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The topic of ionic liquids is typically not taught at the undergraduate level. Many properties, such as conductivity, vapor pressure, and viscosity, of these so-called "green solvents" are unique compared to traditional molecular solvents. Using active learning techniques, we introduced an ionic liquid module in the physical chemistry laboratory where their structures and physical properties, namely, viscosity, conductivity, and vapor pressure, were explored in relation to molecular solvents. Summative and formative assessments show that a majority of the participants were able to grasp the key concepts of ionic liquids. We envision that our methods and strategies can be one of the building blocks of introducing ionic liquids into the undergraduate chemistry curriculum.

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The development of more efficient and sustainable methods for synthesizing substituted urea compounds and directly utilizing CO2 has long been a major focus of synthetic organic chemistry as these compounds serve critical environmental and industrial roles. Herein, we report a green approach to forming the urea compounds directly from CO2 gas and primary amines, triggered by oxygen electroreduction in ionic liquids (ILs). These reactions were carried out under mild conditions, at very low potentials, and achieved high conversion rates. The fact that O2 gas was utilized as the sole catalyst in this electrochemical loop, without additional reagents, is a significant milestone for eco-friendly syntheses of C-N compounds and establishes an effective and green CO2 scavenging method.

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The synthesis and crystal structures of the isomeric mol-ecular salts 2-, 3- and 4-cyano-1-methyl-pyridinium hexa-fluorido-phosphate, C7H7N2+·PF6-, are reported. In 2-cyano-1-methyl-pyridinium hexa-fluorido-phosphate, C-H⋯F hydrogen bonds form chains extending along the c-axis direction, which are associated through C-H⋯F hydrogen bonds and P-F⋯π(ring) inter-actions into stepped layers. For 3-cyano-1-methyl-pyridinium hexa-fluorido-phosphate, corrugated sheets parallel to [001] are generated by C-H⋯F hydrogen bonds and P-F⋯π(ring) inter-actions. The sheets are weakly associated by a weak inter-action of the cyano group with the six-membered ring of the cation. In 4-cyano-1-methyl-pyridinium hexa-fluorido-phosphate, C-H⋯F hydrogen bonds form a more open three-dimensional network in which stacks of cations and of anions are aligned with the b-axis direction. Dispersion-corrected density functional theory (DFT-D) calculations were carried out in order to elucidate some of the energetic aspects of the solid-state structures. The results indicate that the distribution of charge within a mol-ecular ionic cation can play a large role in determining the strength of a cation-anion inter-action within a crystal structure. Crystals of 2-cyano-1-methyl-pyridinium hexa-fluorido-phosphate are twinned by a 180° rotation about the c* axis. The anion in 3-cyano-1-methyl-pyridinium hexa-fluorido-phosphate is rotationally disordered by 38.2 (1)° in an 0.848 (3):0.152 (3) ratio.

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Halogen bonds involving cationic halogen bond donors and anionic halogen bond acceptors have recently been recognized as being important in stabilizing the crystal structures of many salts. Theoretical characterization of these types of interactions, most importantly in terms of their directionality, has been limited. Here we generate high-quality symmetry adapted perturbation theory potential energy curves of a H3N-C[triple bond, length as m-dash]C-Br+Cl- model system in order to characterize halogen bonds involving charged species, in terms of contributions from electrostatics, exchange, induction, and dispersion, with special emphasis on analyzing contributions that are most responsible for the directionality of these interactions. It is found that, as in the case of neutral halogen bonds, exchange forces are important contributors to the directionality of charged halogen bonds, however, it is also found that induction effects, which contribute little to the stability and directionality of neutral halogen bonds, play a large role in the directionality of halogen bonds involving charged species. Potential energy curves based on the ωB97X-D/def2-TZVP/C-PCM method, which includes an implicit solvation model in order to mimic the effects of the crystal medium, are produced for both the H3N-C[triple bond, length as m-dash]C-Br+Cl- model system and for the 4-bromoaniliniumCl- dimer, which is based on the real 4-bromoanilinium chloride salt, whose crystal structure has been determined experimentally. It is found that, within a crystal-like medium, charged halogen bond are significantly weaker than in the gas phase, having optimum interaction energies up to approximately -20 kcal mol-1.

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BACKGROUND: While current therapies for osteoporosis focus on reducing bone resorption, the development of therapies to regenerate bone may also be beneficial. Promising anabolic therapy candidates include phytoestrogens, such as daidzein, which effectively induce osteogenesis of adipose-derived stromal cells (ASCs) and bone marrow stromal cells (BMSCs). PURPOSE: To investigate the effects of glyceollins, structural derivatives of daidzein, on osteogenesis of ASCs and BMSCs. STUDY DESIGN: Herein, the osteoinductive effects of glyceollin I and glyceollin II were assessed and compared to estradiol in ASCs and BMSCs. The mechanism by which glyceollin II induces osteogenesis was further examined. METHODS: The ability of glyceollins to promote osteogenesis of ASCs and BMSCs was evaluated in adherent and scaffold cultures. Relative deposition of calcium was analyzed using Alizarin Red staining, Bichinchoninic acid Protein Assay, and Alamar Blue Assay. To further explore the mechanism by which glyceollin II exerts its osteoinductive effects, docking studies of glyceollin II, RNA isolation, cDNA synthesis, and quantitative RT-PCR (qPCR) were performed. RESULTS: In adherent cultures, ASCs and BMSCs treated with estradiol, glyceollin I, or glyceollin II demonstrated increased calcium deposition relative to vehicle-treated cells. During evaluation on PLGA scaffolds seeded with ASCs and BMSCs, glyceollin II was the most efficacious in inducing ASC and BMSC osteogenesis compared to estradiol and glyceollin I. Dose-response analysis in ASCs and BMSCs revealed that glyceollin II has the highest potency at 10nM in adherent cultures and 1µM in tissue scaffold cultures. At all doses, osteoinductive effects were attenuated by fulvestrant, suggesting that glyceollin II acts at least in part through estrogen receptor-mediated pathways to induce osteogenesis. Analysis of gene expression demonstrated that, similar to estradiol, glyceollin II induces upregulation of genes involved in osteogenic differentiation. CONCLUSION: The ability of glyceollin II to induce osteogenic differentiation in ASCs and BMSCs indicates that glyceollins hold the potential for the development of pharmacological interventions to improve clinical outcomes of patients with osteoporosis.

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Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism. This review provides a summary of known endogenous, naturally occurring, and synthetic ligands. The review also offers considerations from a molecular modeling perspective with which to design more specific LXRß ligands based on the interaction energies of ligands and the important amino acid residues in the LXRß ligand binding domain.

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Halogen bonds involving an aromatic moiety as an acceptor, otherwise known as R-X⋅⋅⋅π interactions, have increasingly been recognized as being important in materials and in protein-ligand complexes. These types of interactions have been the subject of many recent investigations, but little is known about the ways in which the strengths of R-X⋅⋅⋅π interactions vary as a function of the relative geometries of the interacting pairs. Here we use the accurate CCSD(T) and SAPT2+3δMP2 methods to investigate the potential energy landscapes for systems of HBr, HCCBr, and NCBr complexed with benzene. It is found that only the separation between the complexed molecules have a strong effect on interaction strength while other geometric parameters, such as tilting and shifting R-Br⋅⋅⋅π donor relative to the benzene plane, affect these interactions only mildly. Importantly, it is found that the C6v (T-shaped) configuration is not the global minimum for any of the dimers investigated.

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In this work we highlight recent work aimed at the characterization of halogen bonds. Here we discuss the origins of the σ-hole, the modulation of halogen bond strength by changing of neighboring chemical groups (i.e. halogen bond tuning), the performance of various computational methods in treating halogen bonds, and the strength and character of the halogen bond, the dihalogen bond, and two hydrogen bonds in bromomethanol dimers (which serve as model complexes) are compared. Symmetry adapted perturbation theory analysis of halogen bonding complexes indicates that halogen bonds strongly depend on both dispersion and electrostatics. The electrostatic interaction that occurs between the halogen σ-hole and the electronegative halogen bond donor is responsible for the high degree of directionality exhibited by halogen bonds. Because these noncovalent interactions have a strong dispersion component, it is important that the computational method used to treat a halogen bonding system be chosen very carefully, with correlated methods (such as CCSD(T)) being optimal. It is also noted here that most forcefield-based molecular mechanics methods do not describe the halogen σ-hole, and thus are not suitable for treating systems with halogen bonds. Recent attempts to improve the molecular mechanics description of halogen bonds are also discussed.

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O-H...X and O-H...O H-bonds as well as C-X...X dihalogen and C-X...O halogen bonds have been investigated in halomethanol dimers (bromomethanol dimer, iodomethanol dimer, difluorobromomethanol…bromomethanol complex and difluoroiodomethanol…iodomethanol complex). Structures of all complexes were optimized at the counterpoise-corrected MP2/cc-pVTZ level and single-point energies were calculated at the CCSD(T)/aug-cc-pVTZ level. Energy decomposition for the bromomethanol dimer complex was performed using the DFT-SAPT method based on the aug-cc-pVTZ basis set. OH...O and OH...X H-bonds are systematically the strongest in all complexes investigated, with the former being the strongest bond. Halogen and dihalogen bonds, being of comparable strength, are weaker than both H-bonds but are still significant. The strongest bonds were found in the difluoroiodomethanol…iodomethanol complex, where the O-H...O H-bond exceeds 7 kcal mol(-1), and the halogen and dihalogen bonds exceed 2.5 and 2.3 kcal mol(-1), respectively. Electrostatic energy is dominant for H-bonded structures, in halogen bonded structures electrostatic and dispersion energies are comparable, and, finally, for dihalogen structures the dispersion energy is clearly dominant.

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The performance of the second-order Møller-Plesset perturbation theory MP2.5 and MP2.X methods, tested on the S22, S66, X40, and other benchmark datasets is briefly reviewed. It is found that both methods produce highly accurate binding energies for the complexes contained in these data sets. Both methods also provide reliable potential energy curves for the complexes in the S66 set. Among the routinely used wavefunction methods, the only other technique that consistently produces lower errors, both for stabilization energies and geometry scans, is the spin-component-scaled coupled-clusters method covering iterative single- and double-electron excitations, which is, however, substantially more computationally intensive. The structures originated from full geometrical gradient optimizations at the MP2.5 and MP2.X level of theory were confirmed to be the closest to the CCSD(T)/CBS (coupled clusters covering iterative single- and double-electron excitations and perturbative triple-electron excitations performed at the complete basis set limit) geometries among all the tested methods (e.g. MP3, SCS(MI)-MP2, MP2, M06-2X, and DFT-D method evaluated with the TPSS functional). The MP2.5 geometries for the tested complexes deviate from the references almost negligibly. Inclusion of the scaled third-order correlation energy results in a substantial improvement of the ability to accurately describe noncovalent interactions. The results shown here serve to support the notion that MP2.5 and MP2.X are reasonable alternative methods for benchmark calculations in cases where system size or (lack of) computational resources preclude the use of CCSD(T)/CBS computations. MP2.X allows for the use of smaller basis sets (i.e. 6-31G*) with results that are nearly identical to those of MP2.5 with larger basis sets, which dramatically decreases computation times and makes calculations on much larger systems possible.

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We report the performance of composite post-MP2 ab initio methods with small basis sets for description of noncovalent interactions, using the S66 data set as a benchmark. For three representative complexes, it is shown that explicitly correlated coupled cluster (CCSD-F12a) methods yield interaction energies ca. 0.1 kcal/mol from the complete basis set limit with aug-cc-pVDZ. Triple excitations are not explicitly correlated in this approach, but we show that scaling the perturbative triples via the (T*) approximation improves agreement with benchmark values. Across the entire S66 data set, this approach results in a root-mean-square error (RMSE) of 0.13 kcal/mol or 3%, with well-balanced description of all classes of complex. The basis set dependence of traditional CCSD(T) interaction energies is examined, and the small 6-31G*(0.25) basis set is found to give particularly accurate results (RMSE = 0.15 kcal/mol, or 4%). We also employ spin component scaling (SCS) of CCSD-F12a data, which gives slightly better accuracy than CCSD(T*)-F12a if contributions from same- and opposite-spin pairs are optimized for this data set (RMSE = 0.08 kcal/mol, or 2%). Interpolation of local MP2 and MP3 is also shown to accurately reproduce benchmark data with both aug-cc-pVDZ (RMSE = 0.18 kcal/mol or 5%) and 6-31G*(0.25) (RMSE = 0.13 kcal/mol or 4%).

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In a previous study we investigated the effects of aromatic fluorine substitution on the strengths of the halogen bonds in halobenzene…acetone complexes (halo = chloro, bromo, and iodo). In this work, we have examined the origins of these halogen bonds (excluding the iodo systems), more specifically, the relative contributions of electrostatic and dispersion forces in these interactions and how these contributions change when halogen σ-holes are modified. These studies have been carried out using density functional symmetry adapted perturbation theory (DFT-SAPT) and through analyses of intermolecular correlation energies and molecular electrostatic potentials. It is found that electrostatic and dispersion contributions to attraction in halogen bonds vary from complex to complex, but are generally quite similar in magnitude. Not surprisingly, increasing the size and positive nature of a halogen's σ-hole dramatically enhances the strength of the electrostatic component of the halogen bonding interaction. Not so obviously, halogens with larger, more positive σ-holes tend to exhibit weaker dispersion interactions, which is attributable to the lower local polarizabilities of the larger σ-holes.

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Aromatic systems contain both σ- and π-electrons, which in turn constitute σ- and π-molecular orbitals (MOs). In discussing the properties of these systems, researchers typically refer to the highest occupied and lowest unoccupied MOs, which are π MOs. The characteristic properties of aromatic systems, such as their low ionization potentials and electron affinities, high polarizabilities and stabilities, and small band gaps (in spectroscopy called the N → V1 space), can easily be explained based on their electronic structure. These one-electron properties point to characteristic features of how aromatic systems interact with each other. Unlike hydrogen bonding systems, which primarily interact through electrostatic forces, complexes containing aromatic systems, especially aromatic stacked pairs, are predominantly stabilized by dispersion attraction. The stabilization energy in the benzene dimer is rather small (~2.5 kcal/mol) but strengthens with heteroatom substitution. The stacked interaction of aromatic nucleic acid bases is greater than 10 kcal/mol, and for the most stable stacked pair, guanine and cytosine, it reaches approximately 17 kcal/mol. Although these values do not equal the planar H-bonded interactions of these bases (~29 kcal/mol), stacking in DNA is more frequent than H-bonding and, unlike H-bonding, is not significantly weakened when passing from the gas phase to a water environment. Consequently, the stacking of aromatic systems represents the leading stabilization energy contribution in biomacromolecules and in related nanosystems. Therefore stacking (dispersion) interactions predominantly determine the double helical structure of DNA, which underlies its storage and transfer of genetic information. Similarly, dispersion is the dominant contributor to attractive interactions involving aromatic amino acids within the hydrophobic core of a protein, which is critical for folding. Therefore, understanding the nature of aromatic interactions, which depend greatly on quantum mechanical (QM) calculations, is of key importance in biomolecular science. This Account shows that accurate binding energies for aromatic complexes should be based on computations made at the (estimated) CCSD(T)/complete basis set limit (CBS) level of theory. This method is the least computationally intensive one that can give accurate stabilization energies for all common classes of noncovalent interactions (aromatic-aromatic, H-bonding, ionic, halogen bonding, charge-transfer, etc.). These results allow for direct comparison of binding energies between different interaction types. Conclusions based on lower-level QM calculations should be considered with care.

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Here we test the performance of the newly developed MP2.5 and MP2.X methods in terms of their abilities to generate accurate binding energies for noncovalently bound complexes at points away from their minimum energy structures and in terms of the accuracy of their potential energy minima. The MP2.X method is a scaled version of MP2.5 that allows for the use of smaller basis sets for the most computationally demanding (MP3) term, significantly reducing its computational cost. MP2.5 and MP2.X binding energy errors are compared to those of the reference CCSD(T)/CBS method on the dissociation curves associated with the S66 dataset of noncovalent complexes (S66x8). It is found that both the MP2.5 and MP2.X methods produce binding energy errors, as well as potential energy minima, that are significantly more accurate than those of MP2 methods. Thus, these methods are appropriate choices when very high quality geometries of noncovalent complexes are required.

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For many years, MP2 served as the principal method for the treatment of noncovalent interactions. Until recently, this was the only technique that could be used to produce reasonably accurate binding energies, with binding energy errors generally below ~35%, at a reasonable computational cost. The past decade has seen the development of many new methods with improved performance for noncovalent interactions, several of which are based on MP2. Here, we assess the performance of MP2, LMP2, MP2-F12, and LMP2-F12, as well as spin component scaled variants (SCS) of these methods, in terms of their abilities to produce accurate interaction energies for binding motifs commonly found in organic and biomolecular systems. Reference data from the newly developed S66 database of interaction energies are used for this assessment, and a further set of 38 complexes is used as a test set for SCS methods developed herein. The strongly basis set-dependent nature of MP2 is confirmed in this study, with the SCS technique greatly reducing this behavior. It is found in this work that the spin component scaling technique can effectively be used to dramatically improve the performance of MP2 and MP2 variants, with overall errors being reduced by factors of about 1.5-2. SCS versions of all MP2 variants tested here are shown to give similarly accurate overall results.

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We present a set of 40 noncovalent complexes of organic halides, halohydrides, and halogen molecules where the halogens participate in a variety of interaction types. The set, named X40, covers electrostatic interactions, London dispersion, hydrogen bonds, halogen bonding, halogen-π interactions, and stacking of halogenated aromatic molecules. Interaction energies at equilibrium geometries were calculated using a composite CCSD(T)/CBS scheme where the CCSD(T) contribution is calculated using triple-ζ basis sets with diffuse functions on all atoms but hydrogen. For each complex, we also provide 10 points along the dissociation curve calculated at the CCSD(T)/CBS level. We use this accurate reference to assess the accuracy of selected post-HF methods.

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A positive π-hole is a region of positive electrostatic potential that is perpendicular to a portion of a molecular framework. It is the counterpart of a σ-hole, which is along the extension of a covalent bond to an atom. Both σ-holes and π-holes become more positive (a) in going from the lighter to the heavier atoms in a given Group of the periodic table, and (b) as the remainder of the molecule is more electron-withdrawing. Positive σ- and π-holes can interact in a highly directional manner with negative sites, e.g., the lone pairs of Lewis bases. In this work, the complexes of 13 π-hole-containing molecules with the nitrogen lone pairs of HCN and NH(3) have been characterized computationally using the MP2, M06-2X and B3PW91 procedures. While the electrostatic interaction is a major driving force in π-hole bonding, a gradation is found from weakly noncovalent to considerably stronger with possible indications of some degree of coordinate covalency.

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