Towards the systematic crystallisation of molecular ionic cocrystals: insights from computed crystal form landscapes

The underlying molecular and crystal properties affecting the crystallisation of organic molecular ionic cocrystals (ICCs) are investigated.</p

Report on the sixth blind test of organic crystal structure prediction methods.

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.The organisers and participants are very grateful to the crystallographers who supplied the candidate structures: Dr. Peter Horton (XXII), Dr. Brian Samas (XXIII), Prof. Bruce Foxman (XXIV), and Prof. Kraig Wheeler (XXV and XXVI). We are also grateful to Dr. Emma Sharp and colleagues at Johnson Matthey (Pharmorphix) for the polymorph screening of XXVI, as well as numerous colleagues at the CCDC for assistance in organising the blind test. Submission 2: We acknowledge Dr. Oliver Korb for numerous useful discussions. Submission 3: The Day group acknowledge the use of the IRIDIS High Performance Computing Facility, and associated support services at the University of Southampton, in the completion of this work. We acknowledge funding from the EPSRC (grants EP/J01110X/1 and EP/K018132/1) and the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC through grant agreements n. 307358 (ERC-stG- 2012-ANGLE) and n. 321156 (ERC-AG-PE5-ROBOT). Submission 4: I am grateful to Mikhail Kuzminskii for calculations of molecular structures on Gaussian 98 program in the Institute of Organic Chemistry RAS. The Russian Foundation for Basic Research is acknowledged for financial support (14-03-01091). Submission 5: Toine Schreurs provided computer facilities and assistance. I am grateful to Matthew Habgood at AWE company for providing a travel grant. Submission 6: We would like to acknowledge support of this work by GlaxoSmithKline, Merck, and Vertex. Submission 7: The research was financially supported by the VIDI Research Program 700.10.427, which is financed by The Netherlands Organisation for Scientific Research (NWO), and the European Research Council (ERC-2010-StG, grant agreement n. 259510-KISMOL). We acknowledge the support of the Foundation for Fundamental Research on Matter (FOM). Supercomputer facilities were provided by the National Computing Facilities Foundation (NCF). Submission 8: Computer resources were provided by the Center for High Performance Computing at the University of Utah and the Extreme Science and Engineering Discovery Environment (XSEDE), supported by NSF grant number ACI-1053575. MBF and GIP acknowledge the support from the University of Buenos Aires and the Argentinian Research Council. Submission 9: We thank Dr. Bouke van Eijck for his valuable advice on our predicted structure of XXV. We thank the promotion office for TUT programs on advanced simulation engineering (ADSIM), the leading program for training brain information architects (BRAIN), and the information and media center (IMC) at Toyohashi University of Technology for the use of the TUT supercomputer systems and application software. We also thank the ACCMS at Kyoto University for the use of their supercomputer. In addition, we wish to thank financial supports from Conflex Corp. and Ministry of Education, Culture, Sports, Science and Technology. Submission 12: We thank Leslie Leiserowitz from the Weizmann Institute of Science and Geoffrey Hutchinson from the University of Pittsburgh for helpful discussions. We thank Adam Scovel at the Argonne Leadership Computing Facility (ALCF) for technical support. Work at Tulane University was funded by the Louisiana Board of Regents Award # LEQSF(2014-17)-RD-A-10 “Toward Crystal Engineering from First Principles”, by the NSF award # EPS-1003897 “The Louisiana Alliance for Simulation-Guided Materials Applications (LA-SiGMA)”, and by the Tulane Committee on Research Summer Fellowship. Work at the Technical University of Munich was supported by the Solar Technologies Go Hybrid initiative of the State of Bavaria, Germany. Computer time was provided by the Argonne Leadership Computing Facility (ALCF), which is supported by the Office of Science of the U.S. Department of Energy under contract DE-AC02-06CH11357. Submission 13: This work would not have been possible without funding from Khalifa University’s College of Engineering. I would like to acknowledge Prof. Robert Bennell and Prof. Bayan Sharif for supporting me in acquiring the resources needed to carry out this research. Dr. Louise Price is thanked for her guidance on the use of DMACRYS and NEIGHCRYS during the course of this research. She is also thanked for useful discussions and numerous e-mail exchanges concerning the blind test. Prof. Sarah Price is acknowledged for her support and guidance over many years and for providing access to DMACRYS and NEIGHCRYS. Submission 15: The work was supported by the United Kingdom’s Engineering and Physical Sciences Research Council (EPSRC) (EP/J003840/1, EP/J014958/1) and was made possible through access to computational resources and support from the High Performance Computing Cluster at Imperial College London. We are grateful to Professor Sarah L. Price for supplying the DMACRYS code for use within CrystalOptimizer, and to her and her research group for support with DMACRYS and feedback on CrystalPredictor and CrystalOptimizer. Submission 16: R. J. N. acknowledges financial support from the Engineering and Physical Sciences Research Council (EPSRC) of the U.K. [EP/J017639/1]. R. J. N. and C. J. P. acknowledge use of the Archer facilities of the U.K.’s national high-performance computing service (for which access was obtained via the UKCP consortium [EP/K014560/1]). C. J. P. also acknowledges a Leadership Fellowship Grant [EP/K013688/1]. B. M. acknowledges Robinson College, Cambridge, and the Cambridge Philosophical Society for a Henslow Research Fellowship. Submission 17: The work at the University of Delaware was supported by the Army Research Office under Grant W911NF-13-1- 0387 and by the National Science Foundation Grant CHE-1152899. The work at the University of Silesia was supported by the Polish National Science Centre Grant No. DEC-2012/05/B/ST4/00086. Submission 18: We would like to thank Constantinos Pantelides, Claire Adjiman and Isaac Sugden of Imperial College for their support of our use of CrystalPredictor and CrystalOptimizer in this and Submission 19. The CSP work of the group is supported by EPSRC, though grant ESPRC EP/K039229/1, and Eli Lilly. The PhD students support: RKH by a joint UCL Max-Planck Society Magdeburg Impact studentship, REW by a UCL Impact studentship; LI by the Cambridge Crystallographic Data Centre and the M3S Centre for Doctoral Training (EPSRC EP/G036675/1). Submission 19: The potential generation work at the University of Delaware was supported by the Army Research Office under Grant W911NF-13-1-0387 and by the National Science Foundation Grant CHE-1152899. Submission 20: The work at New York University was supported, in part, by the U.S. Army Research Laboratory and the U.S. Army Research Office under contract/grant number W911NF-13-1-0387 (MET and LV) and, in part, by the Materials Research Science and Engineering Center (MRSEC) program of the National Science Foundation under Award Number DMR-1420073 (MET and ES). The work at the University of Delaware was supported by the U.S. Army Research Laboratory and the U.S. Army Research Office under contract/grant number W911NF-13-1- 0387 and by the National Science Foundation Grant CHE-1152899. Submission 21: We thank the National Science Foundation (DMR-1231586), the Government of Russian Federation (Grant No. 14.A12.31.0003), the Foreign Talents Introduction and Academic Exchange Program (No. B08040) and the Russian Science Foundation, project no. 14-43-00052, base organization Photochemistry Center of the Russian Academy of Sciences. Calculations were performed on the Rurik supercomputer at Moscow Institute of Physics and Technology. Submission 22: The computational results presented have been achieved in part using the Vienna Scientific Cluster (VSC). Submission 24: The potential generation work at the University of Delaware was supported by the Army Research Office under Grant W911NF-13-1-0387 and by the National Science Foundation Grant CHE-1152899. Submission 25: J.H. and A.T. acknowledge the support from the Deutsche Forschungsgemeinschaft under the program DFG-SPP 1807. H-Y.K., R.A.D., and R.C. acknowledge support from the Department of Energy (DOE) under Grant Nos. DE-SC0008626. This research used resources of the Argonne Leadership Computing Facility at Argonne National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-06CH11357. This research used resources of the National Energy Research Scientific Computing Center, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DEAC02-05CH11231. Additional computational resources were provided by the Terascale Infrastructure for Groundbreaking Research in Science and Engineering (TIGRESS) High Performance Computing Center and Visualization Laboratory at Princeton University.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1107/S2052520616007447

Report on the sixth blind test of organic crystal-structure prediction methods

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 submissions, 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

Towards crystal structure prediction of complex organic compounds - a report on the fifth blind test

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

Porous organic polymer composites as surging catalysts for visible-light-driven chemical transformations and pollutant degradation

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. (C) 2019 Published by Elsevier B.V

Mechanoelectronics: Flexible Organic Semiconducting Single Crystals for Durable All-Flexible Field-Effect Transistors

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

Investigating the solid-state assembly of pharmaceutically-relevant N,N-dimethyl-O-thiocarbamates in the absence of labile hydrogen bonds

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 versionF.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 A1783c0007D.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

Direct and Telescopic Mechanochemical Synthesis of Higher-order Organic-Inorganic Hybrid Cocrystals: Tuning Order, Functionality and Size in Cocrystal Design

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

Fluoranthene-based derivatives for multimodal anti-counterfeiting and detection of nitroaromatics

In this study, we developed two novel sky blue fluorescent fluorophores comprising ethyl alcohol (FOH) and ethanethiol (FSH) units appended to fluoranthene at the periphery. Single Crystal X-Ray Diffraction (SC-XRD) studies reveal that the molecular flexibility of alkyl chains leads to distinct diagonal (FOH) and ladder (FSH) shaped supramolecular arrangements in the crystal lattices. Detailed photophysical and DFT studies showed that FOH and FSH demonstrate high sensitivity and selectivity towards the detection of trinitrophenol (TNP). FSH exhibits high quenching efficiency (similar to 84%), a rate constant of KSV = 1.1 x 104 M-1 with a limit of detection of similar to 97 ppm in THF, and similar to 76 ppm in river water. Mechanistic investigation through NMR and SC-XRD of the FSH adduct with 1,3-dinitrobenzene (DNB) reveal strong pi-pi interactions (3.518 angstrom). Furthermore, photoinduced electron transfer occurs from the fluorophores to the nitro analytes and leads to strong intermolecular interactions using the static quenching mechanism. Both fluorophores were employed in advanced surveillance to identify finger marks on a wide range of substrates (glass, cellophane tape, aluminium foil and floor tiles) with different resolutions to provide an unadorned and lucrative method for viewing the latent fingerprints (LFPs) with exceptionally consistent evidence of up to level 3 and without the requirement for post-treatments, leading to promising applications for onsite forensic analysis. Furthermore, FOH and FSH were evaluated in 72 hpf zebrafish larvae/embryos to demonstrate the non-toxicological behaviour and fluorescence imaging/tracking. Two novel fluoranthene ensembles with ethyl alcohol (FOH) and ethanethiol (FSH) functionality with distinct diagonal and ladder arrangements in the crystal lattices were developed for Latent Fingerprints (LFPs) towards analysis of explosives.Web of Science4236270625