Static discrete disorder in the crystal structure of iododiflunisal: on the importance of hydrogen bond, halogen bond and π-stacking interactions

This manuscript reports a combined computational/crystallographic analysis of iododiflunisal (IDIF), a difluorophenyl derivative of salicylic acid (2 ',4 '-difluoro-4-hydroxy-5-iodo-[1,1 ']-biphenyl-3-carboxylic acid). This drug is used to target transthyretin related amyloidosis. In the solid state it shows static discrete disorder and forms the typical R2(2)(8) centrosymmetric dimer that is common in carboxylic acids (via double OHMIDLINE HORIZONTAL ELLIPSISO H-bonds). Parallel face-to-face stacking interactions are also observed in its crystal packing where these R2(2)(8) centrosymmetric dimers are propagated forming infinite 1D columns. Moreover, the presence of iodine, which exhibits a region of large and positive electrostatic potential (sigma-hole) along the C-Ha bond and a belt of negative electrostatic potential (sigma-lumps) facilitates the formation of halogen bonds (HaBs) and halogenMIDLINE HORIZONTAL ELLIPSIShalogen contacts that are also relevant in the solid state. The crystalline disorder was analyzed by means of Hirshfeld surfaces, and hydrogen, halogen and pi-pi bonding assemblies were analyzed using density functional theory (DFT) calculations, molecular electrostatic potential (MEP) surfaces, the quantum theory of atom-in-molecules (QTAIM) and the noncovalent interaction plot (NCIplot).

Automated summary

This study conducted a combined computational and crystallographic analysis of iododiflunisal, revealing static discrete disorder in the solid state and the formation of typical R2(2)(8) centrosymmetric dimers. Additionally, the presence of iodine facilitated the formation of halogen bonds and halogen-halogen contacts, as observed in the crystal packing.