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.

A Crystallographic Charge Density Study of the Partial Covalent Nature of Strong N⋠⋠⋠Br Halogen Bonds.

The covalent nature of strong N-Br⋅⋅⋅N halogen bonds in a cocrystal (2) of N-bromosuccinimide (NBS) with 3,5-dimethylpyridine (lut) was determined from X-ray charge density studies and compared to a weak N-Br⋅⋅⋅O halogen bond in pure crystalline NBS (1) and a covalent bond in bis(3-methylpyridine)bromonium cation (in its perchlorate salt (3). In 2, the donor N-Br bond is elongated by 0.0954 Å, while the Br⋅⋅⋅acceptor distance of 2.3194(4) is 1.08 Šshorter than the sum of the van der Waals radii. A maximum electron density of 0.38 e Å-3 along the Br⋅⋅⋅N halogen bond indicates a considerable covalent contribution to the total interaction. This value is intermediate to 0.067 e Å-3 for the Br⋅⋅⋅O contact in 1, and approximately 0.7 e Å-3 in both N-Br bonds of the bromonium cation in 3. A calculation of the natural bond order charges of the contact atoms, and the σ*(N1-Br) population of NBS as a function of distance between NBS and lut, have shown that charge transfer becomes significant at a Br⋅⋅⋅N distance below about 3 Å.

Cyclodextrin encapsulation of daidzein and genistein by grinding: implication on the glycosaminoglycan accumulation in mucopolysaccharidosis type II and III fibroblasts.

This work aimed to investigate the potential effect of cyclodextrin encapsulation on intrinsic ability of daidzein (DAD) and genistein (GEN) to inhibit the glycosaminoglycan (GAG) synthesis in fibroblasts originating from patients with mucopolysaccharidosis (MPS), type II and III. DAD or GEN encapsulation with either 2-hydroxypropyl-ß-cyclodextrin or sulphobuthylether-ß-cyclodextrin were achieved by neat grinding and were characterised by thermal analysis, X-ray powder diffraction, scanning electron microscopy and solubility testing which confirmed the complexes formation with increased solubility with respect to starting compounds. Both isoflavones, as well as their co-ground cyclodextrin complexes reduced GAG levels in the fibroblasts of MPS II and MPS III patients from 54.8-77.5%, in a dose dependent manner, without any significant cytotoxic effect. Cyclodextrin encapsulation did not change the intrinsically high effect of both DAD and GEN on the GAG level reduction in the treated cells, thus could be considered as a part of combination therapies of MPS.

Halogen and Hydrogen Bonding between (N-Halogeno)-succinimides and Pyridine Derivatives in Solution, the Solid State and In Silico.

A study of strong halogen bonding within three series of halogen-bonded complexes, derived from seven para-substituted pyridine derivatives and three N-halosuccinimides (iodo, bromo and chloro), has been undertaken with the aid of single-crystal diffraction, solution complexation and computational methods. The halogen bond was compared with the hydrogen bond in an equivalent series based on succinimide. The halogen-bond energies are in the range -60 to -20 kJ mol-1 and change regularly with pyridine basicity and the Lewis acidity of the halogen. The halogen-bond energies correlate linearly with the product of charges on the contact atoms, which indicates a predominantly electrostatic interaction. The binding enthalpies in solution are around 19 kJ mol-1 less negative due to solvation effects. The optimised geometries of the complexes in the gas phase are comparable to those of the solid-state structures, and the effects of the supramolecular surroundings in the latter are discussed. The bond energies for the hydrogen-bonded series are intermediate between the halogen-bond energies of iodine and bromine, although there are specific differences in the geometries of the halogen- and hydrogen-bonded complexes.

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.

Evaluation of Concomitant Halogen and Pnictogen Bonds in Cocrystals of Imines Derived from 2-Nitrobenzaldehyde and 4-Haloaniline.

Three imines have been prepared by condensation of 2-nitrobenzaldehyde and 4-haloanilines (halo = Cl, Br, and I) with functionalities that enabled them to act as both halogen and pnictogen bond donors; however, both interactions were found to be absent in the solid state. The prepared imines were further cocrystallized with 1,3-diiodotetrafluorobenzene and 1,3,5-triiodotetrafluorobenzene as halogen bond donors. Six novel cocrystals were prepared by means of liquid-assisted mechanochemical synthesis and by crystallization from solution. All six cocrystals were of 1:1 stoichiometry and comprised a N···I halogen bond between an iodine atom of the perhalogenated halogen bond donor and the imino nitrogen atom of the imine acting as an acceptor. Additionally, in all six cocrystals, the imine molecules were interconnected by NO2···NO2 pnictogen bonding interactions. Computational analysis has shown that the NO2···NO2 exhibits bond critical point electron densities in the region (4.897-8.306) × 10-3 e Å-3 and interaction energies of 23.6-27.7 kJ mol-1, whereas the N···I halogen bonds generally have higher critical point electron densities ((1.795-1.937) × 10-2 e Å-3), but the corresponding total interaction energies are lower (19.4-20.4 kJ mol-1). Statistical analysis of the appearance of NO2···NO2 contacts concomitantly with halogen or hydrogen bonds seems to indicate that there is a positive correlation between the presence of NO2···NO2 pnictogen bonding interactions and other directional interactions in crystal structures.

2,2'-Bipyridine Derivatives as Halogen Bond Acceptors in Multicomponent Crystals.

In this work, we present a systematic study of the halogen bonding potential of different 2,2'-bipyridine derivatives in the synthesis of cocrystals by using selected perfluorinated iodobenzenes and N-haloimides as halogen bond donors. These halogen bond acceptor molecules were chosen to explore how different substituents on 2,2'-bipyridine affect halogen bond formation. Out of 24 combinations, we obtained only 8 cocrystals by using two methods, liquid-assisted grinding and crystallization from the solution. Of those 8 cocrystals, one has already been described in the literature. As expected, structural data revealed that 2,2'-bipyridine derivatives act as ditopic halogen bond acceptors in all structures. Dominant interactions in 7 of the cocrystals are I···N or Br···N halogen bonds, while in the one remaining cocrystal it is the I···C(π) halogen bond.

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.

The Halogen Bonding Proclivity of the sp3 Sulfur Atom as a Halogen Bond Acceptor in Cocrystals of Tetrahydro-4H-thiopyran-4-one and Its Derivatives.

In this work, we present a systematic study of the capability of the sp3 hybridized sulfur atom for halogen bonding both in a small building block, tetrahydro-4H-thiopyran-4-one, and two larger ones derived from it, Schiff bases with a morpholine fragment on the other end of the molecule. These three building blocks were cocrystallized with six perhalogenated aromates: 1,4-diiodotetrafluorobenzene, 1,3,5-triiodotrifluorobenzene, 1,3-diiodotetrafluorobenzene, 1,2-diiodotetrafluorobenzene, iodopentafluorobenzene, and 1,4-dibromotetrafluorobenzene. Out of the 18 combinations, only 7 (39%) yielded cocrystals, although with a high occurrence of the targeted I···S halogen bonding motif in all cocrystals (71%), and in imine cocrystals the I···Omorpholine motif (100%) as well as, surprisingly, the I···Nimine motif (100%). The I···S halogen bonds presented in this work feature lower relative shortening values than those for other types of sulfur atoms; however, the sp3 sulfur atom could potentially be more specific an acceptor for halogen bonding.

Conservation of the Hydrogen-Bonded Pyridone Homosynthon in Halogen-Bonded Cocrystals.

Seven cocrystals of pyridone and perfluorinated halocarbons have been prepared. In all cases pairs of pyridone molecules are connected into dimers by two N-H···O hydrogen bonds, forming the characteristic pyridone homosynthon of R2 2(8) topology. These dimers further act as acceptors of halogen bonds through the two pyridone oxygen atoms, forming two (in six cases) or three (in one case) halogen bonds with the donor molecules. The stoichiometry of the cocrystals obtained and the overall topology of the supramolecular architecture depend primarily on the topicity of the halogen bond donor, with the monotopic donor yielding a cocrystal of 1:1 stoichiometry comprising discrete supramolecular complexes, the ditopic donors cocrystals of 1:2 stoichiometry comprising chains, and the tritopic donor a cocrystal of 1:2 stoichiometry comprising hydrogen- and halogen-bonded layers. The results indicate that the pyridone homosynthon is a robust and reliable supramolecular synthon that is conserved in halogen-bonded cocrystals of pyridone.

Halogen Bond Motifs in Cocrystals of N,N,O and N,O,O Acceptors Derived from Diketones and Containing a Morpholine or Piperazine Moiety.

In this study, we investigate the halogen bond acceptor potential of oxygen and nitrogen atoms of morpholine and piperazine fragments when they are peripherally located on N,O,O or N,N,O acceptor molecules. We synthesized four acceptor molecules derived from either acetylacetone or benzoylacetone and cocrystallized them with 1,4-diiodotetrafluorobenzene and 1,3,5-triiodotrifluorobenzene. This resulted in eight cocrystals featuring different topicities and geometric dispositions of donor atoms. In all cocrystals, halogen bonds are formed with either the morpholinyl oxygen atom or the terminal piperazine nitrogen atom. The I···Omorpholine halogen bonds feature lower relative shortening values than I···Nterminal, I···Ocarbonyl, and I···Nproximal halogen bonds. The N and O halogen bond acceptor sites were evaluated through calculations of molecular electrostatic potential values.

Anticooperativity of Multiple Halogen Bonds and Its Effect on Stoichiometry of Cocrystals of Perfluorinated Iodobenzenes.

To investigate influences on the topicity of perfluorinated halobenzenes as halogen bond (XB) donors in the solid state, we have conducted a database survey and prepared 18 novel cocrystals of potentially ditopic (13ditfb, 14ditfb) and tritopic (135titfb) XB donors with 15 monotopic pyridines. 135titfb shows high tendency to be mono- or ditopic, but with strong bases it can act as a tritopic XB donor. DFT calculations have shown that binding of a single acceptor molecule on one of the iodine atoms of the XB donor reduces the ESPmax on the remaining iodine atoms and dramatically decreases their potential for forming further halogen bonds, which explains both the high occurrence of crystal structures where the donors do not achieve their maximal topicity and the observed differences in halogen bond lengths. Despite the fact that this effect increases with the basicity of the acceptor, when the increase of halogen bond energy due to the basicity of the acceptor compensates its decrease due to the reduction of the acidity of the donor, it enables strong bases to form cocrystals in which a potentially polytopic XB donor achieves its maximal topicity.

Halogen and Hydrogen Bond Motifs in Ionic Cocrystals Derived from 3-Halopyridinium Halogenides and Perfluorinated Iodobenzenes.

Four halopyridinium salts, 3-chloro- and 3-bromopyridinium chlorides and bromides, have been successfully cocrystallized with two ditopic perfluorinated iodobenzenes, 1,4-diiodotetrafluorobenzene and 1,2-diiodotetrafluorobenzene. These halogen bond donor molecules were chosen because the different positionings of halogen bond donor atoms can lead to different supramolecular architectures. In this work, we present insight into the halogen bond acceptor potential of chloride and bromide ions, as well as the halogen bond donor potential of chlorine and bromine atoms substituted on the pyridinium ring when combined with the expectedly very strong hydrogen bonds between halopyridinium ions and free halogenide anions. A series of eight cocrystals were obtained in which three pairs of isostructural cocrystals were formed. Dominant interactions in the obtained cocrystals were charge-assisted hydrogen bonds between halopyridinium cations and halogenide ions as well as halogen bonds between halogen atoms on the pyridinium ring and halogenide ions.

Cobaloximes as Building Blocks in Halogen-Bonded Cocrystals.

In this work, we explore the halogen-bonded cocrystallization potential of cobaloxime complexes in the synthesis of cocrystals with perhalogenated benzenes. We demonstrate a strategy for synthesizing halogen-bonded metal-organic cocrystals by utilizing cobaloximes whose pendant bromide group and oxime oxygen enable halogen bonding. By combining three well-known halogen bond donor molecules differing in binding geometry and composition with three cobaloxime units, we obtained a total of four previously unreported cocrystals. Single crystal X-ray diffraction experiments showed that the majority of obtained cocrystals exhibited the formation of the targeted I···O and I···Br motives. These results illustrate the potential of cobaloximes as halogen bond acceptors and indicate that this type of halogen bond acceptors may offer a novel route to metal-organic halogen-bonded cocrystals.

Exploring the Halogen-Bonded Cocrystallization Potential of a Metal-Organic Unit Derived from Copper(ii) Chloride and 4-Aminoacetophenone.

In this work, we describe a novel halogen-bonded metal-organic cocrystal involving a square-planar Cu(ii) complex and 1,4-diiodotetrafluorobenzene (14tfib) by utilizing an amine ligand whose pendant acetyl group enables halogen bonding. The cocrystal was prepared by both mechanochemical synthesis (liquid-assisted grinding) and the conventional solution-based method. Crystal structure determination by single crystal X-ray diffraction revealed that the dominant supramolecular interactions are the I···O halogen bond between 14tfib and CuCl2(aap)2 building blocks, and the N-H···Cl hydrogen bonds between CuCl2(aap)2 molecules. The combination of halogen and hydrogen bonding leads to the formation of a 2D network. Overall, this work showcases an example of the possibility for extending the complexity of metal-organic crystal structures by using halogen bonding in a way that does not affect other hydrogen bonding synthons.

Co-grinding with surfactants as a new approach to enhance in vitro dissolution of praziquantel.

This paper evaluates the process of co-grinding with a surfactant as a new approach to enhance physicochemical and biopharmaceutical properties of praziquantel (PZQ), a poorly soluble drug that is essential for the treatment of schistosomiasis, a neglected tropical disease. Surfactants used in this study were poloxamer F-127 and sucrose stearate (C-1816), selected based on their well-documented biocompatibility and solubilizing activity. A series of products were prepared by mechanochemical activation using vibrational ball-mill at different drug to surfactant ratio and milling times. The obtained products were characterised in terms of drug recovery, solubility and in vitro dissolution rates. The obtained results were correlated to solid-state properties of the products analysed by differential scanning calorimetry, powder X-ray diffraction and particle size analysis. Results of UPLC-MS analysis and 1H-NMR spectroscopy showed that the used surfactants and applied grinding procedures caused no chemical degradation of the PZQ. The physicochemical properties, solubility and the in vitro dissolution enhancement of the co-ground products were related to the drug to surfactant ratio and the grinding protocol applied. The highest enhancement of the in vitro dissolution rate was achieved at the drug to surfactant ratio of 10:3 and 10:2 for F-127 and C-1816, respectively with the milling time of 30 min. The MTT assay on Caco-2 cell line demonstrated the biocompatibility of both co-ground products. Furthermore, the surfactants used did not change intrinsically high intestinal permeability of PZQ (Papp ∼ 4.00 × 10-5 cm s-1). The presented results confirmed that the co-grinding with surfactant is a promising new approach in enhancing in vitro dissolution of poorly soluble drugs like PZQ.

Mechanochemical reactions of cocrystals: comparing theory with experiment in the making and breaking of halogen bonds in the solid state.

Mechanochemical re-investigation of the halogen-bonded cocrystallisation of 1,4-diazabicyclo[2.2.2]-octane and 1,2-diiodotetrafluorobenzene revealed an unexpectedly complex system with three distinct cocrystal compositions, one of which also exhibits temperature-dependent polymorphism. This provided an opportunity to experimentally test the ability of dispersion-corrected periodic density functional theory (DFT) to not only explain the formation, but also predict the interconversion between halogen-bonded cocrystals of different stoichiometries.

Cocrystal trimorphism as a consequence of the orthogonality of halogen- and hydrogen-bonds synthons.

True trimorphic cocrystals, i.e. multi-component molecular crystals of identical composition that exhibit three polymorphic structures, are exceedingly rare and so far no halogen-bonded cocrystal system has been reported to exhibit trimorphism. Here we describe a unique example of a trimorphic cocrystal exhibiting both hydrogen and halogen bonds in which the differences between polymorphs reveal their orthogonality, evident by the apparently independent variation of well-defined hydrogen- and halogen-bonded motifs.

Halogen-bonded cocrystallization with phosphorus, arsenic and antimony acceptors.

The formation of non-covalent directional interactions, such as hydrogen or halogen bonds, is a central concept of materials design, which hinges on using small compact atoms of the 2nd period, notably nitrogen and oxygen, as acceptors. Heavier atoms are much less prominent in that context, and mostly limited to sulfur. Here, we report the experimental observation and theoretical study of halogen bonds to phosphorus, arsenic and antimony in the solid state. Combining 1,3,5-trifluoro-2,4,6-triiodobenzene with triphenylphosphine, -arsine, and -stibine provides cocrystals based on I···P, I···As and I···Sb halogen bonds. The demonstration that increasingly metallic pnictogens form halogen bonds sufficiently strong to enable cocrystal formation is an advance in supramolecular chemistry which opens up opportunities in materials science, as shown by colossal thermal expansion of the cocrystal involving I···Sb halogen bonds.

A stepwise mechanism for the mechanochemical synthesis of halogen-bonded cocrystal architectures.

A molecular-level mechanism is proposed for two cases of mechanochemical cocrystallization via halogen bonds. The proposed stepwise mechanism is based on the observation and structural characterization of intermediates that appear in early stages of the reaction. The mechanism arises from the competition of strong and weak intermolecular halogen bonds of the N...I and S...I type and involves the initial formation of finite molecular assemblies, held together via N...I bonds that subsequently polymerize into infinite chains by cross-linking through S...I bonds. This mechanism has been observed in the synthesis of linear as well as zigzag halogen-bonded chain architectures.