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The electron density distribution (EDD) of a plant cyclic nonapeptide of orbitide type was studied. Crystal X-ray diffraction data was obtained from the Cambridge Structural Database (CSD) and refitted using scattering factors of the invariom library, thereby providing aspherical electron density. Bond topological, atomic properties and molecular surfaces (electrostatic potential and Hirshfeld surfaces) were derived. The partial double bond character of the peptide bond was confirmed by the ellipticity ε = 0.25. For eight N–H⋯O hydrogen bonds, atomic charges of contributing atoms differ depending on the type of the accepting oxygen atom. Atomic charge differences between negative main and positive side chains of this nonapeptide result in characteristic features of the electrostatic potential, which shows a positive isosurface around the molecule leading to repulsive interactions in the solid state structure. Weak intermolecular interactions are indicated by insignificant ED concentrations on the Hirshfeld surface except for weak signals at sites of intermolecular N–H⋯O and C–H⋯O hydrogen bonds. [ABSTRACT FROM AUTHOR]

The electron density distribution (EDD) of a cyclic tetrasaccharide composed of four benzoylated galactopyranosyl units was calculated from refinement with scattering factors from the invariom library based on X-ray diffraction data downloaded from the Crystal Structural Data Base (CSD). Bond topological and atomic properties have been derived. Benzoyl substituents cause weak intermolecular interactions. These are also visible from low electron density concentrations on the Hirshfeld surface and have an influence on a low X-ray density compared to that of non-substituted carbohydrates, where hydrogen bonds allow a 20% more dense packing. On the electrostatic potential (ESP) surface, a strong polarization between the positive outer belt of 12 benzoyl groups and a negative core region composed of the four galactose sugar molecules exists. The positive benzoyl exterior establishes a repulsive wall between adjacent molecules in the structure. [ABSTRACT FROM AUTHOR]

The electron density of a 1:2 complex of valinomycin with calcium triflate consisting of 10 substructures and a total of 279 atoms was examined using the invariom formalism. In addition to geometric properties, sites and strengths of hydrogen bonds were identified from bond topological properties and from electron density concentrations mapped onto Hirshfeld surfaces. In contrast to free valinomycin and corresponding complexes with potassium the hydrogen bonds are all intermolecular and evenly distributed over the complex. A series of electrostatic potential (ESP) surfaces show the mutual influence in the ensemble of this high Z′ structure. [ABSTRACT FROM AUTHOR]

The electron density of a 1:2 complex of valinomycin with calcium triflate consisting of 10 substructures and a total of 279 atoms was examined using the invariom formalism. In addition to geometric properties, sites and strengths of hydrogen bonds were identified from bond topological properties and from electron density concentrations mapped onto Hirshfeld surfaces. In contrast to free valinomycin and corresponding complexes with potassium the hydrogen bonds are all intermolecular and evenly distributed over the complex. A series of electrostatic potential (ESP) surfaces show the mutual influence in the ensemble of this high Z′ structure. [ABSTRACT FROM AUTHOR]

Rotaxanes as well as catenanes are known as potential building blocks of molecular machines. The nanohoop [2]rotaxane investigated is composed of a macrocycle derived from a [6]cycloparaphenylene (CCP, designated as a carbon nanohoop), where one of the six para-linked phenyl rings is replaced by a 2,6-substituted pyridyl ring. This macrocycle is mechanically interlocked with a thread, a linear rod-shaped diyne fragment sitting in the cavity of the macrocycle. Two bulky 3,5-di-t-butyl-phenyl rests as end groups keep the thread fixed. The interplay between macrocycle and thread was examined by means of the electron density distribution (EDD) obtained by application of the invariom formalism, relying on X-ray diffraction data collected earlier. The so-obtained EDD was subjected to topological analysis using the QTAIM formalism. Moreover, molecular Hirshfeld and electrostatic potential (ESP) surfaces were calculated. The 73 C–C bonds were analysed in terms of bond topological properties. For the 46 single and the 22 aromatic bonds, the analysis gave average bond orders of 1.03 and 1.61. The five C–C bonds in the diyne fragment can clearly be distinguished into three types: formal triple bonds with bond orders above 3.0, arene bonds with bond orders of 1.6 and finally bond orders of 1.3 in the adjacent C–C bonds, which indicate a considerable electron delocalization in this fragment. Mapping the ED onto the Hirshfeld surfaces of the macrocycle and the thread does not show strong signals. This shows that in between the molecules only weak non-covalent interactions are present. The electrostatic potentials (ESPs) were mapped onto molecular EDD isosurfaces. For all phenyl rings, small regions of negative ESP are visible on the delocalized π systems. A potential gradient between the mostly positive ESP of the macrocycle and the diyne region of the thread exist, which can be considered the dominant force to hold this rotaxane together. [ABSTRACT FROM AUTHOR]

Single crystal X-ray diffraction is the method of choice to resolve difficult solid-state problems. This is exemplified by analysis of three disordered structures that cease to be disordered depending on the circumstances. Interesting research questions of relevance for the pharmaceutical industry, including possible issues of intellectual property, emerge from disappearing disorder phenomena. Its relationship to polymorphism is discussed, and the term 'archetype structure' that includes both polymorphs and disorder components is recommended for use. X-ray structural studies reported here benefit from refinement with aspherical scattering factors that improve accuracy and precision of the results, thereby providing the confidence required in interpreting comparably small residual electron density features. Full understanding of the mechanism of how disorder can come into existence and disappear with temperature or time (pressure being another factor not exploited here) requires computing the relative energy differences of archetype structures by ONIOM cluster or solid-state computations. [ABSTRACT FROM AUTHOR]

The nonapeptides cyclo(Val-Leu-Pro-Ile-Leu-Leu-Leu-Val-Leu) (I) and cyclo(Val-Leu-Pro-Ala-Leu-Leu-Leu-Val-Leu) (II) were identified as promising candidates for the development as potential anti-cancer drugs. We report a re-refinement of deposited single-crystal X-ray diffraction data with aspherical scattering factors from the invariom database. A subsequent evaluation of the molecular electron density distribution and of the differences in their molecular electrostatic potentials provides insight in their activities. The sequences differ only in residue 4, Ile in (I) and Ala in (II). Since the anti-tumor potency is reduced for the Ala peptide (II), the causes for the differences seen in activity between (I) and (II) were examined from a structural and from an electron density (ED) point of view. The exchange at residue 4 does not lead to significant changes in molecular geometry. Molecular Hirshfeld surfaces and electrostatic potential (ESP) isosurfaces show accumulations of intermolecular interactions in regions adjacent to the Ile/Ala residues indicating preferred interactions with a potential receptor in these regions. The concentrations of intermolecular interactions were localized on the Hirshfeld surfaces through an extended basin of ED concentration close to the Ile/Ala residues. Differences in the electrostatic potentials (ESPs) between (I) and (II) were only found at the Ile/Ala site and were very close to zero otherwise. [ABSTRACT FROM AUTHOR]

A new aspherical scattering factor formalism has been implemented in the crystallographic least‐squares refinement program SHELXL. The formalism relies on Gaussian functions and can optionally complement the independent atom model to take into account the deformation of electron‐density distribution due to chemical bonding and lone pairs. Asphericity contributions were derived from the electron density obtained from quantum‐chemical density functional theory computations of suitable model compounds that contain particular chemical environments, as defined by the invariom formalism. Thanks to a new algorithm, invariom assignment for refinement in SHELXL is automated. A suitable parameterization for each chemical environment within the new model was achieved by metaheuristics. Figures of merit, precision and accuracy of crystallographic least‐squares refinements improve significantly upon using the new model. A new aspherical scattering factor formalism was implemented in SHELXL. It relies on Gaussian functions and can optionally complement the independent atom model to take into account the deformation of electron‐density distribution due to chemical bonding and lone pairs. The automated atom‐type assignment was derived from the invariom formalism. [ABSTRACT FROM AUTHOR]

Catenanes are of considerable interest as potential building blocks for molecular machines. The simplest [2]catenanes, Hopf links, consist of two macrocycles that are mechanically interlocked. This unusual architecture cannot be opened without breaking at least one covalent bond. Based on these structural characteristics, unusual properties on Hirshfeld or electrostatic potential surfaces could be expected. For a comparison of their structural and electronic properties, the electron densities (EDs) of two [2]catenanes, coded H22 and H4L7 in the original papers, were examined after application of the invariom formalism, relying on X-ray diffraction data collected earlier. The obtained electron density distributions were subjected to an analysis using the QTAIM formalism to yield bond and atomic properties. Moreover, molecular Hirshfeld surfaces and electrostatic potentials (ESP) were calculated. There are different types of intra- and intermolecular interactions in these two [2]catenanes. In addition to classical N–H···N and C–H···O hydrogen bonds, various types of π···π interactions in H22 and in H4L7 exist. Most of them are verified by local ED concentrations visible on the corresponding Hirshfeld surfaces, except for the parallel π···π interactions in H22, which are either too weak or too diffuse to generate an ED signal on the Hirshfeld surface between the contributing aromatic rings. The electrostatic potentials (ESPs) were calculated and displayed on molecular surfaces. The interaction in the cavity of one macrocycle with the penetrated fragment of the second one was examined and it was found that corresponding to the above-mentioned contacts attractive and repulsive interactions exist. Additionally the ED was examined using results of density functional calculations, including non-covalent interaction index (NCI) and electron localizability indicator (ELI-D) surface analysis, complementing experimental findings. [ABSTRACT FROM AUTHOR]

The structure of glutathione, γ-l-Glutamyl-l-cysteinyl-glycine (C10H17N3O6S), was studied by multi-temperature single-crystal X-ray diffraction. Residual density maps from conventional independent atom model refinement gave indication of anharmonic motion in the molecule. This was further investigated by invariom refinement with anisotropic displacement parameters for all atoms, which described asphericity due to chemical bonding and lone pairs; afterwards only the residual-density signal of anharmonic motion remained. Treating anharmonicity with third-order Gram-Charlier displacement parameters led to regions with unphysical negative electron density. In contrast, a maximum entropy method (MEM) determination of the electron density successfully takes the features into account. Respective difference electron density plots (MEM minus prior and [Invariom+GC] minus invariom) agree well with each other. Challenges in treating and understanding the phenomenon are discussed. A procedure is proposed how unphysical negative electron density can be avoided. It is closely related to the free lunch algorithm. [ABSTRACT FROM AUTHOR]

Abstract: Crystallography and quantum mechanics have always been tightly connected because reliable quantum mechanical models are needed to determine crystal structures. Due to this natural synergy, nowadays accurate distributions of electrons in space can be obtained from diffraction and scattering experiments. In the original definition of quantum crystallography (QCr) given by Massa, Karle and Huang, direct extraction of wavefunctions or density matrices from measured intensities of reflections or, conversely, ad hoc quantum mechanical calculations to enhance the accuracy of the crystallographic refinement are implicated. Nevertheless, many other active and emerging research areas involving quantum mechanics and scattering experiments are not covered by the original definition although they enable to observe and explain quantum phenomena as accurately and successfully as the original strategies. Therefore, we give an overview over current research that is related to a broader notion of QCr, and discuss options how QCr can evolve to become a complete and independent domain of natural sciences. The goal of this paper is to initiate discussions around QCr, but not to find a final definition of the field. [ABSTRACT FROM AUTHOR]

Motivated by the medical interest in methylene blue as potential anti-Alzheimer agent, the charge densities of three salt structures containing the methylene blue cation with nitrate (as dihydrate), chloride (as pentahydrate) and thiocyanate counter-ions were generated by application of the invariom formalism and examined. The so-obtained charge density distributions were analyzed using the QTAIM formalism to yield bond topological and atomic properties. The atomic charges on the methylene blue cation indicate a delocalized charge distribution; only a small positive charge on the sulfur atom was found. Electrostatic potentials mapped onto iso-surfaces of electron density for the cations, and for the methylene blue cations with anions, were compared. The effect of hydrogen disorder on the molecular electrostatic potential was investigated for the thiocyanate structure. [ABSTRACT FROM AUTHOR]

The trans-epoxysuccinyl amide group as a biologically active moiety in cysteine protease inhibitors such as loxistatin acid E64c has been used as a benchmark system for theoretical studies of environmental effects on the electron density of small active ingredients in relation to their biological activity. Here, the synthesis and the electronic properties of the smallest possible active site model compound are reported to close the gap between the unknown experimental electron density of trans-epoxysuccinyl amides and the well-known function of related drugs. Intramolecular substituent effects are separated from intermolecular crystal packing effects on the electron density, which allows us to predict the conditions under which an experimental electron density investigation on trans-epoxysuccinyl amides will be possible. In this context, the special importance of the carboxylic acid function in the model compound for both crystal packing and biological activity is revealed through the novel tool of model energy analysis. [ABSTRACT FROM AUTHOR]

Although compounds undergoing thermally induced spin crossover have been widely studied, their experimental d-orbital populations from single-crystal X-ray diffraction have rarely been reported. Three pairs of structures of iron/manganese coordination compounds were re-evaluated. Least-squares refinements relied on aspherical scattering factors obtained from molecular quantum-mechanical DFT single-point computations of the respective solid-state conformation, initiated by accurate starting structures from preliminary invariom refinements of the ligand environment. Further evaluation concerned d-orbital populations of metal ions from (a) single-point computations projected onto the Hansen-Coppens multipole model and from (b) experimental refinements of the metal atoms only. The latter were successful for good-quality data, independent of temperature, and provided only one spin state was exclusively present in the crystal. Crystals that underwent light-induced excited spin state trapping were not showing the expected d-orbital populations. [ABSTRACT FROM AUTHOR]

Topological analysis using Bader and co-worker's Atoms in Molecules theory has seen many applications in theoretical chemistry and experimental charge-density research. A brief overview of successful early developments, establishing topological analysis as a research tool for characterizing intramolecular chemical bonding, is provided. A lack of vision in many `descriptive but not predictive' subsequent studies is discussed. Limitations of topology for providing accurate energetic estimates of intermolecular interaction energies are put into perspective. It is recommended that topological analyses of well understood bonding situations are phased out and are only reported for unusual bonding. Descriptive studies of intermolecular interactions should have a clear research focus. [ABSTRACT FROM AUTHOR]

The title compounds have raised considerable medical and broad public interest in that sildenafil is used as an agent against male erectile dysfunction; iso-sildenafil is not in clinical use. A comparison of their structural and electronic properties therefore seems of interest. The electron densities of iso-sildenafil and the cationic and neutral forms of sildenafil were examined by the application of the invariom formalism relying on diffraction data reported in the literature. The electron-density distributions obtained were subjected to topological analysis using the quantum theory of atoms in molecules (QTAIM) formalism to yield bond topological and atomic properties. Moreover, molecular Hirshfeld surfaces and electrostatic potentials (ESPs) were calculated. A number of structural and electronic differences were thus identified between sildenafil and the iso-analog. In both sildenafil structures, the phenyl ring and the pyrazolopyrimidine fragment are practically coplanar (planar conformation), whereas in the iso-analog they exhibit an angle of 44° (inclined form). Related to differences in molecular structure are completely different hydrogen bonding patterns and differences in the ESPs, the latter ones being influenced by different methylation at the pyrazolopyrimidine fragment. Iso-sildenafil is present as a hydrogen-bond dimer in the crystal, and the ESP of this dimer is dominated by a surrounding positive potential. [ABSTRACT FROM AUTHOR]

Reduction of the neutral carbene tetrachlorosilane adduct (cAAC)SiCl4 (cAAC=cyclic alkyl(amino) carbene :C(CMe2)2(CH2)N(2,6-iPr2C6H3) with potassium graphite produces stable (cAAC)3Si3, a carbene-stabilized triatomic silicon(0) molecule. The Si−Si bond lengths in (cAAC)3Si3 are 2.399(8), 2.369(8) and 2.398(8) Å, which are in the range of Si−Si single bonds. Each trigonal pyramidal silicon atom of the triangular molecule (cAAC)3Si3 possesses a lone pair of electrons. Its bonding, stability, and electron density distributions were studied by quantum chemical calculations. [ABSTRACT FROM AUTHOR]

In the crystal structure of the title homoleptic CrII complex, [Cr(CH3CN)6](C24H20B)2·CH3CN, the [Cr(CH3CN)6]2+ cation is a high-spin d4 complex with strong static, rather than dynamic, Jahn-Teller distortion. The electron density of the cation was determined by single-crystal X-ray refinements using aspherical structure factors from wavefunction calculations. The detailed picture of the electronic density allowed us to assess the extent and directionality of the Jahn-Teller distortion of the CrII cation away from idealized octahedral symmetry. The topological analysis of the aspherical d-electron density about the CrII cation showed that there are significant valence charge concentrations along the axial Cr-N axes. Likewise, there were significant valence charge depletions about the CrII cation along the equatorial Cr-N bonds. These charge concentrations are in accordance with a Jahn-Teller-distorted six-coordinate complex. [ABSTRACT FROM AUTHOR]

The temperature dependence of H- Uiso in N-acetyl-L-4-hydroxyproline monohydrate is investigated. Imposing a constant temperature-independent multiplier of 1.2 or 1.5 for the riding hydrogen model is found to be inaccurate, and severely underestimates H- Uiso below 100 K. Neutron diffraction data at temperatures of 9, 150, 200 and 250 K provide benchmark results for this study. X-ray diffraction data to high resolution, collected at temperatures of 9, 30, 50, 75, 100, 150, 200 and 250 K (synchrotron and home source), reproduce neutron results only when evaluated by aspherical-atom refinement models, since these take into account bonding and lone-pair electron density; both invariom and Hirshfeld-atom refinement models enable a more precise determination of the magnitude of H-atom displacements than independent-atom model refinements. Experimental efforts are complemented by computing displacement parameters following the TLS+ONIOM approach. A satisfactory agreement between all approaches is found. [ABSTRACT FROM AUTHOR]