[Show abstract][Hide abstract] ABSTRACT: After a long history of use as a prototype cysteine protease inhibitor, the crystal structure of loxistatin acid (E64c) is finally determined experimentally using intense synchrotron radiation, providing insight into how the inherent electronic nature of this protease inhibitor molecule determines its biochemical activity. Based on the striking similarity of its intermolecular interactions with those observed in a biological environment, the electrostatic potential of crystalline E64c is used to map the characteristics of a pseudo-enzyme pocket.
New Journal of Chemistry 11/2014; · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hirshfeld atom refinement (HAR) is a method which determines structural parameters from single-crystal X-ray diffraction data by using an aspherical atom partitioning of tailor-made ab initio quantum mechanical molecular electron densities without any further approximation. Here the original HAR method is extended by implementing an iterative procedure of successive cycles of electron density calculations, Hirshfeld atom scattering factor calculations and structural least-squares refinements, repeated until convergence. The importance of this iterative procedure is illustrated via the example of crystalline ammonia. The new HAR method is then applied to X-ray diffraction data of the dipeptide Gly-l-Ala measured at 12, 50, 100, 150, 220 and 295 K, using Hartree-Fock and BLYP density functional theory electron densities and three different basis sets. All positions and anisotropic displacement parameters (ADPs) are freely refined without constraints or restraints - even those for hydrogen atoms. The results are systematically compared with those from neutron diffraction experiments at the temperatures 12, 50, 150 and 295 K. Although non-hydrogen-atom ADPs differ by up to three combined standard uncertainties (csu's), all other structural parameters agree within less than 2 csu's. Using our best calculations (BLYP/cc-pVTZ, recommended for organic molecules), the accuracy of determining bond lengths involving hydrogen atoms from HAR is better than 0.009 Å for temperatures of 150 K or below; for hydrogen-atom ADPs it is better than 0.006 Å(2) as judged from the mean absolute X-ray minus neutron differences. These results are among the best ever obtained. Remarkably, the precision of determining bond lengths and ADPs for the hydrogen atoms from the HAR procedure is comparable with that from the neutron measurements - an outcome which is obtained with a routinely achievable resolution of the X-ray data of 0.65 Å.
[Show abstract][Hide abstract] ABSTRACT: High-resolution low-temperature synchrotron X-ray diffraction data of the salt L-phenylalaninium hydrogen maleate are used to test the new automated iterative Hirshfeld atom refinement (HAR) procedure for the modelling of strong hydrogen bonds. The HAR models used present the first examples of Z′ > 1 treatments in the framework of wavefunction-based refinement methods. L-Phenylalaninium hydrogen maleate exhibits several hydrogen bonds in its crystal structure, of which the shortest and the most challenging to model is the O—H...O intramolecular hydrogen bond present in the hydrogen maleate anion (O...O distance is about 2.41 Å). In particular, the reconstruction of the electron density in the hydrogen maleate moiety and the determination of hydrogen-atom properties [positions, bond distances and anisotropic displacement parameters (ADPs)] are the focus of the study. For comparison to the HAR results, different spherical (independent atom model, IAM) and aspherical (free multipole model, MM; transferable aspherical atom model, TAAM) X-ray refinement techniques as well as results from a low-temperature neutron-diffraction experiment are employed. Hydrogen-atom ADPs are furthermore compared to those derived from a TLS/rigid-body (SHADE) treatment of the X-ray structures. The reference neutron-diffraction experiment reveals a truly symmetric hydrogen bond in the hydrogen maleate anion. Only with HAR is it possible to freely refine hydrogen-atom positions and ADPs from the X-ray data, which leads to the best electron-density model and the closest agreement with the structural parameters derived from the neutron-diffraction experiment, e.g. the symmetric hydrogen position can be reproduced. The multipole-based refinement techniques (MM and TAAM) yield slightly asymmetric positions, whereas the IAM yields a significantly asymmetric position.
[Show abstract][Hide abstract] ABSTRACT: The reaction of the intramolecularly coordinated diaryltellurium(IV) oxide (8-Me2NC10H6)2TeO with acetonitrile proceeds with oxygen transfer and gives rise to the formation of the novel zwitterionic diaryltelluronium(IV) acetimidate (8-Me2NC10H6)2-TeNC(O)CH3 (1) in 57% yield. Protolysis of 1 with hydro-chloric acid affords acetamide and the previously known diarylhydroxytelluronium(IV) chloride [(8-Me2NC10H6)2Te(OH)]Cl.
Journal of the American Chemical Society 07/2014; · 11.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Single crystal X-ray structure determinations have previously been described for picrate salts of a variety of nitrogen bases. Herein, these have been extended to encompass monoprotonated mono- and oligo-dentate cyclic nitrogen-donor ligand systems derived from pyridine, some via saturation (piperidine and morpholine) and others via lateral extension of the aromatic system (2,2′-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, bis(2-pyridyl)amine, 2,2′:6′,2′′-terpyridine, and 8-hydroxyquinoline). Hydrogen-bonding interactions are dominant determinants of the structures, complemented by or in competition with parallel stacking of anion and (aromatic) base planes. Furthermore, nitronitro, nitroπ and phenoxy-Oπ inter-species contacts play a significant role in the crystal packing. It also appears that cationanion interactions arising from CH(adjacent to NH)O(o-nitro) interactions are more important than the available secondary bifurcating component associated with any NHO(o-nitro) approach, resulting, in many cases, in a bidentate NHHC base approach to an (ON)OOO(NO) triadic array. The nature of the anion-cation interactions and their importance are explored using the Hirshfeld surface method. The precision of the structure determinations establishes the quinonoid form of the picrate to be a widespread contributor. Theoretical calculations on picric acid and the parent pyridinium-picrate ion-pair confirm the energetic favourability of the base-triad approach and the dominance of the quinonoid resonance form.
[Show abstract][Hide abstract] ABSTRACT: The case of protease inhibitor model compounds incorporating an aziridine or epoxide ring is used to exemplify how application of experimental electron-density techniques can be used to explain the biological properties of low-molecular weight enzyme ligands. This is furthermore seen in the light of a comparison of crystal and enzyme environments employing QM/MM computations to elucidate to which extent the properties in the crystal can be used to predict behavior in the biological surrounding.
[Show abstract][Hide abstract] ABSTRACT: The syntheses and full characterizations of the peri-substituted naphthalenes (Nap) and acenaphthenes (Ace) 1-Br-8-(Ph2P)-Nap (1a) and 5-Br-6-(Ph2P)-Ace (1b), as well as their derivatives 1-Br-8-[Ph2P(E)]-Nap [E = CH3+ (counterion I–) (2a); E = O (3a); E = S (4a); E = Se (5a)] and 5-Br-6-[Ph2P(E)]-Ace [E = CH3+ (counterion I–) (2b); E = O (3b); E = S (4b); E = Se (5b)] are reported. In order to quantify the energetic and electronic effects of the peri-interactions, an additional set of molecules, 1c–5c, with the bromine atom and the Ph2P(E) fragment on opposite sides of the naphthalene group was generated, which serves as reference because 1c–5c exhibit negligible peri-interactions. The molecular arrangements of all 15 compounds were optimized at the B3PW91/6-311+G(2df, p) level of theory. The analysis of the peri-interactions was not only based on the inspection of the molecular arrangement and energies alone, but extended to a set of real-space bonding indicators (RSBI). These indicators were derived from theoretically calculated electron densities and pair densities, respectively. Particularly, the stockholder, Atoms-In-Molecules (AIM) and Electron-Localizability-Indicator (ELI-D) space partitioning schemes were used to produce Hirshfeld surfaces (HS), bond topological properties and basins of localized bonding and nonbonding electron pairs. Since 1c–5c are 35–58 kJ·mol–1 lower in energy than their counterparts 1a–5a, the hypothesis of a mainly repulsive peri-interaction in 1a/b–5a/b was confirmed. The shapes and contact patterns of the HSs of atoms and fragments involved in the peri-interactions (Br, P, E = CH3+, O, S, Se) reveal that only in 1a and 1b are peri-interactions exhibited between the bromine and the phosphorus atoms. In all other cases (2a/b–5a/b), the interaction mainly occurs between the bromine atom and the E atom/fragment. According to the bond topological properties and the electron populations within the (non)bonding ELI-D basins, which both are almost unaffected by the Br-P/E peri-interaction, sterical interactions are characterized essentially by geometrical and energetical changes.
Zeitschrift für anorganische und allgemeine Chemie 10/2013; 639(12-13):2233-2249. · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Salts of the family [M(NCMe)4]+X− (M = Cu, Ag; X− = [BF4]−, [ClO4]−, [PF6]− crystallize in the space groups Pna21 or P212121 with very similar cell dimensions. This gives rise to two sets of true isomorphs (four members in Pna21, two in P212121), and a solvated species (Cu/PF6/MeCN) with a distorted P212121 lattice. Across the two space groups and regardless of the choice of metal atom or anion, the underlying basic structures are virtually identical in the six unsolvated cases, consisting of alternate sheets of cations and anions, mainly held together by C–HC,N and C,NC,N interactions, and a columnar cation–anion motif perpendicular to the sheets maintained by C–HF,O interactions. The pair of concomitant polymorphs found with Cu/BF4 in both Pna21 and P212121 can readily be described as being quasi-isomorphous. Using a Hirshfeld surface approach and a tri-cationic structural synthon extracted from the asymmetric units, the common underlying pattern of close intercomponent approaches has been analysed and quantified. The structure of the Ag/PF6 complex is new; low-temperature redeterminations are recorded for the Ag/ClO4 and the Cu/PF6/MeCN complexes.
[Show abstract][Hide abstract] ABSTRACT: The connectivities (hapticities) of asymmetric cyclopentadienyl zinc compounds are determined by theoretically obtained real-space bonding descriptors. The methods employed herein include the determination of the number of virial paths and electron localizability indicator (ELI-D) basins exhibited between the central Zn atom and the atoms of the ring system. Metal-ring interactions are characterized by flat electron densities and small density gradients, which are related to the high fluxionality of the rings. Due to this, the structures are topologically unstable and the conventional bond-path analysis within the atoms in molecules (AIM) scheme, which in principle can also be applied for experimental electron densities reconstructed from high-resolution X-ray diffraction data, is not a reliable tool for the determination of the hapticity. As a consequence, the theoretical investigation of other real-space bonding descriptors is the necessary primary step for discovering bonding modes that can be applied to molecular geometries obtained by subsequent experiments. By this procedure the common geometrical interpretation of connectivities, which is based on rather arbitrary decisions, is complemented by a self-consistent method using electronic descriptors. Moreover, the two-center σ contributions of all possible bonding scenarios (η(1)-η(5)) were quantified by analyzing the electron populations of the Zn-C σ-bonding basins from the ELI-D analysis inside the AIM Zn atom in relation to the corresponding populations of the C-C π basins of the unsaturated rings. The investigation of the Zn-ring interactions is extended to the delocalization index, the source function, and a new type of electron-density-based surfaces, which we introduce here (ASF = aspherical stockholder fragments). They can be used for visualization of single atoms, fragments (e.g., functional groups), and whole molecules and are based on Hirshfeld's idea of stockholder partitioning, but apply aspherical electron densities. With these surfaces the charge accumulation between the chosen fragments and the steric accessibility of the central Zn atoms become visible, which is a useful tool for explaining and predicting chemical reactivity.
Chemistry - A European Journal 08/2012; 18(37):11647-61. · 5.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eine neue Verfeinerungstechnik für Röntgenbeugungsdaten ermöglicht die experimentelle Bestimmung von S‐O‐Bindungsordnungen. Die Ergebnisse belegen, dass eine ionische Beschreibung der S‐O‐Bindungen in Schwefeldioxid von weitaus größerer Bedeutung ist als eine hypervalente.
[Show abstract][Hide abstract] ABSTRACT: A novel refinement technique for X-ray diffraction data has been employed to derive SO bond orders in sulfur dioxide experimentally. The results show that ionic SO bonding dominates over hypervalency.
Angewandte Chemie International Edition 05/2012; 51(27):6776-9. · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The crystal structures of an array of 2-R,4-oxo-[1,3-b]-naphthodioxanes (R = H, Me, Et, i-Pr, n-Bu, CCl3, i-propylideneglyceral) have been determined at 100 K, together with a more limited series of the isomeric 2-R,4-oxo-[1,3-a]-naphthodioxanes (R = Et, i-Pr, n-Bu, i-propylideneglyceral), permitting a study of the effects of substituent and ring fusion variation on the crystal packing of neutral molecules that are otherwise essentially planar. We have conducted an analysis of Hirshfeld surfaces (a definition of an outer contact surface of a molecule within a crystal) for all eleven compounds and follow the changes of different properties on these surfaces upon systematic variation of the substituent R. Not only qualitative information by means of fingerprint plots, but also quantitative information by means of melting point correlations are presented. The results show the extent to which C–HO hydrogen bonds and C–Hπ/ππ interactions contribute positively to the lattice energies on the one hand, and HH contacts negatively on the other. The percentage of HH contacts as closest contacts on the Hirshfeld surfaces is a universally applicable measure of the crystal lattice energy and can be used as a reference for the importance of other types of contacts.
[Show abstract][Hide abstract] ABSTRACT: A combined experimental and theoretical study of three isoindole derivatives was made on the basis of a topological analysis of their electron-density distributions. Experimental electron densities were determined from high-resolution X-ray diffraction data sets measured with synchrotron radiation at 100 K, whereas theoretical calculations were performed using DFT methods at the B3LYP\6-311++G(3df,3pd) level of approximation. Both experimental and theoretical models are in good agreement with each other. Since the analysed structures possess a variety of hydrogen-bonding interactions, weak intermolecular contacts of C-H···C(π), C,N(π)···C,N(π) and H···H types were subject to our special interest and are discussed in detail. They were characterized quantitatively and qualitatively by topological properties using Bader's Atoms in Molecules theory and by mapping the electron-density distribution, electrostatic potential and a geometric function on the Hirshfeld surface. This way the forces and directions of intermolecular interactions as present on the molecular surfaces were depicted and described. These interactions not only guide crystal packing, but are likewise important for recognition processes involving (aza)isoindole fragments in a biological environment.
[Show abstract][Hide abstract] ABSTRACT: It is still a challenge to predict a compound's reactivity from its ground-state electronic nature although Bader-type topological analyses of the electron density (ED) and electron localizability indicator (ELI) give detailed and useful information on electron concentration and electron-pair localization, respectively. Both ED and ELI can be obtained from theoretical calculations as well as high-resolution X-ray diffraction experiments. Besides ED and ELI descriptors, the delocalization index is used here; it is likewise derived from theoretical calculations as well as from experimental X-ray results, but in the latter case, demonstrated here for the first time. We investigate α,β-unsaturated carbonyl and hydrazone compounds because resonance exhibited by these compounds in the electronic ground-state determines their reactive behavior. The degree of resonance as well as the reactivity contrast are quantified with the electronic descriptors. Moreover, competitive mesomeric substituent effects are studied using the two biologically important compounds acrolein and acrylamide. The reactivity differences predicted from the analyses are in line with the known reactivity of these compounds in organic synthesis. Hence, the capability of the ED and ELI for rationalizing and predicting different and competing substituent effects with respect to reactivity is demonstrated.
The Journal of Physical Chemistry A 07/2011; 115(45):12715-32. · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of acceptor-substituted epoxide derivatives is scrutinized by means of experimental and theoretical electron-density investigations. Due to the possibility of nucleophilic ring-opening, the epoxide ring is not only a very useful functional group in organic synthesis, but acceptor-substituted epoxides are valuable building blocks for the design of protease inhibitors. Therefore, the electron-density analysis in this work focuses on two main aspects that can contribute to rational drug design: (i) the quantification of the electron-withdrawing substituent effects on the epoxide ring and (ii) the intermolecular interactions involving the epoxide ring in combination with different substituents. It can be shown that the electron-withdrawing properties of the substituents cause an elongation of the C-C bonds in the epoxide rings and the loss of electron density can be measured by an analysis of critical points, atomic charges, and the source function. The different strengths of the substituents are reflected in these properties. Covalent and electrostatic contributions to the intermolecular interactions and thus the lattice energies are depicted on different molecular surfaces.
The Journal of Organic Chemistry 03/2011; 76(5):1305-18. · 4.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For two indole and oxindole bioactive molecules, low-order room-temperature X-ray data were used to generate aspherical electron density (ED) distributions by application of the invariom formalism. An analysis of the ED using the quantum theory of atoms in molecules (QTAIM) was carried out, which allowed for quantitatively examining bond orders and charge separations in various parts of the molecules. The inspection of electrostatic potentials (ESPs) and Hirshfeld surfaces provided additional information on the intermolecular interactions. Thus, reactive regions of the molecules could be identified, covalent and electrostatic contributions to interactions could be visualized, and the forces causing the crystal packing scheme could be rationalized. As the used invariom formalism needs no extra experimental effort compared to routine X-ray analysis, its wide application is recommended because it delivers information far beyond the normally obtained steric properties. In this way, complementary contributions to drug design can be given as is demonstrated for indoles in this study, which are involved in the metabolism of plants and animals as well as in cancer therapy.
Chemistry - An Asian Journal 03/2011; 6(6):1390-7. · 4.57 Impact Factor