Experimental and theoretical investigation of a 5-iodo-6-methyluracil derivative as a key intermediate for Elagolix synthesis: crystal structure, Hirshfeld surface analysis and DFT calculations.

The crystal structure of 1-[2-fluoro-6-(trifluoromethyl)benzyl]-5-iodo-6-methylpyrimidine-2,4(1H,3H)-dione (C13H9F4IN2O2, IFMBU), a key intermediate for Elagolix synthesis, was determined and reported for the first time, and further investigated by theoretical calculations. The molecule adopts a twisted `V'-shaped conformation, wherein the substituted benzene ring plane is nearly orthogonal to the uracil plane. In the crystal, molecules are linked by strong intermolecular N-H...O hydrogen bonds into centrosymmetric dimers, generating a highly stable R22(8) supramolecular ring motif. Hirshfeld surface analysis reveals that O...H/H...O (22.0%) and F...H/H...F (18.1%) contacts dominate the molecular packing. Pairwise interaction energy calculations highlight the critical role of strong dispersion forces (Edis = -302.1 kJ mol-1) and electrostatic interactions (Eele = -168.9 kJ mol-1) in stabilizing the 3D supramolecular framework. Furthermore, frontier molecular orbital (FMO) analysis demonstrates a distinct spatial separation of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), establishing a typical donor-acceptor architecture that highly facilitates intramolecular charge transfer. The combined experimental and theoretical results provide a detailed characterization of the molecular geometry, noncovalent interactions and electronic structure of this key Elagolix intermediate, which may serve as a useful reference for understanding its solid-state behaviour.