Process Wednesday: elemental fluorine? Why not?

Credit: Org. Process Res. Dev., Abele et al.

It's not often that you see elemental fluorine in Organic Process Research and Development, so I had to read this article. [1] The authors needed a fluorinated napthyridine and while they decided to go with either purchasing the fluoride (Route 2) or using Select-Fluor (Route 1), they did explore using elemental fluorine, which, um, I would be hesitant to. The authors talk about how elemental fluorine is typically not a very selective reagent nor does it tolerate much functionality, but then are surprised to report the results of their experiments:

Surprisingly, an excellent selectivity was observed when 10% F₂ in N₂ was bubbled through a solution of 10 in conc. H₂SO₄ (100 vol) at 80 °C for 4 h, the IPC (HPLC) indicating a 89:11 mixture of starting material and product without any byproducts or side products (Table 1, entry 1). Heating to higher
temperatures to accelerate the reaction led to significant byproduct formation (entry 2, byproducts were not identified). The use of a sintered glass frit for a better dispersion of F₂ doubled the reaction velocity (entry 3). 

When the concentration was increased by a factor of 10 to 10 vol, excessive foaming resulted in a slower reaction rate (entry 4). A higher concentration is desirable as it will reduce the amount of base required for the quench. The slower reaction rate could successfully be compensated by the use of a glass frit with double-sized pores (20 instead of 10 μm, entry 5). On 50-g scale, 10% F₂ in N₂ was bubbled into the solution of 10 in conc. H₂SO₄ (10 vol) via a 20-μm frit at 80 °C for 27 h, leading to 93% conversion (no byproduct by HPLC). 

SiO₂ was added as antifoaming agent and the flow rate was varied between 30 and 60 L/h to control remaining foaming (entry 6). 27 was obtained in a moderate yield of 41% yield after a quench with aqueous ammonia and filtration (nonoptimized work-up).  

All six alternative solvents tested (entries 7−15) either led to no conversion or to multiple byproducts. HF would be a preferred solvent due to the ease of its removal by distillation. The reaction in HF was carried out in an autoclave and did give the expected product, albeit accompanied by side products (entry 16). 

Remaining challenges for the scale-up of the orthofluorination with elemental fluorine are the high corrosivity of the reaction media, the foaming, and the isolation of the product from conc. H₂SO₄ leading to large volumes during the aqueous work-up.

I'm a little bit surprised at the foaming problem -- I am not sure that I expected that as an issue. (Does that have to do with the concentrated sulfuric acid as a solvent?) Nevertheless, pretty neat to see that it can be done.

1. Abele, S. Schmidt, G.; Fleming, M.J.; Steiner, H. "A One-Pot Diazotation−Fluorodediazoniation Reaction and Fluorine Gas for the Production of Fluoronaphthyridines." Org. Process Res. Dev. ASAP DOI: dx.doi.org/10.1021/op500100b