A comparative study of the conformational equilibria, vibrational, ¹H and ¹³C NMR spectra of isobutyranilide and its derivative the anticancer drug flutamide

The molecular structure of isobutyranilide and flutamide were investigated by DFT-B3LYP/6-311G^** and MP2/6-311G ^** calculations. Isobutyranilide was predicted to exist predominantly in a planar cis conformation, while flutamide in non-planar structures with the CF₃ and the NO₂ groups adopting an out of the phenyl-plane configuration. The vibrational frequencies of the low energy structures of the two molecules were computed at the DFT-B3LYP level of theory. From the calculated Gibb's free energies, isobutyranilide is estimated to have an equilibrium mixture of 91% cis and 9% trans structures, while flutamide is calculated to have a mixture of 65% cis-cis and 28% trans-cis structures at 298.15 K. The analysis of the observed vibrational spectra supports the presence of isobutyranilide in only one conformation at room temperature. From a 1:1 acetonitrile solvent experiment flutamide is determined to exist in more than one conformation at ambient temperature. Complete vibrational assignments of the normal modes of isobutyranilide and flutamide were provided on the basis of combined normal coordinate calculations and experimental Infrared and Raman spectra. The ¹H and ¹³C NMR spectra of isobutyranilide were measured and their chemical shifts were compared to the corresponding ones of flutamide.