Molecular dynamics investigation of benzoic acid in confined spaces.

Classical molecular dynamics simulations are carried out to investigate the aggregation of supercooled benzoic acid in confined spaces. Nanocavities, nanotubes and nanolayers are defined by restricting the periodicity of the simulation to zero, one or two dimensions, with boundaries set by adjustable, general, and computationally cheap van der Waals barriers. The effect of different confinement geometries is explored. It is found that the confinement impacts the liquid collective dynamics, strengthening the correlations that affect the motion of distant molecules. Overall, confinement determines up to a tenfold increase of the viscosity of the liquid and strongly slows down the rotational correlation times. Aggregation mediated by interactions with the walls and partial polarization of the liquid are observed. Additionally, transitions to high-density liquid states occur when stiffer barriers are used. In general, a reduced accessible amount of phase space fosters the struggle for a closer packing to relieve unfavorable atom-atom contacts, while maximizing the attractive ones. In benzoic acid, this implies that the hydrogen bond network is organized more efficiently in high density states.

Enantiopure ß-isocyano-boronic esters: synthesis and exploitation in isocyanide-based multicomponent reactions.

Various boron-containing isocyanides have been efficiently synthesized from the corresponding enantiopure ß-substituted ß-amino boronic acid pinacol esters, without need for protecting group interconversion, through a two-step, purification-free procedure. They were employed in a variety of isocyanide-based multicomponent reactions, proving to be reliable components for all of them and allowing the efficient synthesis of unprecedented, boron-containing peptidomimetics and heteroatom-rich small molecules, including biologically relevant cyclic boronates. Jointing together the ß-amido boronic acid moiety, deriving from the isocyanide component, with prominent pharmacophoric rings emerging from the multicomponent process, a successful application of the molecular hybridization concept could be realized.

Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines.

Addressing the asymmetric synthesis of oxindole-based α-aminoboronic acids, instead of the expected products we disclosed the efficient homocoupling of oxindole-based N-tert-butanesulfinyl imines, with the generation of chiral, quaternary 1,2-diamines in a mild and completely stereoselective way. The obtained 3,3'-bisoxindole derivatives were fully characterized by NMR and single-crystal X-ray diffraction analysis and proved to be single diastereoisomers and atropisomers. A plausible mechanism for the one-pot Cu(II)-catalyzed Bpin addition to the isatin-derived ketimine substrate and subsequent homocoupling is described.

Highly diastereoselective entry to chiral oxindole-based ß-amino boronic acids and spiro derivatives.

We here describe the first Cu-catalysed, diastereoselective 1,2-addition of 1,1-diborylmethane to chiral ketimines for the synthesis of quaternary stereocenters and spiro compounds. The method provides easy access to a range of chiral, highly functionalized compounds, namely oxindole-based ß,ß'-disubstituted ß-amino boronates, boron-containing peptidomimetics and six-, seven-membered spirocyclic hemiboronic esters. Such unprecedented compounds are mostly obtained in high yields and easily isolated as single diastereoisomers, paving the way to a more intense exploitation of boron-containing compounds in diversity-oriented chemistry and drug-discovery programs. Concerning stereochemistry, the application of Ellman's auxiliary strategy allows in principle to access both steric series of target compounds.

Anharmonic Thermal Motion Modelling in the Experimental XRD Charge Density Determination of 1-Methyluracil at T = 23 K.

The experimental electron density distribution (EDD) of 1-methyluracil (1-MUR) was obtained by single crystal X-ray diffraction (XRD) experiments at 23 K. Four different structural models fitting an extensive set of XRD data to a resolution of (sinθ/λ)max = 1.143 Å-1 are compared. Two of the models include anharmonic temperature factors, whose inclusion is supported by the Hamilton test at a 99.95% level of confidence. Positive Fourier residuals up to 0.5 eÅ-3 in magnitude were found close to the methyl group and in the region of hydrogen bonds. Residual density analysis (RDA) and molecular dynamics simulations in the solid-state demonstrate that these residuals can be likely attributed to unresolved disorder, possibly dynamical and long-range in nature. Atomic volumes and charges, molecular moments up to hexadecapoles, as well as maps of the molecular electrostatic potential were obtained from distributed multipole analysis of the EDD. The derived electrostatic properties neither depend on the details of the multipole model, nor are significantly affected by the explicit inclusion of anharmonicity in the least-squares model. The distribution of atomic charges in 1-MUR is not affected by the crystal environment in a significant way. The quality of experimental findings is discussed in light of in-crystal and gas-phase quantum simulations.

Enantio- and Regioselective Palladium(II)-Catalyzed Dioxygenation of (Aza-)Alkenols.

An oxidative Pd-catalyzed intra-intermolecular dioxygenation of (aza-)alkenols has been reported, with total regioselectivity. To study the stereoselectivity, different chiral ligands as well as different hypervalent-iodine compounds have been compared. In particular, by using a C-6 modified pyridinyl-oxazoline (Pyox) ligand and hypervalent iodine bearing an aromatic ring, an excellent enantio- and diastereoselectivity has been achieved.

Spin Density Topology.

Despite its role in spin density functional theory and it being the basic observable for describing and understanding magnetic phenomena, few studies have appeared on the electron spin density subtleties thus far. A systematic full topological analysis of this function is lacking, seemingly in contrast to the blossoming in the last 20 years of many studies on the topological features of other scalar fields of chemical interest. We aim to fill this gap by unveiling the kind of information hidden in the spin density distribution that only its topology can disclose. The significance of the spin density critical points, the 18 different ways in which they can be realized and the peculiar topological constraints on their number and kind, arising from the presence of positive and negative spin density regions, is addressed. The notion of molecular spin graphs, spin maxima (minima) joining paths, spin basins and of their valence is introduced. We show that two kinds of structures are associated with a spin-polarized molecule: the usual one, defined through the electron density gradient, and the magnetic structure, defined through the spin density gradient and composed in general by at least two independent spin graphs, related to spin density maxima and minima. Several descriptors, such as the spin polarization index, are introduced to characterize the properties of spin density critical points and basins. The study on the general features of the spin density topology is followed by the specific example of the water molecule in the 3B1 triplet state, using spin density distributions of increasing accuracy.

Spin density accuracy and distribution in azido Cu(II) complexes: A source function analysis.

Magnetic properties of open-shell systems depend on their unpaired electron density distribution. Accurate spin density (SD) is difficult to retrieve, both from polarized neutron diffraction (PND) data and from quantum approaches, and its interpretation is not trivial. The Source Function is a useful tool to interpret SD distributions and their accuracy. It is here applied to analyze and compare the theoretical SD in a weakly ferromagnetically coupled end-end azido dicopper complex with that in a strongly-coupled end-on complex. The Source Function enables to highlight the origin of the SD differences between the two dicopper complexes and among adopted computational approaches (CASSCF, DFT, UHF). Further insight is provided by partial Source Function SD reconstructions using given subsets of atoms. DFT methods exaggerate electron sharing between copper and the ligands, causing spin delocalization toward them and overestimating metal-ligand spin polarization, while underestimating CASSCF spin information transmission between atoms. CAS(10,10) SD is closer to the PND SD than other adopted methods © 2018 Wiley Periodicals, Inc.

Asymmetric modular synthesis of a semirigid dipeptide mimetic by cascade cycloaddition/ring rearrangement and borohydride reduction.

A new semirigid dipeptide mimetic was prepared on multigram scale, in good yield, and in a stereocontrolled way, starting from commercially available and unexpensive reagents, i.e., N-benzylpiperidone, tosyl azide, and proline methyl ester. The optimized multicomponent process consisted of a cascade click cycloaddition and a ring rearrangement reaction, followed by a reductive step. Theoretical calculations were performed to elucidate the reaction mechanism and support the stereochemical outcome of the reduction. Finally, the new scaffold was used for the preparation of model peptidomimetics, whose ß turn conformation was confirmed by dynamic NMR experiments.

Direct detection of minimum ionizing charged particles in a perovskite single crystal detector with single particle sensitivity.

We report the detection of high energy electrons of some hundreds of MeV, crossing a methylammonium lead bromide single crystal device with sensitivity down to a single electron. In the device, the released energy is close to the energy released by minimum-ionizing particles. This is the first demonstration of a perovskite-based device that can be used for tracking and counting minimum-ionizing charged particles. The device reaches single particle sensitivity with a low bias voltage of 5 V. It also shows a good linearity of the response as a function of the number of electrons in a dynamic range of approximately 104.

Progress in the understanding of the key pharmacophoric features of the antimalarial drug dihydroartemisinin: an experimental and theoretical charge density study.

The accurate, experimental charge density distribution, ρ(r), of the potent antimalarial drug dihydroartemisinin (DHA) has been derived for the first time from single-crystal X-ray diffraction data at T=100(2) K. Gas-phase and solid-state DFT simulations have also been performed to provide a firm basis of comparison with experimental results. The quantum theory of atoms in molecules (QTAIM) has been employed to analyse the ρ(r) scalar field, with the aim of classifying and quantifying the key real-space elements responsible for the known pharmacophoric features of DHA. From the conformational perspective, the bicyclo[3.2.2]nonane system fixes the three-dimensional arrangement of the 1,2,4-trioxane bearing the active O-O redox centre. This is the most nucleophilic function in DHA and acts as an important CH⋅⋅⋅O acceptor. On the contrary, the rest of the molecular backbone is almost neutral, in accordance with the lipophilic character of the compound. Another remarkable feature is the C-O bond length alternation along the O-C-O-C polyether chain, due to correlations between pairs of adjacent C-O bonds. These bonding features have been related with possible reactivity routes of the α- and ß-DHA epimers, namely 1) the base-catalysed hemiacetal breakdown and 2) the peroxide reduction. As a general conclusion, the base-driven proton transfer has significant non-local effects on the whole polyether chain, whereas DHA reduction is thermodynamically favourable and invariably leads to a significant weakening (or even breaking) of the O-O bond. The influence of the hemiacetal stereochemistry on the electronic properties of the system has also been considered. Such findings are discussed in the context of the known chemical reactivity of this class of important antimalarial drugs.

Phosphine-Catalyzed Domino Regio- and Stereo-Selective Hexamerization of 2-(Bromomethyl)acrylates to 1,2-Bis(cyclohexenyl)ethenyl Derivatives.

A phosphine-catalyzed domino assembly of six units of 2-bromomethyl acrylates afforded polyalkenyl adducts containing two cyclohexenyl rings. This reaction occurs under mild conditions providing the final product by formation of seven carbon-carbon bonds and four stereocenters. Experimental and computational studies support an initial dimerization of the substrate, which in turn trimerizes involving two totally regio- and stereocontrolled Diels-Alder cycloadditions. The yield of the hexamerization of the 2-bromomethyl acrylates depends on the size of the ester function. The protocol has also proved to be practicable on a gram scale.

Revealing non-covalent interactions in molecular crystals through their experimental electron densities.

Non-covalent interactions (NCI) define the rules underlying crystallisation, self-assembly and drug-receptor docking processes. A novel NCI descriptor, based on the reduced electron density gradient (RDG), that enables easy visualisation of the zones of the electron density (ED) involved in either the supposedly attractive (dispersive, hydrogen bonding) or allegedly repulsive (steric) intermolecular interactions, was recently developed by Johnson et al. Here, it is applied for the first time to EDs derived from single-crystal X-ray diffraction data. A computer code handling both experimental and ab initio EDs in the RDG-NCI perspective was purposely written. Three cases spanning a wide range of NCI classes were analysed: 1) benzene, as the prototype of stacking and weak CH···π interactions; 2) austdiol, a heavily functionalised fungal metabolite with a complex hydrogen-bonding network; 3) two polymorphs of the heteroatom-rich anti-ulcer drug famotidine, with van der Waals and hydrogen-bond contacts between N- and S-containing groups. Even when applied to experimental EDs, the RDG index is a valuable NCI descriptor that can highlight their different nature and strength and provide results of comparable quality to ab initio approaches. Combining the RDG-NCI study with Bader's ED approach was a key step forward, as the RDG index can depict inherently delocalised interactions in terms of extended and flat RDG isosurfaces, in contrast to the bond path analysis, which is often bounded to a too localised and possibly discontinuous (yes/no) description. Conversely, the topological tool can provide quantitative insight into the simple, qualitative NCI picture offered by the RDG index. Hopefully, this study may pave the way to a deeper analysis of weak interactions in proteins using structural and ED information from experiment.

Non-Decarboxylative Ruthenium-Catalyzed Rearrangement of 4-Alkylidene-isoxazol-5-ones to Pyrazole- and Isoxazole-4-carboxylic Acids.

Treatment of 4-(2-hydroaminoalkylidenyl)- and 4-(2-hydroxyalkylidenyl)-substituted isoxazol-5(4H)-ones with catalytic amounts of [RuCl2(p-cymene)]2, without any additive, afforded pyrazole- and isoxazole-4-carboxylic acids, respectively. The presence of an intramolecular H-bond in these substrates was the key to divert the classical mechanism toward a ring-opening non-decarboxylative path that is expected to generate a vinyl Ru-nitrenoid intermediate, the cyclization of which affords the rearranged products. A gram scale protocol demonstrated the synthetic applicability of this transformation.

Revealing electron delocalization through the source function.

The source function (SF) introduced in late 90s by Bader and Gatti quantifies the influence of each atom in a system in determining the amount of electron density at a given point, regardless of the atom's remote or close location with respect to the point. The SF may thus be attractive for studying directly in the real space somewhat elusive molecular properties, such as "electron conjugation" and "aromaticity", that lack rigorous definitions as they are not directly associated to quantum-mechanical observables. In this work, the results of a preliminary test aimed at understanding whether the SF descriptor is capable to reveal electron delocalization effects are corroborated by further examination of the previously investigated benzene, 1,3-cyclohexadiene, and cyclohexene series and by extending the analysis to some benchmark organic systems with different unsaturated bond patterns. The SF can actually reveal, order, and quantify π-electron delocalization effects for formal double, single conjugated, and allylic bonds, in terms of the influence of distant atoms on the electron density at given bond critical points. In polycyclic aromatic hydrocarbons, the SF neatly reveals the mutual influence of the benzenoid subunits. In naphthalene it provides a rationale for the changes observed in the local aromatic character of one ring when the other is partially hydrogenated. The SF analysis describes instead biphenyl as made up by two weakly interacting benzene rings, only slightly perturbed by the combination of mutual steric and electronic effects. Eventually, a new SF-based indicator of local aromaticity is introduced, which shows excellent correlation with the aromatic index developed by Matta and Hernández-Trujillo, based on the delocalization indices. At variance with this latter and other commonly employed quantum-mechanical (local) aromaticity descriptors, the SF-based indicator does not require the knowledge of the pair density, nor the system wave function, being therefore promising for applications to experimentally derived charge density distributions.

Rationalizing the effect of halogenation on the molecular structure of simple cyclobutene derivatives by topological real-space analysis of their electron density.

The accurate gas-phase equilibrium structures on the ground-state potential energy surface of the complete series of fluorinated and chlorinated cyclobutene derivatives with C(2v) symmetry have been evaluated at DFT PBE0/6-311++G(d,p) theory level. The optimized geometries have been compared with all the available experimental data reported in the literature, as obtained by microwave spectroscopy (MW) and gas-phase electron diffraction (GED) techniques. For hexafluorocyclobutene and 1,2-dichloro-3,3',4,4'-tetrafluorocyclobut-1-ene, the results of accurate low-temperature single-crystal X-ray diffraction experiments have also been considered. Structural changes within the cyclobutene ring, as induced by fluorination and chlorination at allylic and vinylic positions, have been correlated with changes in the corresponding theoretical charge densities. To this aim, several local and nonlocal topological descriptors provided by the quantum theory of atoms in molecules, QTAIM, have been employed, with particular emphasis on the delocalization indices and integrated source function decomposition schemes. Key factors for the resulting molecular structures are the chemical nature and the steric hindrance of the substituents, as well as quantum-mechanical effects, such as delocalization and partial conjugation. When fluorine atoms replace hydrogens at allylic or vinylic positions, the corresponding Csp(3)-Csp(3) or Csp(2)═Csp(2) bonds between the substituted carbons undergo a significant strengthening, while chlorination has just the opposite effect. In the latter case the steric hindrance between bulky chlorine atoms occupying vicinal positions is crucial in determining the single Csp(3)-Csp(3) bond length. These findings are discussed in the context of the reactivity of chemically related chlorofluorocarbon compounds.

Switchable Oxidative Reactions of N-allyl-2-Aminophenols: Palladium-Catalyzed Alkoxyacyloxylation vs an Intramolecular Diels-Alder Reaction.

The Pd(II)-catalyzed reaction of N-allyl-2-aminophenols in the presence of PhI(OCOR)2 as the oxidant resulted in an alkoxyacyloxylation process, with the formation of functionalized dihydro-1,4-benzoxazines. The reaction performed in the absence of palladium catalyst switched to an intramolecular Diels-Alder reaction (IMDA) pathway, which was the result of an oxidative dearomatization of the 2-aminophenol, nucleophilic addition, and Diels-Alder reaction cascade, highlighting the role of the oxidant as both a nucleophilic donor and an oxidizing agent.

Conformational polymorphism in a Schiff-base macrocyclic organic ligand: an experimental and theoretical study.

Polymorphism in the highly flexible organic Schiff-base macrocycle ligand 3,6,9,17,20,23-hexa-azapentacyclo(23.3.1.1(11,15).0(2,6).0(16,20))triaconta-1(29),9,11,13,15(30),23,25,27-octaene (DIEN, C(24)H(30)N(6)) has been studied by single-crystal X-ray diffraction and both solid-state and gas-phase density functional theory (DFT) calculations. In the literature, only solvated structures of the title compound are known. Two new polymorphs and a new solvated form of DIEN, all obtained from the same solvent with different crystallization conditions, are presented for the first time. They all have P\bar 1 symmetry, with the macrocycle positioned on inversion centres. The two unsolvated polymorphic forms differ in the number of molecules in the asymmetric unit Z', density and cohesive energy. Theoretical results confirm that the most stable form is (II°), with Z' = 1.5. Two distinct molecular conformations have been found, named `endo' or `exo' according to the orientation of the imine N atoms, which can be directed towards the interior or the exterior of the macrocycle. The endo arrangement is ubiquitous in the solid state and is shared by two independent molecules which constitute an invariant supramolecular synthon in all the known crystal forms of DIEN. It is also the most stable arrangement in the gas phase. The exo form, on the other hand, appears only in phase (II°), which contains both the conformers. Similarities and differences among the occurring packing motifs, as well as solvent effects, are discussed with the aid of Hirshfeld surface fingerprint plots and correlated to the results of the energy analysis. A possible interconversion path in the gas phase between the endo and the exo conformers has been found by DFT calculations; it consists of a two-step mechanism with activation energies of the order of 30-40 kJ mol(-1). These findings have been related to the empirical evidence that the most stable phase (II°) is also the last appearing one, in accordance with Ostwald's rule.

A new monoclinic polymorph of 3-diethyl-amino-4-(4-meth-oxy-phen-yl)-1,1-dioxo-4H-1λ,2-thia-zete-4-carbonitrile.

A new monoclinic form of the title compound, C(14)H(17)N(3)O(3)S, has been found upon slow crystallization from water. Another monoclinic form of the compound was obtained previously from a mixture of dichloro-methane and diethyl ether [Clerici et al. (2002 ▶). Tetra-hedron, 58, 5173-5178]. Both phases crystallize in space group P2(1)/n with one mol-ecule in the asymmetric unit. The formally single exocyclic C-N bond that connects the -NEt(2) unit with the thia-zete ring is considerably shorter than the adjacent, formally double, endocyclic C=N bond. This is likely to be due to the extended conjugated system between the electron-donor diethyl-ammine fragment and the electron-withdrawing sulfonyl group. In the newly discovered polymorph, the meth-oxy group is rotated by almost 180° around the phen-yl-OCH(3) bond, resulting in a different mol-ecular conformation.

Intramolecular Aminoazidation of Unactivated Terminal Alkenes by Palladium-Catalyzed Reactions with Hydrogen Peroxide as the Oxidant.

The palladium-catalyzed aminoazidation of aminoalkenes yielding azidomethyl-substituted nitrogen-containing heterocycles was developed. The procedure requires oxidative conditions and occurs at room temperature in the presence of hydrogen peroxide and NaN3 as the azide source. These conditions provide selective exo-cyclization/azidation of the carbon-carbon double bond, furnishing a versatile approach toward five-, six-, and seven-membered heterocyclic rings.