Experimental Charge Density Research Articles

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 β-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.

Noncovalent Interactions in Crystalline Picolinic Acid N-Oxide: Insights from Experimental and Theoretical Charge Density Analysis

This study provides a detailed description of noncovalent interactions of different types and strengths in the title crystal using a combined experimental and theoretical study of the charge density distribution. The nature of the noncovalent interactions is visualized using information theory and through the superposition of the gradient fields in the electron density and electrostatic potential. The energy of the intramolecular O–H···O bond, intermolecular C–H···O bonds, and π-stacking interactions, Eint, are evaluated from empirical correlations between Eint and geometrical and electron-density bond critical point parameters. The complete set of noncovalent interactions including the strong intramolecular O–H···O (Eint > 90 kJ/mol) and weak C–H···O (Eint < 10 kJ/mol) hydrogen bonds, and π-stacking interactions (Eint < 4 kJ/mol) is quantitatively described. The results from the experimental charge density analysis are compared with periodic quantum calculations using density functional theory with the G...

Anharmonic Motion in Experimental Charge Density Investigations

In the charge density study of 9-diphenylthiophosphinoylanthracene the thermal motion of several atoms needed an anharmonic description via Gram-Charlier coefficients even for data collected at 15 K. As several data sets at different temperatures were measured, this anharmonic model could be proved to be superior to a disorder model. Refinements against theoretical data showed the resemblance of an anharmonic model and a disorder model with two positions very close to each other (~0.2 Å), whereas these two models could be clearly distinguished if the second position is 0.5 Å apart. The refined multipole parameters were distorted when the anharmonic motion was not properly refined. Therefore, this study reveals the importance of detecting and properly handling anharmonic motion. Unrefined anharmonic motion leads to typical shashlik-like residual density patterns. Therefore, careful analysis of the residual density and the derived probability density function after the refinement of the Gram-Charlier coefficients proved to be the most useful tools to indicate the presence of anharmonic motion.

Competing protonation sites in sulfadiazine: answers from chemistry and electron density

Sulfadiazine, a common drug, has been studied as anion in its Zn(II) salt, as a neutral compound and as hydrochloride. An unexpected protonation pattern was encountered in the cation of the latter, with a coexisting protonated anilinium and pyridinium functionality and a deprotonated amide group. Experimental charge density provides conclusive evidence about the position of the hydrogen atoms, and these results match the hydrogen bond requirements.

New hydrogen-bond-aided supramolecular synthon: a case study of 2,4,6-trinitroaniline

We have demonstrated that 2-nitroanilines and similar nitro compounds having a six-membered ring closed by an intramolecular H-bond tend to form centrosymmetric dimers in the crystalline phase. The probability of dimer formation is estimated to be 15% according to a database search in the Cambridge Structural Database. Bonding interactions in the dimer are found to be two ON⋯H–N hydrogen bonds and an O⋯O interaction, with the total energy adding up to ca. 6 kcal mol−1. The bonding nature of interactions was proven by means of topological analysis of the experimental charge density obtained from a high-resolution single crystal X-ray diffraction experiment as well as from theoretical results of DFT and MP2 calculations.

3-(4-Pyridyl)-2,4-pentanedione – a bridge between coordinative, halogen, and hydrogen bonds

3-(4-Pyridyl)-2,4-pentanedionate, an established ditopic ligand for metal complexes, offers additional interaction modes which may be exploited for crystal engineering: we have assembled structures in which halogen bonds coexist with coordinative and hydrogen bonds. An adduct of the neutral 3-(4-pyridyl)-2,4-pentanedione to tetrafluorodiiodobenzene proves the suitability of the pyridine N as a nucleophile in halogen bonds. This feature is preserved in Fe and Al complexes of the substituted acetylacetonate. For the latter, an experimental charge density based on high resolution diffraction data gives insight into the halogen bonds.

Halogen bonding in fluorine: experimental charge density study on intermolecular F⋯F and F⋯S donor–acceptor contacts

The enigmatic type II C-F···F-C and C-F···S-C interactions in pentafluorophenyl 2,2'-bithiazole are shown to be realistic "σ-hole" interactions based on high resolution X-ray charge density analysis.

Experimental and Theoretical Charge Densities of a Zinc-Containing Coordination Polymer, Zn(HCOO)2(H2O)2

We present a combined experimental and theoretical charge density study of the coordination polymer Zn(HCOO)(2)(H(2)O)(2), which serves as a nonmagnetic reference for the isostructural magnetic compounds containing 3d transition metals. The charge density has been modeled using the multipole formalism against a high-resolution single-crystal X-ray diffraction data set collected at 100 K. The theoretical model is based on periodic density functional theory calculations in the experimental geometry. To gauge the degree of systematic bias from the multipole model, the structure factors of the theoretical model were also projected into a multipole model and the two theoretical models are compared with the experimental results. All models, both experiment and theory, show that the Zn atom densities are highly spherical but show small accumulations of charge toward the negative ligands. The metal-ligand interactions are found to be primarily ionic, but there are subtle topological indications of covalent contributions to the bonds. The source function calculated at the bond critical points reveals a rather delocalized picture of the density in the bridging carboxylates, and this presumably reflects the exchange pathway in the magnetic analogues.

ChemInform Abstract: Polyimido Sulfur Anions and Ylides

AbstractReview: 127 refs.

Relationship between Stereochemistry and Charge Density in Hydrogen Bonds with Oxygen Acceptors

An extensive survey of Cambridge Structural Database was carried out to study the directionality and stereochemistry of hydrogen bonds with an oxygen acceptor including carbonyl, alcohols, phenols, ethers, and esters groups. The results obtained through this survey are correlated with the charge density of these different chemical groups. The electron density of these different oxygen atom types shows striking dissimilarities in the electron lone pair configuration. Esters and ethers with the C–O–C oxygen atom located in an aromatic cycle display merged lone pairs lobes, which is not the case when one of the bonded carbon atoms has sp3 hybridization. The positions of the lone pairs in the deformation electron density maps derived from theoretical calculation and from experimental charge density generally agree with the notable exception of phenols and C(sp3) esters. The experimental studies show generally lone pairs lobes that are closer to each other. Differences are found within COH groups: the two electron lone pairs are slightly closer in phenol oxygen atoms compared with alcohols in theoretical electron densities. In experimental charge densities, the discrepancy is more drastic because the two lone pair lobes appear merged in phenols; this might be due to a resonance effect with the neighboring sp2 carbon atom. This difference in the configuration of the two electron lone pairs affects the directionality of hydrogen bonds. For phenols, the preferred donor hydrogen atom position is close to the COH plane, while for alcohols, it is out of plane with the direction O···Hdonor forming an angle of around 30° to the COH plane. The number of H-bonds occurring with the donor hydrogen atom pointing toward the middle of the two lone pairs is small for carbonyl, contrary to alcohols and phenols. Also H-bonds involving alcohol/phenol acceptors have a stronger tendency to occur in directions close to the electron lone pair plane than for carbonyl. As expected, the directional attraction of hydrogen bond donors toward the lone pairs is much more pronounced for short H···O distances. This study could have implications in the design of force fields, in molecular recognition, in supramolecular crystal engineering, and in drug design.

Charge Density Analysis of Ferulic Acid: Robustness of a Trifurcated C–H···O Hydrogen Bond

The toplogical features of a sporadic trifurcated C–H···O interaction region, where an oxygen atom acts as an acceptor of three weak hydrogen bonds, has been investigated by experimental and theoretical charge density analysis of ferulic acid. The interaction energy of the asymmetric molecular dimer formed by the trifurcated C–H···O motif, based on the multipolar model, is shown to be greater than the corresponding asymmetric O–H···O dimer in this crystal structure. Further, the hydrogen bond energies associated with these interaction motifs have been estimated from the local kinetic and potential energy densities at the bond critical points. The trends suggest that the interaction energy of the trifurcated C–H···O region is comparable to that of a single O–H···O hydrogen bond.

Charge Density Analysis and Topological Properties of Hal3-Synthons and Their Comparison with Competing Hydrogen Bonds

Trimers based on intermolecular halogen-bonding interactions (Hal3-synthons) have been studied in hexachlorobenzene, hexabromobenzene, pentachlorophenol, and pentabromophenol. Attention is paid to the comparison of Cl3- and Br3-synthons and to their competition with hydrogen bonds (HBs), based on the experimental and theoretical charge density analyses in crystal and gas phases. The main differences between Cl3- and Br3-synthons are established coming from the particular structure of the valence shell charge concentration region in Cl and Br atoms. Electrophilic–nucleophilic interactions take place within the intermolecular regions of Hal3-synthons by putting face-to-face charge depletion (CD) and charge concentration (CC) regions belonging to the valence shell of the halogen atoms. The electrostatic interaction follows the electrophilic and nucleophilic power of these regions and is monitored by the negative Laplacian values normalized to charge density unit (L/ρ) at the corresponding topological critica...

Experimental and Theoretical Charge Density Study of the Chemical Bonding in Chlorokojic Acid Crystal Structure

The experimental charge density in the chlorokojic acid crystal structure was investigated on the basis of high-resolution X-ray diffraction data collected at 80(2) K. The nature of chemical bonding and halogen interactions has been studied by means of deformation densities and by topological analysis using the Bader's quantum theory of atoms in molecules (QTAIM). A comparison between the experimental and theoretical results, from calculations concerning gas phase and periodic DFT/B3LYP, was performed. For the intermolecular hydrogen bonds of O-H···O, C-H···O, and C-H···Cl types, full characteristics of bond critical points (BCP's) were provided indicating closed-shell interactions. The topological analysis of charge density distribution revealed the presence of intermolecular C-Cl···O halogen bridge and halogen-halogen interactions of C-Cl···Cl-C type forming supramolecular Cl(3) synthons, crucial for three-dimensional structure formation of chlorokojic acid. The pronounced anisotropy of electrostatic potential at the Cl atom clarifies both electrophilic and nucleophilic properties of the substituent.

Advances in Understanding of Chemical Bonding: Inputs from Experimental and Theoretical Charge Density Analysis

The development of charge density analysis has undergone a major renaissance in the last two decades. In recent years, the characterization of bonding features associated with atoms in molecules and in crystals has been explored using high-resolution X-ray diffraction data (laboratory or synchrotron) complemented by high level ab initio theoretical calculations. The extraction of one electron topological properties, namely, electrostatic charges, dipole moment and higher moments, electrostatic potential, electric field gradients, in addition to evaluation of the local kinetic and potential energy densities, have contributed toward an understanding of the electron density distributions in molecular solids. New topological descriptors, namely, the source function (SF) and electron localization function (ELF) provide additional information as regards characterization of the topology of the electron density. In addition, delocalization indices have also been developed to account for bonding features pertinent to M-M bonds. The evaluation of these properties have contributed significantly toward the understanding of intra- and intermolecular bonding features in organic, inorganic, and biomolecules in the crystalline phase, with concomitant applications in the understanding of chemical reactivity and material/biological properties. In recent years, the focus has strongly shifted toward the understanding of structure-property relationships in organometallic complexes containing labile M-C bonds in the crystal structure with subsequent implications in catalysis. This perspective aims to highlight the major developments in electron density measurements in the past few years and provides pointers directed toward the potential use of this technique in future applications for an improved understanding of chemical bonding in systems that have been unexplored.

From “Loose” to “Dense” Crystalline Phases of Calcium Carbonate through “Repulsive” Interactions: An Experimental Charge‐Density Study

Anion-anion interactions in an eggshell: experimental electron density analysis for two polymorphs of calcium carbonate revealed why the less stable form, aragonite, has higher density than the most stable form, calcite. Although believed to be exclusively repulsive, the interactions between anions cause them to bind more tightly in a crystal and thus make the aragonite phase denser than its calcite counterpart.

Experimental charge density analysis of the nature of C—Br...N=C interactions in biologically active compound

Experimental charge density analysis of the nature of C—Br...N=C interactions in biologically active compound

Testing the Concept of Hypervalency: Charge Density Analysis of K2SO4

One of the most basic concepts in chemical bonding theory is the octet rule, which was introduced by Lewis in 1916, but later challenged by Pauling to explain the bonding of third-row elements. In the third row, the central atom was assumed to exceed the octet by employing d orbitals in double bonding leading to hypervalency. Ever since, polyoxoanions such as SO(4)(2-), PO(4)(3-), and ClO(4)(-) have been paradigmatic examples for the concept of hypervalency in which the double bonds resonate among the oxygen atoms. Here, we examine S-O bonding by investigating the charge density of the sulfate group, SO(4)(2-), within a crystalline environment based both on experimental and theoretical methods. K(2)SO(4) is a high symmetry inorganic solid, where the crystals are strongly affected by extinction effects. Therefore, high quality, very low temperature single crystal X-ray diffraction data were collected using a small crystal (∼30 μm) and a high-energy (30 keV) synchrotron beam. The experimental charge density was determined by multipole modeling, whereas a theoretical density was obtained from periodic ab initio DFT calculations. The chemical bonding was jointly analyzed within the framework of the Quantum Theory of Atoms In Molecules only using quantities derived from an experimental observable (the charge density). The combined evidence suggests a bonding situation where the S-O interactions can be characterized as highly polarized, covalent bonds, with the "single bond" description significantly prevailing over the "double bond" picture. Thus, the study rules out the hypervalent description of the sulfur atom in the sulfate group.

Experimental and Theoretical Charge Density Distribution in a Host–Guest System: Synthetic Terephthaloyl Receptor Complexed to Adipic Acid

The experimental charge density distributions in a host-guest complex have been determined. The host, 1,4-bis[[(6-methylpyrid-2-yl)amino]carbonyl]benzene (1) and guest, adipic acid (2). The molecular geometries of 1 and 2 are controlled by the presence in the complex of intermolecular hydrogen bonding interactions and the presence in the host 1 of intramolecular hydrogen bonding motifs. This system therefore serves as an excellent model for studying noncovalent interactions and their effects on structure and electron density, and the transferability of electron distribution properties between closely related molecules. For the complex, high resolution X-ray diffraction data created the basis for a charge density refinement using a pseudoatomic multipolar expansion (Hansen-Coppens formalism) against extensive low-temperature (T = 100 K) single-crystal X-ray diffraction data and compared with a selection of theoretical DFT calculations on the same complex. The molecules crystallize in the noncentrosymmetric space group P2(1)2(1)2(1) with two independent molecules in the asymmetric unit. A topological analysis of the resulting density distribution using the atoms in molecules methodology is presented along with multipole populations, showing that the host and guest structures are relatively unaltered by the geometry changes on complexation. Three separate refinement protocols were adopted to determine the effects of the inclusion of calculated hydrogen atom anisotropic displacement parameters on hydrogen bond strengths. For the isotropic model, the total hydrogen bond energy differs from the DFT calculated value by ca. 70 kJ mol(-1), whereas the inclusion of higher multipole expansion levels on anisotropic hydrogen atoms this difference is reduced to ca. 20 kJ mol(-l), highlighting the usefulness of this protocol when describing H-bond energetics.

Experimental and theoretical charge density of hydrated cupric acetate

The charge density of the hydrated cupric acetate Cu2(μ-OOCCH3)4·2H2O has been studied experimentally at 100K and by DFT calculations on the isolated molecule using the Quantum Theory of Atoms In Molecules (QTAIMs). The bimetallic moiety is bridged by four equivalent acetate groups each other perpendicular and forming penta-atomic rings. The QTAIM parameters of charge density, its Laplacian, potential and kinetic energy density, delocalization indexes, static deformation density have been used to describe all intra- and intermolecular interactions. The topological analysis of the charge density maps shows the expected bond critical points with the corresponding bond paths, Cu–Cu bonding included. The data obtained using the different parameters and functions are consistent for all types of interatomic interactions, i.e. covalent, dative and intermetallic. The unpaired electrons responsible of the magnetic properties of d9 Cu(II) ions occupy the orbitals pointing towards the acetate groups. The valence shell orbital populations of Cu(II) are consistent with the distortion of the octahedral coordination due to the Jahn–Teller effect.

Experimental charge density of hematite in its magnetic low temperature and high temperature phases

Structural parameters of hematite (α-Fe(2)O(3)), including the valence electron distribution, were investigated using convergent beam electron diffraction (CBED) in the canted antiferromagnetic phase at room temperature and in the collinear antiferromagnetic phase at 90K. The refined charge density maps are interpreted as a direct result of electron-electron interaction in a correlated system. A negative deformation density was observed as a consequence of closed shell interaction. Positive deformation densities are interpreted as a shift of electron density to antibinding molecular orbitals. Following this interpretation, the collinear antiferromagnetic phase shows the characteristic of a Mott-Hubbard type insulator whereas the high temperature canted antiferromagnetic phase shows the characteristic of a charge transfer insulator. The break of the threefold symmetry in the canted antiferromagnetic phase was correlated to the presence of oxygen-oxygen bonding, which is caused by a shift of spin polarized charge density from iron 3d-orbitals to the oxygen ions. We propose a triangular magnetic coupling in the oxygen planes causing a frustrated triangular spin arrangement with all spins lying in the oxygen planes. This frustrated arrangement polarizes the super-exchange between iron ions and causes the spins located at the iron ions to orient in the same plane, perpendicular to the threefold axis.