Issue 7, 2022

Steric influence on solvate formation – a comparison of resorcylic acid and two brominated derivatives

Abstract

The molecular structure of a candidate pharmaceutical drug compound is routinely modified during lead optimisation. While the difference in pharmacological effect may be subtle, the effect on the solid-state landscape can be unpredictable and dramatic. In the present study we investigate the effect of small changes in steric bulk of a substituent on solvate formation with the model compounds β-resorcylic acid, 5-bromo-β-resorcylic acid and 3,5-dibromo-β-resorcylic acid. Overall, 18 solvates were structurally characterised, half of those are observed for the monobrominated compound. Although none of the crystal structures show isostructurality, there are three major interaction motifs: centrosymmetric carboxylic acid homodimer formation with solvent interaction through the 4-hydroxyl group into finite tetramers, infinite chain formation of these tetramers, and no homodimer formation. Using the first interaction shell around the host (resorcylic acid) molecules, the effect of the steric hindrance by blocking of certain interaction sites can be visualised. The realisation of halogen bonds leads to a loosening of the molecular packing, which likely leads to increased solvent inclusion. It can be concluded that the introduction of steric bulk furthers solvent inclusion, a factor that must be considered during lead optimisation.

Graphical abstract: Steric influence on solvate formation – a comparison of resorcylic acid and two brominated derivatives

Supplementary files

Article information

Article type
Paper
Submitted
29 11 2021
Accepted
18 1 2022
First published
19 1 2022
This article is Open Access
Creative Commons BY-NC license

CrystEngComm, 2022,24, 1368-1376

Steric influence on solvate formation – a comparison of resorcylic acid and two brominated derivatives

K. Edkins, J. Tweedy, S. Fung and R. M. Edkins, CrystEngComm, 2022, 24, 1368 DOI: 10.1039/D1CE01592C

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