Wednesday, November 12, 2014

Process Wednesday: plant preparation for alkyllithium use

"Auntie Markovnikov" and Jyllian Kemsley pointed out a pretty awesome article in Organic Process Research and Development which I somehow missed. It's a long review of the safe use of alkyllithiums in process chemistry. [1] It has a nice overview of what you might have to do to prepare your larger-scale reactors to use alkyllithiums as well: 
In larger pilot plant or production equipment, the equipment can be dried and inerted by applying heat to the jacket of the reactor and vacuum to the equipment itself, isolation of the vacuum, and releasing the vacuum to the vessel with an inert gas. The vacuum/inert gas cycle should be repeated several times. The jacket may then be cooled to allow processing. An alternative is to apply heat to the jacket of the reactor and purge the vessel with an inert gas. It is also possible to dry a reactor train by boiling a water absorbing solvent, such as THF in the reactor under an inert gas. The solvent is then drained from the reactor, along with the water. The water content of the solvent can be determined analytically, for instance via Karl Fischer titration, to determine the efficiency of water removal. If the detected water value is higher than the background, the solvent boil up process can be repeated. 
Sometimes it is more cost efficient to simply charge sufficient excess organolithium solution to account for the water content although all chemistry will not allow this shortcut. 
Another hazard consideration for larger scale equipment is that the heat transfer fluid must be nonreactive with organolithium compounds. If there is a leak in the jacket or condenser and the heat transfer fluid comes in contact with the organolithium solution, the result can be catastrophic. Clearly this is not a risk worth taking on large scale although large-scale equipment rarely leaks into the vessel. Water, glycol, and brine solutions are examples of reactive heat transfer fluids that should not be employed as heat transfer fluids in this service.
The suggestion about heat transfer fluid is something that is really important and (more or less) unique to the plant. To control temperature, reactor jackets are typically filled with either water, steam or ethylene/propylene glycol, all solutions that would happily react with nBuLi. There are silicon-based heat transfer fluids and I think that's what tends to get used in these situations, though I have no direct experience with that.

(Also, I'm amused at the suggestion of adding a little more nBuLi to get things dry -- world's most expensive drying agent? The thrifty process chemist would not agree.)

1. “Preparation, Properties, and Safe Handling of Commercial Organolithiums: Alkyllithiums, Lithium sec-Organoamides, and Lithium Alkoxides” Rathman, T. L.; Schwindeman, J. Org. Process Res. Dev. 2014, 18, 1192.


  1. I was amused at seeing this in a chemistry review.

    1. There is no better way to learn chemistry than to singe your eye brows :). Learning in a flash makes the lessons sort of stick to you.

  2. We are using Syltherm XLT light cyclic oligo-dimethylsiloxane oil for jacket temperature range -30 to 85C in circulator baths - it is quite nice, completely odorless, and not too viscous even at low teperatures. The heat transfer capacity is lower than with glycol and it begins to evaporate noticeably above 120C. But it was good enough for 15L jacketed reactor even with our wimpy circulator. Cleaning the spills is fun - after wiping out the puddle with paper towels the remaining silicone soaks into the concrete floor (or drywall) without much trace... The main complain is that over time, the oil leaches the plasticizers out from common lab grade vinyl tubing and it makes it stiff.

  3. This is right on the money for reactor drying. The two water-sensitive processes that I saw failing were killed by residual water in the overheads. Residual water was left in the P-trap between condensers. Drying that piece requires distillation of lots of solvent without returning the distillate to the reactor.

    P-trap is one spot that would not be dried by the heat/vac method even if the heat transfer fluid was circulated through the condensers. Smaller slugs of water can be stuck in the sample loop, charging dip pipes, and all kinds of valves.

    The compatibility of the heat transfer fluid with the reaction components is something I like to look at for every process. A sample Interaction Matrix for use in early safety review is shown in Stoessel's "Thermal Safety of Chemical Processes" on p.20.

    I have had two cases when glass delaminated from the reactor wall and subsequent corrosion caused a breach of thermal fluid (steam) into the reaction volume. These were 220 gal and 750 gal reactors, so it was just our good luck that the processes were not sensitive to water. However, the steam boiler was sensitive to the reaction mixtures...

  4. I am surprised you find heat transfer liquid safety concern unusual. Did they not teach you in grad school not to use acetone in cold bath when working with things like BuLi?

  5. My boss once told me about a colleague of his who worked with organolithiums on process scale. He said they'd do exactly that, charge an excess of the reagent. There's no better desiccant than n-BuLi.