Issue 16, 2022

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

Abstract

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 R22(8) centrosymmetric dimer that is common in carboxylic acids (via double OH⋯O H-bonds). Parallel face-to-face stacking interactions are also observed in its crystal packing where these R22(8) centrosymmetric dimers are propagated forming infinite 1D columns. Moreover, the presence of iodine, which exhibits a region of large and positive electrostatic potential (σ-hole) along the C–Ha bond and a belt of negative electrostatic potential (σ-lumps) facilitates the formation of halogen bonds (HaBs) and halogen⋯halogen contacts that are also relevant in the solid state. The crystalline disorder was analyzed by means of Hirshfeld surfaces, and hydrogen, halogen and π–π 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).

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

Supplementary files

Article information

Article type
Paper
Submitted
11 Feb 2022
Accepted
25 Mar 2022
First published
25 Mar 2022

CrystEngComm, 2022,24, 3057-3063

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

R. Barbas, M. Font-Bardia, A. Ballesteros, G. Arsequell, R. Prohens and A. Frontera, CrystEngComm, 2022, 24, 3057 DOI: 10.1039/D2CE00202G

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