Experimentally Validated Ab Initio Crystal Structure Prediction of Novel Metal-Organic Framework Materials.

First-principles crystal structure prediction (CSP) is the most powerful approach for materials discovery, enabling the prediction and evaluation of properties of new solid phases based only on a diagram of their underlying components. Here, we present the first CSP-based discovery of metal-organic frameworks (MOFs), offering a broader alternative to conventional techniques, which rely on geometry, intuition, and experimental screening. Phase landscapes were calculated for three systems involving flexible Cu(II) nodes, which could adopt a potentially limitless number of network topologies and are not amenable to conventional MOF design. The CSP procedure was validated experimentally through the synthesis of materials whose structures perfectly matched those found among the lowest-energy calculated structures and whose relevant properties, such as combustion energies, could immediately be evaluated from CSP-derived structures.

Three-in-One: Dye-Volatile Cocrystals Exhibiting Intensity-Dependent Photochromic, Photomechanical, and Photocarving Response.

Cocrystallization of a cis-azobenzene dye with volatile molecules, such as pyrazine and dioxane, leads to materials that exhibit at least three different light-intensity-dependent responses upon irradiation with low-power visible light. The halogen-bond-driven assembly of the dye cis-(p-iodoperfluorophenyl)azobenzene with volatile halogen bond acceptors produces cocrystals whose light-induced behavior varies significantly depending on the intensity of the light applied. Low-intensity (<1 mW·cm-2) light irradiation leads to a color change associated with low levels of cis → trans isomerization. Irradiation at higher intensities (150 mW·mm-2) produces photomechanical bending, caused by more extensive isomerization of the dye. At still higher irradiation intensities (2.25 W·mm-2) the cocrystals undergo cold photocarving; i.e., they can be cut and written on with micrometer precision using laser light without a major thermal effect. Real-time Raman spectroscopy shows that this novel photochemical behavior differs from what would be expected from thermal energy input alone. Overall, this work introduces a rational blueprint, based on supramolecular chemistry in the solid state, for new types of crystalline light-responsive materials, which not only respond to being exposed to light but also change their response based on the light intensity.

Polymorphs and solid solutions: materials with new luminescent properties obtained through mechanochemical transformation of dicyanoaurate(I) salts.

We report the use of mechano- and thermochemical methods to create new solid-state luminescent materials from well-known inorganic salts, potassium dicyanoaurate(I) KAu(CN)2, and potassium dicyanocuprate(I) KCu(CN)2. In particular, manual grinding or ball milling of commercial samples of KAu(CN)2 led to the formation of a novel polymorph of the salt, herein termed m-KAu(CN)2, evident by a significant change in color of the fluorescence emission of the solid material from orange to violet. The formation of m-KAu(CN)2 is reversible upon addition of small amounts of solvents, and powder X-ray diffraction analysis indicates that the structure of m-KAu(CN)2 might be related to that of pristine KAu(CN)2 through a change in ordering of Au(CN)2- ions in a layered structure. Thermal treatment of KAu(CN)2 led to the discovery of another polymorph of this well-known salt, herein termed t-KAu(CN)2, making KAu(CN)2 a rare example of a system in which thermochemical and mechanochemical treatments lead to the formation of different, in each case previously not reported, polymorphic forms. The thermally-induced transformation from KAu(CN)2 to t-KAu(CN)2 takes place around 250 °C and proceeds in a crystal-to-crystal fashion, which enabled the preliminary structural characterisation through single crystal X-ray diffraction, revealing the retention of the layered structure and a change in ordering of Au(CN)2- ions. Milling of the simple salt KAu(CN)2 in the presence of equimolar amounts or less of its copper(I)-based analogue coordination polymer KCu(CN)2 leads to the formation of a series of solid solution materials, isostructural to m-KAu(CN)2 and with visible fluorescence emission distinct from KCu(CN)2 or any herein investigated forms of KAu(CN)2.

Elucidating mechanochemical reactivity of a ternary halogen-bonded cocrystal system by computational and calorimetric studies.

Discovery of a halogen-bonded ternary cocrystal of 1,3,5-trifluoro-2,4,6-triiodobenzene with pyrazine and triphenylphosphine sulfide has revealed a complex landscape of multicomponent phases, all achievable by mechanochemical interconversion. The observed solid-state reaction pathways were explained by periodic density-functional calculations and comprehensive intermolecular interaction analysis, supported by dissolution calorimetry measurements.

Effect of Vehicle Composition on the Preparation of Different Types of Dapsone Crystals for Topical Drug Delivery.

Topical formulations composed of API-pure crystals have been increasingly studied, especially in regards to the impact of particle size in penetration efficiency. Less attention, however, has been devoted to the solid-state properties of drugs delivered to the skin. In this study, we address the effect of formulation composition on the crystal form existing in topical products. Dapsone (DAP) gel formulations were prepared by mixing an organic solution containing DAP with an aqueous solution containing polymers and preservatives. The organic solvent was chosen as ethoxydiglycol (DEGEE), polyethylene glycol (PEG), or 1-methyl-2-pirrolidone (MPR) to assess the impact of composition on DAP crystal form. Such solvent variations resulted in different particulate matter. In terms of crystalline nature, the presence of DEGEE in formulations induced the crystallization of DAP hydrate, while PEG cocrystal and a mixture of hydrate and MPR solvate crystallized from the same amounts of PEG and MPR, respectively. Microscopic analysis of the gels showed heterogeneous particles with different characteristics. The behavior of gels after application to the skin was also tested. Interestingly, the different formulations seemed to accumulate in different regions of the skin. This could be the result of the effect of vehicle composition/excipients on the characteristics of the skin, such as hydration. The site-specific accumulation, however, was more pronounced in crystal-loaded gels as opposed to blank formulations. These results indicate that future studies should consider the effect of formulation composition on the API crystal form landscape as part of the strategies used to successfully target drug delivery to the skin.

Low-Dimensional Magnetism in Multivariate Copper/Zinc MOF-74 Materials Formed via Different Mechanochemical Methods.

MOF-74 is an archetypal magnetic metal-organic framework (MOF) family, with metal nodes bridged by 2,5-dioxido-1,4-benzenedicarboxylic acid (H4dobdc) and arranged into one of the simplest representations of the 1D Ising magnetic model. Recently, a novel mechano-synthetic approach opened a pathway toward a series of bimetallic multivariate (1:1) M1M2-MOF-74 materials, with the uniform distribution of metal cations in the oxometallic chains, offering a unique opportunity to investigate low-dimensional magnetism in these heterometallic MOFs. We explore here how different mechanochemical procedures affect the interaction between the metal nodes of the model system of three multivariate copper(II)/zinc(II)-MOF-74 materials, two of which were obtained through a template-controlled procedure, and the third one was obtained by recently developed mechanical MOF-alloying combined with subsequent accelerated aging. While the three Cu/Zn-MOF-74 products have almost identical powder X-ray diffraction (PXRD) diffractograms and Fourier transform infrared spectra, they differ significantly in their magnetic properties, as revealed through detailed magnetization and X-band and multifrequency high-field electron spin resonance measurements. The magnetic results of the three multivariate Cu/Zn-MOF-74s were compared to the properties of the monometallic Cu-MOF-74, which shows antiferromagnetic intrachain and weaker ferromagnetic interchain interactions. Energy-dispersive X-ray spectroscopy/scanning electron microscopy and solid-state nuclear magnetic resonance spectroscopy helped rationalize the observed differences in magnetization, and in situ synchrotron PXRD monitoring of template-controlled MOF formation revealed different reaction pathways when using the zinc or copper intermediates, involving even the fleeting occurrence of a rare MOF-74 polymorph.

Real-Time Observation of "Soft" Magic-Size Clusters during Hydrolysis of the Model Metallodrug Bismuth Disalicylate.

Colloidal bismuth therapeutics have been used for hundreds of years, yet remain mysterious. Here we report an X-ray pair distribution function (PDF) study of the solvolysis of bismuth disalicylate, a model for the metallodrug bismuth subsalicylate (Pepto-Bismol). This reveals catalysis by traces of water, followed by multistep cluster growth. The ratio of the two major species, {Bi9O7} and {Bi38O44}, depends on exposure to air, time, and the solvent. The solution-phase cluster structures are of significantly higher symmetry in comparison to solid-state analogues, with reduced off-center Bi3+ displacements. This explains why such "magic-size" clusters can be both stable enough to crystallize and sufficiently labile for further growth.

Linker Substituents Control the Thermodynamic Stability in Metal-Organic Frameworks.

We report the first systematic experimental and theoretical study of the relationship between the linker functionalization and the thermodynamic stability of metal-organic frameworks (MOFs) using a model set of eight isostructural zeolitic imidazolate frameworks (ZIFs) based on 2-substituted imidazolate linkers. The frameworks exhibit a significant (30 kJ·mol-1) variation in the enthalpy of formation depending on the choice of substituent, which is accompanied by only a small change in molar volume. These energetics were readily reproduced by density functional theory (DFT) calculations. We show that these variations in the enthalpy of MOF formation are in linear correlation to the readily accessible properties of the linker substituent, such as the Hammett σ-constant or electrostatic surface potential. These results provide the first quantifiable relationship between the MOF thermodynamics and the linker structure, suggesting a route to design and tune MOF stability.

Disappearing Polymorphs in Metal-Organic Framework Chemistry: Unexpected Stabilization of a Layered Polymorph over an Interpenetrated Three-Dimensional Structure in Mercury Imidazolate.

The "disappearing polymorph" phenomenon is well established in organic solids, and has had a profound effect in pharmaceutical materials science. The first example of this effect in metal-containing systems in general, and in coordination-network solids in particular, is here reported. Specifically, attempts to mechanochemically synthesize a known interpenetrated diamondoid (dia) mercury(II) imidazolate metal-organic framework (MOF) yielded a novel, more stable polymorph based on square-grid (sql) layers. Simultaneously, the dia-form was found to be highly elusive, observed only as a short-lived intermediate in monitoring solvent-free synthesis and not at all from solution. The destabilization of a dense dia-framework relative to a lower dimensionality one is in contrast to the behavior of other imidazolate MOFs, with periodic density functional theory (DFT) calculations showing that it arises from weak interactions, including structure-stabilizing agostic C-H⋅⋅⋅Hg contacts. While providing a new link between MOFs and crystal engineering of organic solids, these findings highlight a possible role for agostic interactions in directing topology and stability of MOF polymorphs.

Hypergolic Triggers as Co-crystal Formers: Co-crystallization for Creating New Hypergolic Materials with Tunable Energy Content.

We demonstrate a co-crystal-based strategy to create new solid hypergols, that is, materials exhibiting spontaneous ignition when in contact with an oxidant, from typically non-hypergolic fuel molecules. In these materials, the energy content and density can be changed without affecting the ignition delay. The use of an imidazole-substituted decaborane as a hypergolic "trigger" component in combination with energy-rich but non-hypergolic nitrobenzene or pyrazine yielded hypergolic co-crystals that combine improved combustion properties with ultrashort ignition delays as low as 1 ms.

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

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.

Time-Dependent Density-Functional Theory for Modeling Solid-State Fluorescence Emission of Organic Multicomponent Crystals.

We describe the approach for modeling solid-state fluorescence spectra of organic crystalline materials, using the recent implementation of time-dependent density-functional theory within the plane-wave/pseudopotential code CASTEP. The method accuracy is evaluated on a series of organic cocrystals displaying a range of emission wavelengths. In all cases the calculated spectra are in good to excellent agreement with experiment. The ability to precisely model the emission spectra offers novel insight into the role of intermolecular interactions and crystal packing on solid-state luminescence of organic chromophores, allowing the possibility of in silico design of organic luminescent materials.

Experimental and Theoretical Evaluation of the Stability of True MOF Polymorphs Explains Their Mechanochemical Interconversions.

We provide the first combined experimental and theoretical evaluation of how differences in ligand structure and framework topology affect the relative stabilities of isocompositional (i.e., true polymorph) metal-organic frameworks (MOFs). We used solution calorimetry and periodic DFT calculations to analyze the thermodynamics of two families of topologically distinct polymorphs of zinc zeolitic imidazolate frameworks (ZIFs) based on 2-methyl- and 2-ethylimidazolate linkers, demonstrating a correlation between measured thermodynamic stability and density, and a pronounced effect of the ligand substituent on their stability. The results show that mechanochemical syntheses and transformations of ZIFs are consistent with Ostwald's rule of stages and proceed toward thermodynamically increasingly stable, more dense phases.

Rationalization of the Color Properties of Fluorescein in the Solid State: A Combined Computational and Experimental Study.

Fluorescein is known to exist in three tautomeric forms defined as quinoid, zwitterionic, and lactoid. In the solid state, the quinoid and zwitterionic forms give rise to red and yellow materials, respectively. The lactoid form has not been crystallized pure, although its cocrystal and solvate forms exhibit colors ranging from yellow to green. An explanation for the observed colors of the crystals is found using a combination of UV/Vis spectroscopy and plane-wave DFT calculations. The role of cocrystal coformers in modifying crystal color is also established. Several new crystal structures are determined using a combination of X-ray and electron diffraction, solid-state NMR spectroscopy, and crystal structure prediction (CSP). The protocol presented herein may be used to predict color properties of materials prior to their synthesis.

Influence of N-protonation on electronic properties of acridine derivatives by quantum crystallography.

Applications of 9-aminoacridine (9aa) and its derivatives span fields such as chemistry, biology, and medicine, including anticancer and antimicrobial activities. Protonation of such molecules can alter their bioavailability as weakly basic drugs like aminoacridines exhibit reduced solubility at high pH levels potentially limiting their effectiveness in patients with elevated gastric pH. In this study, we analyse the influence of protonation on the electronic characteristics of the molecular organic crystals of 9-aminoacridine. The application of quantum crystallography, including aspherical atom refinement, has enriched the depiction of electron density in the studied systems and non-covalent interactions, providing more details than previous studies. Our experimental results, combined with a topological analysis of the electron density and its Laplacian, provided detailed descriptions of how protonation changes the electron density distribution around the amine group and water molecule, concurrently decreasing the electron density at bond critical points of N/O-H bonds. Protonation also alters the molecular architecture of the systems under investigation. This is reflected in different proportions of the N⋯H and O⋯H intermolecular contacts for the neutral and protonated forms. Periodic DFT calculations of the cohesive energies of the crystal lattice, as well as computed interaction energies between molecules in the crystal, confirm that protonation stabilises the crystal structure due to a positive synergy between strong halogen and hydrogen bonds. Our findings highlight the potential of quantum crystallography in predicting crystal structure properties and point to its possible applications in developing new formulations for poorly soluble drugs.

Perhalogenated Anilines as Bifunctional Donors of Hydrogen and Halogen Bonds in Cocrystals with Ditopic Nitrogen-Containing Acceptors.

In this study, we examine the experimental and theoretical capabilities of two perhalogenated anilines, 2,3,5,6-tetrafluoro-4-bromoaniline (btfa) and 2,3,5,6-tetrafluoro-4-iodoaniline (itfa) as hydrogen and halogen bond donors. A series of 11 cocrystals derived from the two anilines and selected ditopic nitrogen-containing acceptors (4,4'-bipyridine, 1,2-bis(4-pyridyl)ethane, and 1,4-diazabicyclo[2.2.2]octane) in 1:1 and 2:1 stoichiometries were prepared by liquid-assisted grinding and crystallization from solution. Crystallographic analysis revealed bifunctional donor properties in both anilines. The dominant supramolecular interaction in four cocrystals of btfa is the N-H···Nacceptor hydrogen bond between btfa and acceptor molecules, while in the one remaining cocrystal, donor and acceptor molecules are connected via the N-H···Nacceptor hydrogen bond and the Br···Nacceptor halogen bond. In two cocrystals of itfa, the dominant supramolecular interaction is the I···Nacceptor halogen bond between itfa and acceptor molecules, while in the remaining four cocrystals, donor and acceptor molecules are additionally connected by the N-H···Nacceptor hydrogen bond. Periodic density-functional theory (DFT) calculations have been conducted to assess the formation energies of these cocrystals and the strengths of the established halogen and hydrogen bonds. Molecular DFT calculations on btfa and itfa indicate that the differences in electrostatic potential between the competing sites on the molecules are 261.6 and 157.0 kJ mol-1 e-1, respectively. The findings suggest that itfa, with a smaller electrostatic potential difference between donor sites, is more predisposed to act as a bifunctional donor.

Experimental and Theoretical Evaluation of the Thermodynamics of the Carbonation Reaction of ZIF-8 and Its Close-Packed Polymorph with Carbon Dioxide.

We report the first experimental and theoretical evaluation of the thermodynamic driving force for the reaction of metal-organic framework (MOF) materials with carbon dioxide, leading to a metal-organic carbonate phase. Carbonation upon exposure of MOFs to CO2 is a significant concern for the design and deployment of such materials in carbon storage technologies, and this work shows that the formation of a carbonate material from the popular SOD-topology framework material ZIF-8, as well as its dense-packed dia-topology polymorph, is significantly exothermic. With knowledge of the crystal structure of the starting and final phases in the carbonation reaction, we have also identified periodic density functional theory approaches that most closely reproduce the measured reaction enthalpies. This development now permits the use of advanced theoretical calculations to calculate the driving forces behind the carbonation of zeolitic imidazolate frameworks with reasonable accuracy.

Computational evaluation of halogen-bonded cocrystals enables prediction of their mechanochemical interconversion reactions.

Periodic density-functional theory (DFT) calculations were used to predict the thermodynamic stability and the likelihood of interconversion between a series of halogen-bonded cocrystals. The outcomes of mechanochemical transformations were in excellent agreement with the theoretical predictions, demonstrating the power of periodic DFT as a method for designing solid-state mechanochemical reactions prior to experimental work. Furthermore, the calculated DFT energies were compared with experimental dissolution calorimetry measurements, marking the first such benchmark for the accuracy of periodic DFT calculations in modelling transformations of halogen-bonded molecular crystals.