Wednesday, August 1, 2012

Process Wednesday: hexafluoroisopropanol as a reaction solvent

Credit: Brenek et al., Org. Process. Res. Dev. 
From a recent Organic Process Research and Development paper [1], an interesting use of a fluorinated solvent in an oxidation to a sulfoxide:
Extensive screening of catalytic (e.g., V, Mo, W, Au) and stoichiometric oxidants was performed. These efforts resulted in identification of two highly regioselective oxidation systems for the formation of sulfoxide 26. A catalytic system utilizing methyltrioxorhenium (MTO) and urea−hydrogen peroxide (UHP) in trifluoroethanol (TFE), as well as a noncatalytic system using urea−hydrogen peroxide (UHP) in hexafluoroisopropanol (HFIP), each produced sulfoxide 26 in 70−75% yield. Due to the limited availability and high cost of MTO, the latter method was selected for further development (Scheme 11).  
HFIP is a highly polar specialty solvent, commercially available on multiton scale from several suppliers. However, due to the relatively high cost of HFIP compared to that of more traditional solvents, it was evident that maximizing concentration and/or recycling this material would be required. Unfortunately, optimal yield and selectivity for the formation of sulfoxide 26 required at least 4−5 volumes of HFIP. The use of polar cosolvents (e.g., THF, ethyl acetate, acetonitrile, and ethanol) inhibited the reaction, while nonpolar cosolvents (e.g., toluene and heptanes) could be used successfully. The use of toluene significantly slowed the reaction rate, but reactions eventually reached completion with similar yield. Heptanes and HFIP are immiscible, but use of the biphasic mixture produced desired sulfoxide 26 in similar yield and selectivity to that using neat HFIP, without a significant rate reduction. Presumably, the desired oxidation occurs in the HFIP layer. Although the use of heptanes cosolvent did not decrease the required HFIP volume, it enabled the development of a suitable recycling process for this expensive solvent. 
The reaction could be run in the presence of heptanes. However, the optimal process was carried out in neat HFIP (4−5 L/kg), and upon reaction completion, heptanes were added. The biphasic solution could then be distilled under reduced pressure. The distillate was collected as a biphasic mixture, and the lower HFIP layer could be easily separated and reused without further purification. The concentrated reaction mixture was carried on to the next step without isolation. 
I think this counts as green chemistry, right? Performing an oxidation without a heavy metal component (and with a relatively benign reagent) probably counts as a win, as does being able to recycle your reaction solvent. (It is a little unclear to me if they carried some of the HFIP to the following step.)

[On a slight tangent, what is people's experience with solvent recycling? I'm always more than a little suspicious of recycled solvent, but I am aware of the potential for cost savings. In this particular case, it sounds like the authors were able to distill and reuse, without any further purification, which I would think would be ideal.]

Nevertheless, it will be fascinating to see if fluorinated solvents pop up more and more in process-oriented papers.

[1]: Brenek, S.J.; Caron, S.; Chisowa, E.; Delude, M.P.; Drexler, M.T.; Ewing, M.D.; Handfield, R.E.; Ide, N.D.; Nadkarni, D.V.; Nelson, J.D.; Olivier, M.; Perfect, H.H.; Phillips, J.E.; Teixeira, J.J.; Weekly, R.M.; Zelina, J.P. "Development of a Practical and Convergent Process for the Preparation of Sulopenem." Org. Process. Res. Dev. ASAP. DOI: 10.1021/op300131e

*Safety note: the authors include this safety warning about HFIP in the footnotes: "According to HFIP manufacturer, DuPont Chemicals, “HFIP is corrosive to eyes and may cause permanent eye injury on contact. It is also corrosive to skin, and vapors can cause respiratory tract irritation. Care should be taken to avoid contact by wearing appropriate gloves, safety glasses and other protective equipment as needed. Refer to the MSDS for further handling information. This product may also contain a very low level of hexafluoroacetone, which is a potential reproductive hazard”.


  1. First I don't think there is anything that can be called "Green Chemistry".
    Fluorinated compounds are certainly not green. The water purification system cannot handle them. So if they get into the ecosystem you are %&ç*ed.
    They may increase reaction rate etc. but I would not entertain them as my first choice.

  2. The price of HFIP: we were looking into using it as a analytical chromatography solvent (GPC of polymers - it did not unfortunately dissolve our stuff) and the least expensive source on lab scale we found was Oakwood, USD165/kg (the density is 1.6). With distillation -based recycling using heptane as a non-miscible chaser: I would worry about water (from H2O2 - maybe thats why they use anhydrous urea adduct) accumulating in the HFIP after few recycles and slowing down the reaction.
    A cheaper alternative would be 5:1 formic-acetic acid at 0C, and slightly sub-stoechiometric H2O2 very gradually added, maintaining temperature control is essential for good selectivity and safety (the formic acid -peroxide mix is unstable when heated and can run away). Allyl group epoxidation with a peracid at 0C is quite slow - I have done some peracid oxidations in the presence of allyl protecting group and it survived unmolested.