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.