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Inherently chiral calix[4]arenes with C4-symmetry are extremely rare and difficult to synthesise, severely hampering any effort to expand on their potential as chiral supramolecular catalysts and building blocks. Herein we report a reaction of a tetracarbamate calix[4]arene with NBS which results in a high yield of an inherently chiral calix[4]arenes with C4-symmetry. Furthermore, employing a chiral N-Boc proline moiety allows for separation of the diastereomers formed, thus obtaining the pure enantiomers after hydrolysis. The enantiomers could be assigned based on the CD spectra and DFT calculated values.

In silico adsorption of eight antimalarials that inhibit β-hematin (synthetic hemozoin) formation identified a primary binding site on the (001) face, which accommodates inhibitors via formation of predominantly π-π interactions. A good correlation (r(2) = 0.64, P = 0.017) between adsorption energies and the logarithm of β-hematin inhibitory activity was found for this face. Of 53 monocyclic, bicyclic and tricyclic scaffolds, the latter yielded the most favorable adsorption energies. Five new amino-phenoxazine compounds were pursued as β-hematin inhibitors based on adsorption behaviour. The 2-substituted phenoxazines show good to moderate β-hematin inhibitory activity (< 100 μM) and Plasmodium falciparum blood stage activity against the 3D7 strain. N(1),N(1)-diethyl-N(4)-(10H-phenoxazin-2-yl)pentane-1,4-diamine (P2a) is the most promising hit with IC(50) values of 4.7 ± 0.6 and 0.64 ± 0.05 μM, respectively. Adsorption energies are predictive of β-hematin inhibitory activity, and thus the in silico approach is a beneficial tool for structure-based development of new non-quinoline inhibitors.

The supramolecular chemistry of a phenylpyridine-functionalized zwitterion, formed by a simple reaction between acetylenedicarboxylic acid and 4-phenylpyridine, has been investigated. Two polymorph...

The thermal expansion behaviour of a series of 1D coordination polymers has been investigated. Variation of the metal centre allows tuning of the thermal expansion behaviour from colossal positive volumetric to extreme anomalous thermal expansion. Preparation of solid solutions increased the magnitude of the anomalous thermal expansion further, producing two species displaying supercolossal anisotropic thermal expansion (ZnCoCPHTαY2 = −712 MK−1, αY3 = 1632 MK−1 and ZnCdCPHTαY2 = −711 MK−1, αY3 = 1216 MK−1).

This study illustrates mechanochemical control over the formation of three coordination polymer solvates. Variation in the onset of grinding, aging after grinding and solvent water content leads to selective preparation of two solvates, which crystallize concomitantly when prepared solvothermally in DMF. A third solvate may be prepared with DMA. Finally, solvent exchange provides means of interconverting between the three solvates.

Mechanochemistry enables enzymatic cleavage of cellulose into glucose without bulk solvents, acids, other aggressive reagents, or substrate pre-treatment. This clean mechanoenzymatic process (coined RAging) is also directly applicable to biomass, avoids many limitations associated with the use of cellulases, and produces glucose concentrations greater than three times that obtained by conventional methods.

The reaction between acetylenedicarboxylic acid and nicotinamide or isonicotinamide produces two new zwitterionic molecules, namely (Z)-2-(3-carbamoylpyridin-1-ium-1-yl)-3-carboxyacrylate (1) and (Z)-2-(4-carbamoylpyridin-1-ium-1-yl)-3-carboxyacrylate (2), as well as a salt by-product, 4-carbamoylpyridinium acetylenedicarboxylate (2a). The solid-state behaviour of the zwitterions has been investigated by altering variables such as the solvent(s) used for synthesis and crystallisation, and the temperature at which these occur. Zwitterions 1 and 2, as well as a previously reported zwitterion, (Z)-2-(4-cyanopyridin-1-ium-1-yl)-3-carboxyacrylate (3), were combined with various small organic co-formers in an attempt to form multi-component crystals via both mechanochemical and solution methods. Three new hydrated salts were formed with melamine (1·melamine, 2·melamine, and 3·melamine), all of which display extensive charge-assisted hydrogen-bonding networks. Zwitterions 1 and 2 also form the characteristic R22(8) hydrogen-bond motif between the amide group and melaminium. Based on these observed trends in hydrogen bonding, further crystallisation experiments were attempted with molecules with similar hydrogen bonding capability to melamine. Although single crystals were not obtained, six potential salts have been identified based on PXRD, NMR and IR data. Compared to the number of co-formers used, the discovery of only three salts per zwitterion is unusual – a Cambridge Structural Database analysis indicates that this may be due to the robust nature of the hydrogen bonds between zwitterions themselves.

Two new ligands, pyridylamido-sulfadoxine (L1) and quinolylamido-sulfadoxine (L2), were prepared by the reaction of the antimicrobial sulfadrug, sulfadoxine, with either 2-picolinic acid or 2-quinaldic acid. Subsequent reaction with a [CpxIrCl2]2 dimer (where Cpx = pentamethylcyclopentadiene, tetramethylphenylcyclopentadiene or tetramethylbiphenylcyclopentadiene) yielded six new amidosulfadoxine-derivatized iridium complexes (C1-C6) in moderate to good yields, where the ligands act as N,N’-bidentate chelators. Proton and carbon NMR spectroscopy, mass spectrometry and HPLC data were used to characterize and confirm the purity of all compounds. Aquation chemistry studies on the complexes revealed slow water substitution of the chlorido ancillary ligand. The inhibitory activities of complexes C1-C6 were determined against Mycobacterium tuberculosis (Mtb) H37Rv and Plasmodium falciparum (Pf) strains, 3D7, Dd2 and HB3, as well as the HEK cell line. The ligands showed no appreciable antimicrobial activity, with most of the complexes exhibiting weak to moderate inhibition of Pf and Mtb. However, one complex (C6) displayed potent activity against Pf 3D7 (IC50 of 0.975 µM) and the multidrug-resistant Pf Dd2 (IC50 of 0.766 µM).

This overview highlights the emergent area of mechanochemical reactions for making active pharmaceutical ingredients (APIs), and covers the latest advances in the recently established area of mechanochemical screening and synthesis of pharmaceutical solid forms, specifically polymorphs, cocrystals, salts and salt cocrystals. We also provide an overview of the most recent developments in pharmaceutical uses of mechanochemistry, including real-time reaction monitoring, techniques for polymorph control and approaches for continuous manufacture using twin screw extrusion, and more. Most importantly, we show how the overlap of previously unrelated areas of mechanochemical screening for API solid forms, organic synthesis by milling, and mechanochemical screening for molecular recognition, enables the emergence of a new research discipline in which different aspects of pharmaceutical and medicinal chemistry are addressed through mechanochemistry rather than through conventional solution-based routes. The emergence of such medicinal mechanochemistry is likely to have a strong impact on future pharmaceutical and medicinal chemistry, as it offers not only access to materials and reactivity that are sometimes difficult or even impossible to access from solution, but can also provide a general answer to the demands of the pharmaceutical industry for cleaner, safer and efficient synthetic solutions.

The reaction between acetylenedicarboxylic acid and 4-benzylpyridine yields two products: a salt and a zwitterion. The relationship between these two products has been investigated, revealing that the salt is the kinetic product of the reaction and the zwitterion is the thermodynamic product. The zwitterion has four polymorphs and three solvates. Interconversion between these forms has been studied and was shown to be solvent-mediated when it occurs; conversion between most polymorphic forms cannot be achieved using thermal methods. The temperature at which the reaction to form the zwitterion is carried out and the solvent system used are crucial in determining which polymorphic form crystallizes from the reaction. In addition, polymorphic Form I is shown to be porous to dioxane.

A new class of potential supramolecular building blocks is presented. The synthesis and crystal structures of seven novel pyridinium-derived zwitterionic compounds are discussed, as well as two related pyridinium salts. The synthesis of these compounds was achieved by simple solution methods using mild conditions, and the products were isolated as single crystals with no further purification required. Hydrogen-bonded chains were found to be prevalent in all of the crystal structures of the zwitterions and due to the robust nature of this motif, these compounds have the potential to be exploited in future supramolecular studies. There is a large scope for the synthesis of related zwitterionic compounds using a range of pyridyl substituents with varied functional groups. These zwitterionic compounds show great potential as a new class of supramolecular building block in the formation of ionic- as well as metal–organic frameworks.

This overview highlights the emergent area of mechanochemical reactions for making active pharmaceutical ingredients (APIs), and covers the latest advances in the recently established area of mechanochemical screening and synthesis of pharmaceutical solid forms, specifically polymorphs, cocrystals, salts and salt cocrystals. We also provide an overview of the most recent developments in pharmaceutical uses of mechanochemistry, including real-time reaction monitoring, techniques for polymorph control and approaches for continuous manufacture using twin screw extrusion, and more. Most importantly, we show how the overlap of previously unrelated areas of mechanochemical screening for API solid forms, organic synthesis by milling, and mechanochemical screening for molecular recognition, enables the emergence of a new research discipline in which different aspects of pharmaceutical and medicinal chemistry are addressed through mechanochemistry rather than through conventional solution-based routes. The emergence of such medicinal mechanochemistry is likely to have a strong impact on future pharmaceutical and medicinal chemistry, as it offers not only access to materials and reactivity that are sometimes difficult or even impossible to access from solution, but can also provide a general answer to the demands of the pharmaceutical industry for cleaner, safer and efficient synthetic solutions.

A simple approach is described for the identification of packing motifs in crystal structures of aromatic molecules using Hirshfeld surfaces and fingerprint plot analysis. The method was first validated by investigating previously studied molecules and establishing trends within these data, and then applied to the analysis of crystal structures of heteroaromatic molecules extracted from the Cambridge Structural Database. A series of cocrystal structures containing these same heteroaromatic molecules were also extracted and investigated using the same method. This simple method appears to be both consistent and robust in distinguishing the different types of packing motifs in structures of aromatic molecules.

Phenanthrenyl-based metallocycles are mechanically interlinked to form an infinite catenated chain. The formation of the catenane is governed by an infinite π···π stack involving the phenanthrenyl moieties.

A second polymorphic form of a 1 : 2 : 3 pamoate : DABCO : water salt has been obtained by liquid-assisted grinding, and it is shown that interconversion between this salt and a salt with 1 : 1 : 2 stoichiometry is facile via liquid-assisted grinding with additional amounts of pamoic acid (to generate the 1 : 1 : 2 salt) or DABCO (to generate the 1 : 2 : 3 salt).

In the title compound, C16H14S5, the non-bonded intramolecular distances between the non-terminal S atoms are 2.808 (16) and 2.784 (16) Å, shorter than the typical distance of 2.9 Å. One phenyl ring participates in an offset π-π interaction with another phenyl ring related by a centre of inversion; the interplanar distance is 3.41 (2) Å. The crystal structure also exhibits edge-to-face C—H...π stacking of the phenyl rings, thus forming a herring-bone packing motif.

Flexible metal–organic materials that exhibit stimulus-responsive switching between closed (non-porous) and open (porous) structures induced by gas molecules are of potential utility in gas storage and separation. Such behaviour is currently limited to a few dozen physisorbents that typically switch through a breathing mechanism requiring structural contortions. Here we show a clathrate (non-porous) coordination network that undergoes gas-induced switching between multiple non-porous phases through transient porosity, which involves the diffusion of guests between discrete voids through intra-network distortions. This material is synthesized as a clathrate phase with solvent-filled cavities; evacuation affords a single-crystal to single-crystal transformation to a phase with smaller cavities. At 298 K, carbon dioxide, acetylene, ethylene and ethane induce reversible switching between guest-free and gas-loaded clathrate phases. For carbon dioxide and acetylene at cryogenic temperatures, phases showing progressively higher loadings were observed and characterized using in situ X-ray diffraction, and the mechanism of diffusion was computationally elucidated.