musings on music and life

June 13, 2013

Trifluoromethylation on scale

Filed under: Chemistry — Tags: , , — sankirnam @ 5:24 pm

I came across this interesting paper in OPRD yesterday. It’s a shame that most research chemists in academia do not read OPRD; process chemistry is much, much different from laboratory research-scale chemistry. The principles of process chemistry are not taught in most universities and most academic chemists have no idea how challenging simply scaling up a reaction can be. Some of my own work (superelectrophilic Friedel-Crafts reactions in triflic acid, for example) would be unthinkable on scale. Temperature regulation and mixing (especially for heterogeneous reactions) become major considerations at a large scale; exotherms have to be managed, and you cannot afford to have poor conversions due to inefficient mixing. At the mmol scale, when doing reactions in a RBF, those things are usually not considered, and with good reason – at that scale, and with the apparatus used, one is usually at (or very close to) the mass and heat transfer limits anyway. Environmental considerations (reflected in the E value of a given reaction or process) are also important; while solvents such as dichloromethane or chloroform are OK in research, they cannot be used in 500-1000L quantities!

I had the opportunity to meet with Dr. Margaret Faul (of Amgen) recently, and learned a little bit about process chemistry from discussions we had over dinner. I was under the impression previously that anhydrous solvents were also prohibitive on scale, since the usual methods for drying solvents in the lab involve distillation of the solvent over some very reactive dehydrating agents (sodium/benzophenone ketyl or phosphorous pentoxide). In process chemistry, they can repeatedly azeotrope off the water with another solvent in order to obtain very dry solvent – in fact Dr. Faul had boasted that she could probably get drier THF than I could!

In the paper linked above, Chris Senanayake and coworkers describe the optimization of a process in the synthesis of a trifluoromethylated nicotinate molecule for pharma research. What I found interesting was their claim that the Ruppert-Prakash reagent, generally considered the mainstay reagent for trifluoromethylation, was too expensive to use on scale! They opted to use Chen’s reagent (methyl chlorodifluoroacetate) with KF and stoichiometric CuI as the trifluoromethylation system. This (the cost issues associated with TMSCF3) is something I never would have learned otherwise, since I use TMSCF3 on a regular basis (especially since my advisor was the person who pioneered it’s use as a reagent!).

Ultimately, the goal of academic research, especially for those doing research in synthetic organic methodology development, is to develop scalable reactions. As I mentioned above, what constitutes a scalable reaction is not necessarily obvious, and so it is always worth reading journals like OPRD or books on process chemistry to learn these things.


1 Comment »

  1. […] article last week on process chemistry in which they discussed in detail a paper I had talked about here last year! People need to get with the […]

    Pingback by Way ahead of you, C&EN | musings on music and life — March 31, 2014 @ 6:38 pm

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