Solvents


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