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.

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.

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.

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.

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.

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.

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.

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.

Calix[6]arenes with halogen bond donor groups as selective and efficient anion transporters.

Here we present the anion binding and anion transport properties of a series of calix[6]arenes decorated on their small rim with either halogen bond or hydrogen bond donating groups. We show that the halogen bond donating iodotriazole groups enable highly selective transport of chloride and nitrate anions, without transport of protons or hydroxide, at rates similar to those observed with thiourea or squaramide groups.

Structural study of bioisosteric derivatives of 5-(1H-indol-3-yl)-benzotriazole and their ability to form chalcogen bonds.

Recently, inter-est in the isosteric replacement of a nitro-gen atom to selenium, sulfur or oxygen atoms has been highlighted in the design of potential inhibitors for cancer research. In this context, the structures of 5-(1H-indol-3-yl)-2,1,3-benzotriazole derivatives [5-(1H-indol-3-yl)-2,1,3-benzo-thia-diazole (bS, C14H9N3S) and 5-(1H-indol-3-yl)-2,1,3-benzoxa-diazole (bO, C14H9N3O)], as well as a synthesis inter-mediate of the selenated bioisostere [5-[1-(benzensulfon-yl)-1H-indol-3-yl]-2,1,3-benzoselena-diazole (p-bSe, C20H13N3O2SSe)] were determined using single-crystal X-ray diffraction (SCXRD) analyses. Despite being analogues, different crystal packing, torsion angles and supra-molecular features were observed, depending on the substitution of the central atoms of the benzotriazole. In particular, chalcogen inter-actions were described in the case of p-bSe and not in the bS and bO derivatives. An investigation by ab initio computational methods was therefore conducted to understand the effect of the substitution on the ability to form chalcogen bonds and the flexibility of the compounds.

Synthesis, Characterization, Biological Activity and Molecular Docking Studies of Novel Organotin(IV) Carboxylates.

Four new carboxylates complexes with general formula R2SnL2 and R3SnL, where R = n-butyl (1, 3), methyl (2, 4) and L = 4-Chlorophenoxyacetate, were synthesized in significant yields. FT-IR analysis revealed a chelating (1 and 2) and a bridging bidentate (3 and 4) coordination modes for the carboxylate ligand in solid state which was further confirmed by the single crystal X-ray analysis of complex 4. The NMR data (1H, 13C and 119Sn) revealed a higher coordination number around the tin center in R2SnL2 (1 and 2) compared to R3SnL (3 and 4). A close matching was observed between the experimental and calculated structures (obtained at B3LYP/6-31G* + LANL2DZ basis set). Quantum chemical analysis indicates that the carboxylate moiety has the major contribution in the formation of filled and unfilled orbitals as well as in ligand to ligand intramolecular charge transfer during the electronic transitions. The cytotoxicity data of the screened compounds evaluated against lung cancer cell line (A549) and normal lung fibroblast cell line (MRC-5) revealed that 1, 3 and 4 have shown dose dependent cytotoxic effects while HL and 2 have shown steady and low cytotoxic activities. The antibacterial activity of complexes 1-4 is higher than that of HL. Molecular docking study showed an intercalation binding mode for complex 3 with DNA (docking score = -3.6005) involving four polar interactions. Complex 3 docking with tubulin (PDB ID 1SA0) with colchicine as a target protein resulted in three polar interactions (docking score -5.2957). Further, the docking analysis of the HL and 1-4 has shown an adequate interactions with the coronavirus SARS-CoV-2 spike protein, nucleocapsid protein and human angiotensin converting enzyme (ACE2).

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.

Crystal structures of two alanyl-piperidine analogues.

The structure of ethyl 1-[N-(4-methyl-phen-yl)-N-(methyl-sulfon-yl)alan-yl]piperidine-4-carboxyl-ate, C19H28N2O5S, I, a compound of inter-est as activator of Ubiquitin C-terminal Hydro-lase-L1 (UCH-L1), was determined by single-crystal X-ray diffraction (SCXRD) analysis. In order to find new activators, a derivative of compound I, namely, 1-[N-(4-methyl-phen-yl)-N-(methyl-sulfon-yl)alan-yl]piperidine-4-carb-oxy-lic acid, C17H24N2O5S, II, was studied. The synthesis and crystal structure are also reported. Despite being analogues, different crystal packings are observed. Compound II bears a carb-oxy-lic group, which favors a strong hydrogen bond. A polymorph risk assessment was carried out to study inter-actions in compound II.

Oxalamide-Functionalized Metal Organic Frameworks for CO2 Adsorption.

Metal-organic frameworks (MOFs) have received great attention in recent years as potential adsorbents for CO2 capture due to their unique properties. However, the high cost and their tedious synthesis procedures impede their industrial application. A series of new CO2-philic oxalamide-functionalized MOFs have been solvothermally synthesized: {[Zn3(µ8-OATA)1.5(H2O)2(DMF)]·5/2H2O·5DMF}n (Zn-OATA), {[NH2(CH3)2][Cd(µ4-HOATA)]·H2O·DMF}n (Cd-OATA), and {[Co2(µ7-OATA)(H2O)(DMF)2]·2H2O·3DMF}n (Co-OATA) (H4OATA = N,N'-bis(3,5-dicarboxyphenyl)oxalamide). In Zn-OATA, the [Zn2(CO2)4] SBUs are connected by OATA4- ligands into a 3D framework with 4-connected NbO topology. In Cd-OATA, two anionic frameworks with a dia topology interpenetrated each other to form a porous structure. In Co-OATA, [Co2(CO2)4] units are linked by four OATA4- to form a 3D framework with binodal 4,4-connected 42·84 PtS-type topology. Very interestingly, Cu-OATA can be prepared from Zn-OATA by a facile metal ions exchange procedure without damaging the structure while the CO2 adsorption ability can be largely enhanced when Zn(II) metal ions are exchanged to Cu(II). These new MOFs possess channels decorated by the CO2-philic oxalamide groups and accessible open metal sites, suitable for highly selective CO2 adsorption. Cu-OATA exhibits a significant CO2 adsorption capacity of 25.35 wt % (138.85 cm3/g) at 273 K and 9.84 wt % (50.08 cm3/g) at 298 K under 1 bar with isosteric heat of adsorption (Qst) of about 25 kJ/mol. Cu-OATA presents a very high selectivity of 5.5 for CO2/CH4 and 43.8 for CO2/N2 separation at 0.1 bar, 298 K. Cd-OATA exhibits a CO2 sorption isotherm with hysteresis that can be originated from structural rearrangements. Cd-OATA adsorbs CO2 up to 11.90 wt % (60.58 cm3/g) at 273 K and 2.26 wt % (11.40 cm3/g) at 298 K under 1 bar. Moreover, these new MOFs exhibit high stability in various organic solvents, water, and acidic or basic media. The present work opens a new opportunity in the development of improved and cost-effective MOF adsorbents for highly efficient CO2 capture.

Copper(ii) complexes with tridentate halogen-substituted Schiff base ligands: synthesis, crystal structures and investigating the effect of halogenation, leaving groups and ligand flexibility on antiproliferative activities.

To investigate the effect of different halogen substituents and leaving groups and the flexibility of ligands on the anticancer activity of copper complexes, sixteen copper(ii) complexes with eight different tridentate Schiff-base ligands containing pyridine and 3,5-halogen-substituted phenol moieties were synthesized and characterized by spectroscopic methods. Four of these complexes were also characterized by X-ray crystallography. The cytotoxicity of the complexes was determined in three different tumor cell lines (i.e. the A2780 ovarian, HCT116 colorectal and MCF7 breast cancer cell line) and in a normal primary fibroblast cell line. Complexes were demonstrated to induce a higher loss of cell viability in the ovarian carcinoma cell line (A2780) with respect to the other two tumor cell lines, and therefore the biological mechanisms underlying this loss of viability were further investigated. Complexes with ligand L1 (containing a 2-pycolylamine-type motif) were more cytotoxic than complexes with L2 (containing a 2-(2-pyridyl)ethylamine-type motif). The loss of cell viability in A2780 tumor cells was observed in the order Cu(Cl2-L1)NO3 > Cu(Cl2-L1)Cl > Cu(Br2-L1)Cl > Cu(BrCl-L1)Cl. All complexes were able to induce reactive oxygen species (ROS) that could be related to the loss of cell viability. Complexes Cu(BrCl-L1)Cl and Cu(Cl2-L1)NO3 were able to promote A2780 cell apoptosis and autophagy and for complex Cu(BrCl-L1)Cl the increase in apoptosis was due to the intrinsic pathway. Cu(Cl2-L1)Cl and Cu(Br2-L1)Cl complexes lead to cellular detachment allowing to correlate with the results of loss of cell viability. Despite the ability of the Cu(BrCl-L1)Cl complex to induce programmed cell death in A2780 cells, its therapeutic window turned out to be low making the Cu(Cl2-L1)NO3 complex the most promising candidate for additional biological applications.

Sterically hindered ortho-substituted phosphatriptycenes as configurationally stable P-chirogenic triarylphosphines.

ortho-Substituted and unsymmetrical 9-phospha-triptycenes were synthesized via two synthetic approaches involving densely functionalized ortho-halogenated triarylmethane or phosphine precursors. ortho-Substituents imposed a considerable steric shielding due to the tricyclic cage-shaped structure with the aryl rings p-systems orthogonal to the phosphorus electron pair. A series of Au(i) and Rh(i) complexes were analysed in the solid state to determine Tolman electronic parameters, cone angles and buried volumes of these unprecedented functionalized phosphines. Quantum chemical calculations of electronic and steric descriptors revealed that these cage-shaped phosphines are electron-poor and that single methyl substituent is enough to provide the largest effect on steric shielding reported so far in triarylphosphines. An unsymmetrically substituted 9-phosphatriptycene was resolved by chiral HPLC, opening the avenue towards stable P-chirogenic triarylphosphines with unlimited configurational stability for new catalyst development in asymmetric transition-metal catalysis.

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.

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.

(3E)-4-[(Naphthalen-1-yl)amino]-pent-3-en-2-one hemihydrate.

The title compound, C15H15NO·0.5H2O, was prepared from α-naphthyl-amine and 2,4-penta-nedione in a 1:1 ratio. An intra-molecular N-H⋯O hydrogen bond in the N-naphthyl-pent-3-en-2-one mol-ecule involving the amine and carbonyl groups strengthens the structure. The water mol-ecule interacts with two symmetry-related N-naphthyl-pent-3-en-2-one mol-ecules viaby O-H⋯O hydrogen bonds.

Combining API in a dual-drug ternary cocrystal approach.

A new strategy is developed to design multi-drug solid forms. Using an inorganic salt as the glue sticking together two different APIs in a "drug-bridge-drug" approach, we successfully created and characterized three different ternary ionic cocrystals (TICCs). The link between binary and ternary ICCs and the importance of reaction stoichiometry was investigated using ternary solid-state phase diagrams. In addition, we highlighted the crucial role of water for the stability of these systems, as well as the impact on solubility compared to the respective parent compounds. We expect the strategy presented here to be applicable to a large series of drug combinations, opening up a promising new way of building multi-drug systems.