Investigating the Role of Weak Interactions to Explore the Polymorphic Diversity in Difluorinated Isomeric N-Phenylcinnamamides

Abstract

A total of nine difluoro derivatives of N-phenylcinnamamides have been synthesized from fluoro-substituted cinnamic acids and anilines in order to investigate the formation of polymorphs arising due to the conformational flexibility around the amide and vinyl group. Among them, four compounds have been found to exist in multiple polymorphic forms, which includes concomitant polymorphism, solvatomorphism, and packing polymorphism, while the remaining five compounds display monomorphic behavior. Crystal structure analyses of all the forms belonging to these four compounds reveal that, although the molecules are primarily held by strongand π•••π interactions allows the flexible molecules to adopt different orientations and exhibit polymorphism. These forms interestingly also display different thermal stabilities, and they have been quantified by intermolecular interaction topological analyses. The occurrence of different primary packing motifs in these crystal structures has been further investigated by the crystal structure prediction (CSP) computational method, wherein an energy landscape of an unsubstituted N-phenylcinnamamide was generated and a number of hypothetical structures were accessed with experimentally obtained crystal structures of its difluoro-substituted derivatives.

Experimental and Computational Investigation of Benperidol and Droperidol Solid Solutions in Different Crystal Structures

“…Crystal engineering has been used to successfully design strong intermolecular interactions in the solid state, ,, but a belief that crystal structures can now be easily designed is overly optimistic, as often only the dominant supramolecular synthons are designed and part of the success lies in the exploitation of the limited number of functional groups having notably different properties. − For example, it has been shown , that in the case of competing interactions, successful prediction is highly challenging or impossible. Moreover, weak intermolecular interactions, their contribution to the stability of the crystal structure, and the effect of slight alteration of such interactions is even harder to be predicted and estimated. − However, polymorph structures often are a result of an interplay of weak intermolecular interactions and conformation, while strong interactions could be unaltered. − The rationalization of interactions in multicomponent phases is often even more challenging, and the propensity of a compound to form solvates and cocrystals in general cannot be reliably predicted. Nevertheless, factors responsible for solvate formation for specific compounds have been identified, − and there are strategies for the prediction of formation of multicomponent phases for defined compounds. − …”

Zwitterionic or Not? Fast and Reliable Structure Determination by Combining Crystal Structure Prediction and Solid-State NMR

“…In this context, computational methods, such as Crystal Structure Prediction (CSP), have taken hold more and more in the last decades [ 2 , 3 , 4 ]. Originally developed for screening the polymorph landscape [ 5 , 6 , 7 , 8 ], CSP has proved to be a very useful tool for crystal structure determination as well, as confirmed also by the results of six blind tests [ 9 ] promoted by the Cambridge Crystallographic Data Centre (CCDC). However, CSP still exhibits some limitations, such as the fact that it does not consider the effects due to temperature [ 10 ] (calculations are usually performed at 0 K) or that all predicted structures are generally optimised by ab initio quantum mechanical methods, requiring considerable computational resources which increase with the system size.…”

Investigation of crystal structures, energetics and isostructurality in halogen-substituted phosphoramidates

“…Two crystals are said to be isostructural if they have the same structure, but not necessarily the same unit-cell dimensions nor the same chemical composition. The existence of two similar crystal structures for different molecules with 3D supramolecular construct, 2D layer, 1D chain, 0D dimer , 1993;Reddy et al, 2006;Bhattacharya & Saha, 2012;Chennuru et al, 2017;Portalone, 2020;Bhowal & Chopra, 2021). As well highlighted by Corpinot & Buc ˇar in a detailed article guiding towards the design of molecular crystals, crystal isomorphism was considered to be a sufficient condition for the formation of continuous solid solution (Corpinot & Buc ˇar, 2019) but not an essential condition (Schur et al, 2015).…”