Conformational Energy Research Articles

A Theoretical and Experimental Study on the Potential Luminescent and Biological Activities of Diaminodicyanoquinodimethane Derivatives.

Recently, several studies have demonstrated that diaminodicyanoquinone derivatives (DADQs) could present interesting fluorescence properties. Furthermore, some DADQs under the solid state are capable of showing quantum yields that can reach values of 90%. Besides, the diaminodiacyanoquinone core represents a versatile building block propense either to modification or integration into different systems to obtain and provide them unique photophysical features. Herein, we carried out a theoretical study on the fluorescence properties of three different diaminodicyanoquinodimethane systems. Therefore, time-dependent density functional theory (TD-DFT) was used to obtain the values associated with the dipole moments, oscillator strengths, and the conformational energies between the ground and the first excited states of each molecule. The results suggest that only two of the three studied systems possess significant luminescent properties. In a further stage, the theoretical insights were confirmed by means of experimental measurements, which not only retrieved the photoluminescence of the DADQs, but also suggest a preliminary and promising antibacterial activity of these systems.

Mapping Conformational Space of All 8000 Tripeptides by Quantum Chemical Methods: What Strain Is Affordable within Folded Protein Chains?

To gain more insight into the physicochemical aspects of a protein structure from the first principles, conformational space of all 8000 "capped" tripeptides (i.e., N-Ac-X1X2X3-NH-CH3, where Xi is one of the 20 natural amino acids) was investigated computationally. An enormous dataset (denoted P-CONF_1.6M and containing close to 1 600 000 conformers in total) has been obtained by employing a composite protocol combining density functional theory, semiempirical quantum mechanics (SQM), and state-of-the-art solvation methods with 1000 K molecular dynamics (MD) used to generate initial structures (200 snapshots for each tripeptide). This allowed us to present the first rigorous QM-based glimpse at the vast conformational space spanned by small protein fragments. The same computational procedure was repeated for tripeptide fragments taken from the SCOPe database of three-dimensional protein folds, by restraining them to their geometry in a protein. Such complementary data allowed us to compare the distribution of conformational strain energies of unrestrained tripeptidic fragments "in solvent" with those in existing protein chains. Besides providing a rigorous (ab initio) proof of a few well-known concepts and hypotheses concerning protein structures, such as the distribution of (φ, ψ) angles in Ramachandran plots, we have made several observations that came as a certain surprise: (1) distribution of conformational energies does not significantly differ between the "unbiased/unrestrained" conformers obtained from MD sampling in solvent and the biased conformers, i.e., those of a given tripeptide obtained from protein structures; (2) conformational (strain) energy window up to ∼20 to 25 kcal·mol-1 is readily available to tripeptide fragments within the context of a protein chain; (3) overpopulation in certain regions of Ramachandran plot was observed for the unbiased conformers. Last but not least, the massive dataset of accurate (DFT-D3//COSMO-RS) conformational (free) energies of ∼1.6 M peptide conformers, P-CONF_1.6M, obtained throughout this work may serve as excellent dataset for calibrating and benchmarking of popular force fields.

Theoretical study on conformational energies of transition metal complexes.

Conformational energies are an important chemical property for which a performance assessment of theoretical methods is mandatory. Existing benchmark sets are often limited to biochemical or main group element containing molecules, while organometallic systems are generally less studied. A key problem herein is to routinely generate conformers for these molecules due to their complexity and manifold of possible coordination patterns. In this study we used our recently published CREST protocol [Pracht et al., Phys. Chem. Chem. Phys., 2020, 22, 7169-7192] to generate conformer ensembles for a variety of 40 challenging transition metal containing molecules, which were then used to form a comprehensive conformational energy benchmark set termed TMCONF40. Several low-cost semiempirical, density functional theory (DFT) and force-field methods were compared to high level DLPNO-CCSD(T1) and double-hybrid DFT reference values. Close attention was paid to the energetic ordering of the conformers in the statistical evaluation. With respect to the double-hybrid references, both tested low-cost composite DFT methods produce high Pearson correlation coefficients of rp,mean,B97-3c//B97-3c = 0.922 and rp,mean,PBEh-3c//B97-3c = 0.890, with mean absolute deviations close to or below 1 kcal mol-1. This good performance also holds for a comparison to DLPNO-CCSD(T1) reference energies for a smaller subset termed TMCONF5. Based on DFT geometries, the GFNn-xTB methods yield reasonable Pearson correlation coefficients of rp,mean,GFN1-xTB//B97-3c = 0.617 (MADmean = 2.15 kcal mol-1) and rp,mean,GFN2-xTB//B97-3c = 0.567 (MADmean = 2.68 kcal mol-1), outperforming the widely used PMx methods on the TMCONF40 test set. Employing the low-cost composite DFT method B97-3c on GFN2-xTB geometries yields an slightly improved correlation of rp,mean,B97-3c//GFN2-xTB = 0.632. Furthermore, for 68% of the investigated complexes at least one low-energy conformer was found that is more stable than the respective crystal structure conformation, which signals the importance of conformational studies. General recommendations for the application of the CREST protocol and DFT methods for transition metal conformational energies are given.

Interplay between the crystal stability and the energy of the molecular conformation

The lattice energy is the main factor in determining the structure even if the molecules adopt a less energetically favorable conformation.

Generalized energy-based fragmentation approach for calculations of solvation energies of large systems.

A generalized energy-based fragmentation (GEBF) approach has been combined with a universal solvation model based on solute electron density (SMD) to compute the solvation energies of general large systems (such as protein molecules) in solutions. In the GEBF-SMD method, the solvation energy of a target system could be combined by the corresponding solvation energies of various subsystems, each of which is embedded in the background point charges and surface charges on the surface of solute cavity at the positions of its atoms and neighbouring atoms outside of the subsystem. Our results show that the GEBF-SMD model could reproduce the conventional SMD solvation energies quite well for various proteins in solutions, and could significantly reduce the computational costs for the SMD calculations of large proteins. In addition, the GEBF-SMD approach is almost independent of the basis sets and the types of solvents (including protic, polar, and nonpolar ones). Also, the GEBF-SMD approach could reproduce the relative energies of various conformers of large systems in solutions. Therefore, the GEBF-SMD method is expected to be applicable for computing the solvation energies of a broad range of large systems.

Photophysical and molecular docking studies of photoinduced electron transfer (PET) and non-PET based fluorophores of acridinedione derivatives with a glycoprotein: Ovalbumin

Photophysical studies of resorcinol-based family of acridinedione (ADR) dyes with a glycoprotein, ovalbumin (OVA) were carried out in water. Addition of OVA to photoinduced electron transfer (PET) based dye (ADR1) resulted in a considerable red shift of emission maxima with a slight increase in the fluorescence intensity, whereas no significant variation in the fluorescence intensity or shift of emission maxima results in the case of a non-PET dye. Fluorescence lifetime studies illustrates that the PET lifetime component enhances by several fold on the introduction of OVA which is accompanied with the formation of multi lifetime components in the aqueous phase of varying distribution as observed in well-known globular protein, bovine serum albumin (BSA). Interestingly, a decrease in the fluorescence lifetime of non-PET dye (ADR2) with the evolution of more than one distinct lifetime species results with OVA. This behaviour ascertains the presence of at least two different micro environment of dye residing in aqueous phase on the addition of OVA. The introduction of OVA induces the formation of several distinguishable micro environments around the close vicinity of the dye molecule that are subjected to various binding forces. Further, the dye bound to several amino acid residues through conventional and non-conventional hydrogen-bonding interactions accompanied with hydrophobic interactions, pi-pi, pi-alkyl interactions and weak van der Waals forces also coexist. The variation in binding energies of various dye-OVA conformations are established from molecular docking (MD) techniques. The combination of docking techniques validates and authenticates the origin of multi decay characteristics of dye-OVA complex that correlates dye bound to different binding sites in protein. A combined approach of fluorescence techniques along with MD methods and Isothermal Calorimetric Titration (ITC) studies provides an excellent approach in determining the nature of interaction and binding stability of dye-protein system in a micro heterogeneous environment.

An experimental approach probing the conformational transitions and energy landscape of antibodies: a glimmer of hope for reviving lost therapeutic candidates using ionic liquid.

Understanding protein folding in different environmental conditions is fundamentally important for predicting protein structures and developing innovative antibody formulations. While the thermodynamics and kinetics of folding and unfolding have been extensively studied by computational methods, experimental methods for determining antibody conformational transition pathways are lacking. Motivated to fill this gap, we prepared a series of unique formulations containing a high concentration of a chimeric immunoglobin G4 (IgG4) antibody with different excipients in the presence and absence of the ionic liquid (IL) choline dihydrogen phosphate. We determined the effects of different excipients and IL on protein thermal and structural stability by performing variable temperature circular dichroism and bio-layer interferometry analyses. To further rationalise the observations of conformational changes with temperature, we carried out molecular dynamics simulations on a single antibody binding fragment from IgG4 in the different formulations, at low and high temperatures. We developed a methodology to study the conformational transitions and associated thermodynamics of biomolecules, and we showed IL-induced conformational transitions. We showed that the increased propensity for conformational change was driven by preferential binding of the dihydrogen phosphate anion to the antibody fragment. Finally, we found that a formulation containing IL with sugar, amino acids and surfactant is a promising candidate for stabilising proteins against conformational destabilisation and aggregation. We hope that ultimately, we can help in the quest to understand the molecular basis of the stability of antibodies and protein misfolding phenomena and offer new candidate formulations with the potential to revive lost therapeutic candidates.

Propensity, free energy contributions and conformation of primary n-alcohols at a water surface.

Atmospheric aerosols contain organic molecules that serve as cloud condensation nucleation sites and affect the climate. Several experimental and simulation studies have been dedicated to investigate their surface propensity, but the mechanisms that drive them to the water surface are still not fully understood. In this molecular dynamics (MD) simulation study, primary alcohols are considered as a model system representing polar organic molecules. We find that the surface affinity of n-alcohols increases linearly with the length of the hydrophobic tail. By decomposing the adsorption free energy into enthalpy and entropy contributions, we find that the transition from bulk to surface is entropically driven, compatible with the fact that the hydrophobic effect of small solutes is of entropic origin. The enthalpy of surface adsorption is nearly invariant among different n-alcohols because the loss of solvent-alcohol interactions is balanced by a gain in solvent-solvent interactions. Structural analysis shows that, at the surface, the linear alcohols prefer an orientation with the hydrophobic tail pointing out from the surface, whereas the hydroxyl group remains buried in the water. This general behaviour is likely transferable to other small molecules with similar structures but other functional groups that are present in the atmosphere. Therefore, the present study is a step forward toward a general description of organic molecules in aerosols.

Simple models for the quick estimation of ground state hydrogen tunneling splittings in alcohols and other compounds.

Models for the quick estimation of energy splittings caused by coherent tunneling of hydrogen atoms are evaluated with available experimental data for alcohols and improvements are proposed. The discussed models are mathematically simple and require only results from routine quantum chemical computations, i.e. hybrid DFT calculation of the equilibrium geometry and the transition state within the harmonic approximation. A benchmark of experimental splittings spanning four orders of magnitude for 27 alcohol species is captured by three evaluated models with a mean symmetric deviation factor of 1.7, 1.5 and 1.4, respectively, i.e. the calculated values deviate on average by this factor in either direction. Limitations of the models are explored with alcohols featuring uncommon properties, such as an inverted conformational energy sequence, a very light molecular frame, an elevated torsional frequency, or a coupling with a second internal degree of freedom. If the splitting of either the protiated or deuterated form of an alcohol is already experimentally determined, the one of the second isotopolog can be estimated by three additional models with a mean symmetric deviation factor of 1.14, 1.19 and 1.15, respectively. It is shown that this can be achieved with a novel approach without any quantum chemical calculation by directly correlating experimental splittings of isotopologs across related species. This is also demonstrated for other classes of compounds with hydrogen tunneling, such as amines, thiols, and phenols. Furthermore, it is found that the isotope effect can even be anticipated without any further knowledge about the system solely from the size of either splitting with a mean symmetric deviation factor of 1.3. This is based on an extensive sample of 77 pairs of splittings spanning eight orders of magnitude for isotopologs of chemically diverse compounds.

Twistable dipolar aryl rings as electric field actuated conformational molecular switches.

The ability to control the chemical conformation of a system via external stimuli is a promising route for developing molecular switches. For eventual deployment as viable sub-nanoscale components that are compatible with current electronic device technology, conformational switching should be controllable by a local electric field (i.e. E-field gateable) and accompanied by a rapid and significant change in conductivity. In organic chemical systems the degree of π-conjugation is linked to the degree of electronic delocalisation, and thus largely determines the conductivity. Here, by means of accurate first principles calculations, we study the prototypical biphenyl based molecular system in which the dihedral angle between the two rings determines the degree of conjugation. In order to make this an E-field gateable system we create a net dipole by asymmetrically functionalising one ring with: (i) electron withdrawing (F, Br and CN), (ii) electron donating (NH2), and (iii) mixed (NH2/NO2) substituents. In this way, the application of an E-field interacts with the dipolar system to influence the dihedral angle, thus controlling the conjugation. For all considered substituents we consider a range of E-fields, and in each case extract conformational energy profiles. Using this data we obtain the minimum E-field required to induce a barrierless switching event for each system. We further extract the estimated switching speeds, the conformational probabilities at finite temperatures, and the effect of applied E-field on electronic structure. Consideration of these data allow us to assess which factors are most important in the design of efficient gateable electrical molecular switches.

Benchmark comparison of dual-basis double-hybrid density functional theory and a neural-network-optimized method for intermolecular interactions

We present a computationally efficient implementation of double-hybrid density functional theory (DH-DFT) leveraging the dual basis methods of Head-Gordon and co-workers and the resolution-of-the-identity second-order Møller-Plesset (RI-MP2) theory. The B2PLYP, B2GP-PLYP, DSD-BLYP and DSD-PBEP86 density functionals are applied to assess the performance of dual-basis methods on several benchmark test cases, including the CONF set of conformational energy differences in C4-C7 alkanes, the S22 set of noncovalent interaction energies, and the RGC10 noble-gas dimer dissociation curves. The dual-basis DH-DFT approach is shown to give results in excellent agreement with conventional methods at a reduced computational cost. For noncovalent interaction energies, DH-DFT is compared against a leading neural-network-based approach, namely the SNS-MP2 method of McGibbon and coworkers (McGibbon et al., 2017). The DH-DFT and SNS-MP2 methods are shown to produce similar accuracies when compared to the established benchmark values.

General Theory of Fragment Linking in Molecular Design: Why Fragment Linking Rarely Succeeds and How to Improve Outcomes.

Linking two fragments binding in nearby subpockets together has become an important technique in fragment-based drug discovery to optimize the binding potency of fragment hits. Despite the expected favorable translational and orientational entropic contribution to the binding free energy of the linked molecule, brute force enumeration of chemical linker for linking fragments is rarely successful, and the vast majority of linked molecules do not exhibit the expected gains of binding potency. In this paper, we examine the physical factors that contribute to the change of binding free energy from fragment linking and develop a method to rigorously calculate these different physical contributions. We find from these analyses that multiple confounding factors make successful fragment linking strategies rare, including (1) possible change of the binding mode of the fragments in the linked state compared to separate binding of the fragments, (2) unfavorable intramolecular strain energy of the bioactive conformation of the linked molecule, (3) unfavorable interaction between the linker and the protein, (4) favorable interaction energies between two fragments in solution when not chemically linked that offset the expected entropy loss for the formation of fragment pair, (5) complex compensating configurational entropic effects beyond the simplistic rotational and translational analysis. We here have applied a statistically mechanically rigorous approach to compute the fragment linking coefficients of 10 pharmaceutically interesting systems and quantify the contribution of each physical component to the binding free energy of the linked molecule. Based on these studies, we have found that the change in the relative configurational entropy of the two fragments in the protein binding pocket (a term neglected to our knowledge in all previous analyses) substantially offsets the favorable expected rotational and translational entropic contributions to the binding free energy of the linked molecule. This configurational restriction of the fragments in the binding pocket of the proteins is found to be, in our analysis, the dominant reason why most fragment linking strategies do not exhibit the expected gains of binding potency. These findings have further provided rich physical insights, which we expect should facilitate more successful fragment linking strategies to be formulated in the future.

On the Use of the Discrete Constant pH Molecular Dynamics to Describe the Conformational Space of Peptides

Solvent pH is an important property that defines the protonation state of the amino acids and, therefore, modulates the interactions and the conformational space of the biochemical systems. Generally, this thermodynamic variable is poorly considered in Molecular Dynamics (MD) simulations. Fortunately, this lack has been overcome by means of the Constant pH Molecular Dynamics (CPHMD) methods in the recent decades. Several studies have reported promising results from these approaches that include pH in simulations but focus on the prediction of the effective pKa of the amino acids. In this work, we want to shed some light on the CPHMD method and its implementation in the AMBER suitcase from a conformational point of view. To achieve this goal, we performed CPHMD and conventional MD (CMD) simulations of six protonatable amino acids in a blocked tripeptide structure to compare the conformational sampling and energy distributions of both methods. The results reveal strengths and weaknesses of the CPHMD method in the implementation of AMBER18 version. The change of the protonation state according to the chemical environment is presumably an improvement in the accuracy of the simulations. However, the simulations of the deprotonated forms are not consistent, which is related to an inaccurate assignment of the partial charges of the backbone atoms in the CPHMD residues. Therefore, we recommend the CPHMD methods of AMBER program but pointing out the need to compare structural properties with experimental data to bring reliability to the conformational sampling of the simulations.

Identification and verification of effective components of Huanghuai for dysfunctional uterine bleeding based on network pharmacology and molecular docking

ObjectiveThe Huanghuai (HH), which is made from the dried roots of Scutellaria baicalensis (Huangqin in Chinese) and the dried flowers and buds of Sophora japonica (Huaihua in Chinese), is a traditional Chinese formula used to treat dysfunctional uterine bleeding (DUB) (Benglou in Chinese) and proven to treat hemostasis effectively in our previous study. Network pharmacology and molecule docking were performed to study the underlying mechanism of Huanghuai (HH), and pharmacodynamic experiments were conducted to verify its curative effect. MethodsTCMSP, UniProt, GeneCards, STRING, DAVID databases, and Cytoscape 3.7.2 were utilized for the construction of a compound-target-pathway network. Docking the potential effective components with potential targets. The HPLC analysis of the potential effective components was performed. In vivo, the hot plate test model was used to study the analgesic activity, the egg white was used to study the swollen reaction in the sole in mice, and the hemostasis effect was studied by the capillary method, tail-breaking method and abortion uterus test. ResultsThe results showed that six compounds (acacetin, beta-sitosterol, wogonin, baicalein, kaempferol and quercetin) and four potential targets (PTGS2, AKT1, TP53 and TNF) in the compound-target-pathway network were the potential material basis for HH to treat DUB. It can be seen that the binding energy of the acacetin, wogonin, baicalein, beta-sitosterol, kaempferol and quercetin in HH docked with the receptor proteins PTGS2, AKT1, TP53, and TNF were far less than −5.0 kJ/mol, which means the molecules have low conformational energy, stable structure and high binding activity. And the result of HPLC analysis showed that acacetin, wogonin, baicalein, kaempferol and quercetin were the potential effective components of the hemostasis mechanism of HH, beta-sitosterol was removed due to low content. In vivo testing of the potential effective components, it revealed that the group of potential effective components identified by HPLC could increase the pain threshold, inhibit the swelling hind paws of mice induced by egg white, reduce the bleeding time and clotting time, reduce uterine bleeding, decrease the uterine weight, increase the content of Ca and ET-1, and reduce the content of NO in uterine homogenate tissue, and decrease of E2 and P content in uterine serum in aborted rats, whose efficacy was equal to HH. ConclusionThe results indicated that HH and potential active ingredient groups obtained from network pharmacology can treat DUB and play a hemostatic effect. The results obtained by network pharmacology have certain reliability. This study provides new indications for further mechanism research of HH on DUB and the development of HH or its components as an alternative therapy for patients with DUB. At the same time, the application of network pharmacology strategy may provide a powerful tool for exploring the mechanism of traditional Chinese medicine and discovering new biologically active ingredients.

Benchmark assessment of molecular geometries and energies from small molecule force fields

Background: Force fields are used in a wide variety of contexts for classical molecular simulation, including studies on protein-ligand binding, membrane permeation, and thermophysical property prediction. The quality of these studies relies on the quality of the force fields used to represent the systems. Methods: Focusing on small molecules of fewer than 50 heavy atoms, our aim in this work is to compare nine force fields: GAFF, GAFF2, MMFF94, MMFF94S, OPLS3e, SMIRNOFF99Frosst, and the Open Force Field Parsley, versions 1.0, 1.1, and 1.2. On a dataset comprising 22,675 molecular structures of 3,271 molecules, we analyzed force field-optimized geometries and conformer energies compared to reference quantum mechanical (QM) data. Results: We show that while OPLS3e performs best, the latest Open Force Field Parsley release is approaching a comparable level of accuracy in reproducing QM geometries and energetics for this set of molecules. Meanwhile, the performance of established force fields such as MMFF94S and GAFF2 is generally somewhat worse. We also find that the series of recent Open Force Field versions provide significant increases in accuracy. Conclusions: This study provides an extensive test of the performance of different molecular mechanics force fields on a diverse molecule set, and highlights two (OPLS3e and OpenFF 1.2) that perform better than the others tested on the present comparison. Our molecule set and results are available for other researchers to use in testing.

Systematic Evaluation of ReaxFF Reactive Force Fields for Biochemical Applications

Four established ReaxFF force fields, trained on biochemical systems, have been systematically benchmarked on 20 proteinogenic amino acids and 11 dipeptides. The force fields were compared with respect to geometries, energetics, and atomic charges of conformers for the amino acids. To assess the performance with respect to reactivity, the condensation reactions for the formation of dipeptides were investigated by calculating the reaction energetics and pathways. We found systematic errors in the torsion angles for the amino acids, with deviations over 100°, and a generally incorrect account of relative energies for amino acid conformers. In describing the reactivity, only one of the force fields could reproduce the reaction energies of amino acid condensations quantitatively. All four force fields predict unphysical mechanisms for these reactions, involving highly unstable intermediate structures, proton transfers involving aliphatic protons, and even five-coordinate carbon atoms. The corresponding energy landscapes exhibit fluctuations on small length scales and artificial minima.

Benchmark assessment of molecular geometries and energies from small molecule force fields.

Background: Force fields are used in a wide variety of contexts for classical molecular simulation, including studies on protein-ligand binding, membrane permeation, and thermophysical property prediction. The quality of these studies relies on the quality of the force fields used to represent the systems. Methods: Focusing on small molecules of fewer than 50 heavy atoms, our aim in this work is to compare nine force fields: GAFF, GAFF2, MMFF94, MMFF94S, OPLS3e, SMIRNOFF99Frosst, and the Open Force Field Parsley, versions 1.0, 1.1, and 1.2. On a dataset comprising 22,675 molecular structures of 3,271 molecules, we analyzed force field-optimized geometries and conformer energies compared to reference quantum mechanical (QM) data. Results: We show that while OPLS3e performs best, the latest Open Force Field Parsley release is approaching a comparable level of accuracy in reproducing QM geometries and energetics for this set of molecules. Meanwhile, the performance of established force fields such as MMFF94S and GAFF2 is generally somewhat worse. We also find that the series of recent Open Force Field versions provide significant increases in accuracy. Conclusions: This study provides an extensive test of the performance of different molecular mechanics force fields on a diverse molecule set, and highlights two (OPLS3e and OpenFF 1.2) that perform better than the others tested on the present comparison. Our molecule set and results are available for other researchers to use in testing.

Thermochemistry of neutral and anionic sulfur fluorides SFn (n = 1–6): Revisited with theoretical G4/W1/W2 composite methods and the roles of metastable conformer of SF4− anion

To augment previous theoretical studies of thermochemical properties such as the electron affinity (EA) and bond dissociation enthalpy (D298o) of neutral and anionic SFn (with n = 1–6), further extensive theoretical computations using Gaussian-4 and Weizmann-1 and Weizmann-2 (G4/W1/W2) methods were carried out with extensive consideration of the role of the metastable conformational isomer of the SF4− anion. The energy of the metastable conformer is 39 kJ/mol higher than that of the global minimum structure, and the barrier height between the metastable conformer and its global minimum was calculated to be 27 kJ/mol by the CCSD(T)/Aug-cc-pvQZ+d//MP2/cc-pvQZ+d method. Many of the discrepancies that have persisted between previous theoretical and experimental data can be explained more adequately by considering the metastable conformer. The difference in the EA calculated using the Gaussian-3 (G3) vs the W2 method for SFn with n = 2–6 ranges from 0.12 eV to 0.21 eV, which is much larger than ±0.041 eV of the expected error for the G3 method. The difference in D298o calculated using G3 vs W2 was also significant in several cases, especially for hypervalent fluorides with n = 3–6. The final results obtained with the W2 procedure are sufficiently converged to a chemical accuracy of ±4 kJ/mol ≈ ±0.04 eV for not only the EA but also D298o, for all neutral and anionic SFn species with n = 1–6.

Cataloguing the Energetic Contributions to the Supramolecular Assembly of para-Substituted N,N′-Diphenylureas and Their Organometallic Derivatives in the Solid State: A Density Functional Theory Approach

Crystal engineering relies on the predictability of the elaborate interplay of cohesive and conformational energies driven by both intra- and intermolecular interactions of the constituent molecules. In an effort to better understand these influences on the crystal packing of para-substituted N,N′-diphenylureas (pDPUs) and organometallic derivatives, we present a detailed computational investigation of pDPU species utilizing solid-state density functional theory (DFT) and demonstrate the applicability of predictive supramolecular synthons applied toward the growth of related organometallic complexes. Dominant noncovalent interactions of pDPUs can be tuned by altering the electron-withdrawing character of the para substituents. The strength of this electron-withdrawing nature governs the inclination of the molecules to form either dominant electrostatic or π-stacking intermolecular interactions in the crystal structure due to potential molecular conformational stabilization through intramolecular C–H···O electrostatic interactions between ortho phenyl hydrogens and the urea oxygen atoms. This propensity is also influenced by the symmetry of para substitutions in mono- and disubstituted DPUs. The results of the holistic DFT investigation show a relationship between gas-phase and solid-state conformations and also present evidence of mechanisms leading to deviations in predicted crystallization behaviors on the basis of the balance of intra- and intermolecular interactions. The foundational computational study was expanded to build on previous experimental and theoretical work involving zerovalent transition-metal complexes in which p-isocyanophenyl DPUs were appended with group IV metal carbonyl fragments. In this study, we synthesized an asymmetric analogue of the latter in which N-(p-isocyanophenyl)-N′-phenylurea (pCNHDPU) was appended to a Mo(CO)5 metal carbonyl fragment, allowing us to associate the crystallization behaviors and interactions of organometallic DPU derivatives with those of simpler pDPUs. It was observed that the supramolecular assembly of the organometallic complexes display similar predictive patterns as well as additional complexities to molecular packing arising from the bulkier metal carbonyl substituents. An inclusive computational categorization of DPU-based systems in complement to experimental data will aid in the advancement of design rules for the patterned crystal growth of DPU and related systems for the development of innovative materials having unique solid-state properties.

CONFORMATIONAL ANALYSIS OF THIAZOLE-5-CARBOXYLIC ACID USING DFT/TD-DFT METHODS

In this work, structures of the conformations of the thiazole-5-carboxylic acid (T5CA) were studied using density functional theory (DFT) with B3LYP/6-311++G(d,p) level of approximation. From calculations of the potential energy distribution depending on the orientation of the carboxylic group (C-C-OH and O=C-OH) attached to the five-membered heterocyclic ring, four conformers were found at minimum energy. Considering that the relative energy in the most stable structure is zero. The relative energies of the other conformations were found to be about 0.14, 27.11, 29.84 kJ mol-1, respectively. It was found that the carboxylic acid group of the T5CA_3 and 4 were not planar, while T5CA_1 and T5CA_2 were planar. Stabilization and donor-acceptor orbital interaction energies were calculated for all conformations and orbitals were plotted using natural bond orbital analysis (NBO) method. The excited state energies were calculated and graphed using Time-Dependent Density Functional Theory (TD-DFT) calculations. The singlet state energies were tabulated for all conformations and it was seen that the most stable form with the highest oscillator strength was at the second singlet state (S2). In addition, HOMO-LUMO energy gaps were calculated and electrostatic potential surface maps were drawn for all conformations.