A comparative study on the effect of solvent on nucleophilic fluorination with [¹⁸F]fluoride: protic solvents as co-solvents in S_N2 and S_NAr reactions

Abstract

The effect of solvent on nucleophilic substitution with cyclotron-produced [¹⁸F]fluoride was studied in polar aprotic (CH₃CN and DMF) and protic solvent (t-BuOH and t-amyl alcohol) mixtures (CH₃CN/co-solvent, 2:8) in a series of model compounds, 4-(R¹-methyl)benzyl R²-benzoates, using a K2.2.2/[ ¹⁸F]KF phase transfer system (R¹=–Cl, –OMs or –OH; R²=–Cl, –I or –NO₂). ¹⁸F-fluorination of compounds 1–3, with chloride or mesylate as a leaving group in the benzylic position (R¹), afforded the desired 4-([ ¹⁸F]fluoromethyl)benzyl analogues in all solvents during 15ߙmin reaction time. The highest radiochemical yields (RCY) in all the studied reaction temperatures (80, 120 and 160ºC) were achieved in CH₃CN. Radiochemical yields in protic solvents were comparable to RCY in CH₃CN only with the sulfonate ester 3 as a starting material. ¹⁸F-Fluorination of the benzylic halides 1 and 2 was not promoted in the same extent; in addition, labelled side-products were detected at higher reaction temperatures. Radiofluorination in tert-alcohols was also studied using [¹⁸F]CsF with and without added phase transfer catalyst, resulting in both conditions lower RCY when compared to K2.2.2/[¹⁸F]KF system. Protic solvents were not able to promote aromatic ¹⁸F-fluorination. ¹⁸F-Fluorination of compound 5, having para-activated nitro group in the aromatic position (R²), failed in tert-alcohols even at the highest temperature, but it was labelled successfully in DMF and to some extent in CH₃CN.