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Acta Cryst. (2014). A70, C286
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"Anisotropic parametrisation of the thermal displacements of hydrogen atoms in single-crystal X-ray structure refinement is not possible with independent atom model (IAM) scattering factors. This is due to the weak scattering contribution of hydrogen atoms. Only when aspherical scattering factors are used can carefully measured Bragg data provide such information. For conventional structure determinations parameters of ""riding"" hydrogen atoms are frequently constrained to values of their ""parent"" heavy atom. Usually values of 1.2 and 1.5 times X-U_eq are assigned to H-U_iso in these cases. Such constraints yield reasonable structural models for room-temperature data. However, todays small molecule X-Ray diffraction experiments are usually carried out at significantly lower temperatures. To further study the temperature dependence of ADPs we have evaluated several data sets of N-Acetyl-L-4-Hydroxyproline Monohydrate at temperatures ranging from 9 K to 250 K. Methods compared were HAR [1], Invariom refinement [2], time-of-flight Neutron diffraction and the TLS+ONIOM approach [3]. In the TLS+ONIOM approach non-hydrogen ADPs from Invariom refinement provided ADPs for the TLS-fit. Hydrogen atoms in all methods were grouped and analyzed according to their Invariom name. We reach a good agreement of the temperature dependence of H-U_iso/X-U_eq. At very low temperatures the ratio H-U_iso/X-U_eq can be as high as 4, e.g. for Hydrogen attached to a sp3 carbon atom with three non-Hydrogen atom neighbors. Since all methods consistently show that the H-U_iso/X-U_eq ratio is temperature dependent, this effect should be taken into account in conventional structure determinations."

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The temperature dependence of hydrogen Uiso and parent Ueq in the riding hydrogen model is investigated by neutron diffraction, aspherical-atom refinements and QM/MM and MO/MO cluster calculations. Fixed values of 1.2 or 1.5 appear to be underestimated, especially at temperatures below 100 K.

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Acta Cryst. (2014). A70, C965
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The determination of the absolute configuration for light-atom structures is central to research in pharmaceuticals and natural-product synthesis [1]. In the absence of elements heavier than silicon, it is often problematic to make a significant assignment of absolute configuration. Traditionally, heavy-atom derivatives were prepared which have a stronger anomalous signal compared to the native compound. However, this is not always feasible. The assignment of the absolute structure of pure organic compounds has become somewhat easier with the advent of high-intensity microfocus sources [2], as the increased flux density improves the anomalous signal through improvements in counting statistics. In order to maximize the anomalous signal, X-ray sources with Cu anodes are usually used for the absolute structure determination. However, these data are usually limited to a maximum resolution of about 0.80 Å. High-brilliance microfocus X-ray sources with Mo targets enable the collection of high quality data beyond 0.40 Å within a reasonable amount of time. This allows not only a more accurate modelling of the electron density by using aspherical scattering factors, but also enables a reliable determination of the absolute structure, despite the significantly lower anomalous signal obtained with Mo Kα radiation. With the recently introduced liquid-Gallium-jet X-ray source unprecedented beam intensities can be achieved [3]. The shorter wavelength of Ga Kα compared to Cu Kα slightly weakens the anomalous signal of a typical light-atom structure. However, due to the shorter wavelength, the highest resolution for the liquid metal-jet source is typically at about 0.70 Å, compared to about 0.80 Å for Cu Kα. Hence, about 50% more unique reflections can be recorded. This clearly improves the structural model and the quality of the Flack parameter. Selected results on the absolute structure and charge density determinations for light-atom structures will be presented.

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Acta Cryst. (2014). A70, C969
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The average age of people is increasing continuously thanks to the progress in the medicinal sciences and further social advances. As a consequence, however, diseases which affect people more likely at a higher age also increase. In this course Alzheimer's disease (AD) and related brain disorders distribute rapidly and have to be taken more serious. One of the most frequently applied drugs against AD is donepezil®. Its function is a reversible inhibition of acetylcholinesterase (AChE), thereby reducing the deficit of acetylcholine associated with the occurrence of AD. As one result from the charge density (CD) of the small-molecule structure containing the donepezilium cation comparable electronic interactions were identified as in the macromolecular TcAChE-donepezil complex which were made visible by electrostatic potential and Hirshfeld surfaces.[1] Two newer developments of Alzheimer agents are bexarotene and methylene blue. For the first one a therapeutic effect on AD in a mouse model was recently reported. From a comparative CD study on bexarotene and its disila analogue differences in the electrostatic potentials were identified, while the spherical structures showed no significant differences. The second one, methylene blue, targets the abnormal tangle type tau protein aggregation inside the nerve cells in the brain and stops its spread. The molecule is positively charged with various counterions. From the CD an answer to the not yet understood question is expected whether the formal positive charge is localized or delocalized.

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Acta Cryst. (2014). A70, C973
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The invariom database [1] is known to provide aspherical scattering factors for atoms in different chemical environments. It contains more than 1450 geometry optimized model compounds. Underlying the database is a formalism of assigning the atoms according to their local bonding situation. An atom in such a specific intramolecular environment is called an invariom (invariant atom) because the properties related to it are invariant of the molecule. Besides aspherical scattering factors this formalism, combined with a model compound database, automatically provides point charges for atoms in common organic compounds as soon as 3D-coordinates are available. This could be especially useful for improving molecular mechanics simulations based on force fields like AMBER [2] in drug development, where point charges often have to be established manually. The invariom classification accounts for a more detailed description than a general atom force field, especially for hydrogen atoms. These are closest to the molecular surface and have a big impact on intermolecular interactions. Since the database already contains optimized structures of model compounds and their electron density, it only takes a restrained fit to the electrostatic potential (resp) [3] to obtain charges, which were designed to be transferable and are therefore ideally suited for application in force fields. Amber suggests the use of hf/6-31g* resp computations. The model compounds in the invariom database have been optimized using more extensive basis sets and DFT (M06/TZVP). A revision of the database that can in principle cover elements up to Krypton will be provided. Results from invariom point charges are compared with those from existing methods. Furthermore, some improvements to the invariom notation will be discussed.

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Acta Cryst. (2014). A70, C1346
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"Element assignment in single-crystal X-ray diffraction (XRD) is based on the number of electrons of a particular atom, so that neighboring elements in the periodic table are often hard to distinguish. 3d-block carbene complexes, e.g. [1], provide examples where the situation is even worse: use of the independent-atom model (IAM) leads to significantly better figures of merit for the element left to the correct one in the periodic table, and the element can hence not be identified by XRD using the IAM without prior chemical knowledge. This is readily explained by the characteristics of the ligand, which can cause electron-deficiency at the metal center. Hence Cu instead of Zn gives a significantly better fit to the diffraction data in the IAM in our example, although the heavier element is unambiguously present. Rearrangements in the aspherical valence electron-density distribution (EDD) hence forbid to reliably distinguish and to correctly identify the metal atom in such coordination compounds with conventional methodology, whereas aspherical scattering factors allow a correct assignment. These findings clearly illustrate the need to sometimes go beyond ""spherical-atoms"". We show how ""whole molecule"" aspherical scattering factors derived from theoretical computations within the Hansen/Coppens mutlipole model EDD description [2a] can be successfully used in least-squares refinement. A related approach is Hirshfeld-atom refinement [2b], but for network structures, disordered molecules and those with atoms on special positions this approach is not always technically feasible. The suggested modeling procedure is based on the invariom database [3] and its capability to predict quantum chemical X-H bond distances involving hydrogen, and is amenable to d-block compounds where all-electron calculations are possible. Due to the important role of aspherical EDD in the vicinity of the central atom we expect that similar behavior will occur in linear and square-planar, but not in tetrahedral and octahedral coordination."
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