Molecular Cocrystals Research Articles

Porphyrin/Fullerene Porous Molecular Cocrystal Featuring a Robust One-Dimensional Channel.

Microporous molecular crystals are promising materials because of their designable porosity as well as their resistance to chemical and other stimuli. Here, we developed microporous molecular cocrystals by taking advantage of the specific interactions between porphyrins and fullerene molecules. Single-crystal X-ray diffraction analysis revealed that one nickel(II) porphyrin interacts with two fullerene molecules to form a two-dimensional honeycomb network with an eclipsed stacking mode, providing one-dimensional void channels. After the pores were activated by heat treatment or mechanical grinding, the prepared cocrystal can incorporate gas and solvent molecules reversibly while maintaining its single-crystallinity. Also, it retained its single-crystallinity in the presence of water, acid-base, or high pressure. These findings in this study expand the availability of molecular crystals based on intermolecular interactions as porous materials, which are expected to work under conditions that have not been applicable to other molecule-based porous materials.

Crystallography, Charge Transfer, and Two‐Photon Absorption Relations in Molecular Cocrystals for Two‐Photon Excited Fluorescence Imaging (Small 17/2024)

Crystallography, Charge Transfer, and Two‐Photon Absorption Relations in Molecular Cocrystals for Two‐Photon Excited Fluorescence Imaging (Small 17/2024)

Interactions and reactivity in crystalline intermediates of mechanochemical cyclorhodation reactions.

There is experimental evidence that solid mixtures of the rhodium dimer [Cp*RhCl2]2 and benzo[h] quinoline (BHQ) produce two different polymorphic molecular cocrystals called 4α and 4β under ball milling conditions. The addition of NaOAc to the mixture leads to the formation of the rhodacycle [Cp*Rh-(BHQ)Cl], where the central Rh atom retains its tetracoordinate character. Isolate 4β reacts with NaOAc leading to the same rhodacycle while isolate 4α does not under the same conditions. We show that the puzzling difference in reactivity between the two cocrystals can be traced back to fundamental aspects of the intermolecular interactions between the BHQ and [Cp*RhCl2]2 fragments in the crystalline environment. To support this view, we report a number of descriptors of the nature and strength of chemical bonds and intermolecular interactions in the extended solids and in a cluster model. We calculate formal quantum mechanical descriptors based on electronic structure, electron density, and binding and interaction energies including an energy decomposition analysis. Without exception, all descriptors point to 4β being a transient structure higher in energy than 4α with larger local and global electrophilic and nucleophilic powers, a more favorable spatial and energetic distribution of the frontier orbitals, and a more fragile crystal structure.

Crystallography, Charge Transfer, and Two-Photon Absorption Relations in Molecular Cocrystals for Two-Photon Excited Fluorescence Imaging.

Two-photon excited fluorescence imaging requires high-performance two-photon absorption (TPA) active materials, which are commonly intramolecular charge transfer systems prepared by traditional chemical synthesis. However, this typically needs harsh conditions and new methods are becoming crucial. In this work, based on a collaborative intermolecular charge transfer (inter-CT) strategy, three centimeter-sized organic TPA cocrystals are successfully obtained. All three cocrystals exhibit a mixed stacking arrangement, which can effectively generate inter-CT between the donor and acceptor. The ground and excited state characterizations compare their inter-CT ability: 1,2-BTC > 2D-BTC > 1D-BTC. Transient absorption spectroscopy detects TCNB•-, indicating that the TPA mechanism arises from molecular polarization caused by inter-CT. Meanwhile, 1,2-BTC exhibits the highest excited-state absorption and the longest excited-state lifetime, suggesting a stronger TPA response. First-principles calculations also confirm the presence of inter-CT interactions, and the significant parameter Δµ which can assess the TPA capability indicates that inter-CT enhances the TPA response. Besides, cocrystals also demonstrate excellent water solubility and two-photon excited fluorescence imaging capabilities. This research not only provides an effective method for synthesizing TPA crystal materials and elucidates the connection between inter-CT ability and TPA property but also successfully applies them in the fields of multi-photon fluorescence bioimaging.

Cocrystal Approach to Modulate the Photoluminescent Properties of a GFP Chromophore Analogue: Role of Halogen/Hydrogen Bonding in Achieving a Wide Range of Solid-State Fluorescence Emissions

Fine-tuning the photophysical properties of fluorescent organic solids is essential to attain multicolor displays and meet the demand for futuristic light-emitting materials. Here, we report the tunable luminescence of a green fluorescent protein (GFP) chromophore analogue, 3,4,5-TIA (A), based on the formation of two-component molecular cocrystals with six different coformers. Coformers selected to synthesize the binary cocrystals include 1,4-diiodotetrafluorobenzene (B), perfluoronaphthalene (C), 1,4-dibromotetrafluorobenzene (D), 2,3,5,6-tetrafluoroterephthalic acid (E), benzene-1,2,4,5-tetracarbonitrile (F), and benzene-1,2,4,5-tetracarboxylic acid (G). Interestingly, the cocrystals A•C and A•F showed molecular crystal polymorphism with a slight variation in fluorescence, revealing an aggregation-induced emission (AIE). A crystal structure analysis showed the interplay of hydrogen bonding, halogen bonding, and aromatic π-stacking interactions in associating neutral solid components in the cocrystal. All of the novel cocrystals displayed a wide range of photoluminescence ranging from blue to dark orange. The time-dependent density functional theory (TD-DFT) calculations indicate the changes in the energy level structures (HOMO to LUMO) in cocrystals that resulted in variations in fluorescence emission. The study aims to further understand the structure–property relationship between molecular arrangement and photoluminescence.

Simulation of Cocrystal Formation in Planetary Atmospheres: The C6H6:C2H2 Cocrystal Produced by Gas Deposition.

The formation of molecular cocrystals in condensed aerosol particles has been recently proposed as an efficient pathway for generation of complex organics in Titan's atmosphere. It follows that cocrystal precipitation may facilitate the transport of biologically important precursors to the surface to be sequestered in an organic karstic and sand environment. Recent laboratory studies on these planetary minerals have predominantly synthesized cocrystals by the controlled freezing of binary mixtures from the liquid phase, allowing for their structural and spectroscopic characterization. However, these techniques are perhaps not best representative of aerosol nucleation and growth microphysics in planetary atmospheres. Herein, we report the first synthesis of the known 1:1 C6H6:C2H2 cocrystal using vapor deposition methods onto a cryogenically cooled substrate. Subsequent transmission FTIR spectroscopy has confirmed the formation of the empirical C6H6:C2H2 cocrystal structure via the observation of diagnostic infrared spectral features. Predicted by periodic-DFT calculations, altered vibrational profiles depict a changing site symmetry of the C6H6 and C2H2 components after transition to the cocrystal unit cell geometry. The 80 K temperature of the cocrystal phase transition overlaps with the condensation curves obtained for both species in Titan's lower stratosphere, revealing that the cocrystal may act as an important environment for photo- and radio-lytic processes leading to the formation of higher order organics in Titan's atmosphere. Such solid-state astrochemistry can now be pursued in oxygen-free laboratory settings under (ultra)high vacuum using standard surface science setups.

KNO3⋅3H2SeO3 and NaHSeO3⋅3H2SeO3: Two non-centrosymmetric co-crystals

A new compound KNO3⋅3H2SeO3 was synthesized via reaction of KNO3 and H2SeO3 in an acidic aqueous solution. Its crystal structure (P21, a = 10.2709 (8) Å, b = 6.2840 (3) Å, c = 10.3886 (8) Å, β = 118.83 (1)°, R1 = 0.036) can be described as a monoclinically distorted hydrogen-bonded hexagonal net of KO9 tricapped trigonal prisms linked by H2SeO3 molecules. The nitrate anions behave as hydrogen bond acceptors filling the channels in the [K(H2SeO3)3]+ net. The structure is totally different from that of the chemically related NaHSeO3⋅3H2SeO3 compound, for which a new structural solution was obtained (Pc, a = 5.7803 (3) Å, b = 4.9390 (2) Å, c = 21.283 (1) Å, β = 111.836 (6)°, R1 = 0.028). Yet, there are some common features in the mode of KO9 and NaO6 polyhedra linkage by the HSeO3− and H2SeO3 species in two studied compounds. The SHG signal from KNO3⋅3H2SeO3 was registered using the Kurtz – Perry technique. A moderate SHG signal of 5–6 SiO2 units was observed. Relationships to other salt-selenious acid molecular co-crystals and hydrogen selenites are discussed.

Controlling polymorphism in molecular cocrystals by variable temperature ball milling.

Mechanochemistry offers a unique opportunity to modify and manipulate crystal forms, often providing new products as compared with conventional solution methods. While promising, there is little known about how to control the solid form through mechanochemical means, demanding dedicated investigations. Using a model organic cocrystal system (isonicotinamide:glutaric acid), we here demonstrate that with mechanochemistry, polymorphism can be induced in molecular solids under conditions seemingly different to their conventional thermodynamic (thermal) transition point. Whereas Form II converts to Form I upon heating to 363 K, the same transition can be initiated under ball milling conditions at markedly lower temperatures (348 K). Our results indicate that mechanochemical techniques can help to reduce the energy barriers to solid form transitions, offering new insights into controlling polymorphic forms. Moreover, our results suggest that the nature of mechanochemical transformations could make it difficult to interpret mechanochemical solid form landscapes using conventional equilibrium-based tools.

Arene–perfluoroarene interactions in molecular cocrystals for enhanced photocatalytic activity

Cocrystals based on arene–perfluoroarene interactions exhibit better photocatalytic activity than monocrystals for pollutant degradation in water, with implications for the design of next generation photocatalyst materials.

Controllable Fabrication of Organic Cocrystals with Interior Hollow Structure Based on Donor-Acceptor Charge Transfer Molecules

Fluorescent hollow organic molecular cocrystals comprised of (E)-4-(2(anthracen-9-yl)vinyl)pyridine-1,2,4,5-tetracyanobenzene (APE-TCNB) were prepared via a surfactant-mediated co-precipitation method. The size and morphology of these cocrystals could be easily tuned by varying the type and concentration of the surfactant, incubation time, and temperature. Moreover, optical fluorescence and scanning electron microscopy characterization indicated that the APE-TCNB microcrystals contained two symmetric empty cavities when 3-(N, N-dimethyldodecylammonio)propane sulfonate (BS12) was used as the surfactant. The cross-polarized microscope and powder X-ray diffraction (PXRD) measurements both showed that the prepared microcrystals exhibited high crystallinity. APE and TCNB molecules were found to align parallelly along the crystallographic a-axis in the crystal lattice, and the strong π–π intermolecular interactions facilitated the formation of unique crystal chambers. A series of measurements and characterization, including UV-Vis absorption spectroscopy, infrared spectroscopy, steady-state, and time-resolved fluorescence spectroscopy, also verified that strong charge–transfer (CT) interactions had been established in the APE-TCNB microcrystals. Moreover, these APE-TCNB microcrystals could emit bright red luminescence, which extended to the near-infrared region (~800 nm), displaying a strong charge-transfer property. Here, we have shown a general facile way to make organic cocrystals with complex structures and topologies using a self-assembly method.

Crystal Engineering of Ionic Cocrystals Sustained by Azolium···Azole Heterosynthons.

Crystal engineering of multi-component molecular crystals, cocrystals, is a subject of growing interest, thanks in part to the potential utility of pharmaceutical cocrystals as drug substances with improved properties. Whereas molecular cocrystals (MCCs) are quite well studied from a design perspective, ionic cocrystals (ICCs) remain relatively underexplored despite there being several recently FDA-approved drug products based upon ICCs. Successful cocrystal design strategies typically depend on strong and directional noncovalent interactions between coformers, as exemplified by hydrogen bonds. Understanding of the hierarchy of such interactions is key to successful outcomes in cocrystal design. We herein address the crystal engineering of ICCs comprising azole functional groups, particularly imidazoles and triazoles, which are commonly encountered in biologically active molecules. Specifically, azoles were studied for their propensity to serve as coformers with strong organic (trifluoroacetic acid and p-toluenesulfonic acid) and inorganic (hydrochloric acid, hydrobromic acid and nitric acid) acids to gain insight into the hierarchy of NH+···N (azolium-azole) supramolecular heterosynthons. Accordingly, we combined data mining of the Cambridge Structural Database (CSD) with the structural characterization of 16 new ICCs (11 imidazoles, 4 triazoles, one imidazole-triazole). Analysis of the new ICCs and 66 relevant hits archived in the CSD revealed that supramolecular synthons between identical azole rings (A+B-A) are much more commonly encountered, 71, than supramolecular synthons between different azole rings (A+B-C), 11. The average NH+···N distance found in the new ICCs reported herein is 2.697(3) Å and binding energy calculations suggested that hydrogen bond strengths range from 31-46 kJ mol-1. The azolium-triazole ICC (A+B-C) was obtained via mechanochemistry and differed from the other ICCs studied as there was no NH+···N hydrogen bonding. That the CNC angles in imidazoles and 1,2,4-triazoles are sensitive to protonation, the cationic forms having larger (approximately 4.4 degrees) values than comparable neutral rings, was used as a parameter to distinguish between protonated and neutral azole rings. Our results indicate that ICCs based upon azolium-azole supramolecular heterosynthons are viable targets, which has implications for the development of new azole drug substances with improved properties.

Molecular Cocrystals with Hydrogen-Bonded Polymeric Structures and Polarized Luminescence.

Crystalline materials with appealing luminescent properties are attractive materials for various optoelectronic applications. The in situ bicomponent reaction of 1,2-ethylenedisulfonic acid with 1,4-di(pyrid-2-yl)benzene, 1,4-di(pyrid-3-yl)benzene, or 1,4-di(pyrid-4-yl)benzene affords luminescent crystals with hydrogen-bonded polymeric structures. Variations in the positions of the pyridine nitrogen atoms lead to alternating polymeric structures with either a ladder- or zigzag-type of molecular arrangement. By using a nanoprecipitation method, microcrystals of these polymeric structures are prepared, showing polarized luminescence with a moderate degree of polarization.

(Invited) Pressure-Induced New Carbon Materials with New Properties

Design and synthesis of new carbon materials have been attracting intensive attention due to their application in various fields. The study of carbon nanostructures under high pressure provides us a very effective method to create new carbon material which is hardly discovered at ambient conditions because of the appearance of nanometer scale size effect and the novel high pressure behavior. In this presentation, several examples on high pressure induced novel structures in recently studied fullerene based molecular cocrystals will be outlined. Particularly, anomalous negative volume compressibility observed in the eutectic Sc3N@C80 -cubane crystal under high pressure will be introduced. The charge transfer from fullerene cage to cubane promotes the configuration change of cubane, which transforms into a “low density” configuration, resulting in an abnormal lattice expansion of the crystal. This is the first experimentally discovered crystal which has negative volume compressibility. We will also present the synthesis of nearly all sp3 amorphous carbon bulk material from high temperature and high pressure (HPHT)-treated C60 for the first time. This new sp3 amorphous carbon material shows an optical band gap of ~2.7eV and extremely high Vickers hardness of 102 GPa under 9.8N load, close to that of diamond, which is a multifunctional superhard amorphous carbon material with the highest thermal conductivity and hardness known in the amorphous materials up to now.

Investigation of the Mechanism of Cocrystal Formation at the Polarized Liquid-Liquid Interface

The cocrystals of two reagents of mismatch solubility, hydrophilic caffeine and lipophilic 1-hydroxy-2-naphthoic acid, were obtained at a water-oil interface. 1 By analysing the product collected at the phase interface by X-ray diffraction and Raman spectroscopy, we confirmed that we obtained the molecular cocrystals of caffeine and 1-hydroxy-2-naphthoic acid, free of starting reagents and solvents. Polarisation of the interface allowed the electrochemical control of the cocrystallisation process: for non-polarised interfaces, a mixture of phase I and II cocrystals were obtained, whereas cocrystals of phase I were formed when a high interfacial potential was applied. The difference between the polymorphs obtained in the absence or in the presence of interfacial polarisation is attributed to the different cocrystallisation mechanisms. In the absence of interfacial polarisation, caffeine and 1-hydroxy-2-naphthoic acid are cocrystallising through an interfacial process. When the interface is positively polarised, cationic form of caffeine is transferred to the organic phase, the complex with naphthoic acid is formed and the proton is released. The pH increased after cocrystallisation, suggesting that the liberated H+ remained in the organic phase. On the contrary, in the absence of polarisation or in the case of low interfacial potential the protons are remaining in the aqueous phase what resulted in a decrease in pH after cocrystallisation process. We demonstrated an indirect evidence of the transfer of caffeine upon chemical polarization of the interface. We observed almost no deposits in the organic phase by analysing it with a scanning electron microscope.We investigated here the mechanism behind the formation of cocrystals by using the polarized interface between two immiscible electrolyte solutions (ITIES).2 For the purpose of this study, the two solutions have been placed in contact3 : one being an aqueous solution of caffeine, as a model drug substance, and the second being organic solution of 1-hydroxy-2-naphthoic acid (cocrystal component) and the salt inducing the suitable imposed potential difference. The formation of the caffeine: 1-hydroxy-2-naphthoic acid complex was studied by changing the salts present in the aqueous phase, the chemical compounds imposing potential in organic phase, varying the organic solvents and the temperature at the liquid-liquid interface. The cocrystals collected at the interface were analysed by X-ray diffraction (XRD), scanning electron microscopy (SEM) and low frequency Raman spectroscopy. We studied the proportions of polymorphic phases as a function of changing conditions. To understand the mechanism behind the caffeine transfer and the formation of different forms of polymorphic crystals at the water-oil interface, Electrochemical Noise Experiments4 have been carried out. A four-electrode system was used to apply zero volts between the working electrode and the counter electrode and then measuring the current and the potential versus the reference electrode. Such a setup allows the measurement of potential and current as the function of time simultaneously. We could thus follow the phenomena that are taking place at the interface. The measurements were carried out by varying the cations (tetraalkylammoniums, Li+, K+) in aqueous and organic phase as well as the anions (derivatives of tetrakis(phenyl-borate) in organic phase). The experimental results were supported by theoretical equations and applied to the system containing caffeine.This novel strategy of cocrystallization, was followed by the investigation of other coformers (3-hydroxy-2-naphthoic acid) and drugs (cocrystals of ketoprofen with amino acids and carboxylic acids) in order to validate the method. Such an electrocrystallization process at the ITIES will open new opportunities for the formation of drugs cocrystals. M. Kaliszczak et al., CrystEngComm (2022) doi: 10.1039/D1CE01281A.Z. Samec, Pure Appl. Chem., 76, 2147–2180 (2004).S. J. Diez et al., Cryst. Growth Des., 18, 3263–3268 (2018).I. B. Obot, I. B. Onyeachu, A. Zeino, and S. A. Umoren, J. Adhes. Sci. Technol., 33, 1453–1496 (2019).

Crystal Engineering of Ionic Cocrystals Sustained by the Phenol-Phenolate Supramolecular Heterosynthon.

Although crystal engineering strategies are generally well explored in the context of multicomponent crystals (cocrystals) formed by neutral coformers (molecular cocrystals), cocrystals comprised of one or more salts (ionic cocrystals, ICCs) are understudied. We herein address the design, preparation, and structural characterization of ICCs formed by phenolic moieties, a common group in natural products and drug molecules. Organic and inorganic bases were reacted with the following phenolic coformers: phenol, resorcinol, phloroglucinol, 4-methoxyphenol, and 4-isopropylphenol. Nine ICCs were crystallized, each of them sustained by the phenol–phenolate supramolecular heterosynthon (PhOH···PhO–). Such ICCs are of potential utility, and there are numerous examples of phenolic compounds that are biologically active, some of which suffer from low aqueous solubility. The propensity to form ICCs sustained by the PhOH···PhO– supramolecular heterosynthon was evaluated through a combination of Cambridge Structural Database (CSD) mining, structural characterization of nine novel ICCs, and calculation of interaction energies. Our analysis of these 9 ICCs and the 41 relevant entries archived in the CSD revealed that phenol groups can reliably form ICCs through charge-assisted PhOH···PhO– interactions. This conclusion is supported by hydrogen-bond strength calculations derived from CrystalExplorer that reveal the PhOH···PhO– interaction to be around 3 times stronger than the phenol–phenol hydrogen bond. The PhOH···PhO– supramolecular heterosynthon could therefore enable crystal engineering studies of a large number of phenolic pharmaceutical and nutraceutical compounds with their conjugate bases.

Importance of Nuclear Quantum Effects for Molecular Cocrystals with Short Hydrogen Bonds.

Many efforts have been recently devoted to the design and investigation of multicomponent pharmaceutical solids, such as salts and cocrystals. The experimental distinction between these solid forms is often challenging. Here, we show that the transformation of a salt into a cocrystal with a short hydrogen bond does not occur as a sharp phase transition but rather a smooth shift of the positional probability of the hydrogen atoms. A combination of solid-state NMR spectroscopy, X-ray diffraction, and diffuse reflectance measurements with density functional theory calculations that include nuclear quantum effects (NQEs) provides evidence of temperature-induced hydrogen atom shift in cocrystals with short hydrogen bonds. We demonstrate that for the predictions of the salt/cocrystal solid forms with short H-bonds, the computations have to include NQEs (particularly hydrogen nuclei delocalization) and temperature effects.

Three-primary-color molecular cocrystals showing white-light luminescence, tunable optical waveguide and ultrahigh polarized emission

Three-primary-color molecular cocrystals showing white-light luminescence, tunable optical waveguide and ultrahigh polarized emission

Screening and Preparation of Cocrystals: A Comparative Study of Mechanochemistry vs Slurry Methods.

Cocrystals of biologically active molecular compounds have potential utility in drug products thanks to their effect upon physicochemical properties such as aqueous solubility. The fact that control of cocrystallization can be more challenging than crystallization of single-component crystals means that systematic studies that address the methodology of cocrystal screening, production, and purification are a topical subject. We previously reported a comparison of slow evaporation vs mechanochemistry for a library of 25 molecular cocrystals. Herein, we compare the previously reported mechanochemistry results (solvent-drop grinding (SDG) with eight solvents) with new results obtained from slurrying in five preferred solvents using the same library of 25 cocrystals. Overall, both methods were found to be effective with slurrying and SDG being 94 and 78.5% successful, respectively. Importantly, 96% of the cocrystals formed via slurrying were observed to be free of starting materials (coformers) according to powder X-ray diffraction (PXRD), whereas this was the case for only 72% of the cocrystals prepared by SDG. Slurrying therefore compared favorably with mechanochemistry, which tends to leave small amounts of unreacted coformer(s) as byproducts, and solution crystallization, which often affords crystals of the least soluble coformer because it can be difficult to control the saturation of three or more solids. Perhaps the most interesting and surprising result of this study was that water slurrying proved to be highly effective, even for low-solubility coformers. Indeed, water slurrying was found to be effective for 21 of the 25 cocrystals studied.

Recent Advances on Molecular Crystalline Luminescent Materials for Optical Waveguides

AbstractMolecule‐based fluorescent materials with optical waveguides (MFOWs) have attracted great research interest in the optoelectronic and photonic fields due to their unique photoluminescence properties. Theoretically, the waveband of propagated light within the MFOWs can cover the entire visible light region, which has been one of the important branches in micro/nanophotonics. In this review, the research progress of MFOWs during the last few years, including the basic emission parameters, waveguiding mechanisms, and design methods including adjustments of size, dimension, and shape at the micro/nano‐scales is systematically summarized. New emerging materials (such as flexible nanostructures, molecular cocrystals, and organic–inorganic hybrids) are described towards the high‐performance MFOWs applications. Although tremendous researches for developing MFOWs have been conducted, there remain several dilemmas, such as the deep understanding on elucidated mechanisms and the difficulty for commercialization. Thus, this work also presents the existing challenges and insightful trends, which offer potential guidance for the design and development of MFOWs in future.

Generating Cocrystal Polymorphs with Information Entropy Driven by Molecular Dynamics-Based Enhanced Sampling.

Predicting structures of organic molecular cocrystals is a challenging task when considering the immense number of possible intermolecular orientations. Use of the Shannon information entropy, constructed from an intermolecular orientational spatial distribution function, to drive a search for crystal structures via enhanced molecular dynamics can be an efficient way to map out a landscape of putative polymorphs. Here, the Shannon entropy is used to generate a set of collective variables for differentiating polymorphs of a 1:1 cocrystal of resorcinol and urea. We show that driven adiabatic free energy dynamics, a particular enhanced-sampling approach, combined with these entropy variables, can transform the stable phase into alternate polymorphs. Density functional theory calculations confirm that a structure obtained from the enhanced molecular dynamics is stable at pressures above 1 GPa. We thus show that enhanced sampling should be considered an integral component of crystal structure searching protocols for systems with multiple independent molecules.