Sulfur(VI)-Fluoride Exchange (SuFEx)

07 December, 2015 / by SK / in Reactions

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General Characteristics

Sulfur(VI) fluoride compounds (e.g. RSO₂F, SO₂F₂) are stable under a wide range of conditions, yet their S-F bonds can be activated for exchange reactions in the presence of proton or silicon reagents.

Thanks to the high chemoselectivity and functional group tolerance, sulfur-fluoride exchange (“SuFEx”) is proposed as a new reaction for click chemistry.

General References

Steinkopf, W. J. Prakt. Chem. 1927, 1, 1. DOI: 10.1002/prac.19271170101
Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed.2014, Early View. DOI: 10.1002/anie.201309399

Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004. [abstract]

Reaction Mechanism

Sulfur(VI) fluorides generally exist as stable compounds for the following reasons.

The bond energy of S(VI)-F is about 80-90 kcal/mol (SO₂F₂), which is much higher than that of S(VI)-Cl (SO₂Cl₂: 46 kcal/mol).

The nucleophilic addition-elimination reactions at S(VI) centers are relatively slow. For example, the Nu-Cl byproduct is sometimes observed in reactions between RSO₂Cl and a nucleophile, which is considered to occur as a result of the nucleophile attacking the chloride instead of the sulfur center.

The activation of stable sulfur(VI) fluorides for exchange reactions requires assistance from proton (H⁺) or silicon (R₃Si⁺).

Examples

Preparation of sulfonyl fluorides: Sulfonyl chlorides can be easily converted to the corresponding fluorides. Alkyl sulfonyl fluorides can be synthesized by the Michael addition of various nucleophiles to vinyl sulfonyl fluoride.

Gaseous SO₂F₂ and ROH react to form fluorosulfates. Since –OSO₂F is a good leaving group, the application to functionalize phenols is common. Sulfamoyl fluorides are synthesized similarly from SO₂F₂ and secondary amines. The products formed from primary amines tend to be unstable due to the elimination of HF.

The exchange reaction with silyl protected phenols in the presence of a catalytic amount of base is also known. As shown below, it can couple two very large fragments. The silyl fluoride byproduct is unreactive and thus minimally interferes with the reaction.