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Abstract: Fumaric acid and alkyl fumarates are a family of structurally related compounds with a wide spectrum of potential or effective therapeutic applications. The series consisting of fumaric acid (FA), monomethyl fumarate (MMF), dimethyl fumarate (DMF), monoethyl fumarate (MEF), and diethyl fumarate (DEF) was studied in this work to address the following main questions: how does the number of OH···O hydrogen bonds that may be established due to systematic differences in molecular structure impacts on the molecular packing and lattice energetics? Is there evidence of a cooperative hydrogen bond strengthening when infinite 1D chains sustained by OH···O hydrogen bonds are formed? How well can the structural and energetic features of this series of related molecules be predicted by state-of-the art force field and periodic DFT procedures that are used in the rationalization or prediction of crystal structures and physical properties of molecular organic solids? By combining results from a variety of experimental (X-ray diffraction, Raman spectroscopy, DSC, Calvet drop-sublimation calorimetry) and theoretical (quantum mechanical, molecular dynamics simulations) methods, it was found that (i) in all cases, the molecular packing leads to layered solids, where each layer consists of 1D chain motifs linked to each other through C–H···O interactions. (ii) The 1D arrangements are determined by two main motifs: the R22(8) carboxyl dimer, typically found in mono- and di-n-alkyl carboxylic acids, and the staggered CH3···H3C synthon, which is present in mono-n-alkyl carboxylic acids and n-alkanes. This leads to the formation of carboxyl–carboxyl and alkyl–alkyl domains that are structurally isolated from each other. (iii) The lattice energy, as measured by the enthalpy of sublimation (ΔsubHmo), varies according to FA > MMF ∼ MEF > DMF ∼ DEF and is linearly correlated with the number of OH···O hydrogen bonds present in the structures. (iv) The larger enthalpy of sublimation of FA compared to MMF and MEF is linked to the number of OH···O hydrogen bonds but does not seem to be related to their individual strength. Examination of O···O distance and C═O stretching frequency as well as theoretically computed dissociation energies of dimeric FA, MMF, and MEF species suggests that the OH···O interaction is weaker in FA than in MMF and MEF. As such, the present study showed no evidence of a cooperative OH···O bond strengthening in FA, relative to MMF and MEF, due to the presence of infinite 1D chains sustained by carboxylic acid dimers. (v) No evident connection between ΔsubHmo and compactness indicators such as density or Kitaigorodski packing index was also found. Finally, (vi) MD simulations and periodic DFT calculations were both able to reproduce the above-mentioned ΔsubHmo trend and capture the main structural features of the family of crystalline materials studied in this work. In terms of accuracy, better overall performance was observed for the force field method developed for this particular type of compounds.

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Abstract: Alkali metal imidazolates are important compounds, serving as intermediates in organic synthesis and additives in alkali ion electrolytes. However, their solid-state structures and thermal behaviors remain largely unexplored. In this study, we present the synthesis, structural analysis, and thermal characterization of lithium and sodium benzimidazolate (bim–). The crystal structures of these microcrystalline materials, determined by 3D electron diffraction, reveal closely related layered coordination networks. In these structures, 4-fold N-coordinated alkali ions are bridged in two dimensions by bim– linkers, with the networks’ surfaces decorated by the phenyl rings of the bim– linkers, stacking atop one another in the solid state. Differential scanning calorimetry combined with variable temperature X-ray powder diffraction indicates that both materials melt above 450 °C. Additionally, Na(bim) undergoes a displacive phase transition from an ordered α-phase to a highly disordered β-phase before melting. Structural variations, primarily attributable to the differing ionic radii of Li+ and Na+, result in distinct coordination environments of the alkali metal ions and varying orientations of the bim– linkers. These differences lead to markedly distinct thermal behaviors: Li(bim) exhibits positive thermal expansion along all crystal axes, whereas Na(bim) switches from area negative thermal expansion (NTE) to linear NTE during the α → β phase transition.

Open Access

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Abstract: A novel monoacylglycerol, 7.10 MAG, has been produced for use in the in meso (lipid cubic phase) crystallization of membrane proteins and complexes. 7.10 MAG differs from monoolein, the most extensively used lipid for in meso crystallization, in that it is shorter in chain length by one methylene and its cis olefinic bond is two carbons closer to the glycerol headgroup. These changes in structure alter the phase behavior of the hydrated lipid and the microstructure of the corresponding mesophases formed. Temperature–composition phase diagrams for 7.10 MAG have been constructed using small- and wide-angle X-ray scattering over a range of temperatures and hydration levels that span those used for crystallization. The phase diagrams include lamellar crystalline, fluid isotropic, lamellar liquid-crystalline, cubic-Ia3d, and cubic-Pn3m phases, as observed with monoolein. Conspicuous by its absence is the inverted hexagonal phase which is rationalized on the basis of 7.10 MAG’s chemical constitution. The cubic phase prepared with the new lipid facilitates the growth of crystals that were used to generate high-resolution structures of intramembrane β-barrel and α-helical proteins. Compatibility of fully hydrated 7.10 MAG with cholesterol and phosphatidylcholine means that these two lipids can be used as additives to optimize crystallogenesis in screening trials with 7.10 MAG as the host lipid.

Open Access

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Abstract: We present an extensive exploration of the solid-form landscape of chlorpropamide (CPA) using a combined experimental–computational approach at the frontiers of both fields. We have obtained new conformational polymorphs of CPA, placing them into context with known forms using flexible-molecule crystal structure prediction. We highlight the formation of a new polymorph (ζ-CPA) via spray-drying experiments despite its notable metastability (14 kJ/mol) relative to the thermodynamic α-form, and we identify and resolve the ball-milled η-form isolated in 2019. Additionally, we employ impurity- and gel-assisted crystallization to control polymorphism and the formation of novel multicomponent forms. We, thus, demonstrate the power of this collaborative screening approach to observe, rationalize, and control the formation of new metastable forms.

Open Access

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Abstract: Phase transitions in crystalline molecular solids have important implications in the fundamental understanding of materials properties and in the development of materials applications. Herein, we report the solid-state phase transition behavior of 1-iodoadamantane (1-IA) investigated using a multi-technique strategy [synchrotron powder X-ray diffraction (XRD), single-crystal XRD, solid-state NMR, and differential scanning calorimetry (DSC)], which reveals complex phase transition behavior on cooling from ambient temperature to ca. 123 K and on subsequent heating to the melting temperature (348 K). Starting from the known phase of 1-IA at ambient temperature (phase A), three low-temperature phases are identified (phases B, C, and D); the crystal structures of phases B and C are reported, together with a re-determination of the structure of phase A. Remarkably, single-crystal XRD shows that some individual crystals of phase A transform to phase B, while other crystals of phase A transform instead to phase C. Results (from powder XRD and DSC) on cooling a powder sample of phase A are fully consistent with this behavior while also revealing an additional transformation pathway from phase A to phase D. Thus, on cooling, a powder sample of phase A transforms partially to phase C (at 229 K), partially to phase D (at 226 K) and partially to phase B (at 211 K). During the cooling process, each of the phases B, C, and D is formed directly from phase A, and no transformations are observed between phases B, C, and D. On heating the resulting triphasic powder sample of phases B, C, and D from 123 K, phase B transforms to phase D (at 211 K), followed by the transformation of phase D to phase C (at 255 K), and finally, phase C transforms to phase A (at 284 K). From these observations, it is apparent that different crystals of phase A, which are ostensibly identical at the level of information revealed by XRD, must actually differ in other aspects that significantly influence their low-temperature phase transition pathways. This unusual behavior will stimulate future studies to gain deeper insights into the specific properties that control the phase transition pathways in individual crystals of this material.