Complex structures arising from the self-assembly of a simple organic salt.

Molecular self-assembly is the spontaneous association of simple molecules into larger and ordered structures1. It is the basis of several natural processes, such as the formation of colloids, crystals, proteins, viruses and double-helical DNA2. Molecular self-assembly has inspired strategies for the rational design of materials with specific chemical and physical properties3, and is one of the most important concepts in supramolecular chemistry. Although molecular self-assembly has been extensively investigated, understanding the rules governing this phenomenon remains challenging. Here we report on a simple hydrochloride salt of fampridine that crystallizes as four different structures, two of which adopt unusual self-assemblies consisting of polyhedral clusters of chloride and pyridinium ions. These two structures represent Frank-Kasper (FK) phases of a small and rigid organic molecule. Although discovered in metal alloys4,5 more than 60 years ago, FK phases have recently been observed in several classes of supramolecular soft matter6-11 and in gold nanocrystal superlattices12 and remain the object of recent discoveries13. In these systems, atoms or spherical assemblies of molecules are packed to form polyhedra with coordination numbers 12, 14, 15 or 16. The two FK structures reported here crystallize from a dense liquid phase and show a complexity that is generally not observed in small rigid organic molecules. Investigation of the precursor dense liquid phase by cryogenic electron microscopy reveals the presence of spherical aggregates with sizes ranging between 1.5 and 4.6 nanometres. These structures, together with the experimental procedure used for their preparation, invite interesting speculation about their formation and open different perspectives for the design of organic crystalline materials.

A Semiflexible Tetrahydrazone Macrocycle for Binding of Pyrophosphate and Smaller Anions.

Macrocyclization has proven to be a useful design strategy in the development of efficient anion receptors. In addition to the ring size, the overall preorganization due to structural rigidity is key. To explore this in the context of developing an efficient pyrophosphate receptor, three macrocycles featuring a 26-membered interior ring size and similar H-bonding motifs have been synthesized, and their anion binding ability has been investigated. Computational studies and nuclear magnetic resonance (NMR) data showed different degrees of preorganization as a result of differences in flexibility. The interaction of the three macrocycles with chloride, dihydrogen phosphate, and dihydrogen pyrophosphate was investigated in solution by NMR and ultraviolet-visible spectroscopy and in the solid state by X-ray crystallography. The tetrahydrazone-based macrocycle featuring intermediate flexibility exhibited the best affinity for all three anions investigated. Our results suggest that in addition to the proper preorganization of binding groups in a macrocycle a certain degree of flexibility is also required for an optimal affinity with the target guest.

Reactivity and Steric Parameters from 2D to 3D Bulky Pyridines: Increasing Steric Demand at Nitrogen with Chiral Azatriptycenes.

Sterically hindered pyridines embedded in a three-dimensional triptycene framework have been synthesized, and their resolution by chiral HPLC enabled access to unprecedented enantiopure pyridines exceeding the known steric limits. The design principles for new axially chiral pyridine derivatives are then described. To rationalize their associations with Lewis acids and transition metals, a comprehensive determination of the steric and electronic parameters for this new class of pyridines was performed. This led to the general parameterization of the steric parameters (percent buried volume %VBur, Tolman cone angle θ, and He8_steric descriptor) for a large set of two- and three-dimensional pyridine derivatives. These parameters are shown to describe quantitatively their interactions with carbon- and boron-centered Lewis acids and were used to predict the ΔG° of association with the prototypical B(C6F5)3 Lewis acid widely used in frustrated Lewis pair catalysis. This first parameterization of pyridine sterics is a fundamental basis for the future development of predictive reactivity models and for guiding new applications of bulky and chiral pyridines in organocatalysis, frustrated Lewis pairs, and transition-metal catalysis.

From Proton to Boron: The Lewis Analogs of Protonated Brønsted Super Acids.

Isolation and characterization of highly reactive intermediates are crucial to understand the nature of chemical reactivity. Accordingly, the reactivity of weakly coordinating anions (WCA), usually used to stabilized cationic super electrophiles are of fundamental interest. When a variety of WCA are known to form stable σ-complexes with a proton, inducing Brønsted super acidity, bis-coordinated weak-coordinated anions are much more elusive and considered as long-sought reactive species. In this work, the chemistry of borylated sulfate, triflimidate and triflate anions were scouted in details with the aim of synthetizing the unique analogs of protonated Brønsted superacids. Those complexes were formed by successive borylation with a 9-boratriptycene derived Lewis super acid paired with a weak coordinated anion, characterized in solution and in the solid state and exhibit unique structures and reactivities.

The Facile Hydrolysis of Imidazolinium Chlorides (N-Heterocyclic Carbene Precursors) Under Basic Aqueous Conditions.

The hydrolysis of imidazolinium chlorides takes place readily in a basic water/dichloromethane biphasic mixture at room temperature. Experimental parameters were optimized to afford full conversions and high yields of γ-aminoformamides starting from twelve symmetrical substrates with alkyl or aryl substituents on their nitrogen atoms, and five unsymmetrical 1-alkyl-3-arylimidazolinium chlorides. NMR and XRD analyses showed that the cleavage of unsymmetrical salts led to γ-alkylamino-N-arylformamides with a high regioselectivity and that bulky alkyl or aryl groups on the formamide moiety led to the isolation of the (E)-isomer in high stereoisomeric purity (>95 %), whereas smaller and more flexible alkyl substituents afforded mixtures of (E)- and (Z)-rotamers. Control experiments showed that the hydrolysis of 1,3-dimesitylimidazolinium chloride (SIMes ⋅ HCl) did not occur readily in pure or acidic water and that the presence of bulky aromatic substituents on the nitrogen atoms of 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (SIDip ⋅ HCl) efficiently slowed down its hydrolysis under basic aqueous conditions. Most strikingly, this work highlighted the critical influence of the counteranion on the reactivity of imidazolinium cations. Indeed, the chloride salts underwent a facile hydrolysis in the presence of water and Na2 CO3 , whereas various other NHC ⋅ HX derivatives reacted much slower or remained essentially inert under these conditions.

Taming the Lewis Superacidity of Non-Planar Boranes: C-H Bond Activation and Non-Classical Binding Modes at Boron.

The rational design of a geometrically constrained boron Lewis superacid featuring exceptional structure and reactivity is disclosed. It enabled the formation of non-classical electron deficient B-H-B type of bonding, which was supported by spectroscopic and structural parameters as well as computational studies. Taming the pyramidal Lewis acid electrophilicity through weak coordinating anion dissociation enabled a series of highly challenging chemical transformations, such as Csp2 -H and Csp3 -H activation under a frustrated Lewis pair regime and the cleavage of Csp3 -Si bonds. The demonstration of such rich chemical behaviour and flexibility on a single molecular compound makes it a unique mediator of chemical transformations generally restricted to transition metals.

Methylene Bridging Effect on the Structures, Lewis Acidities and Optical Properties of Semi-planar Triarylboranes.

Three synthetic methods towards semi-planar triarylboranes with two aryl rings connected by a methylene bridge have been developed. The fine-tuning of their stereoelectronic properties and Lewis acidities was achieved by introducing fluorine, methyl, methoxy, n-butyl and phenyl groups either at their exocyclic or bridged aryl rings. X-ray diffraction analysis and quantum-chemical calculations provided quantitative information on the structural distortion experienced by the near planar hydro-boraanthracene skeleton during the association with Lewis bases such as NH3 and F- . Though the methylene bridge between the ortho-positions of two aryl rings of triarylboranes decreased the Gibbs free energies of complexation with small Lewis bases by less than 5 kJ mol-1 relative to the classical Lewis acid BAr3 , the steric shielding of the CH2 bridge is sufficient to avoid the formation of Lewis adducts with larger Lewis bases such as triarylphosphines. A newly synthesized spirocyclic amino-borane with a long intramolecular B-N bond that could be dissociated under thermal process, UV-irradiation, or acidic conditions might be a potential candidate in Lewis pairs catalysis.

Controlled Generation of 9-Boratriptycene by Lewis Adduct Dissociation: Accessing a Non-Planar Triarylborane.

A highly bent triarylborane, 9-boratriptycene, was generated in solution by selective protodeboronation of the corresponding tetra-aryl boron ate complex with the strong Brønsted acid HNTf2 . The iptycene core confers enhanced Lewis acidity to 9-boratriptycene, making it unique in terms of structure and reactivity. We studied the stereoelectronic properties of 9-boratriptycene by quantifying its association with small N- and O-centered Lewis bases, as well as with sterically hindered phosphines. The resultant Lewis adducts exhibited unique structural, spectroscopic, and photophysical properties. Beyond the high pyramidalization of the 9-boratriptycene scaffold and its low reorganization energy upon Lewis base coordination, quantum chemical calculations revealed that the absence of π donation from the triptycene aryl rings to the boron vacant pz orbital is one of the main reasons for its high Lewis acidity.

Complementary Synthetic Approaches toward 9-Phosphatriptycene and Structure-Reactivity Investigations of Its Association with Sterically Hindered Lewis Acids.

Two practical and high-yielding syntheses of 9-phosphatriptycene are reported. In both approaches, the key step is based on the cyclization of a (tris)lithio-triphenylmethane or a (tris)lithio-triphenylphosphine intermediate on a phosphorus or a carbon electrophile, respectively. The association of 9-phosphatriptycene with representative boron- and carbon-centered Lewis acids was investigated by IR, NMR, and UV-vis titration experiments and by computational methods, shedding light on its steric hindrance, σ-donating ability, and Brønsted and Lewis basicities.

Design and Synthesis of a New Soluble Natural ß-Carboline Derivative for Preclinical Study by Intravenous Injection.

Harmine is a natural ß-carboline compound showing several biological activities, including antiproliferative properties, but this soluble natural molecule lacks selectivity. Harmine derivatives were reported to overcome this problem, but they are usually poorly soluble. Here, we designed and synthesized a new 2, 7, 9-trisubstituted molecule (1-methyl-7-(3-methylbutoxy)-9-propyl-2-[(pyridin-2-yl)methyl]-9H-pyrido[3,4-b]indol-2-ium bromide) with a solubility of 1.87 ± 0.07 mg/mL in a simulated injection vehicle. This compound is stable for at least 72 h in acidic and physiological conditions (pH 1.1 and 7.4) as well as in a simulated injection vehicle (physiological liquid + 0.1% Tween80®). Solubility in those media is 1.06 ± 0.08 mg/mL and 1.62 ± 0.13 mg/mL at pH 7.4 and 1. The synthesized molecule displays a significant activity on five different cancer cell lines (IC50 range from 0.2 to 2 µM on A549, MDA-MB-231, PANC-1, T98G and Hs683 cell lines). This compound is also more active on cancer cells (MDA-MB-231) than on normal cells (MCF-10a) at IC50 concentrations. Due to its high activity at low concentration, such solubility values should be sufficient for further in vivo antitumoral activity evaluation via intravenous injection.

A Simple and Efficient Mechanochemical Route for the Synthesis of Salophen Ligands and of the Corresponding Zn, Ni, and Pd Complexes.

A number of salophen ligands and their Zn, Ni, and Pd complexes were synthesized by an efficient one-pot mechanosynthesis protocol. The reaction products were characterized by means of complementary solid-state techniques, i.e., powder X-ray diffraction, single-crystal X-ray diffraction, and solid-state NMR spectroscopy. Four new crystal structures of metal salophen complexes as DMSO solvates are here reported. The described simple and relatively fast (about 1 h for all derivatives) procedure is a good alternative to classical methods performed in organic solvents.

Pushing the Lewis Acidity Boundaries of Boron Compounds With Non-Planar Triarylboranes Derived from Triptycenes.

Bending the planar trigonal boron center of triphenylborane by connecting its aryl rings with carbon or phosphorus linkers gave access to a series of 9-boratriptycene derivatives with unprecedented structures and reactivities. NMR spectroscopy and X-ray diffraction of the Lewis adducts of these non-planar boron Lewis acids with weak Lewis base revealed particularly strong covalent bond formation. The first Lewis adduct of a trivalent boron compounds with the Tf2 N- anion illustrates the unrivaled Lewis acidity of these species. Increasing the pyramidalization of the boron center and using a cationic phosphonium linker resulted in an exceptional enhancement of Lewis acidity. Introduction of a phosphorus and a boron atom at each edge of a triptycene framework, allowed access to new bifunctional Lewis acid-base 9-phospha-10-boratriptycenes featuring promising reactivity for the activation of carbon-halogen bonds.

Innovative in Situ Ball Mill for X-ray Diffraction.

The renewed interest of mechanochemistry as an ecofriendly synthetic route has inspired original methodologies to probe reactions, with the aim to rationalize unknown mechanisms. Recently, Friscic et al. ( Nat. Chem. 2013 , 5 , 66 - 73 , DOI: 10.1038/nchem.1505 ) monitored the progress of milling reactions by synchrotron X-ray powder diffraction (XRPD). For the first time, it was possible to acquire directly information during a mechanochemical process. This new methodology is still in its early stages, and its development will definitively transform the fundamental understanding of mechanochemistry. A new type of in situ ball mill setup has been developed at the Materials Science beamline (Swiss Light Source, Paul Scherrer Institute, Switzerland). Its particular geometry, described here in detail, results in XRPD data displaying significantly lower background and much sharper Bragg peaks, which in turn allow more sophisticated analysis of mechanochemical processes, extending the limits of the technique.

In situ diffraction study of catalytic hydrogenation of VO2: stable phases and origins of metallicity.

Controlling electronic population through chemical doping is one way to tip the balance between competing phases in materials with strong electronic correlations. Vanadium dioxide exhibits a first-order phase transition at around 338 K between a high-temperature, tetragonal, metallic state (T) and a low-temperature, monoclinic, insulating state (M1), driven by electron-electron and electron-lattice interactions. Intercalation of VO2 with atomic hydrogen has been demonstrated, with evidence that this doping suppresses the transition. However, the detailed effects of intercalated H on the crystal and electronic structure of the resulting hydride have not been previously reported. Here we present synchrotron and neutron diffraction studies of this material system, mapping out the structural phase diagram as a function of temperature and hydrogen content. In addition to the original T and M1 phases, we find two orthorhombic phases, O1 and O2, which are stabilized at higher hydrogen content. We present density functional calculations that confirm the metallicity of these states and discuss the physical basis by which hydrogen stabilizes conducting phases, in the context of the metal-insulator transition.

Regulating iminophosphorane PN bond reactivity through geometric constraints with cage-shaped triarylphosphines.

Structure-reactivity investigations and quantum-chemical parametrization of steric and electronic properties of geometrically constrained iminophosphoranes enabled the design of new frustrated Lewis pairs and revealed unusual properties at the phosphonium center embedded in the cage-shaped triptycene tricyclic scaffold.

Small-pore hydridic frameworks store densely packed hydrogen.

Nanoporous materials have attracted great attention for gas storage, but achieving high volumetric storage capacity remains a challenge. Here, by using neutron powder diffraction, volumetric gas adsorption, inelastic neutron scattering and first-principles calculations, we investigate a magnesium borohydride framework that has small pores and a partially negatively charged non-flat interior for hydrogen and nitrogen uptake. Hydrogen and nitrogen occupy distinctly different adsorption sites in the pores, with very different limiting capacities of 2.33 H2 and 0.66 N2 per Mg(BH4)2. Molecular hydrogen is packed extremely densely, with about twice the density of liquid hydrogen (144 g H2 per litre of pore volume). We found a penta-dihydrogen cluster where H2 molecules in one position have rotational freedom, whereas H2 molecules in another position have a well-defined orientation and a directional interaction with the framework. This study reveals that densely packed hydrogen can be stabilized in small-pore materials at ambient pressures.

A new structure of a serotonin salt: comparison and conformational analysis of all known serotonin complexes.

Four serotonin salt structures (serotonin adipate, C10H13N2O(+)·C6H9O4(-), is a previously unknown structure) were analysed to understand the influence of the anion on serotonin conformation. Hydrogen bonding alone favours a flat conformation, whereas additional stacking interactions between ions may possibly account for the nonplanar conformation. Since molecular conformation, stability and biological activity are interrelated, one can consider influencing the chemical and biological properties of serotonin by selecting an appropriate counter-ion for salt formation.

Single crystal formation in core-shell capsules.

This work extends the scope of microfluidic-based crystallization methods by introducing solid microcapsules. Hundreds of perfectly similar microcapsules were generated per second, allowing a fast screening of crystallization conditions. XRD analyses were performed directly on encapsulated single crystals demonstrating the potential of this process for the characterization of compounds, including screening polymorphism.

Secondary ion mass spectrometry, a powerful tool for revealing ink formulations and animal skins in medieval manuscripts.

Book production by medieval scriptoria have gained growing interest in recent studies. In this context, identifying ink compositions and parchment animal species from illuminated manuscripts is of great importance. Here, we introduce time-of-flight secondary ion mass spectrometry (ToF-SIMS) as a non-invasive tool to identify both inks and animal skins in manuscripts, at the same time. For this purpose, both positive and negative ion spectra in inked and non-inked areas were recorded. Chemical compositions of pigments (decoration) or black inks (text) were determined by searching for characteristic ion mass peaks. Animal skins were identified by data processing of raw ToF-SIMS spectra using principal component analysis (PCA). In illuminated manuscripts from the fifteenth to sixteenth century, malachite (green), azurite (blue), cinnabar (red) inorganic pigments, as well as iron-gall black ink, were identified. Carbon black and indigo (blue) organic pigments were also identified. Animal skins were identified in modern parchments of known animal species by a two-step PCA procedure. We believe the proposed method will find extensive application in material studies of medieval manuscripts, as it is non-invasive, highly sensitive and able to identify both inks and animal skins at the same time, even from traces of pigments and tiny scanned areas.

X-ray diffraction and Raman study of DL-alanine at high pressure: revision of phase transitions.

The effect of pressure on DL-alanine has been studied by X-ray powder diffraction (up to 8.3 GPa), single-crystal X-ray diffraction and Raman spectroscopy (up to ~6 GPa). No structural phase transitions have been observed. At ~1.5-2 GPa, cell parameters b and c become accidentally equal to each other, but the space-group symmetry does not change. There is no phase transition between 1.7 and 2.3 GPa, contrary to what has been reported earlier [Belo et al. (2010). Vibr. Spectrosc. 54, 107-111]. The presence of the second phase transition, which was claimed to appear within the pressure range from 6.0 to 7.3 GPa (Belo et al., 2010), is also argued. The changes in the Raman spectra have been shown to be continuous in all the pressure ranges studied.