Accelerating SN2 nucleophilic fluorination of primary alkyl bromide using an 18-crown-6 and fluorinated bulky alcohol phase transfer system

A new phase transfer system for nucleophilic fluorination of alkyl halides with potassium fluoride, based on the combination of 18-crown-6 and the bulky fluorinated alcohol 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, was found to be very effective. A primary alkyl bromide was fluorinated in 24 h of reaction time with a mild temperature of 82 degrees C using acetonitrile solvent, obtaining 80% yield and only a trace of elimination product. The rational choice of this alcohol was based on a free energy profile of a reaction model including the solubilization of the KF salt and on the theoretical calculations of the stability of the KF(18-crown-6)(alcohol) complexes. The fluorinated bulky alcohol leads to a substantial increase in the concentration of KF complexed with 18-crown-6, which compensates for the decreased reactivity of the solubilized complex. The present study shows the importance of the modulation of the hydrogen bonding strength to obtain the rate acceleration effect.

Automated summary

A new phase transfer system combining 18-crown-6 and the bulky fluorinated alcohol was effective for the nucleophilic fluorination of alkyl halides. Under mild conditions with acetonitrile solvent, a primary alkyl bromide was fluorinated in 24 hours, yielding 80% and minimal elimination product. The choice of the fluorinated alcohol was based on thermodynamic analysis and theoretical calculations regarding complex stability and solubilization of the KF salt.