Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.     

Chemistry of superheavy elements

The number of chemical elements has increased considerably in the last few decades. Most excitingly, these heaviest, man-made elements at the far-end of the Periodic Table are located in the area of the long-awaited superheavy elements. While physical techniques currently play a leading role in these discoveries, the chemistry of superheavy elements is now beginning to be developed. Advanced and very sensitive techniques allow the chemical properties of these elusive elements to be probed. Often, less than ten short-lived atoms, chemically separated one-atom-at-a-time, provide crucial information on basic chemical properties. These results place the architecture of the far-end of the Periodic Table on the test bench and probe the increasingly strong relativistic effects that influence the chemical properties there. This review is focused mainly on the experimental work on superheavy element chemistry. It contains a short contribution on relativistic theory, and some important historical and nuclear aspects.     

From self-assembly to noncovalent synthesis of programmable porphyrins' arrays in aqueous solution

Self-organization is the driving force that led to the evolution of life. Rationalization of the spontaneous self-assembly paradigm will offer tremendous potentialities to obtain a wide variety of complex systems, having specific functionality and properties. Herein, we will propose an overview of the developments in non-covalent syntheses of multi-porphyrin supramolecular species in aqueous solution. This work took inspiration from the pioneering studies aimed at rationalizing the spontaneous aggregation processes, governed by conventional solution properties (i.e. pH, ionic strength, and concentration). The more recent chemical strategies, to hierarchically manipulate the cooperative nature of weak interactions to design and synthesize supramolecular entities having pre-determined structure and properties, demonstrate the feasibility to attain, in a reproducible manner, molecular organization to supramolecular levels. In particular, calixarene-porphyrin species represents concrete evidence of a quantitative complexation, governed by precise hierarchical rules, which together with a rational functionalization of the molecular components leads to supramolecular entities of well-defined and tunable stoichiometry. These systems, thus, represent fertile ground to envisage and implement controlled self-organization strategies as bottom up methodologies to obtain supramolecular nanostructures and smart nanomachines.     

Theoretical predictions of nuclear magnetic resonance parameters in a novel organo-xenon species: chemical shifts and nuclear quadrupole couplings in HXeCCH

We calibrate the methodology for the calculation of nuclear magnetic resonance (NMR) properties in novel organo-xenon compounds. The available state-of-the-art quantum-chemical approaches are combined and applied to the HXeCCH molecule as the model system. The studied properties are (129)Xe, (1)H, and (13)C chemical shifts and shielding anisotropies, as well as (131)Xe and (2)H nuclear quadrupole coupling constants. The aim is to obtain, as accurately as currently possible, converged results with respect to the basis set, electron correlation, and relativistic effects, including the coupling of relativity and correlation. This is done, on one hand, by nonrelativistic correlated ab initio calculations up to the CCSD(T) level and, on the other hand, for chemical shifts and shielding anisotropies by the leading-order relativistic Breit-Pauli perturbation theory (BPPT) with correlated ab initio and density-functional theory (DFT) reference states. BPPT at the uncorrelated Hartree-Fock level as well as the corresponding fully relativistic Dirac-Hartree-Fock method are found to be inapplicable due to a dramatic overestimation of relativistic effects, implying the influence of triplet instability in this multiply bonded system. In contrast, the fully relativistic second-order Moller-Plesset perturbation theory method can be applied for the quadrupole coupling, which is a ground-state electric property. The performance of DFT with various exchange-correlation functionals is found to be inadequate for the nonrelativistic shifts and shielding anisotropies as compared to the CCSD(T) results. The relativistic BPPT corrections to these quantities can, however, be reasonably predicted by DFT, due to the improved triplet excitation spectrum as compared to the Hartree-Fock method, as well as error cancellation within the five main BPPT contributions. We establish three computationally feasible models with characteristic error margins for future calculations of larger organo-xenon compounds to guide forthcoming experimental NMR efforts. The predicted (129)Xe chemical shift in HXeCCH is in a novel range for this nucleus, between weakly bonded or solvated atomic xenon and xenon in the hitherto characterized molecules.     

Relativistic and non-relativistic local-density functional, benchmark results and investigation on the dimers

Using two spinor minimax method combined with finite element methods accompanied with extrapolation and counterpoise techniques enable us to obtain relativistic highly accurate results for two atomic molecules. Like in our previous work for the (Hartree-) Dirac–Fock–Slater (DFS) functional we investigate in this work the density functional approximations of the relativistic and non-relativistic local-density functional, presenting highly accurate benchmark results of chemical properties on the dimers of the group 11 (Ib) of the periodic table of elements. The comparison with experimental values and literature’s results shows that DFS is better behaved than the other two local functionals.     

Quantification of "fuzzy" chemical concepts: a computational perspective

Chemists recurrently utilize "fuzzy" chemical concepts (e.g. atomic charges, the chemical bond, strain, aromaticity, branching, etc.), which lack unique quantitative assessments but, nonetheless, are frequently employed as tools for understanding the intricacies of chemical behaviour. This tutorial review provides an overview of the computational schemes specifically developed to quantify four of the most commonly employed, yet debated, chemical concepts: the chemical bond, atomic charges, (hyper)conjugation, and molecular strain. The enhanced knowledge gained from these schemes not only helps in the depiction of molecules with unique properties, but also provides breadth to our fundamental understanding of chemistry. Nevertheless, the numerous existing methodologies often result in different interpretations that culminate in discrepancies. Through recent examples in the literature, guidelines are provided which illustrate the strengths and weaknesses of various schemes for each individual concept.     

Calculations of electronic structure of the UF<Subscript>6</Subscript> molecule and the UO<Subscript>2</Subscript> crystal with a relativistic pseudopotential

The influence of relativistic effects on the properties of uranium hexafluoride was considered. Detailed comparison of the spectrum of one-electron energies obtained in the nonrelativistic (by the Hartree-Fock method), relativistic (by the Dirac-Fock method), and scalar-relativistic (using a relativistic potential of the uranium atom core) calculations was carried out. The methods of optimization of atomic basis in the LCAO calculations of molecules and crystals are discussed which make it possible to consider distortion of atomic orbitals upon the formation chemical bonds. The influence of the atomic basis optimization on the results of scalar-relativistic calculations of the molecule UF₆ properties is analyzed. Calculations of the electronic structure and properties of UO₂ crystals with relativistic and nonrelativistic pseudopotentials are fulfilled.     

Relativistic (SR‐ZORA) quantum theory of atoms in molecules properties

The Quantum Theory of Atoms in Molecules (QTAIM) is used to elucidate the effects of relativity on chemical systems. To do this, molecules are studied using density‐functional theory at both the nonrelativistic level and using the scalar relativistic zeroth‐order regular approximation. Relativistic effects on the QTAIM properties and topology of the electron density can be significant for chemical systems with heavy atoms. It is important, therefore, to use the appropriate relativistic treatment of QTAIM (Anderson and Ayers, J. Phys. Chem. 2009, 115, 13001) when treating systems with heavy atoms. © 2016 Wiley Periodicals, Inc.     

Bonding trends in MCH2 systems: Simple orbital interpretation and evidence for double bonds

MCH₂ systems, where M is a metal from 4th up to 7th period, are studied at DFT level using B3LYP functional and small-core quasirelativistic pseudopotential or fully relativistic four-component methodology. We obtained structural data for 44 elements, M, and our results can be used to infer double-bond lengths for these elements. Our results also suggest that the bonding of these MCH₂ systems can be understood by a simple pictorial approach, even when spin–orbit effects are present.     

The any particle molecular orbital approach: A short review of the theory and applications

The any particle molecular orbital (APMO) approach extends regular electronic structure methods to study atomic and molecular systems in which electrons and other particles are treated simultaneously as quantum waves. A number of electronic structure methodologies have been extended under the APMO framework and applied to investigate nuclear quantum effects including isotope effects and nuclear delocalization and to calculate proton binding energies and affinities. In addition, APMO methodologies have been employed to analyze physical and chemical properties of atomic and molecular systems containing exotic subatomic particles.     

Density functional calculations of 19F and 235U NMR chemical shifts in uranium (VI) chloride fluorides UF6−nCln: Influence of the relativistic approximation and role of the exchange‐correlation functional

Relativistic density functional theory (DFT) has been applied to the calculation of the ¹⁹F nuclear magnetic resonance (NMR) chemical shifts of the title compounds. It is shown that, while large‐core effective core potentials (ECP) fail completely for the calculation of ligand NMR chemical shifts in uranium compounds, small‐core ECPs are a valid relativistic method for this purpose. In an earlier study of the same systems, certain differences between theory and experiment had been observed, for instance, in the relative chemical shift of the A₄ and X sites in UF₅Cl. The reason for these deviations has been investigated further in the current paper. By comparing different relativistic methods, it is shown that the relativistic approximation is not responsible for these deviations. The role of the approximation to the exchange‐correlation (XC) functional of DFT has been probed, and generalized gradient approximations (GGA) as well as hybrid DFT methods have been investigated. None of these methods corrects the mentioned errors. It is argued that the neglect of environmental factors (solvent effects) remains as a possible error source, although the approximate XC functional appears to be the more likely cause of the problem. ²³⁵U NMR shieldings and chemical shifts have been calculated, and the trends predicted earlier have been confirmed. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

The electronic structure of alkali aurides. A four-component Dirac-Kohn-Sham study

Spectroscopic constants, including dissociation energies, harmonic and anharmonic vibrational frequencies, and dipole moments, are calculated for the complete alkali auride series (LiAu, NaAu, KAu, RbAu, CsAu). The four-component formulation of relativistic density functional theory has been employed in this study, using the G-spinor basis sets implemented recently in the program BERTHA. The performance of four standard nonrelativistic density functionals employed is investigated by comparing the results with the best available theoretical and experimental data. The present work provides the first theoretical predictions on the molecular properties of RbAu. The intermetallic bond that occurs in the alkali auride series is highly polar and is characterized by a large charge transfer from the alkali metals to gold. The extent of this electron transfer has been investigated using several different charge analysis methods, enabling us to reach some general conclusions on their relative performance. We further report a detailed analysis of the topological properties of relativistic electron density in the bonding region, discussing the features of this approach which characterize the nature of the chemical bond. We have also computed the fully relativistic density for the alkali halides MBr and MI (M = Li, Na, K, Rb, and Cs). The comparative study shows that, on the basis of several topological properties and the variation in bond lengths, the gold atom behaves similarly to a halogen intermediate between Br and I.     

Frontiers and opportunities in chemoenzymatic synthesis

Natural product biosynthetic pathways have evolved enzymes with myriad activities that represent an expansive array of chemical transformations for constructing secondary metabolites. Recently, harnessing the biosynthetic potential of these enzymes through chemoenzymatic synthesis has provided a powerful tool that often rivals the most sophisticated methodologies in modern synthetic chemistry and provides new opportunities for accessing chemical diversity. Herein, we describe our research efforts with enzymes from a broad collection of biosynthetic systems, highlighting recent progress in this exciting field.     

Graphdiyne-actinyl complexes as potential catalytic materials: A DFT perspective from their structural,bonding, electronic and redox properties

Versatile graphdiyne (GDY) substrate has been modified by numerous transition metals and resulting composites showed excellent photo/electro-catalytic performance. However, GDY materials modified by actinides that are stockpiled waste product due to large-scale use in nuclear industry, are particularly scarce and remains great challenge. To deeply understand the structural properties, GDY complexating actinyl (An^mO₂)ⁿ⁺ (An = U, Np, Pu; m = VI, V) species with its atomistic pore was investigated by relativistic density functional theory (DFT). The GDY pore was found suitable to hold actinyl species, by forming organometallic AnC dative bonds. This chemical coupling interaction was further confirmed by quantum theory of atoms-in-molecule and electronic structure calculations. The GDY-uranyl(V), for instance, shows a π(UC) bonding HOMO, which is anticipated to improve electron transfer between ligand and metal. Orbital structures and compositions of complexes suggest their implication towards catalysis, which were further corroborated by calculations on redox potentials of GDY-actinyl complexes. Hence, our results show the potential applications of GDY complexating actinyl species towards novel catalytic surfaces.     

Relativistic effects on the Fukui function

The extent of relativistic effects on the Fukui function, which describes local reactivity trends within conceptual density functional theory (DFT), and frontier orbital densities has been analysed on the basis of three benchmark molecules containing the heavy elements: Au, Pb, and Bi. Various approximate relativistic approaches have been tested and compared with the four-component fully relativistic reference. Scalar relativistic effects, as described by the scalar zeroth-order regular approximation methodology and effective core potential calculations, already provide a large part of the relativistic corrections. Inclusion of spin–orbit coupling effects improves the results, especially for the heavy p-block compounds. We thus expect that future conceptual DFT-based reactivity studies on heavy-element molecules can rely on one of the approximate relativistic methodologies.     

Recent advances in planar tetracoordinate carbon chemistry

We summarize our contributions on the quest of new planar tetracoordinate carbon entities (new carbon molecules with exotic chemical structures and strange bonding schemes). We give special emphasis on the rationalization why in this type of molecules the planar configuration is favored over the tetrahedral one. We will concentrate on the latter and will show that molecules containing planar tetracoordinate carbons have a stabilizing system of delocalized pi electrons, which shows similar properties as pi systems in aromatic molecules.     

Synthetic strategy of dendrimers: A review

Dendrimer chemistry is a fascinating and growing area of modern chemistry. Dendrimers are macromolecular entities with unique three-dimensional topologies, multi-functionality, and unique chemical and physical properties. Because of these characteristics, they are particularly well suited for applications in nanotechnology, pharmaceuticals, and medicinal chemistry. The study of dendrimers and hyperbranched polymers is gaining widespread interest from researchers in academia and industry for their unique structure and properties. This review article focused on dendrimer structure and the different synthetic strategies employed at the laboratory and commercial levels. This review covers convergent and divergent approaches, as well as accelerated approaches to dendrimer synthesis.     

Prediction of the adsorption behavior of elements 112 and 114 on inert surfaces from ab initio Dirac-Coulomb atomic calculations

The interaction of elements 112 and 114 with inert surfaces has been studied on the basis of fully relativistic ab initio Dirac-Coulomb CCSD(T) calculations of their atomic properties. The calculated polarizabilities of elements 112 and 114 are significantly lower than corresponding Hg and Pb values due to the relativistic contraction of the valence ns and np(12) orbitals, respectively, in the heavier elements. Due to the same reason, the estimated van der Waals radius of element 114 is smaller than that of Pb. The enthalpies of adsorption of Hg, Pb, and elements 112 and 114 on inert surfaces such as quartz, ice, and Teflon were predicted on the basis of these atomic calculations using a physisorption model. At the present level of accuracy, -DeltaH(ads) of element 112 on these surfaces is slightly (about 2 kJ/mol) larger than -DeltaH(ads)(Hg). The calculated -DeltaH(ads) of element 114 on quartz is about 7 kJ/mol and on Teflon is about 3 kJ/mol smaller than the respective values of -DeltaH(ads)(Pb). The trend of increasing -DeltaH(ads) in group 14 from C to Sn is thus reversed, giving decreasing values from Sn to Pb to element 114 due to the relativistic stabilization and contraction of the np(12) atomic orbitals. This is similar to trends shown by other atomic properties of these elements. The small difference in DeltaH(ads) of Pb and element 114 on inert surfaces obtained within a picture of physisorption contrasts with the large difference (more than 100 kJ/mol) in the chemical reactivity between these elements.     

Ab initio calculations of NMR chemical shifts

The nuclear magnetic resonance chemical shift is one of the most powerful properties available for structure determination at the molecular level. A review of advances made in the ab initio calculation of chemical shielding during the past five years is presented. Specifically, progress in the areas including the effects of an unpaired electron, electron correlation, and relativistic effects into ab initio chemical shielding calculations, the tensor nature of the chemical shift, and intramolecular and intermolecular effects on the chemical shift will be covered.