Isothiocyanate Sulfur Atom as an Acceptor Site for Halogen-Bonded Cocrystallization of Werner Ni(II) Coordination Compounds and Perfluorinated Iodobenzenes.

We explore the halogen bond acceptor potential of the isothiocyanate sulfur atom in the synthesis of cocrystals involving metal-organic building blocks by using Werner Ni(II) coordination compounds whose pendant isothiocyanate group enables halogen bonding. A series of 14 cocrystals involving octahedral Ni(L)(NCS) coordination compounds (L = pyridine or 4-methylpyridine) has been prepared by both crystallization from solution and liquid-assisted grinding. The effectiveness of this strategy is demonstrated by the assembly of a large family of cocrystals involving five perfluorinated iodobenzenes.

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 () and 2,3,5,6-tetrafluoro-4-iodoaniline () 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.

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.

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 -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.

Product contamination during mechanochemical synthesis of praziquantel co-crystal, polymeric dispersion and cyclodextrin complex.

This paper aims to evaluate the product contamination by elemental impurities during the mechanochemical synthesis of praziquantel (PZQ) co-crystal, polymeric dispersion and cyclodextrin complex by grinding. To assess that, PZQ was co-ground with malic acid (MA), Poloxamer F-127 (F-127) and hydroxypropyl-β-cyclodextrin (HPβCD) in high-energy vibrational mills using stainless steel and agate grinding tools, applying different processing time (30 and 90 min). Differential scanning calorimetry and X-ray powder diffraction confirmed the formation of the targeted products, regardless of applied processing time and grinding tool type.

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.

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 sp Sulfur Atom as a Halogen Bond Acceptor in Cocrystals of Tetrahydro-4-thiopyran-4-one and Its Derivatives.

In this work, we present a systematic study of the capability of the sp hybridized sulfur atom for halogen bonding both in a small building block, tetrahydro-4-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···O motif (100%) as well as, surprisingly, the I···N motif (100%).

Halogen Bond Motifs in Cocrystals of ,, and ,, 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 ,, or ,, 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.

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 (, ) and tritopic () XB donors with 15 monotopic pyridines. 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 ESP 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.

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 R (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.

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.

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.

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.

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 () 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 and CuCl() building blocks, and the N-H···Cl hydrogen bonds between CuCl() molecules.

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.

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.

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.

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.

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-β-cyclodextrin or sulphobuthylether-β-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.

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 and change regularly with pyridine basicity and the Lewis acidity of the halogen.

Biopharmaceutical characterization of praziquantel cocrystals and cyclodextrin complexes prepared by grinding.

Mechanochemical activation using several different co-grinding additives was applied as a green chemistry approach to improve physiochemical and biopharmaceutical properties of praziquantel (PZQ). Liquid assisted grinding with an equimolar amount of citric acid (CA), malic acid (MA), salicylic acid (SA) and tartaric acid (TA) gained in cocrystal formation, which all showed pH-dependent solubility and dissolution rate. However, the most soluble cocrystal of PZQ with MA was chemically unstable, as seen during the stability testing.

Effect of atmosphere on solid-state amine-aldehyde condensations: gas-phase catalysts for solid-state transformations.

The presence of water or organic solvent vapour accelerates the solid-state condensation of solid aromatic amines and aromatic aldehydes into Schiff bases; we show the important role of catalytic triethylamine in the vapour phase in such vapour digestion synthesis, as well as in the liquid phase in synthesis via liquid-assisted grinding.

New insight into solid-state molecular dynamics: mechanochemical synthesis of azobenzene/triphenylphosphine palladacycles.

Solid-state reactions of dicyclopalladated azobenzenes and triphenylphosphine lead to the thermodynamically favorable bridged complexes. It was demonstrated for the first time that very complex molecular dynamics involving a series of structural transformations is also feasible in the solid state.

3-Acetylanilinium bromide, nitrate and dihydrogen phosphate: hydrogen-bonding motifs in one, two and three dimensions.

In the title compounds, namely 3-acetylanilinium bromide, C(8)H(10)NO(+) x Br(-), (I), 3-acetylanilinium nitrate, C(8)H(10)NO(+) x NO(3)(-), (II), and 3-acetylanilinium dihydrogen phosphate, C(8)H(10)NO(+) x H(2)PO(4)(-), (III), each asymmetric unit contains a discrete cation, with a protonated amino group, and an anion. In the crystal structure of (I), the ions are connected via N-H..