Nonempirical Prediction of the Relative Electrospray Ionization Efficiencies of Nitroanilines by Combined CBS-QB3 and SCC-DFTB Calculations.

Computational study for three isomeric nitroanilines was carried out to find a nonempirical model to predict their relative ionization efficiencies compared to the corresponding experimental logIE values. The CBS-QB3 method was used for the gas-phase calculations of protonated nitroanilines, and the SCC-DFTB method for the calculations of spherical droplets, containing one protonated nitroaniline molecule, one hydronium cation, and 48 acetonitrile molecules, randomly generated by the PACKMOL program. The obtained results show that neither the gas-phase energy of protonated nitroaniline (or gas-phase basicity) nor the average energy of droplets can be used to predict the ionization efficiency ordering of those isomers. However, the difference of gas-phase and droplet energies gives a good correlation with logIE values and, thus, can be used for the prediction of relative ionization efficiencies.

An Integrated Data-Driven Strategy for Safe-by-Design Nanoparticles: The FP7 MODERN Project.

The development and implementation of safe-by-design strategies is key for the safe development of future generations of nanotechnology enabled products. The safety testing of the huge variety of nanomaterials that can be synthetized is unfeasible due to time and cost constraints. Computational modeling facilitates the implementation of alternative testing strategies in a time and cost effective way. The development of predictive nanotoxicology models requires the use of high quality experimental data on the structure, physicochemical properties and bioactivity of nanomaterials. The FP7 Project MODERN has developed and evaluated the main components of a computational framework for the evaluation of the environmental and health impacts of nanoparticles. This chapter describes each of the elements of the framework including aspects related to data generation, management and integration; development of nanodescriptors; establishment of nanostructure-activity relationships; identification of nanoparticle categories; hazard ranking and risk assessment.

Catalytic effect of cesium cation adduct formation on the decarboxylation of carboxylate ions in the gas phase.

The effect of Cs(+) ligation on the decarboxylation of malonic acids (unsubstituted and methyl-, dimethyl-, ethyl-, and phenyl-substituted) in their carboxylate form was studied in the gas phase using tandem mass spectrometry. The study is based on the comparison of the decarboxylation of the bare monoanion (hydrogen malonates) and of the cesium adduct of the cesium salt (Cs(+) [cesium hydrogen malonates]) under collisional activation. Energy-resolved dissociation curves of the negative and positive ions exhibit major differences. Decarboxylation of the cationic adducts of substituted malonic acid salts occurs at significantly lower collisional activation than for the corresponding bare hydrogen malonate anions. The conclusions from these experiments are supported by DFT calculations. The calculated activation parameters (enthalpy and Gibbs energy) confirm that the cesium cation coordination assists the decarboxylation of the carboxylate form.

Evaluation of alkali metal cation affinities and basicities using extrapolation to the complete basis set limit.

The complete basis set (CBS) extrapolation is used at Hartree-Fock and second-order Møller-Plesset perturbation theory levels and with the def2-xZVP x-ζ basis set (x = 2-4). This approach leads to general, robust, and well-calibrated methods, especially when Hartree-Fock energy (E(HF)) and correlation energies (E(CE)) are extrapolated separately. Indeed, the absolute deviations between theoretical and experimental data are usually smaller than the reported experimental errors. We also point out the need to change usual parameters utilized in CBS methods when calculations involve atoms from third and subsequent rows. The best CBS scheme studied in the current work for obtaining energies for the estimation of alkali metal cation affinities and basicities is E(CBS)[∞] = 1.10529·E(HF)[4] - 0.10529·E(HF)[2] + 0.92703·E(CE)[4] - 0.07297·E(CE)[2], where E(HF)[2], E(HF)[4], E(CE)[2], and E(CE)[4] are the Hartree-Fock energy (E(HF)) and MP2 correlation energies (E(CE)) obtained with def2-QZVP (x = 4) and def2-SV(p) (x = 2) basis sets.

Relativistic effects on acidities and basicities of Brønsted acids and bases containing gold.

It is usually believed that relativistic effects as described by the Dirac-Schrödinger equation (relative to the classical or time-independent Schrödinger equation) are of little importance in chemistry. A closer look, however, reveals that some important and widely known properties (e.g., gold is yellow, mercury is liquid at room temperature) stem from relativistic effects. So far the influence of relativistic effects on the acid-base properties has been mostly ignored. Here we show that at least for compounds of gold such omission is completely erroneous and would lead to too high basicity and too low acidity values with errors in the range of 25-55 kcal mol(-1) (or 20 to 44 powers of ten in pK(a) units) in the gas-phase. These findings have important implications for the design of new superstrong acids and bases, and for the understanding of gold-catalysed reactions.

Dihydrogen generation from amine/boranes: synthesis, FT-ICR, and computational studies.

A Fourier transform ion cyclotron resonance spectrometry (FT-ICR) study of the gas-phase protonation of ammonia-borane and sixteen amine/boranes R(1)R(2)R(3)N-BH(3) (including six compounds synthesized for the first time) has shown that, without exception, the protonation of amine/boranes leads to the formation of dihydrogen. The structural effects on the experimental energetic thresholds of this reaction were determined experimentally. The most likely intermediate and the observed final species (besides H(2)) are R(1)R(2)R(3)N-BH(4)(+) and R(1)R(2)R(3)N-BH(2)(+), respectively. Isotopic substitution allowed the reaction mechanism to be ascertained. Computational analyses ([MP2/6-311+G(d,p)] level) of the thermodynamic stabilities of the R(1)R(2)R(3)N-BH(3) adducts, the acidities of the proton sources required for dihydrogen formation, and the structural effects on these processes were performed. It was further found that the family of R(1)R(2)R(3)N-BH(4)(+) ions is characterized by a three-center, two-electron bond between B and a loosely bound H(2) molecule. Unexpected features of some R(1)R(2)R(3)N-BH(4)(+) ions were found. This information allowed the properties of amine/boranes most suitable for dihydrogen generation and storage to be determined.

Acidity of anilines: calculations vs experiment.

The gas-phase acidities of ca. 60 monosubstituted anilines (with acidity span of almost 50 kcal mol(-1)) have been calculated using density functional theory (DFT) at the B3LYP/6-311+G** level. At this relatively simple level of theory the calculated (ΔG(calc)) and available experimental (ΔG(exp)) acidities are in reasonable quantitative correlation according to the following equation: ΔG(obs) = a + bΔG(calc), where a=20.79, b=0.942, n=27, R(2)=0.990, and s=0.78 kcal·mol(-1). The slope is not far from its ideal value. Substituent effects on the acidities were dissected separately into those operating in the neutral acid molecule and in its conjugated anion using the isodesmic homodesmotic reactions. All in all, both forms, neutral and anionic, are contributing in combination to make up the gross acidity of anilines. However, the contributions of the anions into the gross substituent effects are much larger than the substituent effects in the neutral anilines. Some of the systems were used in testing a relatively new theoretical model, COSMO-RS (conductor-like screening model for real solvents), using it for the prediction of pK(a) values in DMSO. The method proved to be rather accurate for showing pK(a) trends (R(2)=0.980 in DMSO). However, the predicted absolute pK(a) values were all somewhat lower (rmsd=2.49 kcal·mol(-1)) than the respective experimental values.

Computational study on the reactivity of tetrazines toward organometallic reagents.

The possible reaction pathways between methyllithium and disubstituted 1,2,4,5-tetrazines (bearing methyl, methylthio, phenyl, and 3,5-dimethylpyrazolyl groups) were investigated by means of the density functional theory B3LYP/6-31G* method. Solvation was modeled using the supermolecule approach, adding one tetrahydrofuran molecule to the complexes. Comparison of the calculated energies and structures for the alternate azaphilic and nucleophilic addition pathways showed that the azaphilic addition is kinetically favored over nucleophilic addition, while thermodynamically the nucleophilic addition is usually preferred. The coordination of the tetrazine molecule with methyllithium was found to play a crucial role in the process. These findings provide the first rationale for the experimentally observed unique reactivity of tetrazines toward polar organometallic reagents, suggesting the presence of a kinetically controlled process.

Gas-phase basicities around and below water revisited.

This work employs Fourier transform ion cyclotron resonance (FT-ICR) and the Gaussian quantum chemistry composite methods W1 and G2 to experimentally and computationally analyze gas-phase basicities (GB) for a series of weak bases in the basicity region around and below water. The study aims to clarify the long-standing discrepancy between reported GB values for weak bases obtained via high-pressure mass spectrometry (HPMS) and ICR; the ICR scale is observed to be more than 2 times contracted compared to the HPMS scale. The computational results of this work support published HPMS data. This agreement improves with increasing sophistication of the computational method and is excellent at the W1 level. Several equilibria were also re-examined experimentally using FT-ICR. In the experiments with some polyfluorinated weak bases (hexafluoro-2-propanol and nonafluoro-2-methyl-2-propanol), it was found that two protonation processes compete in the gas phase: protonation on oxygen and protonation on fluorine. In these species, protonation on fluorine proceeds faster and is statistically favored over protonation on oxygen but leads to cations that are thermodynamically less stable than oxygen-protonated cations. The process may also lead to the irreversible loss of HF. The rearrangement of fluorine-protonated cations to oxygen-protonated cations is very slow and is further suppressed by the process of HF abstraction. These results at least partially explain the discrepancy between published HPMS data and earlier FT-ICR findings and call for the utmost care in using FT-ICR for gas-phase basicity measurements of heavily fluorinated compounds. The narrower dynamic range of ICR necessitates the measurement of several problematic bases and produces some differences between the ICR results in the present work and the published HPMS data; the wider dynamic range allows HPMS to overcome these difficulties in connecting the ladder.

Predicting Cytotoxicity of Metal Oxide Nanoparticles using Isalos Analytics Platform.

A literature curated dataset containing 24 distinct metal oxide (MexOy) nanoparticles (NPs), including 15 physicochemical, structural and assay-related descriptors, was enriched with 62 atomistic computational descriptors and exploited to produce a robust and validated in silico model for prediction of NP cytotoxicity. The model can be used to predict the cytotoxicity (cell viability) of MexOy NPs based on the colorimetric lactate dehydrogenase (LDH) assay and the luminometric adenosine triphosphate (ATP) assay, both of which quantify irreversible cell membrane damage. Out of the 77 total descriptors used, 7 were identified as being significant for induction of cytotoxicity by MexOy NPs. These were NP core size, hydrodynamic size, assay type, exposure dose, the energy of the MexOy conduction band (EC), the coordination number of the metal atoms on the NP surface (Avg. C.N. Me atoms surface) and the average force vector surface normal component of all metal atoms (v⟂ Me atoms surface). The significance and effect of these descriptors is discussed to demonstrate their direct correlation with cytotoxicity. The produced model has been made publicly available by the Horizon 2020 (H2020) NanoSolveIT project and will be added to the project's Integrated Approach to Testing and Assessment (IATA).

IEF-PCM calculations of absolute pKa for substituted phenols in dimethyl sulfoxide and acetonitrile solutions.

Absolute (nonrelative) pKa calculations for substituted phenols were carried out in nonaqueous media, demonstrating the predictive power of the integral equation formalism PCM method with a mean unsigned error of 0.6 pKa units for DMSO and 0.7 pKa units for MeCN at the B3LYP/6-31+G** level of theory combined with the scaled B3LYP/6-311+G** gas-phase data. At the same time, the correlation between the calculated and experimental pKa values yielded the value of the linear regression slope very close to unity for both DMSO and MeCN. Computation of pKa of neutral acids in nonaqueous solutions with a reasonable precision obviously depends on carefully tuned cavities, optimized for nonaqueous solutions. The ability of continuum solvation model to compensate charge escape from the cavity, which is prominent in the case of anions, is also required. And finally, good quality gas-phase data is essential to achieve required pKa precision.

Computational study of cesium cation interactions with neutral and anionic compounds related to soil organic matter.

The gas-phase cesium cation affinities (CsCAs) and basicities (CsCBs) for 56 simple neutral compounds (mostly aromatic molecules) and 41 anions (carboxylates and phenolates) were calculated using density functional theory (DFT), in the context of the interaction of Cs(+) with soil organic matter (SOM). The B3LYP/def2-TZVP method gives in general CsCAs and CsCBs in a good agreement with experimental data. The strong deviations in case of NO(3)(-) and CsSO(4)(-) anions need further experimental investigations as the high-level CCSD(T) calculations support B3LYP results. Different cesium cation complexation patterns between Cs(+) and the neutral and anionic systems are discussed. As expected, the strongest CsCAs are observed for anions. The corresponding quantities are approximately by 4-5 times higher than for the neutral counterparts, being in the range 90-118 kcal/mol. The weakest cesium cation bonding is observed in the case of unsubstituted aromatic systems (11-15 kcal/mol).

Supramolecular chirogenesis in zinc porphyrins by enantiopure hemicucurbit[n]urils (n = 6, 8).

Chiral cyclohexanohemicucurbit[n]urils (n = 6, 8) (cycHCs) are able to bind guests through multiple "outer surface interactions", which in the case of planar zinc porphyrins leads to induction of chirality. Crystal structures of complexes of complementary sized hosts revealed social self-sorting, while in the solution phase one cycHC can accommodate up to three porphyrin molecules with log Ktotal 9.

Fe-Doped ZnO nanoparticle toxicity: assessment by a new generation of nanodescriptors.

In the search for novel tools to combat cancer, nanoparticles (NPs) have attracted a lot of attention. Recently, the controlled release of cancer-cell-killing metal ions from doped NPs has shown promise, but fine tuning of dissolution kinetics is required to ensure specificity and minimize undesirable toxic side-effects. Theoretical tools to help in reaching a proper understanding and finally be able to control the dissolution kinetics by NP design have not been available until now. Here, we present a novel set of true nanodescriptors to analyze the charge distribution, the effect of doping and surface coating of whole metal oxide NP structures. The polarizable model of oxygen atoms enables light to be shed on the charge distribution on the NP surface, allowing the in detail study of the factors influencing the release of metal ions from NPs. The descriptors and their capabilities are demonstrated on a Fe-doped ZnO nanoparticle system, a system with practical outlook and available experimental data.

Robust Modeling and Scaffold Hopping: Case Study Based on HIV Reverse Transcriptase Inhibitors Type-1 Data.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS occurs across mucosal surfaces or by direct inoculation. OBJECTIVE: The objective of this study was to consider chemically diverse scaffold sets of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) subjected to ideal oriented QSAR with large descriptor space. METHOD: We generated a four-parameter QSAR model based on 111 data points, which provided an optimum prediction of HIV-1 RTI for overall 367 experimentally measured compounds. RESULTS: The robustness of the model is demonstrated by its statistical validation (Ntraining = 111, R2 = 0.85, Q2lmo = 0.84) and by the prediction of HIV-1 inhibition activity for experimentally measured compounds. CONCLUSION: Finally, 5 novel hit compounds were designed in silico by using a virtual screening approach. The new hits met all the pharmacophore constraints and predicted pIC50 values within the binding ability of HIV-1 RT protein targets.

Critical test of some computational methods for prediction of NMR ¹H and ¹³C chemical shifts.

Performance of 18 DFT functionals (B1B95, B3LYP, B3PW91, B97D, BHandHLYP, BMK, CAM-B3LYP, HSEh1PBE, M06-L, mPW1PW91, O3LYP, OLYP, OPBE, PBE1PBE, tHCTHhyb, TPSSh, wB97xD, VSXC) in combinations with six basis sets (cc-pVDZ, aug-cc-pVDZ, cc-pVTZ, aug-cc-pVTZ, IGLO-II, and IGLO-III) and three methods for calculating magnetic shieldings (GIAO, CSGT, IGAIM) was tested for predicting (1)H and (13)C chemical shifts for 25 organic compounds, for altogether 86 H and 88 C atoms. Proton shifts varied between 1.03 ppm to 12.00 ppm and carbon shifts between 7.87 ppm to 209.28 ppm. It was found that the best method for calculating (13)C shifts is PBE1PBE/aug-cc-pVDZ with CSGT or IGAIM approaches (mae = 1.66 ppm), for (1)H the best results were obtained with HSEh1PBE, mPW1PW91, PBE1PBE, CAM-B3LYP, and B3PW91 functionals with cc-pVTZ basis set and with CSGT or IGAIM approaches (mae = 0.28 ppm). We found that often larger basis sets do not give better results for chemical shifts. The best basis sets for calculating (1)H and (13)C chemical shifts were cc-pVTZ and aug-cc-pVDZ, respectively. CSGT and IGAIM NMR approaches can perform really well and are in most cases better than popular GIAO approach.

Gas-phase lithium cation basicity: revisiting the high basicity range by experiment and theory.

According to high level calculations, the upper part of the previously published FT-ICR lithium cation basicity (LiCB at 373 K) scale appeared to be biased by a systematic downward shift. The purpose of this work was to determine the source of this systematic difference. New experimental LiCB values at 373 K have been measured for 31 ligands by proton-transfer equilibrium techniques, ranging from tetrahydrofuran (137.2 kJ mol(-1)) to 1,2-dimethoxyethane (202.7 kJ mol(-1)). The relative basicities (ΔLiCB) were included in a single self-consistent ladder anchored to the absolute LiCB value of pyridine (146.7 kJ mol(-1)). This new LiCB scale exhibits a good agreement with theoretical values obtained at G2(MP2) level. By means of kinetic modeling, it was also shown that equilibrium measurements can be performed in spite of the formation of Li(+) bound dimers. The key feature for achieving accurate equilibrium measurements is the ion trapping time. The potential causes of discrepancies between the new data and previous experimental measurements were analyzed. It was concluded that the disagreement essentially finds its origin in the estimation of temperature and the calibration of Cook's kinetic method.

Theoretical modeling of HPV: QSAR and novodesign with fragment approach.

Structure-activity relationships in a data set of HPV6-E1 helicase ATPase inhibitors were investigated based on two different sets of descriptors. Statistically significant four parameter Quantitative Structure-Activity Relationships (QSAR) models were constructed and validated in both cases (R(2)=0.849; R(2) cv=0.811; F=52.20; s(2)=0.25; N=42). A Fragment based QSAR (FQSAR) approach was applied for developing a fragment-QSAR equation, which enabled the construction of virtual structures for novel ATPase inhibitors with desired or pre-defined activity.

Critical Test of Some Computational Chemistry Methods for Prediction of Gas-Phase Acidities and Basicities.

Gas-phase acidities and basicities were calculated for 64 neutral bases (covering the scale from 139.9 kcal/mol to 251.9 kcal/mol) and 53 neutral acids (covering the scale from 299.5 kcal/mol to 411.7 kcal/mol). The following methods were used: AM1, PM3, PM6, PDDG, G2, G2MP2, G3, G3MP2, G4, G4MP2, CBS-QB3, B1B95, B2PLYP, B2PLYPD, B3LYP, B3PW91, B97D, B98, BLYP, BMK, BP86, CAM-B3LYP, HSEh1PBE, M06, M062X, M06HF, M06L, mPW2PLYP, mPW2PLYPD, O3LYP, OLYP, PBE1PBE, PBEPBE, tHCTHhyb, TPSSh, VSXC, X3LYP. The addition of the Grimmes empirical dispersion correction (D) to B2PLYP and mPW2PLYP was evaluated, and it was found that adding this correction gave more-accurate results when considering acidities. Calculations with B3LYP, B97D, BLYP, B2PLYPD, and PBE1PBE methods were carried out with five basis sets (6-311G**, 6-311+G**, TZVP, cc-pVTZ, and aug-cc-pVTZ) to evaluate the effect of basis sets on the accuracy of calculations. It was found that the best basis sets when considering accuracy of results and needed time were 6-311+G** and TZVP. Among semiempirical methods AM1 had the best ability to reproduce experimental acidities and basicities (the mean absolute error (mae) was 7.3 kcal/mol). Among DFT methods the best method considering accuracy, robustness, and computation time was PBE1PBE/6-311+G** (mae = 2.7 kcal/mol). Four Gaussian-type methods (G2, G2MP2, G4, and G4MP2) gave similar results to each other (mae = 2.3 kcal/mol). Gaussian-type methods are quite accurate, but their downside is the relatively long computational time.

Gas phase acidities of N-substituted amine-boranes.

Complexation energies and acidities of 19 primary, secondary and tertiary amine-boranes were investigated using MP2/6-311+G(d,p) and B3LYP/6-311+G(d,p) methods. Gas phase acidities for free amines were also calculated. Acidity values for studied complexes range from 327.3 to 349.1 kcal mol(-1) and the most acidic are the ones with direct connection between deprotonation center and a π-system. Results obtained by both computational methods are in good agreement with each other and with known experimental data. Addition of BH3 increases the acidity of amines by 30 to 50 kcal mol(-1). This enhancement effect was compared to the respective effect witnessed in phosphine-boranes and traced back to changes of charge delocalization on nitrogen. A question about the structural stability of several deprotonated amine-borane anions in the gas phase was also raised.