Comment on "Causation or only correlation? Application of causal inference graphs for evaluating causality in nano-QSAR models" by N. Sizochenko, A. Gajewicz, J. Leszczynski and T. Puzyn, Nanoscale, 2016, 8, 7203.

In this comment we show that the accuracy of a recent nano-QSAR model for toxicity predictions of metal oxide nanoparticles towards bacteria E. coli can be greatly improved. On one hand, the experimental ionization energies of metal atoms could be substituted for the erroneous semi-empirically derived heat of formation values of metal ions as descriptors to construct a more reliable nano-QSAR model based on weighted linear least-squares fittings. On the other hand, if no experimental data is available, a model relying on ionization energy descriptors from quantum chemical calculations could also be used producing exactly the same toxicity values as the experimental model.

Definitive thermochemistry and kinetics of the interconversions among conformers of n-butane and n-pentane.

The focal-point analysis (FPA) technique is used for the definitive characterization of conformational interconversion parameters, including activation energy barriers, activation free energies, and kinetic rate coefficients at 298 K, of two n-alkanes, n-butane, and n-pentane, yielding the first complete analysis of their interconversion kinetics. The FPA implementation developed in this study is based on geometry optimizations and harmonic frequency computations carried out with density functional theory methods and single-point energy computations up to the CCSD(T) level of electronic structure theory using atom-centered Gaussian basis sets as large as cc-pV5Z. The anharmonic vibrational computations are carried out, at the MP2/6-31G* level of theory. Reflecting the convergence behavior of the Gibbs free-energy terms and the interconversion parameters, well-defined uncertainties, mostly neglected in previous theoretical studies, are provided. Finally, the effect of these uncertainties on the concentrations of the conformers of n-butane and n-pentane is examined via a global Monte-Carlo uncertainty analysis. © 2017 Wiley Periodicals, Inc.

Enthalpy Differences of the n-Pentane Conformers.

The energy and enthalpy differences of alkane conformers in various temperature ranges have been the subject for both experimental and theoretical studies over the last few decades. It was shown previously for the conformers of butane [G. Tasi et al., J. Chem. Theory Comput. 2012, 8, 479-486] that quantum chemical results can compete with spectroscopic techniques and results obtained even from the most carefully performed experiments could be biased due to the improper statistical model utilized to evaluate the raw experimental data. In the current study, on one hand, the experimental values and their uncertainties for the enthalpy differences for pentane conformers are re-evaluated using the appropriate statistical model. On the other hand, a coupled-cluster-based focal-point analysis has been performed to calculate energy and enthalpy differences for the conformers of pentane. The model chemistry defined in this study includes contributions up to the perturbative quadruple excitations augmented with further small correction terms beyond the Born-Oppenheimer and nonrelativistic approximations. Benchmark quality energy and enthalpy differences for the pentane conformers are given at temperatures 0 and 298.15 K as well as for the various temperature ranges used in the gas-phase experimental measurements. Furthermore, a slight positive shift for the experimental enthalpy differences is also predicted due to an additional Raman active band belonging to the gauche-gauche conformer.

Benchmarking Experimental and Computational Thermochemical Data: A Case Study of the Butane Conformers.

Due to its crucial importance, numerous studies have been conducted to determine the enthalpy difference between the conformers of butane. However, it is shown here that the most reliable experimental values are biased due to the statistical model utilized during the evaluation of the raw experimental data. In this study, using the appropriate statistical model, both the experimental expectation values and the associated uncertainties are revised. For the 133-196 and 223-297 K temperature ranges, 668 ± 20 and 653 ± 125 cal mol(-1), respectively, are recommended as reference values. Furthermore, to show that present-day quantum chemistry is a favorable alternative to experimental techniques in the determination of enthalpy differences of conformers, a focal-point analysis, based on coupled-cluster electronic structure computations, has been performed that included contributions of up to perturbative quadruple excitations as well as small correction terms beyond the Born-Oppenheimer and nonrelativistic approximations. For the 133-196 and 223-297 K temperature ranges, in exceptional agreement with the corresponding revised experimental data, our computations yielded 668 ± 3 and 650 ± 6 cal mol(-1), respectively. The most reliable enthalpy difference values for 0 and 298.15 K are also provided by the computational approach, 680.9 ± 2.5 and 647.4 ± 7.0 cal mol(-1), respectively.

High-accuracy theoretical thermochemistry of atmospherically important sulfur-containing molecules.

In this study, several sulfur-containing molecules with atmospherical importance were investigated by means of high-accuracy quantum chemical calculations including: HSO, HOS, HOSO2, HSNO, SH, CH2SO, CH2SH, S2COH, and SCSOH. After identifying the stable conformers of the molecules, a coupled-cluster-based composite model chemistry, which includes contributions up to quadruple excitations as well as corrections beyond the nonrelativistic and Born­Oppenheimer approximations, was applied to calculate the corresponding heat of formation (Δ(f)H(0)° and Δ(f)H(298)°) and entropy (S(298)°) values. In most of the cases, this study delivers more reliable estimates for the investigated thermodynamic properties than those reported in previous investigations. Our data also suggest that the experimental heats of formation associated with the HSO molecule are very likely to belong to its structural isomer, HOS. It is also confirmed by the calculated thermodynamic properties including standard reaction entropies, enthalpies, and equilibrium constants that, in the reaction CS2 + OH CS2OH, the SCSOH structural isomer is produced. It is also noted that the currently accepted Δ(f)H(0)°(S(gas)) = 274.73 ± 0.3 kJ/mol value is in need of revision, and based on a recent measurement, which is also confirmed by our computations, it is advised to update it to Δ(f)H(0)°(S(gas)) = 277.25 ± 0.3 kJ/mol.

High-accuracy theoretical study on the thermochemistry of several formaldehyde derivatives.

In the case of several formaldehyde derivatives, with importance in atmospheric and combustion chemistry, the currently available thermochemical values suffer from considerably large uncertainties. In this study a high-accuracy theoretical model chemistry has been used to provide accurate thermochemical data including heats of formation at 0 and 298 K and standard molar entropies at 298 K for CF(2)O, FCO, HFCO, HClCO, FClCO, HOCO, and NH(2)CO. For most of the thermochemical quantities studied here, this investigation delivers the best available estimate.

Adiabatic Jacobi corrections on the vibrational energy levels of H2(+) isotopologues.

The effect of an adiabatic approximation, named adiabatic Jacobi correction (AJC) and introduced in J. Chem. Phys. 126, 024102 (2007), was investigated on the complete set of vibrational levels of H(2)(+) and its isotopologues, most importantly on the highest-lying vibrational states of HD(+). In order to perform clamped nuclei calculations employing finite nuclear masses a constrained Hamiltonian has been derived utilizing interparticle coordinates. The Born-Oppenheimer (BO) potential, the adiabatic potential obtained after taking into account the traditional diagonal Born-Oppenheimer correction (DBOC), as well as the AJC-corrected potential have been determined by an accurate fitting to computed energy values. These potentials were included in one-dimensional variational computations and yielded the complete set of energy levels for H(2)(+), D(2)(+), and HD(+). A detailed investigation of the potential and the complete set of vibrational energy levels show the merits and the deficiencies of the BO, DBOC, and AJC treatments. In particular, it is shown that the AJC corrections are systematically smaller and have a different distance dependence than the DBOC corrections. For a large part of the spectrum of H(2)(+) and its isotopologues the adiabatic correction to the vibrational energy levels is smaller than the nonadiabatic correction, the adiabatic DBOC correction has the highest overall accuracy for the prediction of vibrational energy levels, it is surpassed by the AJC correction only for the highest energy levels of HD(+), and thus the use of the AJC correction is clearly the best choice only for states close to the dissociation limit of nonsymmetric isotopologues.

The effect of electron correlation on the conformational space of melatonin.

The pineal gland hormone melatonin regulates several physiological processes including circadian rhythm and also alleviates oxidative stress-induced degenerative diseases. In spite of its important biological roles, no high level ab initio conformational study has been conducted to reveal its structural features. In this work, the conformational flexibility of melatonin was investigated using correlated ab initio calculations. Conformers, obtained previously at the Hartree-Fock level (HF/6-31G*), were fully optimized using second order Møller-Plesset perturbation theory applying the frozen core approximation (MP2(FC)/6-31G*). Furthermore, single-point MP4(SDQ,FC)/6-31G*//MP2(FC)/6-31G* computations were performed to investigate the effect of higher order perturbation terms. The HF and MP2 conformational spaces are considerably different: the initial 128 structures converged into 102 different local minima as confirmed by frequency calculations; 28 new minima appeared and 26 previous HF local minima disappeared; no "all-trans" C3 side chain conformations are seen at the MP2(FC) level. The MP2 global minimum conformation is stabilized by an aromatic-side chain interaction.

Semispectroscopic and quantitative structure-property relationship estimates of the equilibrium and vibrationally averaged structure and dipole moment of 1-buten-3-yne.

Systematic quantum chemical calculations have been performed to obtain precise estimates of the equilibrium and vibrationally averaged molecular structure and electric dipole moment of vinylacetylene (VA, 1-buten-3-yne). Anharmonic (cubic and semi-diagonal quartic) MP2/cc-pVTZ force fields in normal coordinates were computed to account for anharmonic vibrational effects, including zero-point contributions to the rotational constants and the electric dipole moment. A simultaneous weighted least-squares structural refinement was performed, resulting in the best semispectroscopic estimate of the re structure of VA. The refinement was based on experimentally measured ground-state rotational constants of two isotopologs of VA corrected to equilibrium values using MP2/cc-pVTZ vibration-rotation interaction constants and all-electron CCSD(T)/aug-cc-pVTZ structural constraints. The semispectroscopic re structure of VA agrees excellently with the high-level CCSD(T)/aug-cc-pVTZ ab initio structure. The most dependable, CCSD(T)/cc-pVQZ//CCSD(T)/aug-cc-pVTZ equilibrium electric dipole moment of VA, in D, is mua= 0.4088, mub= 0.0004, and muc= 0. The vibrationally corrected a-component of 0.4214 D is in excellent agreement with one of the available experimental values. The present analysis shows that mub is negligible even after vibrational correction. A simple quantitative structure-property relationship (QSPR) model resulted in a highly similar estimate, 0.45 D, for the electric dipole moment of VA.

1,5-Hydride shift in Wolff-Kishner reduction of (20R)-3beta,20, 26-trihydroxy-27-norcholest-5-en-22-one: synthetic, quantum chemical, and NMR studies.

Heating (20R)-3beta,20,26-trihydroxy-27-norcholest-5-en-22-one (1) with hydrazine and KOH at 160 degrees C completely converted the steroid to a diastereoisomeric mixture of the new (20R,22RS)-27-norcholest-5-ene-3beta,20,22-triols (2). Exclusive formation of 2 suggests that the expected Wolff-Kishner reduction to a methylene group at the C-22 ketone in 1 was diverted to the C-26 position by a 1,5-hydride shift. All attempts under acid conditions failed to produce a C-22 phenyl hydrazone from 1. However, reaction of 1 was reacted with phenylhydrazine in hot KOH, gave the C-26 phenylhydrazone 4 as the sole product. Evidently, under alkaline conditions, first a hydride ion undergoes an intramolecular transfer from the C-26 CH(2)OH group to the C-22 ketone in 1, and then the phenylhydrazine traps the newly formed aldehyde. To examine this hypothesis, we constructed computer-simulated transition state models from quantum chemical calculations and then compared data from these models with NMR measurements of the reaction mixtures containing 2. The NMR data showed that the C-22 diastereoisomers of 2 are formed in a nearly 1:1 ratio exactly as predicted from the energy-optimized transition states, which were calculated for intramolecular 1,5-hydride shifts that produced each of the two C-22 diastereoisomers. Accordingly, these results support the hypothesis that an intramolecular 1,5-hydride shift mechanism promotes complete conversion of 1 to 2 under classical Wolff-Kishner reduction conditions.