Development of Quantum-Crystallographic Methods for Chemical and Biochemical Applications

The field of crystallography is a key branch of natural sciences, important not only for physics, geology, biology or chemistry, but it also provides crucial information for life sciences and materials science. It laid the foundations of our textbook knowledge of matter in general. In this thesis, the field of quantum crystallography – a synergistic approach of crystallography and quantum mechanics – is used as a tool to predict and understand processes of molecules and their interactions. New methods are proposed and used that provide deeper insight into the influence of local molecular environments on molecules and allows advanced predictions of the biochemical effect of drugs. Ultimately, this means that we can now understand interactions between molecules in crystal structures more completely that were long thought to be fully characterized. As part of this work, new software was developed to handle theoretical simulations as well as experimental data – and also both of them together at the same time. The introduction of non-spherical refinements in standard software for crystallography opens the field of quantum crystallography to a wide audience and will hopefully strengthen the mutual ground between experimentalists and theoreticians. Specifically, we created a new native interface between Olex2 and non-spherical refinement techniques, which we called NoSpherA2. This interface has been designed in such a way that it can be used for any kind of non-spherical atom descriptions. This will allow refinement of modern diffraction data employing modern quantum crystallographic models, leaving behind the century old Independent Atom Model (IAM). New software was also developed to provide novel models and descriptors for understanding environmental effects on the electron density and electrostatic potential of a molecule. This so-called Quantum Crystallographic Toolbox (QCrT) provides a framework for the fast and easy implementation of various methods and descriptors. File conversion tools allow the interfacing with many existing software packages and might provide useful information for future method development, experimental setups and data evaluation, as well as chemical insight into intra- and intermolecular interactions. It is fully parallelized and portable to graphic card processors (GPUs), which provide extraordinary amounts of computational power with moderate resource requirements. Especially in the context of ultra-bright X-ray sources like X-ray free electron lasers and electron diffraction these new models become crucial to have a better description of experimental findings. In applying this new framework of quantum crystallographic methods, we analyze a type of bonding at the edge of conventional organic chemistry: The push-pull systems of ethylenes. We show how X-ray constrained bonding analysis leads to the unambiguous determination of the behavior and type of bonding present in a series of compounds which are contradicting the Lewis-picture of a double-bond. This new understanding has led to the development of a new potential drug, namely a silicon analogue of ibuprofen; one of the most important drugs known to humankind. We determined its physical properties, investigated its stability and potency as a more soluble and novel alternative of ibuprofen: While retaining the same pharmaceutical activity of ibuprofen, making it a bioisoster for ibuprofen, this material shows a better applicability in aqueous media

Refinement of X‐ray and electron diffraction crystal structures using analytical Fourier transforms of Slater‐type atomic wavefunctions in Olex2

An implementation of Slater‐type spherical scattering factors for X‐ray and electron diffraction for elements in the range Z = 1–103 is presented within the software Olex2. Both high‐ and low‐angle Fourier behaviour of atomic electron density and electrostatic potential can thus be addressed, in contrast to the limited flexibility of the four Gaussian plus constant descriptions which are currently the most widely used method for calculating atomic scattering factors during refinement. The implementation presented here accommodates the increasing complexity of the electronic structure of heavier elements by using complete atomic wavefunctions without any interpolation between precalculated tables or intermediate fitting functions. Atomic wavefunctions for singly charged ions are implemented and made accessible, and these show drastic changes in electron diffraction scattering factors compared with the neutral atom. A comparison between the two different spherical models of neutral atoms is presented as an example for four different kinds of X‐ray and two electron diffraction structures, and comparisons of refinement results using the existing diffraction data are discussed. A systematic but slight improvement in R values and residual densities can be observed when using the new scattering factors, and this is discussed relative to effects on the atomic displacement parameters and atomic positions, which are prominent near the heavier elements in a structure

Aurophilic Interactions Studied by Quantum Crystallography.

This is the first use of a wave-function-based crystallographic method to characterize aurophilic interactions from X-ray diffraction data. Theoretical calculations previously suggested the importance of electron correlation and dispersion forces, but no influence of relativistic corrections to the Au...Au interaction energy was found. In this study, we confirm the importance of relativistic corrections in the characterization of aurophilic interactions in addition to electron correlation and dispersion

Influence of modelling disorder on Hirshfeld atom refinement results of an organo-gold(I) compound.

Details of the validation of disorder modelling with Hirshfeld atom refinement (HAR) for a previously investigated organo-gold(I) compound are presented here. The impact of refining disorder on HAR results is discussed using an analysis of the differences of dynamic structure factors. These dynamic structure factor differences are calculated from thermally smeared quantum mechanical electron densities based on wavefunctions that include or exclude electron correlation and relativistic effects. When disorder is modelled, the electron densities stem from a weighted superposition of two (or more) different conformers. Here this is shown to impact the relative importance of electron correlation and relativistic effect estimates expressed by the structure factor magnitudes. The role of disorder modelling is also compared with the effect of the treatment of hydrogen anisotropic displacement parameter (ADP) values and atomic anharmonicity of the gold atom. The analysis of ADP values of gold and disordered carbon atoms showed that the effect of disorder significantly altered carbon ADP values and did not influence those of the gold atom

[ A ([18]crown‐6)] 2 [Pt(CO) 3 ] ⋅ 10 NH 3 ( A =K, Rb) – A crystal structure containing the long postulated [Pt(CO) 3 ] 2−

The compound [A([18]crown-6]2[Pt(CO)3] ⋅ 10 NH3 (A=K, Rb, [18]crown- 6=1,4,7,10,13,16-Hexaoxacyclooctadecane) containing the anion [Pt(CO)3]2− was the unexpected result of a reaction between K6Rb6Ge17, Pt(CO)2(PPh3)2, [18]crown-6 and [2.2.2]-crypt. This compound represents the first example of a mononuclear carbonyl platinate and expands the list of known group 10 carbonyl metallates. The central anion has a trigonal planar shape with an approximate D3h symmetry. Theoretical investigations confirm the trigonal planar structure of the carbonylate and give insight into the electronic structure. The calculations reveal a strong charge density at the central platinum atom, while the HOMO shows a dispersion of the residual electrons under and over the carbonyl plane

Single Crystal X‐Ray Structure Analyses of Binary and Ternary Compounds A 49 Tl 108+x ( A =K, Rb, Cs; x=0–1.76) Related to the K 49 Tl 108 Type Structure

The structural chemistry of alkali metal thallides shows a broad range of type structures. At an alkali metal : thallium proportion A : Tl 1 : 2 the perceived dependency on the alkali metal involved is conspicuous. Two main structure types are reported with A15Tl27 (A=K, Rb, Cs) and K49Tl108. The compound K49K108 with a 3-dimensional Tl-substructure has been known since 1993 from Cordier and Müller but so far only with potassium. We here present single crystal X-Ray structure analyses of the compounds K49-yRbyTl108, and K49-yCsyTl108 (urn:x-wiley:00442313:media:zaac202200117:zaac202200117-math-0001 belonging to the K49Tl108 type structure. Additionally, structures of Rb49Tl109.67, Cs3.35Rb45.65Tl109.71 and Cs7.49Rb41.51Tl109.76 are introduced, which prove the possibility of Tl incorporation in the Tl12 icosahedra in K49Tl108 type structures. The effects of the change in alkali metals on the thallium substructure are discussed as well as the preferred Wyckoff sites of the different alkali metals

Accurate H-atom parameters for the two polymorphs of L-histidine at 5, 105 and 295 K

The crystal structure of the monoclinic polymorph of the primary amino acid l-histidine has been determined for the first time by single-crystal neutron diffraction, while that of the orthorhombic polymorph has been reinvestigated with an untwinned crystal, improving the experimental precision and accuracy. For each polymorph, neutron diffraction data were collected at 5, 105 and 295 K. Single-crystal X-ray diffraction experiments were also performed at the same temperatures. The two polymorphs, whose crystal packing is interpreted by intermolecular interaction energies calculated using the Pixel method, show differences in the energy and geometry of the hydrogen bond formed along the c direction. Taking advantage of the X-ray diffraction data collected at 5 K, the precision and accuracy of the new Hirshfeld atom refinement method implemented in NoSpherA2 were probed choosing various settings of the functionals and basis sets, together with the use of explicit clusters of molecules and enhanced rigid-body restraints for H atoms. Equivalent atomic coordinates and anisotropic displacement parameters were compared and found to agree well with those obtained from the corresponding neutron structural models

On the Role of Hydrogen Bonding in Gas-Phase S N 2 Reactions at Silicon

The shape of the potential energy surface (PES) of gas-phase SN2reactions at silicon is determined by the type of nucleophile, the leaving group, andsubstituents which remain bonded to silicon. In this study, we present PES scans alongthe reaction coordinate of six symmetrical SN2 reactions: X−+ SiR3X→XSiR3+X−,where X = Cl or F and R = H, Me, or OMe. While thefluorine systems and theClSiH3Cl system only give single-well PESs, ClSiMe3Cl and ClSi(OMe)3Cl give triple-and double-well PESs with stable pre- and post-reaction complexes. A complementarybonding analysis (energy decomposition analysis, quantum theory of atoms in molecules, and natural bond orbitals) reveals that theleaving group (X−) is stabilized by hydrogen bonding in the XSiMe3X and XSi(OMe)3X systems. It is shown that this so farneglected stabilizing contribution, along withσ-hole bonding, is responsible for the shapes of the PESs of ClSiMe3Cl andClSi(OMe)3Cl in the gas phase

Relativistic Hirshfeld atom refinement of an organo-gold(I) compound

The main goal of this study is the validation of relativistic Hirshfeld atom refinement (HAR) as implemented in Tonto for high-resolution X-ray diffraction datasets of an organo-gold(I) compound. The influence of the relativistic effects on statistical parameters, geometries and electron density properties was analyzed and compared with the influence of electron correlation and anharmonic atomic motions. Recent work in this field has indicated the importance of relativistic effects in the static electron density distribution of organo-mercury compounds. This study confirms that differences in electron density due to relativistic effects are also of significant magnitude for organo-gold compounds. Relativistic effects dominate not only the core region of the gold atom, but also influence the electron density in the valence and bonding region, which has measurable consequences for the HAR refinement model parameters. To study the effects of anharmonic motion on the electron density distribution, dynamic electron density difference maps were constructed. Unlike relativistic and electron correlation effects, the effects of anharmonic nuclear motion are mostly observed in the core area of the gold atom