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Fluorous Liquid Liquid Extraction (FLLE)

Introduction

Fluorous Liquid Liquid Extraction (FLLE) utilizes a fluorous solvent as the fluorous phase to extract fluorous molecules from an organic or aqueous solvent. FLLE has been used in biphasic catalysis and small molecule synthesis.

Solvent Tuning

Recently, the use of hydrofluoroethers (HFEs) and solvent tuning have significantly enhanced FLLE. Solvent tuning of both the fluorous and non-fluorous phase can result in very high partition coefficients even for those molecules with only one or two fluorous chains.

In a qualitative sense, the further apart two solvents are in any direction, the more likely they are to be immiscible. Solvent pairings that are miscible can be rendered immiscible by appropriate increase or decrease of the fluorophilicity or polarity by blending with a cosolvent further out towards one of the two extremes.

A non-fluorous phase like DMF can be tuned by addition of water. Even polar fluorous molecules are much less soluble in aqueous DMF and prefer to partition into the fluorous phase. Five percent water is often enough. A fluorous phase like FC-72 can be made more polar by addition of a solvent like HFE-7100.

Heavy Fluorous

One of the first fluorous separation techniques, FLLE has been extensively used in biphasic catalysis and other preparative applications. It has been called a "heavy" fluorous technique, since multiple fluorous chains on a molecule may be necessary to enact good separation. This is particularly true when using perfluorocarbons (PFCs) as the fluorous extraction solvent.

Liquid-liquid extractions work well when fluorous domains are relatively large. In the best cases, only a single separation is needed. With lower partition coefficients, the organic fraction is washed several times with the fluorous solvent. Thanks to the exceedingly low solubilities of organic compounds in fluorous solvents, the washing process can be conducted repeatedly without extractive loss of the organic product. Liquid-liquid extractive methods are typically used when the desired product is organic and some other reaction component (reactant, reagent, catalyst, scavenged product) is fluorous.

FLLE Example

A photograph of a three-phase liquid-liquid extraction is shown above. Such extractions are readily automated, and can be used to quickly partition reaction mixtures into organic (yellow), inorganic (blue) and fluorous (clear) fractions. In many cases, the crude organic products are pure enough to be taken on to the next reaction, and the fluorous products can usually be recycled, if desired.

Selected References

  • "Increasing Fluorous Partition Coefficients by Solvent Tuning" Marvin S. Yu, Dennis P. Curran, Tadamichi Nagashima. Organic Letters 2005 7 (17), 3677-3680 DOI:10.1021/ol051170p
  • "New fluorous/organic biphasic systems achieved by solvent tuning" Qianli Chu, Marvin S. Yu, Dennis P. Curran. Tetrahedron. Vol 63, 39, 2007, 9890-9895 DOI:10.1016/j.tet.2007.06.092