Structure of 3-acetyl-5-fluorouracil (5-FU): implication for its rearrangements during hydrolysis and upon heating

Single-crystal X-ray diffraction data show that the 3-acetyl group in 1,3-diacetyl-5-FU (FU = fluorouracil) is perpendicular to the plane of the 5-FU ring, while the 1-acetyl group is coplanar with the ring. Analyses of 1H NMR and IR spectra provide evidence that the 1- and 3-acyl groups are in different electronic environments, which is consistent with the X-ray diffraction structure. 3-Acetyl-5-FU is thermally unstable, giving mainly 1-acetyl-5-FU (80%) and 5-FU (20%) upon heating. The hydrolysis of 3-acyl derivatives of 5-FU showed a biexponential relationship between in concentration and time which had not been previously observed. The behavior of 3-acetyl-5-FU during hydrolysis can be explained by postulating its initial rapid equilibrium with an intermediate, 2-acetyl-5-FU, which subsequently hydrolyzes to 5-FU or rearranges to 1-acetyl-5-FU, which hydrolyzes to 5-FU. The 2-acetyl intermediate was trapped by its reaction with formaldehyde. The formaldehyde adducts of the symmetrical 2-acetyl intermediate rearranged to yield equal amounts of 1- and 3-acetyloxymethyl-5-FU.