Influence of Bio-Isosteric Replacement on the Formation of Templating Methanol and Acetonitrile Solvates in Lophines

Abstract

Bio-isosteric replacement is a frequently used tool in medicinal chemistry. While the pharmacological activity is not influenced by the exchange of substituents, the solid-state characteristics and formation of different crystal forms may well be altered dramatically, jeopardizing the processability and safety of the drug compound. In this study we investigate a series of triphenylimidazole (TPI) derivatives as model compounds with the bio-isosteric exchange of only one halogen position (F, Cl, Br, I). Crystallization from two industrially used solvents (methanol and acetonitrile) reveals solvate formation of all TPIs, for which the basic hydrogen bonded motif does not change. The three-dimensional packing depends on the size of the substituent and changes from fluoroto chloro-and bromo-substitution but remains the same for the larger iodo-substituent. From acetonitrile, only F-TPI and Cl-TPI form an isomorphic channel solvate, which in both cases desolvates reversibly to an isomorphic crystal form. Due to the halogen atom lining of the channels, bromine and iodine are too large to generate a stable packing. This study illustrates the importance of understanding the influence of bio-isosteric substitution on the solid state, in order to best utilize this common tool.

Supramolecular Gelation as the First Stage in Ostwald’s Rule

“…The crystallographic data for all five crystal forms of I-TPI identified in this work are given in Table 1. 37,40 This arrangement is observed in both anhydrous polymorphs of I-TPI, Forms V and VI ( Fig. 5).…”

“…73 High-temperature crystallisations were also undertaken, aiming to produce the anhydrous forms identified in previous work by PXRD. 37 Two non-solvated forms (Forms V and VI) were successfully identified and fully characterised by single-crystal X-ray diffraction. Form V was crystallised from pure methanol at 50 °C, a condition under which the gel did not form, even at sufficient concentration.…”

“…showed that changing the substituent in a single position has a significant effect on the solid state structure and properties of these materials. 37 A key finding was that there was a much more significant change in properties between the chloro-and bromo-derivatives, than between any other adjacent pair in the series. In all cases, the crystal structures contained hydrogen-bonded chains of imidazole units, which is the dominant motif observed in other imidazole derivatives.…”

“…In all cases, the crystal structures contained hydrogen-bonded chains of imidazole units, which is the dominant motif observed in other imidazole derivatives. [37][38][39][40] All studied halogenated TPI derivatives formed methanol solvates, and in this case, the solvent intercalates into the imidazole N N H I hydrogen-bonded chains. 37 Our previous work characterised the methanol solvates of all halogenated TPI derivatives by powder X-ray diffraction (PXRD) and reported single-crystal structures for the fluoro-and bromo-TPI solvates.…”

“…[37][38][39][40] All studied halogenated TPI derivatives formed methanol solvates, and in this case, the solvent intercalates into the imidazole N N H I hydrogen-bonded chains. 37 Our previous work characterised the methanol solvates of all halogenated TPI derivatives by powder X-ray diffraction (PXRD) and reported single-crystal structures for the fluoro-and bromo-TPI solvates. These layered structures were closely related but revealed a shift in the layers due to the increasing size of the halogen substituent.…”