Controlling anisotropic properties by manipulating the orientation of chiral small molecules.

Chiral π-conjugated molecules bring new functionality to technological applications and represent an exciting, rapidly expanding area of research. Their functional properties, such as the absorption and emission of circularly polarized light or the transport of spin-polarized electrons, are highly anisotropic. As a result, the orientation of chiral molecules critically determines the functionality and efficiency of chiral devices. Here we present a strategy to control the orientation of a small chiral molecule (2,2'-dicyano[6]helicene) by the use of organic and inorganic templating layers. Such templating layers can either force 2,2'-dicyano[6]helicene to adopt a face-on orientation and self-assemble into upright supramolecular columns oriented with their helical axis perpendicular to the substrate, or an edge-on orientation with parallel-lying supramolecular columns. Through such control, we show that low- and high-energy chiroptical responses can be independently 'turned on' or 'turned off'. The templating methodologies described here provide a simple way to engineer orientational control and, by association, anisotropic functional properties of chiral molecular systems for a range of emerging technologies.

A Universal Force Field for Materials, Periodic GFN-FF: Implementation and Examination.

In this study, the adaption of the recently published molecular GFN-FF for periodic boundary conditions (pGFN-FF) is described through the use of neighbor lists combined with appropriate charge sums to handle any dimensionality from 1D polymers to 2D surfaces and 3D solids. Numerical integration over the Brillouin zone for the calculation of π bond orders of periodic fragments is also included. Aside from adapting the GFN-FF method to handle periodicity, improvements to the method are proposed in regard to the calculation of topological charges through the inclusion of a screened Coulomb term that leads to more physical charges and avoids a number of pathological cases. Short-range damping of three-body dispersion is also included to avoid collapse of some structures. Analytic second derivatives are also formulated with respect to both Cartesian and strain variables, including prescreening of terms to accelerate the dispersion/coordination number contribution to the Hessian. The modified pGFN-FF scheme is then applied to a wide range of different materials in order to examine how well this universal model performs.

What is "many-body" dispersion and should I worry about it?

Inclusion of dispersion effects in density-functional calculations is now standard practice in computational chemistry. In many dispersion models, the dispersion energy is written as a sum of pairwise atomic interactions consisting of a damped asymptotic expansion from perturbation theory. There has been much recent attention drawn to the importance of "many-body" dispersion effects, which by their name imply limitations with a pairwise atomic expansion. In this perspective, we clarify what is meant by many-body dispersion, as this term has previously referred to two very different physical phenomena, here classified as electronic and atomic many-body effects. Atomic many-body effects refer to the terms in the perturbation-theory expansion of the dispersion energy involving more than two atoms, the leading contribution being the Axilrod-Teller-Muto three-body term. Conversely, electronic many-body effects refer to changes in the dispersion coefficients of the pairwise terms induced by the atomic environment. Regardless of their nature, many-body effects cause pairwise non-additivity in the dispersion energy, such that the dispersion energy of a system does not equal the sum of the dispersion energies of its atomic pairs taken in isolation. A series of examples using the exchange-hole dipole moment (XDM) method are presented to assess the relative importance of electronic and atomic many-body effects on the dispersion energy. Electronic many-body effects can result in variation in the leading-order C6 dispersion coefficients by as much as 50%; hence, their inclusion is critical for good performance of a pairwise asymptotic dispersion correction. Conversely, atomic many-body effects represent less than 1% of the total dispersion energy and are much less significant than higher-order (C8 and C10) pairwise terms. Their importance has been previously overestimated through empirical fitting, where they can offset underlying errors stemming either from neglect of higher-order pairwise terms or from the base density functional.

Asymptotic Pairwise Dispersion Corrections Can Describe Layered Materials Accurately.

A recent study by Tawfik et al. [ Phys. Rev. Mater. 2018, 2, 034005] found that few density functionals, none of which are asymptotic pairwise dispersion methods, describe the geometry and binding of layered materials accurately. Here, we show that the exchange-hole dipole moment (XDM) dispersion model attains excellent results for graphite, hexagonal BN, and transition-metal dichalcogenides. Contrary to what has been argued, successful modeling of layered materials does not necessitate meta-GGA exchange, nonlocal correlation functionals, or the inclusion of three-body dispersion terms. Rather, a GGA functional, combined with a simple asymptotic pairwise dispersion correction, can be reliably used, provided that it properly accounts for the geometric dependence of the dispersion coefficients. The overwhelming contribution to the variation of the pairwise dispersion coefficients comes from the immediate vicinity of an atom and is already present for single layers. Longer-range and interlayer effects are examined in detail for graphite.

Dispersion XDM with Hybrid Functionals: Delocalization Error and Halogen Bonding in Molecular Crystals.

The accurate calculation of relative lattice energies of molecular crystals is important in polymorph ranking and crystal structure prediction. Delocalization error has been shown to affect calculated intermolecular binding energies in DFT and is similarly expected to affect the lattice energies of some classes of molecular crystals. In this work, we explore the use of dispersion-corrected hybrid functionals in the planewave-pseudopotentials approach to reduce delocalization error. We combine several hybrid functionals with the exchange-hole dipole moment (XDM) model for dispersion and show that they generally outperform GGA functionals in the calculation of both gas-phase binding energies and molecular crystal lattice energies. We apply the resulting XDM-corrected functionals to four halogen-bonded crystals: Cl2, Br2, I2, and ICl. GGA functionals severely overestimate their lattice energies, while hybrid functionals give accurate values. The preference of GGA functionals for monatomic structures in the Br2 and Cl2 crystals is also explained. Finally, we apply a recently developed method to calculate Bader's delocalization indices to examine the extent of intermolecular delocalization in the halogen molecular crystals. It is shown that intermolecular delocalization indices can be used to measure the strength of halogen bonds within the crystal, as well as detect the presence of delocalization error.

Clusters in Liquid Fatty Acids: Structure and Role in Nucleation.

Saturated fatty acids are used in many consumer products and have considerable promise as phase change materials for thermal energy storage, in part because they crystallize with minimal supercooling. The latter property correlates with the existence of molecular clusters in the liquid; when heated above a threshold temperature, clusters do not immediately re-form on cooling, and supercooling results. Raman spectroscopy, density functional theory calculations, and small-angle X-ray scattering were used to reveal the size, structure, and temperature dependence of the clusters. We found that the liquid phases of fatty acids contain some ordering at all temperatures, with the molecules showing, on average, short-range alignment along their long axes. At temperatures below the threshold temperature for increased susceptibility to supercooling, clusters of more highly ordered fatty acid dimers, several hundred molecules in size, exist in the liquid. Within these clusters, the alkyl chains of the fatty acid dimers are essentially completely inserted between the alkyl chains of their longitudinal neighbors. Above the threshold temperature, fatty acid clusters are smaller in size and number. We explored how the fatty acid clusters promote bulk crystallization and show quantitatively that their presence reduces the energy barrier to crystal growth, likely by a particle-attachment-type mechanism.

Non-Covalent Interactions in Molecular Crystals: Exploring the Accuracy of the Exchange-Hole Dipole Moment Model with Local Orbitals.

We present the first implementation of the exchange-hole dipole moment (XDM) model in combination with a numerical finite-support local orbital method (the SIESTA method) for the modeling of non-covalent interactions in periodic solids. The XDM model is parametrized for both the B86bPBE and PBE functionals using double-ζ- and triple-ζ-quality basis sets (DZP and TZP). The use of finite-support local orbitals is shown to have minimal impact on the computed dispersion coefficients for van der Waals molecular dimers and small molecular solids. However, the quality of the basis set affects the accuracy of calculated dimer binding energies and molecular-crystal lattice energies quite significantly; the size of the counterpoise correction indicates that this is caused by basis-set incompleteness error. In the case of the DZP basis set, its performance for weakly bound gas-phase dimers is similar to that of a double-ζ Gaussian basis set without diffuse functions. The new XDM implementation was tested on graphite and phosphorene exfoliation, and on the X23 benchmark set of molecular-crystal lattice energies. Our results indicate that lattice energies similar to plane-wave calculations can be obtained only if the counterpoise correction is applied. Alternatively, the calculated equilibrium geometries are reasonably close to the plane-wave equivalents, and composite approaches in which a single-point plane-wave calculation is used at the XDM/DZP equilibrium geometry yield good accuracy at a significantly lower computational cost.

Pervasive Delocalisation Error Causes Spurious Proton Transfer in Organic Acid-Base Co-Crystals.

Dispersion-corrected density-functional theory (DFT-D) methods have become the workhorse of many computational protocols for molecular crystal structure prediction due to their efficiency and convenience. However, certain limitations of DFT, such as delocalisation error, are often overlooked or are too expensive to remedy in solid-state applications. This error can lead to artificial stabilisation of charge transfer and, in this work, it is found to affect the correct identification of the protonation site in multicomponent acid-base crystals. As such, commonly used DFT-D methods cannot be applied with any reliability to the study of acid-base co-crystals or salts, while hybrid functionals remain too restrictive for routine use. This presents an impetus for the development of new functionals with reduced delocalisation error for solid-state applications; the structures studied herein constitute an excellent benchmark for this purpose.

Correction: A computational exploration of the crystal energy and charge-carrier mobility landscapes of the chiral [6]helicene molecule.

Correction for 'A computational exploration of the crystal energy and charge-carrier mobility landscapes of the chiral [6]helicene molecule' by Beth Rice et al., Nanoscale, 2018, 10, 1865-1876.

Composite and Low-Cost Approaches for Molecular Crystal Structure Prediction.

Molecular crystal structure prediction (CSP) requires evaluating differences in lattice energy between candidate crystal structures accurately and efficiently. In this work, we explore and compare several low-cost alternatives to dispersion-corrected density-functional theory (DFT) in the plane-waves/pseudopotential approximation, the most accurate and general approach used for CSP at present. Three types of low-cost methods are considered: DFT with a small basis set of finite-support numerical orbitals (the SIESTA method), dispersion-corrected Gaussian small or minimal-basis-set Hartree-Fock and DFT with additional empirical corrections (HF-3c and PBEh-3c), and self-consistent-charge dispersion-corrected density-functional tight binding (SCC-DFTB3-D3). In addition, we study the performance of composite methods that comprise a geometry optimization using a low-cost approach followed by a single-point calculation using the accurate but comparatively expensive B86bPBE-XDM functional. All methods were tested for their abilities to produce absolute lattice energies, relative lattice energies, and crystal geometries. We show that assessing various methods by their ability to produce absolute lattice energies can be misleading and that relative lattice energies are a much better indicator of performance in CSP. The EE14 set of relative solubilities of homochiral and heterochiral chiral crystals is proposed for relative lattice-energy benchmarking. Our results show that PBE-D2 plus a DZP basis set of numerical orbitals coupled with a final B86bPBE-XDM single-point calculation gives excellent performance at a fraction of the cost of a full B86bPBE-XDM calculation, although the results are sensitive to the particular details of the computational protocol. The B86bPBE-XDM//PBE-D2/DZP method was subsequently tested in a practical CSP application from our recent work on the crystal structure of the enantiopure and racemate forms of 1-aza[6]helicene, a chiral organic semiconductor. Our results show that this multilevel method is able to correctly reproduce the energy ranking of both crystal forms.

A computational exploration of the crystal energy and charge-carrier mobility landscapes of the chiral [6]helicene molecule.

The potential of a given π-conjugated organic molecule in an organic semiconductor device is highly dependent on molecular packing, as it strongly influences the charge-carrier mobility of the material. Such solid-state packing is sensitive to subtle differences in their intermolecular interactions and is challenging to predict. Chirality of the organic molecule adds an additional element of complexity to intuitive packing prediction. Here we use crystal structure prediction to explore the lattice-energy landscape of a potential chiral organic semiconductor, [6]helicene. We reproduce the experimentally observed enantiopure crystal structure and explain the absence of an experimentally observed racemate structure. By exploring how the hole and electron-mobility varies across the energy-structure-function landscape for [6]helicene, we find that an energetically favourable and frequently occurring packing motif is particularly promising for electron-mobility, with a highest calculated mobility of 2.9 cm2 V-1 s-1 (assuming a reorganization energy of 0.46 eV). We also calculate relatively high hole-mobility in some structures, with a highest calculated mobility of 2.0 cm2 V-1 s-1 found for chains of helicenes packed in a herringbone fashion. Neither the energetically favourable nor high charge-carrier mobility packing motifs are intuitively obvious, and this demonstrates the utility of our approach to computationally explore the energy-structure-function landscape for organic semiconductors. Our work demonstrates a route for the use of computational simulations to aid in the design of new molecules for organic electronics, through the a priori prediction of their likely solid-state form and properties.

Structure-activity relationship of caffeic acid phenethyl ester analogs as new 5-lipoxygenase inhibitors.

Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti-LTs activity through the inhibition of 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5-LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties (4a-i and 5a-i, respectively) were synthesized by Sonogashira and Heck cross-coupling reactions to probe the effects of flexibility and aryl substitution on 5-LO inhibition. Caffeoyl alcohol and ethers (6, 7a-b) as well as caffeoyl aldehyde and ketones (8a-e) were synthesized to elucidate the importance of the ester linkage for inhibitory activity. All tested compounds proved to be good radical scavengers (IC50 of 10-30 µm). After preliminary anti-LTs activity screening in HEK293 cell models, 5-LO inhibition potential of selected compounds was determined in human polymorphonuclear leukocytes (PMNL). Most screened compounds outperformed CAPE 3 in concentration-dependent assays on PMNL, with ester dimers 4i and 5i along with caffeoyl ethers 7a-b being roughly eight-, seven-, and 16-fold more potent than Zileuton, with IC50 values of 0.36, 0.43, and 0.18 µm, respectively.

Competing fragmentation processes of ß-substituted propanoate ions upon collision-induced dissociation.

RATIONALE: When subjected to collisional activation, gas-phase carboxylate ions typically undergo decarboxylation. However, alternative fragmentation processes dominate when the carboxylate group is located within certain structural motifs. In this work, the fragmentation processes of ß-substituted carboxylate ions are characterized to improve correlations between reactivity and structure. METHODS: Mass spectra were collected using both ion trap and triple quadrupole mass spectrometers operating in the negative ion mode; collision-induced dissociation (CID) of ions was used to study the relationship between product ions and the structures of their precursor ions. Quantum mechanical computations were performed on a full range of reaction geometries at the MP2/6-311++G(2d,p)//B3LYP/6-31++G(2d,p) level of theory. RESULTS: For a series of ß-substituted carboxylate ions, a product ion corresponding to the anion of the ß-substituent was obtained upon CID. Detailed computations indicated that decarboxylative elimination and at least one other fragmentation mechanism had feasible energetics for the formation of substituent anions differing in their gas-phase basicities. Predicted energetics for anti- and synperiplanar alignments in the transition structures for decarboxylative elimination correlated with the positions of crossover points in breakdown curves acquired for conformationally constrained ions. CONCLUSIONS: The feasibility of more than one mechanism was established for the fragmentation of ß-substituted propanoates. The contribution of each mechanistic pathway to the formation of the substituent anion was influenced by structural variations and conformational constraints, but mostly depended on the nature of the substituent. Copyright © 2016 John Wiley & Sons, Ltd.

Phenyl group participation in rearrangements during collision-induced dissociation of deprotonated phenoxyacetic acid.

RATIONALE: The identification of trace constituents in biological and environmental samples is frequently based on the fragmentation patterns resulting from the collision-induced dissociation (CID) of gas-phase ions. Credible mechanistic characterization of fragmentation processes, including rearrangements, is required to make reliable assignments for structures of precursor and product ions. METHODS: Mass spectra were collected using both ion trap and triple quadrupole mass spectrometers operating in the negative ion mode. Precursor ion scans and CID of ions generated in-source were used to establish precursor-product ion relationships. Density functional theory (DFT) computations were performed at the MP2/6-311++G(2d,p)//B3LYP/6-31++G(2d,p) level of theory. RESULTS: Product ions at m/z 93 and 107 obtained upon CID of phenoxyacetate were attributed to phenoxide and o-methylphenoxide, respectively. An isotopic labeling experiment and computations showed that the phenoxide ion was formed by intramolecular displacement with formation of an α-lactone and also by a Smiles rearrangement. Rearrangement of phenoxyacetate via the ion-neutral complex formed in the α-lactone displacement pathway gave the isomeric o-hydroxyphenylacetate ion which yielded o-methylphenoxide upon decarboxylation. Computations provided feasible energetics for these pathways. CONCLUSIONS: Previously unrecognized and energetically favorable rearrangements during the collision-induced fragmentation of phenoxyacetate have been characterized using isotopic labeling and DFT computations. Notably, the phenyl substituent plays an indispensable role in each rearrangement process resulting in multiple pathways for the fragmentation of phenoxyacetate.

Density Functional Theory Study of BF3-Mediated Additions of Enols and [(Trimethylsilyl)oxy]alkenes to an Oxyallyl Cation: Homologous Mukaiyama Reactions.

The addition of enols and [(trimethylsilyl)oxy]alkenes, bearing methyl substituents at various positions, to a cyclic, BF3-complexed oxyallyl cation has been studied at the M06/6-311G(d)//B3LYP/6-31G(d) level of theory. The reactions with the [(trimethylsilyl)oxy]alkenes are homologous Mukaiyama reactions, which have not been examined computationally previously. In most instances a number of transition states were located, and the difference in energy between these transition states was not large, which pointed to low levels of diastereoselectivity in the reactions of the oxyallyl cation model compound. The lowest energy transition states were those with a synclinal geometry in which the alkene was positioned over the cyclic oxyallyl cation, and the relative orientation of the alkene and the oxyallyl cation was rationalized in terms of stabilizing intermolecular interactions, revealed by NBO analysis, between one or more fluorines of the complexed BF3 and hydrogens on the alkene moiety, and between the oxygen on the alkene and the π-system of the oxyallyl cation. Because, in most instances with these simple models, two or more transition states of relatively low energy were located, predictions of diastereoselectivity in more complex examples that are based on simple models cannot be recommended.

Torquoselectivity in the Nazarov reactions of allenyl vinyl ketones.

Nazarov reactions mediated by BF3-etherate of a series of carbon-substituted allenyl vinyl ketones provided intermediates in which substituents on the termini of the allenes had rotated away from the vinyl moieties, and these intermediates were trapped by (4 + 3)-cyclizations. A computational examination of the torquoselectivity of these Nazarov reactions confirmed a kinetic preference for the observed isomers and pointed to steric interactions and the degree of allene deformation as significant factors in determining the torquoselectivity. The study also suggested that the high proportion of one geometrical isomer in the Nazarov products might also be due to some preferential trapping of the major Nazarov intermediate.

NMR metabolomics analysis of the effects of 5-lipoxygenase inhibitors on metabolism in glioblastomas.

Changes across metabolic networks are emerging as an integral part of cancer development and progression. Increasing comprehension of the importance of metabolic processes as well as metabolites in cancer is stimulating exploration of novel, targeted treatment options. Arachidonic acid (AA) is a major component of phospholipids. Through the cascade catalyzed by cyclooxygenases and lipoxygenases, AA is also a precursor to cellular signaling molecules as well as molecules associated with a variety of diseases including cancer. 5-Lipoxygenase catalyzes the transformation of AA into leukotrienes (LT), important mediators of inflammation. High-throughput analysis of metabolic profiles was used to investigate the response of glioblastoma cell lines to treatment with 5-lipoxygenase inhibitors. Metabolic profiling of cells following drug treatment provides valuable information about the response and metabolic alterations induced by the drug action and give an indication of both on-target and off-target effects of drugs. Four different 5-lipoxygenase inhibitors and antioxidants were tested including zileuton, caffeic acid, and its analogues caffeic acid phenethyl ester and caffeic acid cyclohexethyl ester. A NMR approach identified metabolic signatures resulting from application of these compounds to glioblastoma cell lines, and metabolic data were used to develop a better understanding of the mode of action of these inhibitors.

Synthesis and antiradical/antioxidant activities of caffeic acid phenethyl ester and its related propionic, acetic, and benzoic acid analogues.

Caffeic acid phenethyl ester (CAPE) is a bioactive component isolated from propolis. A series of CAPE analogues was synthesized and their antiradical/antioxidant effects analyzed. The effect of the presence of the double bond and of the conjugated system on the antioxidant effect is evaluated with the analogues obtained from 3-(3,4-dihydroxyphenyl) propanoic acid. Those obtained from 2-(3,4-dihydroxyphenyl) acetic acid and 3,4-dihydroxybenzoic acid allow the evaluation of the effect of the presence of two carbons between the carbonyl and aromatic system.

Caffeic acid phenethyl ester and its amide analogue are potent inhibitors of leukotriene biosynthesis in human polymorphonuclear leukocytes.

BACKGROUND: 5-lipoxygenase (5-LO) catalyses the transformation of arachidonic acid (AA) into leukotrienes (LTs), which are important lipid mediators of inflammation. LTs have been directly implicated in inflammatory diseases like asthma, atherosclerosis and rheumatoid arthritis; therefore inhibition of LT biosynthesis is a strategy for the treatment of these chronic diseases. METHODOLOGY/PRINCIPAL FINDINGS: Analogues of caffeic acid, including the naturally-occurring caffeic acid phenethyl ester (CAPE), were synthesized and evaluated for their capacity to inhibit 5-LO and LTs biosynthesis in human polymorphonuclear leukocytes (PMNL) and whole blood. Anti-free radical and anti-oxidant activities of the compounds were also measured. Caffeic acid did not inhibit 5-LO activity or LT biosynthesis at concentrations up to 10 µM. CAPE inhibited 5-LO activity (IC(50) 0.13 µM, 95% CI 0.08-0.23 µM) more effectively than the clinically-approved 5-LO inhibitor zileuton (IC(50) 3.5 µM, 95% CI 2.3-5.4 µM). CAPE was also more effective than zileuton for the inhibition of LT biosynthesis in PMNL but the compounds were equipotent in whole blood. The activity of the amide analogue of CAPE was similar to that of zileuton. Inhibition of LT biosynthesis by CAPE was the result of the inhibition of 5-LO and of AA release. Caffeic acid, CAPE and its amide analog were free radical scavengers and antioxidants with IC(50) values in the low µM range; however, the phenethyl moiety of CAPE was required for effective inhibition of 5-LO and LT biosynthesis. CONCLUSIONS: CAPE is a potent LT biosynthesis inhibitor that blocks 5-LO activity and AA release. The CAPE structure can be used as a framework for the rational design of stable and potent inhibitors of LT biosynthesis.