The mechanism for H(2) cleavage in NiFe-hydrogenase has been reinvestigated with large models using both hybrid DFT by itself, or in a QM/MM scheme following the ONIOM approach. Heterolytic cleavage, with one hydrogen ending up as a bridging hydride and one as a proton on a cysteine ligand, was found to have a barrier slightly too high to be compatible with measured catalytic turnover rates. Alternative mechanisms were therefore investigated. In the finally suggested mechanism, heterolytic cleavage is used only as an initial step to generate a complex with nickel in oxidation state Ni(I). In the following cycles, H(2) is instead cleaved on nickel using an oxidative addition mechanism with a lower barrier. It was found that the ONIOM results for the reaction mechanism in NiFe-hydrogenase needed to be corrected by large model DFT results to be more reliable. This was mainly an effect of overestimation of polarization effects of the QM region by the MM region due to the particular treatment of the electrostatic interactions and the use of a standard (nonpolarizable) force field.

NMR crystallographic techniques are used to validate a structure of -piroxicam determined from powder X-ray diffraction (PXRD) with a relatively poor R-factor. Geometry optimisation of PXRD-and singlecrystal XRD-derived structures results in convergence to the same energy of the structures, with minimal atomic displacements, and good agreement of gauge-included projector augmented wave (GIPAW) calculated and experimentally determined NMR 1 H, 13 C and 15 N chemical shifts and 14 N quadrupolar parameters. Calculations on isolated molecules combined with 2D magic-angle spinning (MAS) 1 H doublequantum (DQ) and 14 N-1 H NMR experiments confirm the 3D packing arrangement of -piroxicam. NMR crystallography is shown to be an effective means of validating crystal structures that might otherwise be considered sceptically on the basis of diffraction data alone.

The Buchwald-Hartwig amination has been investigated theoretically and experimentally to examine the scope of possible bases under different reaction conditions. Nonpolar solvents resist the formation of new charges. Therefore, the base should be anionic to be able to deprotonate the neutral palladium-amine complex and/or expel the anionic leaving group (bromide). The calculated barrier for the organic base DBU was found to be prohibitively high. In polar solvent, dissociation of bromide becomes possible, but here the base will instead form a complex with palladium, creating an overly stable resting state. The conclusions for both solvent classes hold for both a hindered monodentate phosphine and the labile bidentate ligand BINAP. The computational studies were supported by experimental testing of a range of bases using BINAP in two different solvents, toluene and DMF.

Knowledge of the structure of amorphous solids can direct, for example, the optimization of pharmaceutical formulations, but atomic-level structure determination in amorphous molecular solids has so far not been possible. Solid-state nuclear magnetic resonance (NMR) is among the most popular methods to characterize amorphous materials, and molecular dynamics (MD) simulations can help describe the structure of disordered materials. However, directly relating MD to NMR experiments in molecular solids has been out of reach until now because of the large size of these simulations. Here, using a machine learning model of chemical shifts, we determine the atomic-level structure of the hydrated amorphous drug AZD5718 by combining dynamic nuclear polarization-enhanced solid-state NMR experiments with predicted chemical shifts for MD simulations of large systems. From these amorphous structures we then identify H-bonding motifs and relate them to local intermolecular complex formation energies.

A new efficient protocol for the nickel-catalyzed Heck reaction of aryl triflates with vinyl ethers is presented. Mild reaction conditions that equal those of the corresponding palladium-catalyzed Heck reaction are applied, representing a practical and more sustainable alternative to the conventional regioselective arylation of vinyl ethers. A catalytic system comprised of Ni(COD)(2) and 1,1'-bis(diphenylphosphino)ferrocene (DPPF) in combination with the tertiary amine Cy(2)NMe proved effective in the olefination of a wide range of aryl triflates. Both electron-deficient and electron-rich arenes proved compatible, and the corresponding aryl methyl ketone could be secured after hydrolysis in yields approaching quantitative. Good functional group tolerance was observed matching the characteristics of the analogous Pd-catalyzed Heck reaction. The high levels of catalytic activity were explained by the intermediacy of a cationic nickel(II) complex potentially responsible for the successive β-hydride elimination and base promoted catalyst regeneration. Although these elementary reactions are normally considered challenging, DFT calculations suggested this pathway to be favorable under the applied reaction conditions.

The transition states for methane activation in liquid superacid have been studied by experimentally determined secondary kinetic deuterium isotope effects (SKIEs) and computational chemistry. For the first time, the SKIEs on hydrogen/deuterium exchange of methane have been measured by using the methane isotopologues in homogeneous liquid superacid (2HF/SbF5). To achieve high accuracy of the SKIEs, the rate constants for pairs of methane isotopologues were simultaneously measured in the same superacid solution by using NMR spectroscopy. Density functional theory (DFT) and high-level ab initio methods have been employed to model possible intermediates and transition states, assuming that the superacids involved in the exchange reactions are H2F+ ions solvated by HF. Only the unsolvated superacid H2F+ is found to be strong enough to protonate methane, yielding the methonium ion solvated by HF as a potential energy minimum. In contrast, the (HF)x-solvated H2F+ superacids (x = 1-4) do not appear to be strong enough to yield stable solvated methonium ions. However, such ions show up as parts of the transition states of the exchange in which the methonium ions are solvated by (HF)x. The calculated DFT activation barrier is in good agreement with that experimentally observed.

The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion σ-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the σ-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.

The micronization process of new compounds is usually performed based on an empirical basis with a limited understanding of input material properties and potential challenges. This study focuses on the understanding of the fracture behavior of small organic molecular crystals, by using particle shape and surface energy analysis techniques as well as molecular modeling tools. These methodologies enable us to generate new data and new ways of working that can provide crucial information for future pharmaceutical development. The shape, surface energy, and mechanical properties for four different drug substances were studied. This study showed that the crystal shape and the intermolecular interactions influence the dominant fracture mechanism. An in-depth knowledge of these together with the mechanical properties gives an insight of the fracture mechanism of small organic molecular crystals. In a second part, Partial Least Squares regression was applied to the data sets to model the size reduction ratio and d 90 of the micronized materials. Models were derived using multiple parameters.