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Molecular crystals have shown remarkable adaptability in response to a range of external stimuli. Here, we survey this emerging field and provide a critical overview of the experimental, computational and instrumental tools being used to design and apply such materials.

Two-dimensional (2D) materials have been developed intensively over the last decade, and combining different 2D materials to form heterogeneous 2D materials is anticipated to be more attractive with broader applications. The precise evaluation and prediction of interfacial properties of 2D heterostructures are critical for designing more robust heterostructures and developing advanced, engineered molecular devices. Here, we present a brief review on experimental (namely, atomic force microscopy (AFM), in situ peel test, double cantilever beam, pressurized blister test and sheet-on-bead method) and theoretical techniques (namely, molecular dynamics and density functional theory) for probing the adhesion/interaction energy of the interface of 2D heterogeneous materials and paving the way for future applications.

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.

Although many examples of mechanically flexible crystals are currently known, their utility in all-flexible devices is not yet demonstrated, despite their immense potential for fabricating high-performance flexible devices. We report two alkylated diketopyrrolopyrrole (DPP) semiconducting single crystals, one of which displays impressive elastic mechanical flexibility whilst the other is brittle. Using the single crystal structures and density functional theory (DFT) calculations, we show that the methylated diketopyrrolopyrrole (DPP-diMe) crystals, with dominant π-stacking interactions and large contributions from dispersive interactions, are superior in terms of their stress tolerance and field-effect mobility (µFET) when compared to the brittle crystals of ethylated diketopyrrolopyrrole derivative (DPP-diEt). The field effect transistors (FETs) made of flexible substrates using elastic microcrystals of DPPdiMe retained µFET (from 0.019 cm2/Vs to 0.014 cm2/Vs ) more efficiently even after 40 bending cycles when compared to the brittle microcrystals of DPP-diEt which showed a significant drop in µFET just after 10 bending cycles. Our results not only provide valuable insights into bending mechanism but also demonstrate the untapped potential of mechanically flexible semiconducting crystals for designing all flexible durable devices.

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.

Dynamic organic crystals are rapidly gaining traction as a new class of smart materials for energy conversion, however, they are only capable of very small strokes (

Organic crystals are emerging as mechanically compliant, light-weight and chemically versatile alternatives to the commonly used silica and polymer waveguides. However, the previously reported organic crystals were shown to be able to transmit visible light, whereas actual implementation in telecommunication devices requires transparency in the near-infrared spectral range. Here we demonstrate that single crystals of the amino acid L-threonine could be used as optical waveguides and filters with high mechanical and thermal robustness for transduction of signals in the telecommunications range. On their (00\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\bar 1$$\end{document}1¯) face, crystals of this material have an extraordinarily high Young’s modulus (40.95 ± 1.03 GPa) and hardness (1.98 ± 0.11 GPa) for an organic crystal. First-principles density functional theory calculations, used in conjunction with analysis of the energy frameworks to correlate the structure with the anisotropy in the Young’s modulus, showed that the high stiffness arises as a consequence of the strong charge-assisted hydrogen bonds between the zwitterions. The crystals have low optical loss in the O, E, S and C bands of the spectrum (1250−1600 nm), while they effectively block infrared light below 1200 nm. This property favors these and possibly other related organic crystals as all-organic fiber-optic waveguides and filters for transduction of information., Fiber-optics based on organic crystals could have potential for unique telecommunications applications but typically transmit visible wavelengths. Here the authors present mechanically robust organic crystals with favourable optical properties across the main telecommunication bands in the near-infrared.

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.

A set of calculated structural descriptors [% solvent accessible volumes per unit cell (% SAVs), the relative packing index and the estimated distance of polar/non-polar groups on the acid relative to the lattice positions corresponding to crystal voids] were used to assess the utility of predicted crystal form landscapes (CFLs) in warning against the risks of crystal hydration using model carboxylic acids that are known to crystallise as anhydrate, monohydrate and dihydrate crystal phases, respectively. The crystal structures of 1-adamantaneacetic acid and 3-bromoadamantane-1-acetic acid are reported as anhydrates following crystallisation screens for possible hydrates of both. The results show that % SAVs are a poor predictor of crystal hydration as the majority of the predicted anhydrate polymorphs (up to a relative lattice energy range of 10 kJ mol−1) for all systems did not display packings with solvent accessible voids. The relative packing index (ΔPI) of the known hydrates and the set of low energy predicted anhydrate polymorphs was found to be a useful predictor of crystal packing frustration. 4-Oxocyclohexanecarboxylic acid which crystallises as a monohydrate (INOGEX) displayed a CFL where 86% of the predicted anhydrate polymorphs within a relative lattice energy range of 10 kJ mol−1 displayed poorer crystal packings than the monohydrate. By contrast, in 2-pyrone-4,6-dicarboxylic acid which crystallises as a dihydrate (KISJEC), only 15% of predicted anhydrate polymorphs had a lower packing efficiency than the dihydrate, indicating that the crystal hydration for this system is not driven by poor crystal packing of the acid. Careful inspection of the hydrogen bond motifs adopted by the predicted anhydrate polymorphs has shown that crystal hydration in 2-pyrone-4,6-dicarboxylic acid may be driven by the need to satisfy all hydrogen bond donor/acceptor groups on the acid whilst in 4-oxocyclohexanecarboxylic acid, water inclusion is likely to be driven by poor crystal packing of the low energy anhydrate polymorphs for this molecule. The results suggest that careful analysis of the packing efficiencies and the lattice positions of the crystal voids in predicted anhydrate polymorphs can provide clues to the driving force for crystal hydration as well as the types of intermolecular acid–water interactions that may be observed in hydrated crystal forms.

The discovery of molecular ionic cocrystals (ICCs) of active pharmaceutical ingredients (APIs) widens the opportunities for optimizing the physicochemical properties of APIs whilst facilitating the delivery of multiple therapeutic agents. However, ICCs are often observed serendipitously in crystallization screens and the factors dictating their crystallization are poorly understood. We demonstrate here that mechanochemical ball milling is a versatile technique for the reproducible synthesis of ternary molecular ICCs in less than 30 min of grinding with or without solvent. Computational crystal structure prediction (CSP) calculations have been performed on ternary molecular ICCs for the first time and the observed crystal structures of all the ICCs were correctly predicted. Periodic dispersion‐corrected DFT calculations revealed that all the ICCs are thermodynamically stable (mean stabilization energy=−2 kJ mol−1) relative to the crystallization of a physical mixture of the binary salt and acid. The results suggest that a combined mechanosynthesis and CSP approach could be used to target the synthesis of higher‐order molecular ICCs with functional properties., Spot on predictions! The mechanosynthesis of ternary molecular ionic cocrystals (ICCs) with significantly different physicochemical properties has been achieved in less than 30 min of grinding. The crystal structures of the ICCs were successfully predicted by using computational methods. The results pave the way for the efficient screening of higher‐order multicomponent crystal forms with functional properties (see figure).

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.

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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.

Over the past two decades, computational methods of crystal structure prediction (CSP) have shown enormous potential in complementing the efforts of crystal engineers to synthesise and characterise new solid forms of organic molecules. This chapter summarises the insights that can be gained from computational methods of CSP when integrated as part of experimental efforts to synthesise and characterise the crystal structures of organic molecules. The value of CSP methods is that they allow us to map the range of packing alternatives that a single-component or multi-component molecular system may adopt in the crystal as a function of the lattice energy. CSP methods can now handle large flexible organic molecules with the sort of complexity typically seen in pharmaceutical drug development pipelines, and it is now not unusual to find the experimentally observed crystal structure at, or close to, the global minimum in the crystal lattice energy landscape with the use of accurate dispersion-corrected density functional theory methods. The fundamental promise of CSP methods is to move us to a point where we can generate a set of plausible low-energy predicted structures for any molecule and be able to target the crystallisation and characterisation of a preferred structure.

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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 sixth blind test of organic crystal structure prediction (CSP) methods has been held, with five target systems: a small nearly rigid molecule, a polymorphic former drug candidate, a chloride salt hydrate, a co-crystal and a bulky flexible molecule. This blind test has seen substantial growth in the number of participants, with the broad range of prediction methods giving a unique insight into the state of the art in the field. Significant progress has been seen in treating flexible molecules, usage of hierarchical approaches to ranking structures, the application of density-functional approximations, and the establishment of new workflows and `best practices´ for performing CSP calculations. All of the targets, apart from a single potentially disordered Z?? = 2 polymorph of the drug candidate, were predicted by at least one submission. Despite many remaining challenges, it is clear that CSP methods are becoming more applicable to a wider range of real systems, including salts, hydrates and larger flexible molecules. The results also highlight the potential for CSP calculations to complement and augment experimental studies of organic solid forms. Fil: Reilly, Anthony M.. Cambridge Crystallographic Data Centre; Fil: Cooper, Richard I.. Chemistry Research Laboratory; Fil: Adjiman, Claire S.. Imperial College London; Reino Unido Fil: Bhattacharya, Saswata. Fritz Haber Institute Of The Max Planck Society; Fil: Boese, A. Daniel. Karl-franzens-universitat Graz; Austria Fil: Brandenburg, Jan Gerit. Colegio Universitario de Londres; Reino Unido. Universitat Bonn; Alemania Fil: Bygrave, Peter J.. University of Southampton; Reino Unido Fil: Bylsma, Rita. Radboud Universiteit Nijmegen; Países Bajos Fil: Campbell, Josh E.. University of Southampton; Reino Unido Fil: Car, Roberto. University of Princeton; Estados Unidos Fil: Case, David H.. University of Southampton; Reino Unido Fil: Chadha, Renu. University Institute Of Pharmaceutical Sciences India; India Fil: Cole, Jason C.. Cambridge Crystallographic Data Centre; Fil: Cosburn, Katherine. University of Tulane; Estados Unidos. University of Toronto; Canadá Fil: Cuppen, Herma M.. Radboud Universiteit Nijmegen; Países Bajos Fil: Curtis, Farren. University of Tulane; Estados Unidos. University of Carnegie Mellon; Estados Unidos Fil: Day, Graeme M.. University of Southampton; Reino Unido Fil: DiStasio, Robert A.. University of Princeton; Estados Unidos. Cornell University; Estados Unidos Fil: Dzyabchenko, Alexander. Karpov Institute Of Physical Chemistry; Fil: Van Eijck, Bouke P.. University of Utrecht; Países Bajos. Utrecht University; Países Bajos Fil: Elking, Dennis M.. Openeye Scientific Software, Inc; Fil: Van Den Ende, Joost A.. Radboud Universiteit Nijmegen; Países Bajos Fil: Facelli, Julio C.. University of Utah; Estados Unidos Fil: Ferraro, Marta B.. Universidad de Buenos Aires; Argentina Fil: Fusti-Molnar, Laszlo. Openeye Scientific Software, Inc; Fil: Gatsiou, Christina-Anna. Imperial College London; Reino Unido Fil: Gee, Thomas S.. University of Southampton; Reino Unido Fil: De Gelder, René. Radboud Universiteit Nijmegen; Países Bajos Fil: Ghiringhelli, Luca M.. Fritz Haber Institute Of The Max Planck Society; Fil: Goto, Hitoshi. Toyohashi University Of Technology; Fil: Grimme, Stefan. Universitat Bonn; Alemania Fil: Guo, Rui. Colegio Universitario de Londres; Reino Unido Fil: Hofmann, Detlef W. M.. Flexcryst; . Polaris; Fil: Hoja, Johannes. Fritz Haber Institute Of The Max Planck Society; Fil: Hylton, Rebecca K.. Colegio Universitario de Londres; Reino Unido Fil: Iuzzolino, Luca. Colegio Universitario de Londres; Reino Unido Fil: Jankiewicz, Wojciech. University Of Silesia In Katowice; Fil: De Jong, Daniël T.. Radboud Universiteit Nijmegen; Países Bajos Fil: Kendrick, John. University Of Bradford; Fil: De Klerk, Niek J. J.. Radboud Universiteit Nijmegen; Países Bajos Fil: Ko, Hsin-Yu. University of Princeton; Estados Unidos Fil: Kuleshova, Liudmila N.. Flexcryst; Fil: Li, Xiayue. University of Tulane; Estados Unidos. Argonne National Laboratory; Estados Unidos Fil: Lohani, Sanjaya. University of Tulane; Estados Unidos Fil: Leusen, Frank J. J.. University Of Bradford; Fil: Lund, Albert M.. University of Utah; Estados Unidos. Openeye Scientific Software, Inc; Fil: Lv, Jian. Jilin University; China Fil: Ma, Yanming. Jilin University; China Fil: Marom, Noa. University of Carnegie Mellon; Estados Unidos. University of Tulane; Estados Unidos Fil: Masunov, Artëm E.. University Of Central Florida; . National Research Nuclear University Mephi; Fil: McCabe, Patrick. Cambridge Crystallographic Data Centre; Fil: McMahon, David P.. University of Southampton; Reino Unido Fil: Meekes, Hugo. Radboud Universiteit Nijmegen; Países Bajos Fil: Metz, Michael P.. University Of Delaware; Fil: Misquitta, Alston J.. Queen Mary, University Of London; Fil: Mohamed, Sharmarke. Khalifa University Of Science And Technology; Fil: Monserrat, Bartomeu. Rutgers, The State University Of New Jersey; . University of Cambridge; Estados Unidos Fil: Needs, Richard J.. University of Cambridge; Estados Unidos Fil: Neumann, Marcus A.. No especifica; Fil: Nyman, Jonas. University of Southampton; Reino Unido Fil: Obata, Shigeaki. Toyohashi University Of Technology; Fil: Oberhofer, Harald. Universitat Technical Zu Munich; Alemania Fil: Oganov, Artem R.. Northwestern Polytechnical University; China. Skolkovo Institute Of Science And Technology; . Moscow Institute Of Physics And Technology; . Stony Brook University; Fil: Orendt, Anita M.. University of Utah; Estados Unidos Fil: Pagola, Gabriel Ignacio. Universidad de Buenos Aires; Argentina Fil: Pantelides, Constantinos C.. Imperial College London; Reino Unido Fil: Pickard, Chris J.. University of Cambridge; Estados Unidos. Colegio Universitario de Londres; Reino Unido Fil: Podeszwa, Rafal. University Of Silesia In Katowice; Fil: Price, Louise S.. Colegio Universitario de Londres; Reino Unido Fil: Price, Sarah L.. Colegio Universitario de Londres; Reino Unido Fil: Pulido, Angeles. University of Southampton; Reino Unido Fil: Read, Murray G.. Cambridge Crystallographic Data Centre; Fil: Reuter, Karsten. Universitat Technical Zu Munich; Alemania Fil: Schneider, Elia. University of New York; Estados Unidos Fil: Schober, Christoph. Universitat Technical Zu Munich; Alemania Fil: Shields, Gregory P.. Cambridge Crystallographic Data Centre; Fil: Singh, Pawanpreet. University Institute Of Pharmaceutical Sciences India; India Fil: Sugden, Isaac J.. Imperial College London; Reino Unido Fil: Szalewicz, Krzysztof. University Of Delaware; Fil: Taylor, Christopher R.. University of Southampton; Reino Unido Fil: Tkatchenko, Alexandre. University Of Luxembourg; . Fritz Haber Institute Of The Max Planck Society; Fil: Tuckerman, Mark E.. University of New York; Estados Unidos. New York University Shanghai; China. Courant Institute Of Mathematical Sciences; Fil: Vacarro, Francesca. University of Tulane; Estados Unidos. Loyola University New Orleans; Fil: Vasileiadis, Manolis. Imperial College London; Reino Unido Fil: Vazquez-Mayagoitia, Alvaro. Argonne National Laboratory; Estados Unidos Fil: Vogt, Leslie. University of New York; Estados Unidos Fil: Wang, Yanchao. Jilin University; China Fil: Watson, Rona E.. Colegio Universitario de Londres; Reino Unido Fil: De Wijs, Gilles A.. Radboud Universiteit Nijmegen; Países Bajos Fil: Yang, Jack. University of Southampton; Reino Unido Fil: Zhu, Qiang. Stony Brook University; Fil: Groom, Colin R.. Cambridge Crystallographic Data Centre

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 results of the fifth blind test of crystal structure prediction, which show important success with more challenging large and flexible molecules, are presented and discussed., Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories – a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.

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 ...

A combined computational and experimental polymorph search was undertaken to establish the crystal forms of 7-fluoroisatin, a simple molecule with no reported crystal structures, to evaluate the value of crystal structure prediction studies as an aid to solid form discovery. Three polymorphs were found in a manual crystallisation screen, as well as two solvates. Form I (P21/c, Z′ = 1), found from the majority of solvent evaporation experiments, corresponded to the most stable form in the computational search of Z′ = 1 structures. Form III (P21/a, Z′ = 2) is probably a metastable form, which was only found concomitantly with form I, and has the same dimeric R22(8) hydrogen bonding motif as form I and the majority of the computed low energy structures. However, the most thermodynamically stable polymorph, form II (P, Z′ = 2), has an expanded four molecule R44(18) hydrogen bonding motif, which could not have been found within the routine computational study. The computed relative energies of the three forms are not in accord with experimental results. Thus, the experimental finding of three crystalline polymorphs of 7-fluoroisatin illustrates the many challenges for computational screening to be a tool for the experimental crystal engineer, in contrast to the results for an analogous investigation of 5-fluoroisatin.

This article analyses the evolution of the market for genomic sequencing technologies in the light of major reductions in sequencing costs and time, and the growth in potential pharmacogenomics applications.

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.