There is a need for fast, efficient and accurate solid-state structure optimization for imprecise crystal structures (`augmentation') for subsequent property prediction in the pharmaceutical industry. Crystal structures from single-crystal X-ray, 3D electron or powder diffraction are widely available but require augmentation to the same quality level for comparative studies. Properties can be best calculated when the level of theory is alike and the accuracy, as well as the precision, are high. Moreover, the size of molecules and the complexity of structures encountered in pharmaceutical research are increasing. Efficient procedures are thus required that can also treat structures with disorder and several molecules in the asymmetric unit of the unit cell. Hence, we investigated whether `molecule-in-cluster' (MIC) computations [Dittrich et al. (2020). CrystEngComm 22, 7420-7431] can reach the accuracy of full-periodic (FP) computations. Selected quantum mechanical methods are assessed. The evaluation criterion is how well the structures of 22 very low temperature high-quality structures are reproduced. Computational efficiency is also considered. A novel approach to evaluating the accuracy of quantum mechanical predictions is enforcing computed structure-specific restraints in crystallographic least-squares refinements. To complement this approach, root mean square Cartesian displacements of computed and experimental structures were also compared. Analysis shows that (a) MIC DFT-D computations in a quantum mechanics/molecular mechanics (QM:MM) framework provide improved restraints and coordinates over earlier MIC GFN2-xTB computations, (b) increasing QM basis-set size in MIC QM:MM does not systematically improve computations, and (c) the choice of DFT functional is less important than the choice of the basis set. Overall, MIC computations are an accurate and computationally efficient tool for solid-state structure optimization that can match FP computations to augment experimental structures.

Two polymorphs of L-Asp-L-Asp-L-Asp (DDD) trihydrate as model compounds for biologically important proton-shuttle reactions were investigated with the quantum-crystallographic refinement technique Hirshfeld atom refinement (HAR). With HAR, hydrogen-atom positions are refined freely against the X-ray diffraction data and yield X-H bond distances close to those from neutron diffraction. However, the X-ray data of DDD trihydrate do not contain sufficient information to refine anisotropic displacement parameters (ADPs) for the hydrogen atoms, although the data quality is comparable to that of typical oligopeptide or protein datasets, including those with disordered fragments. Therefore, the following restraints were tested for the hydrogen-atom ADPs using NoSpherA2/olex2.refine: a restraint that approximates isotropic behaviour (ISOR), a restraint that enforces similar movement in any direction (SIMU), a rigid-bond restraint (DELU) and an advanced rigid-bond restraint (RIGU). Although it was found that there is no significant influence of the restraint weights and corresponding ADP values on the X-H distances, some recommendations on hydrogen-atom ADP restraint weights to be used in HAR are given. For ISOR, the suggested values are 10 times smaller (stricter) than the default values for non-hydrogen atoms in independent atom model (IAM) refinements, whereas those for RIGU are suggested to be less strict.

Categorization underlies understanding. Conceptualizing solid-state structures of organic molecules with `archetype crystal structures' bridges established categories of disorder, polymorphism and solid solutions and is herein extended to special position and high-Z' structures. The concept was developed in the context of disorder modelling [Dittrich, B. (2021). IUCrJ, 8, 305-318] and relies on adding quantum chemical energy differences between disorder components to other criteria as an explanation as to why disorder - and disappearing disorder - occurs in an average structure. Part of the concept is that disorder, as probed by diffraction, affects entire molecules, rather than just the parts of a molecule with differing conformations, and the finding that an R·T energy difference between disorder archetypes is usually not exceeded. An illustrative example combining disorder and special positions is the crystal structure of oestradiol hemihydrate analysed here, where its space-group/subgroup relationship is required to explain its disorder of hydrogen-bonded hydrogen atoms. In addition, we show how high-Z' structures can also be analysed energetically and understood via archetypes: high-Z' structures occur when an energy gain from combining different rather than overall alike conformations in a crystal significantly exceeds R·T, and this finding is discussed in the context of earlier explanations in the literature. Twinning is not related to archetype structures since it involves macroscopic domains of the same crystal structure. Archetype crystal structures are distinguished from crystal structure prediction trial structures in that an experimental reference structure is required for them. Categorization into archetype structures also has practical relevance, leading to a new practice of disorder modelling in experimental least-squares refinement alluded to in the above-mentioned publication.

Silicon is one of the most important components of electronic devices. Surface passivation of a silicon wafer is an active area of research. The Si(OH)2 sites of partially oxidized silicon surface could exist as hydroxylated [Si(OH)2] or hydrated silanone [SiO∙(OH2)]. The previously reported disiladicarbene (cAAC)2Si2 has been reacted here with water to obtain elusive, hydrated silanone (3) co-crystallized with its silanol analog (2) in a 1:3 molar ratio. The mass spectrometric characterization of acyclic silanone, followed by the isolation and characterization of the zwitterionic hydrated silanone, has been achieved. The detailed energy decomposition analysis coupled with natural orbital for chemical valence (EDA-NOCV) calculations revealed that the central Si(O)OH unit of the hydrated silanone possesses a covalent electron sharing σ- and a dative σ-bonds (CL−Si, Si←CL) with hydrogen-containing cyclic alkyl(amino) carbene ligands. These two bonds are stabilized by 49

The electron density distribution (EDD) of a plant cyclic nonapeptide of orbitide type was studied. Crystal X-ray diffraction data was obtained from the Cambridge Structural Database (CSD) and refitted using scattering factors of the invariom library, thereby providing aspherical electron density. Bond topological, atomic properties and molecular surfaces (electrostatic potential and Hirshfeld surfaces) were derived. The partial double bond character of the peptide bond was confirmed by the ellipticity epsilon = 0.25. For eight N-HMIDLINE HORIZONTAL ELLIPSISO hydrogen bonds, atomic charges of contributing atoms differ depending on the type of the accepting oxygen atom. Atomic charge differences between negative main and positive side chains of this nonapeptide result in characteristic features of the electrostatic potential, which shows a positive isosurface around the molecule leading to repulsive interactions in the solid state structure. Weak intermolecular interactions are indicated by insignificant ED concentrations on the Hirshfeld surface except for weak signals at sites of intermolecular N-H---O and C-H---O hydrogen bonds.

Abstract The electron density distribution (EDD) of a cyclic tetrasaccharide composed of four benzoylated galactopyranosyl units was calculated from refinement with scattering factors from the invariom library based on X-ray diffraction data downloaded from the Crystal Structural Data Base (CSD). Bond topological and atomic properties have been derived. Benzoyl substituents cause weak intermolecular interactions. These are also visible from low electron density concentrations on the Hirshfeld surface and have an influence on a low X-ray density compared to that of non-substituted carbohydrates, where hydrogen bonds allow a 20% more dense packing. On the electrostatic potential (ESP) surface, a strong polarization between the positive outer belt of 12 benzoyl groups and a negative core region composed of the four galactose sugar molecules exists. The positive benzoyl exterior establishes a repulsive wall between adjacent molecules in the structure.

Energy partitioning of pharmaceutical cocrystals by molecule-pair interaction and ONIOM energies identifies the driving force of their formation, leading to in silico conformational sampling for predicting API-cocrystal combinations for experiment.

Abstract The electron density of a 1:2 complex of valinomycin with calcium triflate consisting of 10 substructures and a total of 279 atoms was examined using the invariom formalism. In addition to geometric properties, sites and strengths of hydrogen bonds were identified from bond topological properties and from electron density concentrations mapped onto Hirshfeld surfaces. In contrast to free valinomycin and corresponding complexes with potassium the hydrogen bonds are all intermolecular and evenly distributed over the complex. A series of electrostatic potential (ESP) surfaces show the mutual influence in the ensemble of this high Z′ structure.

Abstract The electron density distribution (EDD) of a tetrasaccharide composed of four benzoylated fructopyranosyl units was obtained by refinement with scattering factors from the invariom library. X-ray diffraction data was downloaded from the Cambridge Structural Database (CSD). Bond topological and atomic properties were obtained by application of Bader’s QTAIM formalism. From a large number of 105 C–C bonds in the molecule average bond orders for 33 single and 72 aromatic bonds were calculated yielding values of 1.33 and 1.61. Molecular Hirshfeld and electrostatic potential (ESP) surfaces show that only weak non-covalent interactions exist. The phenyl rings of the benzoyl fragments in the outer regions of the molecule generate a positive ESP shell with repulsive properties between adjacent molecules. Weak surface interactions result in a rather unusual low density around 1.3 g cm−3, which is understandable when compared to other carbohydrates where strong O–H⋯O hydrogen bonds allow a 20% more dense packing with densities >1.5 g cm−3 as determined by single crystal X-ray diffraction.

Abstract Rotaxanes as well as catenanes are known as potential building blocks of molecular machines. The nanohoop [2]rotaxane investigated is composed of a macrocycle derived from a [6]cycloparaphenylene (CCP, designated as a carbon nanohoop), where one of the six para-linked phenyl rings is replaced by a 2,6-substituted pyridyl ring. This macrocycle is mechanically interlocked with a thread, a linear rod-shaped diyne fragment sitting in the cavity of the macrocycle. Two bulky 3,5-di-t-butyl-phenyl rests as end groups keep the thread fixed. The interplay between macrocycle and thread was examined by means of the electron density distribution (EDD) obtained by application of the invariom formalism, relying on X-ray diffraction data collected earlier. The so-obtained EDD was subjected to topological analysis using the QTAIM formalism. Moreover, molecular Hirshfeld and electrostatic potential (ESP) surfaces were calculated. The 73 C–C bonds were analysed in terms of bond topological properties. For the 46 single and the 22 aromatic bonds, the analysis gave average bond orders of 1.03 and 1.61. The five C–C bonds in the diyne fragment can clearly be distinguished into three types: formal triple bonds with bond orders above 3.0, arene bonds with bond orders of 1.6 and finally bond orders of 1.3 in the adjacent C–C bonds, which indicate a considerable electron delocalization in this fragment. Mapping the ED onto the Hirshfeld surfaces of the macrocycle and the thread does not show strong signals. This shows that in between the molecules only weak non-covalent interactions are present. The electrostatic potentials (ESPs) were mapped onto molecular EDD isosurfaces. For all phenyl rings, small regions of negative ESP are visible on the delocalized π systems. A potential gradient between the mostly positive ESP of the macrocycle and the diyne region of the thread exist, which can be considered the dominant force to hold this rotaxane together.

Distinguishing disorder into static and dynamic based on multi-temperature X-ray or neutron diffraction experiments is the current state of the art, but is only descriptive, not predictive. Here, several disordered structures are revisited from the Cambridge Crystallographic Data Center `drug subset', the Cambridge Structural Database and own earlier work, where experimental intensities of Bragg diffraction data were available. Using the molecule-in-cluster approach, structures with distinguishable conformations were optimized separately, as extracted from available or generated disorder models of the respective disordered crystal structures. Re-combining these `archetype structures' by restraining positional and constraining displacement parameters for conventional least-squares refinement, based on the optimized geometries, then often achieves a superior fit to the experimental diffraction data compared with relying on experimental information alone. It also simplifies and standardizes disorder refinement. Ten example structures were analysed. It is observed that energy differences between separate disorder conformations are usually within a small energy window of RT ( T = crystallization temperature). Further computations classify disorder into static or dynamic, using single experiments performed at one single temperature, and this was achieved for propionamide.

The photochemical activation of the C(sp)-C(sp2) bond in Pt(0)-η2-aryl-phosphaalkyne complexes leads selectively to coordination compounds of the type LnPt(aryl)(C≡P). The oxidative addition reaction is a novel, clean, and atom-economic route for the synthesis of reactive terminal Pt(II)-cyaphido complexes, which can undergo [3 + 2] cycloaddition reactions with organic azides, yielding the corresponding Pt(II)-triazaphospholato complexes. The C-C bond cleavage reaction is thermodynamically uphill. Upon heating, the reverse and quantitative reductive elimination toward the Pt(0)-phosphaalkyne-π-complex is observed.

The solid-state structures of three H-bonded enol forms of 5-substituted 9-hydroxyphenalenones were investigated to accurately determine the H atom positions of the intramolecular hydrogen bond. For this purpose, single-crystal X-ray diffraction (SC-XRD) data were evaluated by invariom-model refinement. In addition, QM/MM computations of central molecules in their crystal environment show that results of an earlier standard independent atom model refinement, which pointed to the presence of a resonance-assisted hydrogen bond in unsubstituted 9-hydroxyphenalone, are misleading: in all our three and the earlier solid-state structures the lowest energy form is that of an asymmetric hydrogen bond (C-s form). Apparent differences of results from SC-XRD and other analytical methods are explained.

Optimizing structures with computations on clusters of molecules permits generation of structure-specific restraints for refinement. Equally importantly, retrospective structure validation and addition of hydrogen atoms consistent with quantum chemistry is possible for experimental structures or the solvent molecules in them, should they be missing in earlier CIF depositions. Revisiting the drug subset structures of the CCDC demonstrates that structure validation through ab initio cluster computations is a tremendous validation tool. The time required for optimization can be similar to the time required to carry out least-squares refinement for small-molecule structures, and becomes feasible for large structures. Several questions arise: is it valid to augment experimental structures with structure-specific restraints, ideally through accompanying refinement with computation? Do energy minimized structures (using the experimental determinations as a starting point) still constitute an experimental result? When re-refinement is impossible in retrospect, like for most of the drug-subset molecules, then additional value lies in completion and validation of existing structures so that they are chemically and crystallographically correct, and contain missing water or solvent hydrogen atoms. Our results suggest that retroactive validation and addition of hydrogen atoms becomes possible for the entire Cambridge Structural Database. Generation of database entries of optimized alongside existing structures will provide the flexibility needed to make full use of the information gained by computation.

Disorder in crystal structures can disappear, depending on the circumstances, as shown by multi-temperature measurements, aspherical-atom refinement and computational analyses.

In this work, the synthesis of four new iron complexes with a Schiff base-like amphiphilic equatorial ligand (L) and dimethylaminopyridine (dmap) or 4,4'-bipyridine (bipy) as axial ligands is reported. Three of the complexes ([FeL(dmap)2] 1, [FeL(dmap)(MeOH)0.5]·MeOH 2, and [FeL(bipy)] n 3 have an iron(II) center, and two of those with an N4O2 coordination sphere (1 and 3) are spin crossover active. Both exhibit a thermal hysteresis (10 K with T1/2 = 131 K for 3 and 23 K with T1/2 = 161 K for 1) where the width depends on the velocity used for the measurement. Additionally, in both cases, the high spin state is trapped by rapid cooling, and a TTIESST was determined to be 121 K (1) and 101 K (3). Single crystals suitable for X-ray structure analysis were obtained for the three different complexes with dmap as axial ligand (1S, 2, and [μ-O-{FeL}2(dmap)] 4). The complex 1S has two dmap molecules in axial position, while the other two structures were obtained for a complex where a dmap ligand is exchanged by methanol and one where the iron(II) center is oxidized to iron(III) to form a dinuclear μ-O-complex. All three complexes were obtained under similar reaction conditions in the presence/absence of oxygen, and all three structures show the formation of lipid layer-like arrangements in the packing.