Reliable Dimerization Energies for Modeling of Supramolecular Junctions.

Accurate estimates of intermolecular interaction energy, ΔE, are crucial for modeling the properties of organic electronic materials and many other systems. For a diverse set of 50 dimers comprising up to 50 atoms (Set50-50, with 7 of its members being models of single-stacking junctions), benchmark ΔE data were compiled. They were obtained by the focal-point strategy, which involves computations using the canonical variant of the coupled cluster theory with singles, doubles, and perturbative triples [CCSD(T)] performed while applying a large basis set, along with extrapolations of the respective energy components to the complete basis set (CBS) limit. The resulting ΔE data were used to gauge the performance for the Set50-50 of several density-functional theory (DFT)-based approaches, and of one of the localized variants of the CCSD(T) method. This evaluation revealed that (1) the proposed "silver standard" approach, which employs the localized CCSD(T) method and CBS extrapolations, can be expected to provide accuracy better than two kJ/mol for absolute values of ΔE, and (2) from among the DFT techniques, computationally by far the cheapest approach (termed "ωB97X-3c/vDZP" by its authors) performed remarkably well. These findings are directly applicable in cost-effective yet reliable searches of the potential energy surfaces of noncovalent complexes.

On the Intermolecular Interactions in Thiophene-Cored Single-Stacking Junctions.

There have been attempts, both experimental and based on density-functional theory (DFT) modeling, at understanding the factors that govern the electronic conductance behavior of single-stacking junctions formed by pi-conjugated materials in nanogaps. Here, a reliable description of relevant stacked configurations of some thiophene-cored systems is provided by means of high-level quantum chemical approaches. The minimal structures of these configurations, which are found using the dispersion-corrected DFT approach, are employed in calculations that apply the coupled cluster method with singles, doubles and perturbative triples [CCSD(T)] and extrapolations to the complete basis set (CBS) limit in order to reliably quantify the strength of intermolecular binding, while their physical origin is investigated using the DFT-based symmetry-adapted perturbation theory (SAPT) of intermolecular interactions. In particular, for symmetrized S-Tn dimers (where "S" and "T" denote a thiomethyl-containing anchor group and a thiophene segment comprising "n" units, respectively), the CCSD(T)/CBS interaction energies are found to increase linearly with n ≤ 6, and significant conformational differences between the flanking 2-thiophene group in S-T1 and S-T2 are described by the CCSD(T)/CBS and SAPT/CBS computations. These results are put into the context of previous work on charge transport properties of S-Tn and other types of supramolecular junctions.

Quantifying the Intrinsic Strength of C-H⋯O Intermolecular Interactions.

It has been recognized that the C-H⋯O structural motif can be present in destabilizing as well as highly stabilizing intermolecular environments. Thus, it should be of interest to describe the strength of the C-H⋯O hydrogen bond for constant structural factors so that this intrinsic strength can be quantified and compared to other types of interactions. This description is provided here for C2h-symmetric dimers of acrylic acid by means of the calculations that employ the coupled-cluster theory with singles, doubles, and perturbative triples [CCSD(T)] together with an extrapolation to the complete basis set (CBS) limit. Dimers featuring the C-H⋯O and O-H⋯O hydrogens bonds are carefully investigated in a wide range of intermolecular separations by the CCSD(T)/CBS approach, and also by the symmetry-adapted perturbation theory (SAPT) method, which is based on the density-functional theory (DFT) treatment of monomers. While the nature of these two types of hydrogen bonding is very similar according to the SAPT-DFT/CBS calculations and on the basis of a comparison of the intermolecular potential curves, the intrinsic strength of the C-H⋯O interaction is found to be about a quarter of its O-H⋯O counterpart that is less than one might anticipate.

A Cost Effective Scheme for the Highly Accurate Description of Intermolecular Binding in Large Complexes.

There has been a growing interest in quantitative predictions of the intermolecular binding energy of large complexes. One of the most important quantum chemical techniques capable of such predictions is the domain-based local pair natural orbital (DLPNO) scheme for the coupled cluster theory with singles, doubles, and iterative triples [CCSD(T)], whose results are extrapolated to the complete basis set (CBS) limit. Here, the DLPNO-based focal-point method is devised with the aim of obtaining CBS-extrapolated values that are very close to their canonical CCSD(T)/CBS counterparts, and thus may serve for routinely checking a performance of less expensive computational methods, for example, those based on the density-functional theory (DFT). The efficacy of this method is demonstrated for several sets of noncovalent complexes with varying amounts of the electrostatics, induction, and dispersion contributions to binding (as revealed by accurate DFT-based symmetry-adapted perturbation theory (SAPT) calculations). It is shown that when applied to dimeric models of poly(3-hydroxybutyrate) chains in its two polymorphic forms, the DLPNO-CCSD(T) and DFT-SAPT computational schemes agree to within about 2 kJ/mol of an absolute value of the interaction energy. These computational schemes thus should be useful for a reliable description of factors leading to the enthalpic stabilization of extended systems.

Anisotropy, segmental dynamics and polymorphism of crystalline biogenic carboxylic acids.

Carboxylic acids of the Krebs cycle possess invaluable biochemical significance. Still, there are severe gaps in the availability of thermodynamic and crystallographic data, as well as ambiguities prevailing in the literature on the thermodynamic characterization and polymorph ranking. Providing an unambiguous description of the structure, thermodynamics and polymorphism of their neat crystalline phases requires a complex multidisciplinary approach. This work presents results of an extensive investigation of the structural anisotropy of the thermal expansion and local dynamics within these crystals, obtained from a beneficial cooperation of NMR crystallography and ab initio calculations of non-covalent interactions. The observed structural anisotropy and spin-lattice relaxation times are traced to large spatial variations in the strength of molecular interactions in the crystal lattice, especially in the orientation of the hydrogen bonds. A completely resolved crystal structure for oxaloacetic acid is reported for the first time. Thanks to multi-instrumental calorimetric effort, this work clarifies phase behavior, determines third-law entropies of the crystals, and states definitive polymorph ranking for succinic and fumaric acids. These thermodynamic observations are then interpreted in terms of first-principles quasi-harmonic calculations of cohesive properties. A sophisticated model capturing electronic, thermal, and configurational-entropic effects on the crystal structure approaches captures the subtle Gibbs energy differences governing polymorph ranking for succinic and fumaric acids, representing another success story of computational chemistry.

A computational inspection of the dissociation energy of mid-sized organic dimers.

The gas-phase value of the dissociation energy (D0) is a key parameter employed in both experimental and theoretical descriptions of noncovalent complexes. The D0 data were obtained for a set of mid-sized organic dimers in their global minima which was located using geometry optimizations that applied ample basis sets together with either the conventional second-order Møller-Plesset (MP2) method or several dispersion-corrected density-functional theory (DFT-D) schemes. The harmonic vibrational zero-point (VZP) and deformation energies from the MP2 calculations were combined with electronic energies from the coupled cluster theory with singles, doubles, and iterative triples [CCSD(T)] extrapolated to the complete basis set (CBS) limit to estimate D0 with the aim of inspecting values that were most recently measured, and an analogous comparison was performed using the DFT-D data. In at least one case (namely, for the aniline⋯methane cluster), the D0 estimate that employed the CCSD(T)/CBS energies differed from experiment in the way that could not be explained by a possible deficiency in the VZP contribution. Curiously, one of the DFT-D schemes (namely, the B3LYP-D3/def2-QZVPPD) was able to reproduce all measured D0 values to within 1.0 kJ/mol from experimental error bars. These findings show the need for further measurements and computations of some of the complexes. In order to facilitate such studies, the physical nature of intermolecular interactions in the investigated dimers was analyzed by means of the DFT-based symmetry-adapted perturbation theory.

Enantiotropy of Simvastatin as a Result of Weakened Interactions in the Crystal Lattice: Entropy-Driven Double Transitions and the Transient Modulated Phase as Seen by Solid-State NMR Spectroscopy.

In crystalline molecular solids, in the absence of strong intermolecular interactions, entropy-driven processes play a key role in the formation of dynamically modulated transient phases. Specifically, in crystalline simvastatin, the observed fully reversible enantiotropic behavior is associated with multiple order-disorder transitions: upon cooling, the dynamically disordered high-temperature polymorphic Form I is transformed to the completely ordered low-temperature polymorphic Form III via the intermediate (transient) modulated phase II. This behavior is associated with a significant reduction in the kinetic energy of the rotating and flipping ester substituents, as well as a decrease in structural ordering into two distinct positions. In transient phase II, the conventional three-dimensional structure is modulated by periodic distortions caused by cooperative conformation exchange of the ester substituent between the two states, which is enabled by weakened hydrogen bonding. Based on solid-state NMR data analysis, the mechanism of the enantiotropic phase transition and the presence of the transient modulated phase are documented.

Modeling the Structure of Crystalline Alamethicin and Its NMR Chemical Shift Tensors.

Alamethicin (ALM) is an antimicrobial peptide that is frequently employed in studies of the mechanism of action of pore-forming molecules. Advanced techniques of solid-state NMR spectroscopy (SSNMR) are important in these studies, as they are capable of describing the alignment of helical peptides, such as ALM, in lipid bilayers. Here, it is demonstrated how an analysis of the SSNMR measurements can benefit from fully periodic calculations, which employ the plane-wave density-functional theory (PW DFT) of the solid-phase geometry and related spectral parameters of ALM. The PW DFT calculations are used to obtain the structure of desolvated crystalline ALM and predict the NMR chemical shift tensors (CSTs) of its nuclei. A variation in the CSTs of the amidic nitrogens and carbonyl carbons along the ALM backbone is evaluated and included in simulations of the orientation-dependent anisotropic 15N and 13C chemical shift components. In this way, the influence of the site-specific structural effects on the experimentally determined orientation of ALM is shown in models of cell membranes.

Reconstructing Reliable Powder Patterns from Spikelets (Q)CPMG NMR Spectra: Simplification of UWNMR Crystallography Analysis.

Spikelets NMR spectra are very popular as they enable the shortening of experimental time and give the possibility to obtain required NMR parameters for nuclei with ultrawide NMR patterns. Unfortunately, these resulted ssNMR spectra cannot be fitted directly in common software. For this reason, we developed UWNMRSpectralShape (USS) software which transforms spikelets NMR patterns into single continuous lines. Subsequently, these reconstructed spectral envelopes of the (Q)CPMG spikelets patterns can be loaded into common NMR software and automatically fitted, independently of experimental settings. This allows the quadrupole and chemical shift parameters to be accurately determined. Moreover, it makes fitting of spikelets NMR spectra exact, fast and straightforward.

Structural Changes of Sodium Warfarin in Tablets Affecting the Dissolution Profiles and Potential Safety of Generic Substitution.

At present, the risk of generic substitutions in warfarin tablets is still being discussed. The aim of this study was to assess whether API interactions with commonly used excipients may affect the safety of generic replacement of warfarin sodium tablets. These interactions were observed during an accelerated stability study, and the effect of the warfarin solid phase (crystalline/amorphous form) as well as the API particle size distribution was studied. Commercial tablets and prepared tablets containing crystalline warfarin or amorphous warfarin were used. In addition, binary mixtures of warfarin with various excipients were prepared. The structural changes before and after the stability study were monitored by dissolution test in different media, solid-state NMR spectroscopy and Raman microscopy. During the stability study, the conversion of the sodium in warfarin to its acid form was demonstrated by some excipients (e.g., calcium phosphate). This change in the solid phase of warfarin leads to significant changes in dissolution, especially with the different particle sizes of the APIs in the tablet. Thus, the choice of suitable excipients and particle sizes are critical factors influencing the safety of generic warfarin sodium tablets.

On the Many-Body Expansion of an Interaction Energy of Some Supramolecular Halogen-Containing Capsules.

A tetramer model was investigated of a remarkably stable iodine-containing supramolecular capsule that was most recently characterized by other authors, who described emergent features of the capsule's formation. In an attempt to address the surprising fact that no strong pair-wise interactions between any of the respective components were experimentally detected in condensed phases, the DFT (density-functional theory) computational model was used to decompose the total stabilization energy as a sum of two-, three- and four-body contributions. This model considers complexes formed between either iodine or bromine and the crucial D4d-symmetric form of octaaryl macrocyclic compound cyclo[8](1,3-(4,6-dimethyl)benzene that is surrounded by arenes of a suitable size, namely, either corannulene or coronene. A significant enthalpic gain associated with the formation of investigated tetramers was revealed. Furthermore, it is shown that the total stabilization of these complexes is dominated by binary interactions. Based on these findings, comments are made regarding the experimentally observed behavior of related multicomponent mixtures.

A Volumetric Analysis of the 1H NMR Chemical Shielding in Supramolecular Systems.

The liquid state NMR chemical shift of protons is a parameter frequently used to characterize host-guest complexes. Its theoretical counterpart, that is, the 1H NMR chemical shielding affected by the solvent (1H CS), may provide important insights into spatial arrangements of supramolecular systems, and it can also be reliably obtained for challenging cases of an aggregation of aromatic and antiaromatic molecules in solution. This computational analysis is performed for the complex of coronene and an antiaromatic model compound in acetonitrile by employing the GIAO-B3LYP-PCM approach combined with a saturated basis set. Predicted 1H CS values are used to generate volumetric data, whose properties are thoroughly investigated. The 1H CS isosurface, corresponding to a value of the proton chemical shift taken from a previous experimental study, is described. The presence of the 1H CS isosurface should be taken into account in deriving structural information about supramolecular hosts and their encapsulation of small molecules.

Parametrizing the Spatial Dependence of 1H NMR Chemical Shifts in π-Stacked Molecular Fragments.

Most recently a renewed interest in several areas has arisen in factors governing the 1H NMR chemical shift (1H CS) of protons in aromatic systems. Therefore, it is important to describe how 1H CS values are affected by π-stacking intermolecular interactions. The parametrization of radial and angular dependences of the 1H CS is proposed, which is based on conventional gauge-independent atomic orbital (GIAO) calculations of explicit molecular fragments. Such a parametrization is exemplified for a benzene dimer with intermonomer vertical and horizontal distances which are in the range of values often found in crystals of organic compounds. Results obtained by the GIAO calculations combined with B3LYP and MP2 methods were compared, and revealed qualitatively the same trends in the 1H CS data. The parametrization was found to be quantitatively correct for the T-shaped benzene dimers, and its limitations were discussed. Parametrized 1H CS surfaces should become useful for providing additional restraints in the search of site-specific information through an analysis of structurally induced 1H CS changes.

Gallium Species Incorporated into MOF Structure: Insight into the Formation of a 3D Polycrystalline Gallium-Imidazole Framework.

The formation of a polycrystalline 3D gallium-imidazole framework (MOF) was closely studied in three steps using ssNMR, XRPD, and TGA. In all steps, the reaction products show relatively high temperature stability up to 500 °C. The final product was examined by structural analysis using NMR crystallography combined with TG and BET analyses, which enabled a detailed characterization of the polycrystalline MOF system on the atomic-resolution level. 71Ga ssNMR spectra provided valuable structural information on the coexistence of several distinct gallium species, including a tunable liquid phase. Moreover, using an NMR crystallography approach, two structurally asymmetric units of Ga(Im6)6- incorporated into the thermally stable polycrystalline 3D matrix were identified. Prepared polycrystalline MOF material with polymorphic gallium species is promising for use in catalytic processes.

Chelating Polymers for Hereditary Hemochromatosis Treatment.

Hemochromatosis (iron overload) encompasses a group of diseases that are characterized by a toxic hyperaccumulation of iron in parenchymal organs. Currently, only few treatments for this disease have been approved; however, all these treatments possess severe side effects. In this study, a paradigm for hemochromatosis maintenance/preventive therapy is investigated: polymers with negligible systemic biological availability form stable complexes with iron ions in the gastrointestinal tract, which reduces the biological availability of iron. Macroporous polymer beads are synthesized with three different iron-chelating moieties (benzene-1,2-diol, benzene-1,2,3-triol, and 1,10-phenanthroline). The polymers rapidly chelate iron ions from aqueous solutions in vitro in the course of minutes, and are noncytotoxic and nonprooxidant. Moreover, the in vivo biodistribution and pharmacokinetics show a negligible uptake from the gastrointestinal tract (using 125 I-labeled polymer and single photon emission computed tomography/computed tomography), which generally prevents them from having systemic side effects. The therapeutic efficacy of the prepared polymers is successfully tested in vivo, and exhibits a significant inhibition of iron uptake from the gastrointestinal tract without any noticeable signs of toxicity. Furthermore, an in silico method is developed for the prediction of chelator selectivity. Therefore, this paradigm can be applied to the next-generation maintenance/preventive treatment for hemochromatosis and/or other diseases of similar pathophysiology.

Transferring Lithium Ions in the Nanochannels of Flexible Metal-Organic Frameworks Featuring Superchaotropic Metallacarborane Guests: Mechanism of Ionic Conductivity at Atomic Resolution.

Metal-organic frameworks (MOFs), owing to their unique architecture, attract consistent attention in the design of high-performance Li battery materials. Here, we report a new category of ion-conducting crystalline materials for all-solid-state electrolytes based on an MIL53(Al) framework featuring a superchaotropic metallacarborane (Li+CoD-) salt and present the first quantitative data on Li+ ion sites, local dynamics, chemical exchange, and the formation of charge-transfer pathways. We used multinuclear solid-state nuclear magnetic resonance (ss-NMR) spectroscopy to examine the mechanism of ionic conductivity at atomic resolution and to elucidate order-disorder processes, framework-ion interactions, and framework breathing during the loading of Li+CoD- species and transfer of Li+ ions. In this way, the MIL53(Al)@LiCoD framework was found to adopt an open-pore conformation accompanied by a minor fraction of narrow-pore channels. The inserted Li+ ions have two states (free and bound), which both exhibit extensive motions. Both types of Li+ ions form mutually communicating chains, which are large enough to enable efficient long-range charge transfer and macroscopic conductivity. The superchaotropic anions undergo high-amplitude uniaxial rotation motions supporting the transfer of Li+ cations along them, while the fluctuations of MOF aromatic linkers support the penetration of Li+ through the channel walls. Our findings provide a detailed atomic-resolution insight into the mechanism of ionic conductivity and thus have significant implications for the design of the next generation of energy-related materials.

Polymorphic Forms of Valinomycin Investigated by NMR Crystallography.

A dodecadepsipeptide valinomycin (VLM) has been most recently reported to be a potential anti-coronavirus drug that could be efficiently produced on a large scale. It is thus of importance to study solid-phase forms of VLM in order to be able to ensure its polymorphic purity in drug formulations. The previously available solid-state NMR (SSNMR) data are combined with the plane-wave DFT computations in the NMR crystallography framework. Structural/spectroscopical predictions (the PBE functional/GIPAW method) are obtained to characterize four polymorphs of VLM. Interactions which confer a conformational stability to VLM molecules in these crystalline forms are described in detail. The way how various structural factors affect the values of SSNMR parameters is thoroughly analyzed, and several SSNMR markers of the respective VLM polymorphs are identified. The markers are connected to hydrogen bonding effects upon the corresponding (13C/15N/1H) isotropic chemical shifts of (CO, Namid, Hamid, Hα) VLM backbone nuclei. These results are expected to be crucial for polymorph control of VLM and in probing its interactions in dosage forms.

Monitoring the Site-Specific Solid-State NMR Data in Oligopeptides.

Reliable values of the solid-state NMR (SSNMR) parameters together with precise structural data specific for a given amino acid site in an oligopeptide are needed for the proper interpretation of measurements aiming at an understanding of oligopeptides' function. The periodic density functional theory (DFT)-based computations of geometries and SSNMR chemical shielding tensors (CSTs) of solids are shown to be accurate enough to support the SSNMR investigations of suitably chosen models of oriented samples of oligopeptides. This finding is based on a thorough comparison between the DFT and experimental data for a set of tripeptides with both 13Cα and 15Namid CSTs available from the single-crystal SSNMR measurements and covering the three most common secondary structural elements of polypeptides. Thus, the ground is laid for a quantitative description of local spectral parameters of crystalline oligopeptides, as demonstrated for the backbone 15Namid nuclei of samarosporin I, which is a pentadecapeptide (composed of five classical and ten nonproteinogenic amino acids) featuring a strong antimicrobial activity.

Interaction Pathways and Structure-Chemical Transformations of Alginate Gels in Physiological Environments.

The remarkably diverse affinity of alginate (ALG) macromolecules for polyvalent metal ions makes cross-linked alginate gels an outstanding biomaterial. Surprisingly, however, very little is known about their interactions and structural transformations in physiological environments. To bridge this gap, we prepared a set of ALG gels cross-linked by various ions and monitored their structural changes at different media simulating gastric and intestinal fluids and cellular environments. For these studies, we used multinuclear solid-state NMR (ss-NMR) spectroscopy, which revealed a range of competitive ion-exchange and interconversion reactions, the rate of which strongly depended on the nature of the cross-linking metal ions. Depending on the environment, ALG chains adopted different forms, such as acidic (hydro)gels stabilized by strong hydrogen bonds, and/or weakly cross-linked Na/H-gels. Simultaneously, the exchanged polyvalent ions extensively interacted with the environment even forming in some cases insoluble phosphate microdomains directly deposited in the ALG bead matrix. The extent of the transformations and incorporation of secondary phases into the alginate beads followed the size and electronegativity of the cross-linking ions. Overall, the applied combination of various macroscopic and biological tests with multinuclear ss-NMR revealed a complex pathway of alginate beads transformations in physiological environments.

Exploring Accuracy Limits of Predictions of the 1H NMR Chemical Shielding Anisotropy in the Solid State.

The 1H chemical shielding anisotropy (CSA) is an NMR parameter that is exquisitely sensitive to the local environment of protons in crystalline systems, but it is difficult to obtain it experimentally due to the need to concomitantly suppress other anisotropic interactions in the solid-state NMR (SSNMR) pulse sequences. The SSNMR measurements of the 1H CSA are particularly challenging if the fast magic-angle-spinning (MAS) is applied. It is thus important to confront the results of both the single-crystal (SC) and fast-MAS experiments with their theoretical counterparts. Here the plane-waves (PW) DFT calculations have been carried out using two functionals in order to precisely characterize the structures and the 1H NMR chemical shielding tensors (CSTs) of the solid forms of maleic, malonic, and citric acids, and of L-histidine hydrochloride monohydrate. The level of agreement between the PW DFT and either SC or fast-MAS SSNMR 1H CSA data has been critically compared. It has been found that for the eigenvalues of the 1H CSTs provided by the fast-MAS measurements, an accuracy limit of current PW DFT predictions is about two ppm in terms of the standard deviation of the linear regression model, and sources of this error have been thoroughly discussed.