Analysis of the molecular interactions governing the polymorphism of benzamide – a guide to syntheses?

Abstract

Dispersion-corrected density functional calculations are used to rationalize the subtle differences in the molecular interactions in benzamide crystals. The potential energy of the different polymorph structures is dominated by the interplay between intermolecular attraction and molecular torsion/deformation to accommodate favourable molecular packing. Using suitable proxies arranged in pseudo-crystalline setups we discriminate the contribution of hydrogen bonding, π-π interactions and intra-molecular interactions to the lattice energies of the most relevant (P1 and P3) benzamide polymorphs. Strikingly, these commonly anticipated binding/packing concepts cannot account for the observed ranking of benzamide structures, thus hinting at the importance of the interactions between the benzene rings and the polar amide groups. Moreover, individual structural motifs that account for the competition between the two crystal structure types are elaborated. On the basis of such in-depth understanding of molecular interactions - in terms of both structure and chemistry - we suggest nucleation scenarios as guides to a more controlled synthesis of the stable P1 form or to direct nucleation in favour of the P3 polymorph.

Nucleation Mechanisms of a Polymorphic Molecular Crystal: Solvent-Dependent Structural Evolution of Benzamide Aggregates

“…Thus, even for the very early stages of aggregation explored in this study, we can relate the favoring of different polymorphic structures to the preferential formation of P1versus P3-type trimer motifs, in agreement to experimental and other theoretical evidence, both collected for macroscale crystallites. 1,17 With growing aggregate size, the importance of surface/interface effects diminishes and the quantitative P1/P3 motif ratio surely changes (to more and more pronounced favoring). Our findings should, therefore, be considered from a more qualitative point of view, i.e., the selectivity of P1-versus P3-type trimers as a consequence of different driving forces to solute association in polar and nonpolar solutions.…”

“…5−11 By the example of an experimentally well-established benchmark system, benzamide, we recently demonstrated the analysis of molecular interactions in different polymorphic forms and its possible implications for polymorph control. 1 From this, the favoring of either P1 or P3 forms of benzamide was attributed to different layer−layer interactions within periodic models of the bulk crystals. Guided by this postulated mechanism of P1 versus P3 polymorph selectivity, in the present study, we aim at the in-depth understanding of the whole morphogenesis of a forming aggregate, i.e., molecule-bymolecule association and subsequent self-organization in favor of crystalline motifs.…”

“…By the example of an experimentally well-established benchmark system, benzamide, we recently demonstrated the analysis of molecular interactions in different polymorphic forms and its possible implications for polymorph control . From this, the favoring of either P1 or P3 forms of benzamide was attributed to different layer–layer interactions within periodic models of the bulk crystals.…”

“…We report on molecular dynamics simulations dedicated to the aggregation and the early stage of nucleation of benzamide molecular crystals. As suggested by an earlier study of the molecular interactions in different benzamide polymorphs, we find the solvent to take a prominent role for polymorph control. The underlying driving forces are now rationalized by in-depth investigation of the formation of dimers, subsequent molecule association, and self-organization into aggregates of up to 100 benzamide molecules.…”

Intermolecular Interactions of Isolated Bio-Oil Compounds and Their Effect on Bitumen Interfaces

“…However, it is unclear exactly how these compounds contribute to the efficacy of bio-oil in modifying the properties of asphalt binder − and what molecular interactions are responsible for their activity. Computational modeling suggests that hexadecanamide can disrupt asphaltene stacking, affecting the rheological and mechanical properties of the binder. , Both H-bonding and dispersion interactions are important in the self-assembly of hexadecanamide, − but their relative impacts may differ in the context of bitumen or bio-oil. Bio-oil is typically a viscous liquid or soft solid at room temperature, whereas pure hexadecanamide and hexadecanoic acid are both waxy solids with melting points above 60 °C.…”