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.