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The ability to rationally design and predictably construct crystalline solids has been the hallmark of crystal engineering research. To date, numerous examples of multicomponent crystals comprising organic molecules have been reported. However, the crystal engineering of cocrystals comprising both organic and inorganic chemical units is still poorly understood and mostly unexplored. Here, we report a new diverse set of higher‐order cocrystals (HOCs) based on the structurally versatile—yet largely unexplored—phosph(V/V)azane heterosynthon building block. The novel ternary and quaternary cocrystals reported are held together by synergistic and orthogonal intermolecular interactions. Notably, the HOCs can be readily obtained either via sequential or one‐pot mechanochemical methods. Computational modelling methods reveal that the HOCs are thermodynamically driven to form and that their mechanical properties strongly depend on the composition and intermolecular forces in the crystal, offering untapped potential for optimizing material properties., Mechanosynthesis gives ternary and quaternary hybrid organic‐inorganic cocrystals held together via synergistic intermolecular interactions. Notably, higher‐order ternary and quaternary cocrystals can be readily obtained either via serial synthetic routes from the individual components or via one‐pot approaches.

There are many active pharmaceutical ingredients that lack N-H, O-H and S-H hydrogen-bond donor functional groups. N,N-disubstituted O-thiocarbamates are examples of molecules that display such a feature. Despite the desirable medicinal properties displayed by some N,N-disubstituted O-thiocarbamates, the study of the solid-state properties of these compounds has been relatively unexplored. Herein, we report the synthesis and analysis of the structures and properties of a series of N,N-dimethyl-O-thiocarbamates, and use X-ray diffraction techniques to gain insight into how these molecules self-assemble in the solid-state. As part of our work, we report for the first time the crystal structure of Tolnaftate, an active pharmaceutical ingredient that is indicated for the treatment of fungal infections. It was observed that the aryl-thiocarbamate C-O bonds are twisted such that the planar aryl and carbamate moieties are orthogonal. Such a non-planar molecular geometry affects the way the molecules pack and crystal structure analyses revealed four general modes in which the molecules can assemble in the solid-state, with some members of the series displaying isostructural relationships. Computational modelling of the cohesive energy densities in the crystals suggests that there is no single stacking type that is associated with greater stability. However, crystals with a combination of high packing index and π···π stacking interactions appear to display large cohesive energy densities. The lack of strong hydrogen bonding interactions in the crystals also leads to relatively low Young’s moduli that are within a narrow range of 10-15 GPa for all 14 crystal structures reported. Agency for Science, Technology and Research (A*STAR) Accepted version F.G. would like to thank A*STAR AME IRG (A1783c0003) and a NTU start-up grant (M4080552) for financial support. H.S.S. is grateful for the Singapore Ministry of Education Academic Research Fund Tier 1 grants RG 111/18 and RT 05/19. H.S.S. also acknowledges that this project is supported by A*STAR under the AME IRG grants A1783c0003, A1783c0002, and A1783c0007 D.T. would like to thank A*STAR for a postdoctoral research fellowship. .M. would like to acknowledge Khalifa University for financial support under the CIRA program (Project Code: CIRA-2018-068). The theoretical calculations were performed using the high-performance computing clusters of Khalifa University and the authors would like to acknowledge the support of the research computing department.

The ability to rationally design and predictably construct crystalline solids has been the hallmark of crystal engineering research over the past two decades. When building higher-order multicomponent cocrystals (i.e. crystals containing more than two constituents), the differential and hierarchical way molecules interact and assemble in the solidstate is of pinnacle importance. To date, numerous examples of multicomponent crystals comprising organic molecules leading to salts, cocrystals or ionic cocrystals have been reported. However, the crystal engineering of hybrid organicinorganic cocrystals with sophisticated inorganic building blocks is still poorly understood and mostly unexplored. Here, we reveal the first efficient mechanochemical synthesis of higher-order hybrid organic-inorganic cocrystals based on the structurally versatile – yet largely unexplored – cyclodiphos(V/V)azane heterosynthon building block. The novel hybrid ternary and quaternary multicomponent cocrystals herein reported are held together by synergistic intermolecular interactions (e.g., hydrogen- and halogen-bonding, Se-π and ion-dipole interactions). Notably, higher-order ternary and quaternary cocrystals can be readily obtained either via direct synthetic routes from its individual components, or via unprecedented telescopic approaches from lower-order cocrystal sets. In addition, computational modelling has also revealed that the formation of higher-order cocrystals is thermodynamically driven, and that bulk moduli and compressibilities are strongly dependent on the chemical composition and intermolecular forces present in the crystals, which offer untapped potential for optimizing material properties.

Energy computations on the title salt show a clear preference for solvated structures, which correlates with the most effective formation of hydrogen bonds., Repeated attempts to crystallize 1-adamantane­methyl­amine hydro­chloride as an anhydrate failed but the salt was successfully crystallized as a solvate (2C11H20N+·2Cl−·0.5C4H8O2·H2O), with water and 1,4-dioxane playing a structural role in the crystal and engaging in hydrogen-bonding inter­actions with the cation and anion. Computational crystal-structure prediction was used to rationalize the solvent-inclusion behaviour of this salt by computing the solvent-accessible voids in the predicted low-energy structures for the anhydrate: the global lattice-energy minimum structure, which has the same packing of the ions as the solvate, has solvent-accessible voids that account for 3.71% of the total unit-cell volume and is 6 kJ mol−1 more stable than the next most stable predicted structure.

The crystal energy landscapes of the salts of two rigid pharmaceutically active molecules reveal that the experimental structure of amantadine hydrochloride is the most stable structure with the majority of low-energy structures adopting a chain hydrogen-bond motif and packings that do not have solvent accessible voids. By contrast, memantine hydrochloride which differs in the substitution of two methyl groups on the adamantane ring has a crystal energy landscape where all structures within 10 kJ mol−1of the global minimum have solvent-accessible voids ranging from 3 to 14% of the unit-cell volume including the lattice energy minimum that was calculated after removing water from the hydrated memantine hydrochloride salt structure. The success in using crystal structure prediction (CSP) to rationalize the different hydration propensities of these substituted adamantane hydrochloride salts allowed us to extend the model to predict under blind test conditions the experimental crystal structures of the previously uncharacterized 1-(methylamino)adamantane base and its corresponding hydrochloride salt. Although the crystal structure of 1-(methylamino)adamantane was correctly predicted as the second ranked structure on the static lattice energy landscape, the crystallization of aZ′ = 3 structure of 1-(methylamino)adamantane hydrochloride reveals the limits of applying CSP when the contents of the crystallographic asymmetric unit are unknown.

The underlying molecular and crystal properties affecting the crystallisation of ionic cocrystals (ICCs) with the general formula A-B+N (A- = anion, B+ = cation and N = neutral acid molecule; 1 : 1 : 1 stoichiometry) are reported for a limited set of known crystal structures determined following the cocrystallisation of either 4-aminopyridine (which forms salts) or 4-dimethylaminopyridine (which forms salts and ICCs) with the same set of monoprotic acids with a single hydroxy or halogen substitution at the ortho or para position. Periodic density functional theory calculations (PBE + D2) on the energetic driving force for ICC crystallisation for a set of known crystal structures with well characterised acid, salt and ICC structures show that all but 1 of the 7 experimental ICC structures surveyed were more stable than the sum of their component salt and acid structures with 4 displaying relative stabilities (ΔEICC) ranging from 2.47-8.02 kJ mol-1. The majority of molecular ICCs that are more stable with respect to their component salt and acid structures display the formation of discrete intermolecular O-HacidOanion hydrogen bonds with the D11(2) graph set between the carboxylic acid OH donor and the carboxylate oxygen acceptor of the anion. Computed crystal form landscapes for model 1 : 1 salts derived from acid-base pairs (involving 4-dimethylaminopyridine) known to form molecular ICCs show that on average the most stable predicted polymorphs of the 1 : 1 salts have efficient packing of the ions with packing coefficients in the range 65-80% and this is comparable to the packing coefficients of the most stable predicted polymorphs of 1 : 1 salts (involving 4-aminopyridine) that have no ICCs reported. This suggests that the cocrystallisation of equimolar amounts of the 1 : 1 salt and the acid to form a 1 : 1 : 1 molecular ICC is a complicated phenomenon that cannot be explained on the basis of inefficiencies in the crystal packing of the salt ions.

The promising aspect of photocatalysis to effectively utilize the abundant solar irradiation for promoting various chemical reactions and environmental remediation at greener, low-energy demanding conditions resulted in the recent surge in this research field. In this review, the synthesis and structure-property relationships of photoactive porous organic polymers (POPs) followed by their environmentally benign applications including various chemical transformations and decontamination of pollutants involving key intermediate reactive species have been critically discussed. The conditions required to generate these active species such as photo-generated electron and hole pair, singlet oxygen, superoxide, organic radical, etc. and their different quenching pathways are initially explained to clearly portray the favourable settings necessary for efficient POP-photocatalysis. This introductory discussion is further extrapolated to systematically illustrate the structure-application correlation of every visible-light-responsive POPs reported to date. The mechanisms adapted by POPs for photocatalytic organic reactions and degradation of wastewater pollutants have been comprehensively depicted. Initial discussion on reactive species is envisioned to provide a clear grasp on these later-explained mechanistic pathways. The review is finally concluded by crucially explaining the existing limitations and future development prospects of this field.

The lattice energy landscape is calculated for three pyridinium carboxylate salts and the corresponding pyridine·carboxylic acid cocrystals. Experimentally, one system crystallizes as a salt, another as a cocrystal and the acidic proton in the third is disordered across the N(arom)...O hydrogen bond vector. A novel structure of a 1:1 4-cyanopyridine·4-fluorobenzoic acid cocrystal (I) was characterized to provide the cocrystal as a system with an isolated carboxylic acid-pyridine heterosynthon. By contrast, the 4-dimethylaminopyridinium maleate salt (GUKVUE) shows the effects of an internal hydrogen bond, and the proton-disordered pyridine·isophthalic acid crystal (IYUPEX) shows the effects of competing intermolecular hydrogen bonds. All three crystal structures were found low in energy on the lattice energy landscape for the correct proton connectivity. For all three systems, comparing the salt and cocrystal energy landscapes shows the importance of the proton position for the relative stabilities of structures, despite the expected similarities between the ionized and neutral forms of the carboxylic acid-pyridine heterosynthon. The systems with additional hydrogen bonds have some hydrogen bonding motifs that are only favourable for the salt or for the cocrystal. This illustrates the sensitivity of the range of thermodynamically plausible crystal structures to whether the molecules are assumed to be ionized or neutral.

The two-component crystals formed from pyridine or 4-dimethylaminopyridine with maleic, fumaric, phthalic, isophthalic, or terephthalic acids were characterized by X-ray diffraction. The two-component solid forms involving pyridine included both salts and cocrystals, while 4-dimethylaminopyridine crystallized exclusively as a salt, in agreement with the differences in the pKa values. Five previously unknown salt solid forms of 4-dimethylaminopyridine and the crystal structure of a pyridine fumaric acid (2:1) cocrystal are reported. An in-situ base catalyzed isomerization of maleic acid was observed in cocrystallization experiments involving pyridine. The salts formed between 4-dimethylaminopyridine and fumaric acid included one or two fumaric acid molecules within the crystal lattice. Thus, the reported grid of crystal forms demonstrates the limitations of empirical rules for predicting the stoichiometry and covalent bonding of the acidic proton within salts and cocrystals. Many of the crystal structures ...

The ability of the pharmaceutically acceptable cocrystallising agents, succinic acid and 4-aminobenzoic acid, to form cocrystals with ten small organic molecules with hydrogen bonding acceptors but no donors, was investigated by grinding, hot-stage microscopy and solution based crystallisation experiments. The reproducible results obtained by different methods showed that only six cocrystals formed. The crystal structures of the four novel cocrystals, succinic acid·2,2′-bipyridine (1 : 1, P21/c, I), succinic acid·diphenylcyclopropenone (1 : 2, P21/c, II), 4-aminobenzoic acid·antipyrine (1 : 1, P21, III) and 4-aminobenzoic acid·phenazine (1 : 2, P, IV), are reported. The computed crystal energy landscapes of the cocrystals and their components show why succinic acid·1,4-dicyanobenzene did not form a cocrystal as well as predicting the observed structure of succinic acid·2,2′-bipyridine as the most stable. The most stable hypothetical structures of a 1 : 1 succinic acid·1,4-dicyanobenzene cocrystal are closely related to those of the components. The results demonstrate that cocrystal formation requires both hydrogen bonding and close packing, and so markedly non-planar pharmaceuticals will be quite specific in the steric and hydrogen bonding disposition requirement of coformers.

The title 1,4-dioxane solvate, C8H4FNO2·C4H8O2, was isolated during a manual crystallization screen on 7-fluoro­isatin (7-fluoro­indoline-2,3-dione). The 7-fluoro­isatin mol­ecule occupies a general position and each of the independent mol­ecules of 1,4-dioxane is disposed about a centre of inversion, with half of each in the asymmetric unit. Hydrogen-bonded ribbons of 7-fluoro­isatin are linked by 1,4-dioxane to form sheets parallel to (30\overline{1}). Whilst one solvent mol­ecule has an active role in the sheet formation, the other simply fills the cavity formed within the sheet.

The title compound, C9H7FN2O4, was isolated during a manual crystallization screen on 5-fluoroisatin (5-fluoroindoline-2,3-dione). Hydrogen-bonded ribbons of the oxindole are formed through pairs of N-H center dot center dot center dot O and O-H center dot center dot center dot O interactions. These ribbons then pack parallel to (09 (2) over bar) and (091) such that a herring-bone motif is established.

The title dimethyl sulfoxide (DMSO) solvate, C8H4FNO2 center dot-C2H6OS, was isolated during a manual crystallization screen on 5-fluoroisatin (5-fluoroindoline-2,3-dione). Molecules of 5-fluoroisatin are linked via C-H center dot center dot center dot O interactions to form chains parallel to (0 (1) over bar1) from which N-H center dot center dot center dot O hydrogen-bonded DMSO molecules protrude.