CAS Electrophile (El) Nucleophile (Nu) Parameter Unit Value Error log(Val) 818-61-1 2-Hydroxyethyl acrylate 4-Nitrobenzenethiol t1/2(NBT) min 2.45E-01 144-48-9 2-Iodoacetamide 4-Nitrobenzenethiol t1/2(NBT) min 1.83E-03 2682-20-4 2-Methyl-2H-isothiazolin-3-one 4-Nitrobenzenethiol t1/2(NBT) min 1.60E-03 25567-67-3 3-Chloro-1.2-dinitrobenzene 4-Nitrobenzenethiol t1/2(NBT) min 1.25E-02 2497-21-4 4-Hexen-3-one 4-Nitrobenzenethiol t1/2(NBT) min 2.77E-02 26172-55-4 5-Chloro-2-methyl-4-isothiazolin-3-one 4-Nitrobenzenethiol t1/2(NBT) min 5.83E-05 108-24-7 Acetic anhydride 4-Nitrobenzenethiol t1/2(NBT) min 9.83E-04 107-02-8 Acrolein 4-Nitrobenzenethiol t1/2(NBT) min 8.25E-02 100-39-0 Benzyl bromide 4-Nitrobenzenethiol t1/2(NBT) min 4.67E-05 57-57-8 beta-Propiolactone 4-Nitrobenzenethiol t1/2(NBT) min 1.62E-04 88-11-9 Diethylthiocarbamoyl chloride 4-Nitrobenzenethiol t1/2(NBT) min 1.52E-03 886-38-4 Diphenylcyclopropenone 4-Nitrobenzenethiol t1/2(NBT) min 1.05E-05 140-88-5 Ethyl acrylate 4-Nitrobenzenethiol t1/2(NBT) min 7.70E-01 50-00-0 Formaldehyde 4-Nitrobenzenethiol t1/2(NBT) min 1.25E-03 55965-84-9 Kathon CG 4-Nitrobenzenethiol t1/2(NBT) min 2.17E-04 124-63-0 Methyl sulfonyl chloride 4-Nitrobenzenethiol t1/2(NBT) min 7.67E-04 128-53-0 N-Ethylmaleimide 4-Nitrobenzenethiol t1/2(NBT) min 3.33E-04 Nitrobenzyl bromide 4-Nitrobenzenethiol t1/2(NBT) min 9.83E-06 15646-46-5 Oxazolone 4-Nitrobenzenethiol t1/2(NBT) min 9.00E-06 106-51-4 p-Benzoquinone 4-Nitrobenzenethiol t1/2(NBT) min 7.33E-06 1939-99-7 Phenylmethanesulfonyl chloride 4-Nitrobenzenethiol t1/2(NBT) min 6.00E-03 2892-51-5 Squaric acid 4-Nitrobenzenethiol t1/2(NBT) min 6.12E-02 584-84-9 Toluene 2.4-diisocyanate 4-Nitrobenzenethiol t1/2(NBT) min 4.50E-04 23726-91-2S2 Schwöbel et al.

A model has been developed to predict the kinetic rate constants (k(GSH)) of α,β-unsaturated Michael acceptor compounds for their reaction with glutathione (GSH). The model uses the local charge-limited electrophilicity index ω(q) [Wondrousch, D., et al. (2010) J. Phys. Chem. Lett. 1, 1605-1610] at the β-carbon atom as a descriptor of reactivity, a descriptor for resonance stabilization of the transition state, and one for steric hindrance at the reaction sites involved. Overall, the Michael addition model performs well (r² = 0.91; rms = 0.34). It includes various classes of compounds with double and triple bonds, linear and cyclic systems, and compounds with and without substituents in the α-position. Comparison of experimental and predicted rate constants demonstrates even better performance of the model for individual classes of compounds (e.g., for aldehydes, r² = 0.97 and rms = 0.15; for ketones, r² = 0.95 and rms = 0.35). The model also allows for the prediction of the RC₅₀ values from the Schultz chemoassay, the accuracy being close to the interlaboratory experimental error. Furthermore, k(GSH) and associated RC₅₀ values can be predicted in cases where experimental measurements are not possible or restricted, for example, because of low solubility or high volatility. The model has the potential to provide information to assist in the assessment and categorization of toxicants and in the application of integrated testing strategies.

A quantum chemical model is introduced to predict the H-bond donor strength of monofunctional organic compounds from their ground-state electronic properties. The model covers -OH, -NH, and -CH as H-bond donor sites and was calibrated with experimental values for the Abraham H-bond donor strength parameter A using the ab initio and density functional theory levels HF/6-31G** and B3LYP/6-31G**. Starting with the Morokuma analysis of hydrogen bonding, the electrostatic (ES), polarizability (PL), and charge transfer (CT) components were quantified employing local molecular parameters. With hydrogen net atomic charges calculated from both natural population analysis and the ES potential scheme, the ES term turned out to provide only marginal contributions to the Abraham parameter A, except for weak hydrogen bonds associated with acidic -CH sites. Accordingly, A is governed by PL and CT contributions. The PL component was characterized through a new measure of the local molecular hardness at hydrogen, eta(H), which in turn was quantified through empirically defined site-specific effective donor and acceptor energies, EE(occ) and EE(vac). The latter parameter was also used to address the CT contribution to A. With an initial training set of 77 compounds, HF/6-31G** yielded a squared correlation coefficient, r(2), of 0.91. Essentially identical statistics were achieved for a separate test set of 429 compounds and for the recalibrated model when using all 506 compounds. B3LYP/6-31G** yielded slightly inferior statistics. The discussion includes subset statistics for compounds containing -OH, -NH, and active -CH sites and a nonlinear model extension with slightly improved statistics (r(2) = 0.92).

A quantum chemical model has been developed for predicting the hydrogen bond (HB) acceptor strength of monofunctional organic compounds from electronic ground-state properties of the single molecules. Local molecular parameters are used to quantify electrostatic, polarizability, and charge transfer components to hydrogen bonding, employing the ab initio and density functional theory levels HF/6-31G** and B3LYP/6-31G**. The model can handle lone pairs of intermediate and strong HB acceptor heteroatoms (N, O, S) as well as of weak HB acceptor halogens (F, Cl, Br) and includes also olefinic, alkyne, and aromatic pi-bonds as weak HB acceptor sites. The model calibration with 403 compounds and experimental values for the Abraham HB acceptor strength B yielded squared correlation coefficients r(2) around 0.95, outperforming existing fragment-based schemes. Model validation was performed applying a leave-50%-out procedure, yielding predictive squared correlation coefficients q(2) of around 0.95 for the subsets that both cover the whole chemical domain as well as (almost) the whole target value range of the data set.

Kinetic rate constants (k(GSH)) for the reaction of compounds acting as Michael acceptors with glutathione (GSH) were modelled by quantum chemical transition-state calculations at the B3LYP/6-31G** and B3LYP/TZVP level. The data set included α, β-unsaturated aldehydes, ketones and esters, with double bonds and triple bonds, linear and cyclic systems, both with and without substituents in the α-position. Predicted values for k(GSH) were found to be in good agreement with experimental k(GSH) values. Factors affecting rate constants have been elucidated, especially solvent effects and the influence of steric hindrance. Solvent effects were examined by adding explicit solvent molecules to the system and by using a polarizable continuum solvent model. Detailed analysis of transition-state energies shows that the reaction is reversible. The reactive enolic intermediate plays an important role in Michael addition to GSH, while the subsequent keto-enol-tautomerism is not rate limiting.

Hydrogen bonding affects the partitioning of organic compounds between environmental and biological compartments as well as the three-dimensional shape of macromolecules. Using the semiempirical quantum chemical AM1 level of calculation, we have developed a model to predict the site-specific hydrogen bond (HB) acceptor strength from ground-state properties of the individual compounds. At present, the model parametrization is confined to compounds with one HB acceptor site of the following atom types: N, O, S, F, Cl, and Br that act as lone-pair HB acceptors, and pi-electron (aromatic or conjugated) systems with the associated C atoms as particularly weak HB acceptors. The HB acceptor strength is expressed in terms of the Abraham parameter B and calculated from local molecular parameters, taking into account electrostatic, polarizability, and charge transfer contributions according to the Morokuma concept. For a data set of 383 compounds, the squared correlation coefficient r2 is 0.97 when electrostatic potential (ESP) derived net atomic charges are employed, and the root-mean-square (rms) error is 0.04 that is in the range of experimental uncertainty. The model is validated using an extended leave-50%-out approach, and its performance is comparatively analyzed with the ones of earlier introduced ab initio (HF/6-31G**) and density functional theory (B3LYP/6-31G**) models as well as of two increment methods with respect to the total compound set as well as HB acceptor type subsets. The discussion includes an explorative model application to amides and organophosphates that demonstrates the robustness of the approach, and further opportunities for model extensions.

A novel combination of quantum chemistry, statistical thermodynamics and state sampling yields an efficient predictive method for the simulation of complex, self-organizing liquid systems.

Hydrogen bonding has a great impact on the partitioning of organic compounds in biological and environmental systems as well as on the shape and functionality of macromolecules. Electronic characteristics of single molecules, localized at the H-bond (HB) donor site, are able to estimate the donor strength in terms of the Abraham parameter A. The quantum chemically calculated properties encode electrostatic, polarizability, and charge-transfer contributions to hydrogen bonding. A recently introduced respective approach is extended to amides with more than one H atom per donor site, and adapted to the semi-empirical AM1 scheme. For 451 organic compounds covering acidic -CH, -NH-, and -OH groups, the squared correlation coefficient is 0.95 for the Hartree-Fock and density functional theory (B3LYP) level of calculation, and 0.84 with AM1. The discussion includes separate analyses for weak, moderate, and strong HB donors, a comparison with the performance of increment methods, and opportunities for consensus modeling through the combined use of increment and quantum chemical methods.where the compound parameters V, E, S, A, and B characterize various types of molecular interactions, and the coefficients v, e, s, a, b, and c encode respective properties of the specific solvent system. V is the McGowan characteristic volume, E is related to the excess molar refraction of the compound, and S is supposed to cover dipolarity and polarizability. Parameter A characterizes the HB donor strength (HB acidity), while B characterizes the HB acceptor strength (HB basicity). This communication deals with the Abraham descriptor A. Further details of the other parameters are described elsewhere. [12,13] Recently, Gilli et al. reported a new method to predict HB strengths by a pK a slide rule with separate scales for HB donors and acceptors. [14] It demonstrates the general interest in methods to predict HB donor and acceptor strengths of chemical compounds from molecular structure.A fast fragment method has been developed for the HB donor strength in the Abraham scale A, based on twodimensional (2D) topological information. [15,16] An independent form of the original model has been implemented into the ChemProp software and analyzed with respect to its prediction performance. [17,18] An updated version is available through easy-to-handle commercial ADME prediction software, [19] but the implemented Absolv module is proprietary and uses unpublished parameters. Independently from the approaches above, Sheldon et al. developed a simple fragment method, based on 41 UNIFAC (wileyonlinelibrary.com) a A min ¼ minimum of experimental A values, A mean ¼ mean of experimental A values, A max ¼ maximum of experimental A values. b In addition, the dataset contained the potentially CH-acidic compounds cinnoline, acetone, methylphenyl sulfoxide and ethylphenyl methanesulfonate; their particular experimental HB donor strength A is 0.00 (acetone A ¼ 0.04).