Automatic Potential Energy Surface Exploration by Accelerated Reactive Molecular Dynamics Simulations: From Pyrolysis to Oxidation Chemistry.

Automatic potential energy surface (PES) exploration is important to a better understanding of reaction mechanisms. Existing automatic PES mapping tools usually rely on predefined knowledge or computationally expensive on-the-fly quantum-chemical calculations. In this work, we have developed the PESmapping algorithm for discovering novel reaction pathways and automatically mapping out the PES using merely one starting species is present. The algorithm explores the unknown PES by iteratively spawning new reactive molecular dynamics (RMD) simulations for species that it has detected within previous RMD simulations. We have therefore extended the RMD simulation tool ChemTraYzer2.1 (Chemical Trajectory Analyzer, CTY) for this PESmapping algorithm. It can generate new seed species, automatically start replica simulations for new pathways, and stop the simulation when a reaction is found, reducing the computational cost of the algorithm. To explore PESs with low-temperature reactions, we applied the acceleration method collective variable (CV)-driven hyperdynamics. This involved the development of tailored CV templates, which are discussed in this study. We validate our approach for known pathways in various pyrolysis and oxidation systems: hydrocarbon isomerization and dissociation (C4H7 and C8H7 PES), mostly dominant at high temperatures and low-temperature oxidation of n-butane (C4H9O2 PES) and cyclohexane (C6H11O2 PES). As a result, in addition to new pathways showing up in the simulations, common isomerization and dissociation pathways were found very fast: for example, 44 reactions of butenyl radicals including major isomerizations and decompositions within about 30 min wall time and low-temperature chemistry such as the internal H-shift of RO2 → QO2H within 1 day wall time. Last, we applied PESmapping to the oxidation of the recently proposed biohybrid fuel 1,3-dioxane and validated that the tool could be used to discover new reaction pathways of larger molecules that are of practical use.

Blind prediction of toluene/water partition coefficients using COSMO-RS: results from the SAMPL9 challenge.

Accurately predicting partition coefficients log P is crucial for reducing costs and accelerating drug design as it provides valuable information about the bioavailability, pharmacokinetics, and toxicity of different drug candidates. However, the performance of the existing methods is ambiguous, making it unclear whether these methods can be effectively utilized in drug discovery. To assess the performance of these methods, a series of SAMPL challenges have been conducted over the past few years, aiming to enable the development and validation of predictive models. In this study, we present two independent contributions to the SAMPL9 challenge for predicting the toluene/water partition coefficients for 16 molecules. Both submissions, A and B, use the COSMO-RS approach, albeit in slightly different procedures, to compute the transfer free energies from water to toluene of the molecules presented in the challenge, and consequently, their corresponding log P values. Based on the results, COSMO-RS submission A achieves the top position with an R2 value of 0.93 while it ranks second in terms of root-mean-square error (RMSE) with a value of 1.23 log P units. COSMO-RS submission B achieves an R2 value of 0.83 and an RMSE value of 1.48 log P units. Following the challenge, we predict the log P values using a neural network model, which was pre-trained on COSMO-RS data achieving an R2 of 0.92 and RMSE of 1.04 log P units. Compared to previous SAMPL challenges, all contributions displayed large deviations in predicting the toluene/water partition coefficient. These large deviations emphasize that further research is needed to develop accurate and reliable methods for modeling solvent effects on small molecule transfer-free energies.

The first HyDRA challenge for computational vibrational spectroscopy.

Vibrational spectroscopy in supersonic jet expansions is a powerful tool to assess molecular aggregates in close to ideal conditions for the benchmarking of quantum chemical approaches. The low temperatures achieved as well as the absence of environment effects allow for a direct comparison between computed and experimental spectra. This provides potential benchmarking data which can be revisited to hone different computational techniques, and it allows for the critical analysis of procedures under the setting of a blind challenge. In the latter case, the final result is unknown to modellers, providing an unbiased testing opportunity for quantum chemical models. In this work, we present the spectroscopic and computational results for the first HyDRA blind challenge. The latter deals with the prediction of water donor stretching vibrations in monohydrates of organic molecules. This edition features a test set of 10 systems. Experimental water donor OH vibrational wavenumbers for the vacuum-isolated monohydrates of formaldehyde, tetrahydrofuran, pyridine, tetrahydrothiophene, trifluoroethanol, methyl lactate, dimethylimidazolidinone, cyclooctanone, trifluoroacetophenone and 1-phenylcyclohexane-cis-1,2-diol are provided. The results of the challenge show promising predictive properties in both purely quantum mechanical approaches as well as regression and other machine learning strategies.

A Reactive Molecular Dynamics Study of Chlorinated Organic Compounds. Part II: A ChemTraYzer Study of Chlorinated Dibenzofuran Formation and Decomposition Processes.

The front cover artwork is provided by Prof. K. Leonhard's group at RWTH Aachen University. The image shows ChemTraYzer, a virtual robot, while analyzing the reaction network related to the formation and oxidation of Chloro-Dibenzofuranes. Read the full text of the Research Article at 10.1002/cphc.202200783.

Improved modeling of anharmonicity for furan microsolvation.

Computational benchmark data for complexes requires accurate models of anharmonic torsional motion. State-of-the-art hindered rotor treatments come with a number of difficulties, regarding discontinuities from badly converged points or coupling, oscillations, or the consideration and correction of stationary points. Their manual handling introduces a level of arbitrariness not suitable for benchmark procedures. This study presents the TAMkinTools extension for improved modeling of one-dimensional hindered rotation which enables a more standardized workflow. We choose the structures from the Goebench challenge as test case, which comprises OH- and π-bonded complexes of methanol and furan, 2-methylfuran, and 2,5-dimethylfuran. Ahlrichs and Dunning basis sets of various sizes and their extrapolations show large differences in efficiency and accuracy for coupled-cluster energies of stationary points of these complexes. The probability density analysis of TAMkinTools provides zero-point energies for all conformations even within the same rotor profile. Zero-point energies show a large effect on the conformational order, especially for the methanol-furan complex with energy differences far below 1 kJ mol-1.

Influence of Oxygen Atoms and Ring Strain on the Low-Temperature Oxidation Pathways of 1,3-Dioxolane.

Biohybrid fuels are a promising solution for making the transportation sector more environmentally friendly. One such interesting fuel candidate is 1,3-dioxolane, which can be produced from inedible biomass. However, very little kinetics data are available for the low-temperature oxidation of this fuel molecule. To remedy this, we present the reaction kinetics of O2 addition to 1,3-dioxolanyl radicals in this work. All energies have been calculated at the DLPNO-CCSD(T)/CBS//B2PLYPD3BJ/6-311+g(d,p) level of theory. Temperature- and pressure-dependent reaction rate constants have been calculated with the RRKM/master equation method. The effects of heterocyclic oxygen atoms and ring strain on the low-temperature oxidation of 1,3-dioxolane are also compared to that of similar fuel molecules containing five heavy atoms: cyclopentane, tetrahydrofuran, and diethyl ether (DEE). The ring-opening ß-scission reactions of the dioxolane hydroperoxy species are found to be the most dominant pathways following the oxidation of 1,3-dioxolanyl radicals. The heterocyclic oxygen atoms in 1,3-dioxolane weaken its C-O bonds, which leads to low barrier heights of the ring-opening reactions. Ring strain in 1,3-dioxolane increases the barriers for isomerization reactions of peroxy radicals compared to the similar reactions of DEE, which has a chain structure.

Geometrical benchmarking and analysis of redox potentials of copper(I/II) guanidine-quinoline complexes: Comparison of semi-empirical tight-binding and DFT methods and the challenge of describing the entatic state (part III).

Copper guanidine-quinoline complexes are an important class of bioinorganic complexes that find utilization in electron and atom transfer processes. By substitution of functional groups on the quinoline moiety the electron transfer abilities of these complexes can be tuned. In order to explore the full substitution space by simulations, the accurate theoretical description of the effect of functional groups is essential. In this study, we compare three different methods for the theoretical description of the structures. We use the semi-empirical tight-binding method GFN2-xTB, the density functional TPSSh and the double-hybrid functional B2PLYP. We evaluate the methods on five different complex pairs (Cu(I) and Cu(II) complexes), and compare how well calculated energies can predict the redox potentials. We find even though B2PLYP and TPSSh yield better accordance with the experimental structures. GFN2-xTB performs surprisingly well in the geometry optimization at a fraction of the computational cost. TPSSh offers a good compromise between computational cost and accuracy of the redox potential for real-life complexes.

A Comparative Study on the Combustion Chemistry of Two Bio-hybrid Fuels: 1,3-Dioxane and 1,3-Dioxolane.

Bio-hybrid fuels are a promising solution to accomplish a carbon-neutral and low-emission future for the transportation sector. Two potential candidates are the heterocyclic acetals 1,3-dioxane (C4H8O2) and 1,3-dioxolane (C3H6O2), which can be produced from the combination of biobased feedstocks, carbon dioxide, and renewable electricity. In this work, comprehensive experimental and numerical investigations of 1,3-dioxane and 1,3-dioxolane were performed to support their application in internal combustion engines. Ignition delay times and laminar flame speeds were measured to reveal the combustion chemistry on the macroscale, while speciation measurements in a jet-stirred reactor and ethylene-based counterflow diffusion flames provided insights into combustion chemistry and pollutant formation on the microscale. Comparing the experimental and numerical data using either available or proposed kinetic models revealed that the combustion chemistry and pollutant formation differ substantially between 1,3-dioxane and 1,3-dioxolane, although their molecular structures are similar. For example, 1,3-dioxane showed higher reactivity in the low-temperature regime (500-800 K), while 1,3-dioxolane addition to ethylene increased polycyclic aromatic hydrocarbons and soot formation in high-temperature (>800 K) counterflow diffusion flames. Reaction pathway analyses were performed to examine and explain the differences between these two bio-hybrid fuels, which originate from the chemical bond dissociation energies in their molecular structures.

A Reactive Molecular Dynamics Study of Chlorinated Organic Compounds. Part II: A ChemTraYzer Study of Chlorinated Dibenzofuran Formation and Decomposition Processes.

In our two-paper series, we first present the development of ReaxFF CHOCl parameters using the recently published ParAMS parametrization tool. In this second part, we update the reactive Molecular Dynamics - Quantum Mechanics coupling scheme ChemTraYzer and combine it with our new ReaxFF parameters from Part I to study formation and decomposition processes of chlorinated dibenzofurans. We introduce a self-learning method for recovering failed transition-state searches that improves the overall ChemTraYzer transition-state search success rate by 10 percentage points to a total of 48 %. With ChemTraYzer, we automatically find and quantify more than 500 reactions using transition state theory and DFT. Among the discovered chlorinated dibenzofuran reactions are numerous reactions that are new to the literature. In three case studies, we discuss the set of reactions that are most relevant to the dibenzofuran literature: (i) bimolecular reactions of the chlorinated-dibenzofuran precursors phenoxy radical and 1,3,5-trichlorobenzene, (ii) dibenzofuran chlorination and pyrolysis, and (iii) oxidation of chlorinated dibenzofurans.

A Reactive Molecular Dynamics Study of Chlorinated Organic Compounds. Part I: Force Field Development.

This work presents a novel parametrization for the ReaxFF formalism as a means to investigate reaction processes of chlorinated organic compounds. Force field parameters cover the chemical elements C, H, O, Cl and were obtained using a novel optimization approach involving relaxed potential energy surface scans as training targets. The resulting ReaxFF parametrization shows good transferability, as demonstrated on two independent ab initio validation sets. While this first part of our two-paper series focuses on force field parametrization, we apply our parameters to the simulation of chlorinated dibenzofuran formation and decomposition processes in Part II.

Completely Computational Model Setup for Spectroscopic Techniques: The Ab Initio Molecular Dynamics Indirect Hard Modeling Approach.

The spectroscopic quantification of mixture compositions usually requires pure compounds and mixtures of known compositions for calibration. Since they are not always available, methods to fill such gaps have evolved, which are, however, not generally applicable. Therefore, calibration can be extremely challenging, especially when multiple unstable species, for example, intermediates, exist in a system. This study presents a new calibration approach that uses ab initio molecular dynamics (AIMD)-simulated spectra to set up and calibrate models for the physics-based spectral analysis method indirect hard modeling (IHM). To demonstrate our approach called AIMD-IHM, we analyze Raman spectra of ternary hydrogen-bonding mixtures of acetone, methanol, and ethanol. The derived AIMD-IHM pure-component models and calibration coefficients are in good agreement with conventionally generated experimental results. The method yields compositions with prediction errors of less than 5% without any experimental calibration input. Our approach can be extended, in principle, to infrared and NMR spectroscopy and allows for the analysis of systems that were hitherto inaccessible to quantitative spectroscopic analysis.

Efficient Reaction Space Exploration with ChemTraYzer-TAD.

The development of a reaction model is often a time-consuming process, especially if unknown reactions have to be found and quantified. To alleviate the reaction modeling process, automated procedures for reaction space exploration are highly desired. We present ChemTraYzer-TAD, a new reactive molecular dynamics acceleration technique aimed at efficient reaction space exploration. The new method is based on the basin confinement strategy known from the temperature-accelerated dynamics (TAD) acceleration method. Our method features integrated ChemTraYzer bond-order processing steps for the automatic and on-the-fly determination of the positions of virtual walls in configuration space that confine the system in a potential energy basin. We use the example of 1,3-dioxolane-4-hydroperoxide-2-yl radical oxidation to show that ChemTraYzer-TAD finds more than 100 different parallel reactions for the given set of reactants in less than 2 ns of simulation time. Among the many observed reactions, ChemTraYzer-TAD finds the expected typical low-temperature reactions despite the use of extremely high simulation temperatures up to 5000 K. Our method also finds a new concerted ß-scission plus O2 addition with a lower reaction barrier than the literature-known and so-far dominant ß-scission.

Determining structure and action mechanism of LBF14 by molecular simulation.

The recently discovered, membrane-active peptide LBF14 contains several non-proteinogenic amino acids and is able to transform vesicles into tubule networks. The exact membrane interaction mechanism and detailed secondary structure are yet to be determined. We performed molecular dynamics simulations of LBF14 and let it fold de novo into its ensemble of native secondary structures. Histidine protonation state effects on secondary structure were investigated. An MD simulation of the peptide with a lipid bilayer was performed. Simulation results were compared to circular dichroism and electron paramagnetic resonance data of previous studies. LBF14 contains a conserved helical section in an otherwise random structure. Helical stability is influenced by histidine protonation. The peptide localized to the polar layer of the membrane, consistent with experimental results. While the overall secondary structure is unaffected by membrane interaction, Ramachandran plot analysis yielded two distinct peptide conformations during membrane interaction. This conformational change was accompanied by residue repositioning within the membrane. LBF14 only affected the local order in the membrane, and had no measurable effect on pressure. The simulation results are consistent with the previously proposed membrane interaction mechanism of LBF14 and can additionally explain the local interaction mechanism. Communicated by Ramaswamy H. Sarma.

Coupled Anharmonic Thermochemistry from Stratified Monte Carlo Integration.

This study presents configuration integral Monte Carlo integration (CIMCI), a new semiclassical method for handling fully coupled anharmonicity in gas-phase thermodynamics that promises to be black boxable, to be applicable to all kinds of anharmonicity, and to scale better at higher dimensionality than other methods for handling gas-phase molecular anharmonicity. The method does so using automatically and recursively stratified, simultaneous Monte Carlo (MC) integration of multiple functions, following a modified version of the standard MISER scheme that converges at a rate of about the square of naïve MC integration. For the small systems analyzed by this study where proper reference data is available (H2O and H2O2), the method's anharmonic entropy corrections match reference data better than those of other black box anharmonic methods, e.g., vibrational perturbation theory (VPT2) and the McClurg hindered rotor model used with automatic detection of rotors; for H2O2 and NH2OH, the method is also in general agreement with one-dimensional hindered rotor treatments at low temperatures. This holds even when sampling with CIMCI is done with primitive force fields, e.g., UFF, while the competing methods are used with proper, comprehensive potentials, e.g., the M06-2X metahybrid density-functional theory (DFT) functional.

Reaction Mechanisms and Rate Constants of Auto-Catalytic Urethane Formation and Cleavage Reactions.

The chemistry of urethanes plays a key role in important industrial processes. Although catalysts are often used, the study of the reactions without added catalysts provides the basis for a deeper understanding. For the non-catalytic urethane formation and cleavage reactions, the dominating reaction mechanism has long been debated. To our knowledge, the reaction kinetics have not been predicted quantitatively so far. Therefore, we report a new computational study of urethane formation and cleavage reactions. To analyze various potential reaction mechanisms and to predict the reaction rate constants quantum chemistry and transition state theory were employed. For validation, experimental data from literature and from own experiments were used. Quantitative agreement of experiments and predictions could be demonstrated. The calculations confirm earlier assumptions that urethane formation reactions proceed via mechanisms where alcohol molecules act as auto-catalysts. Our results show that it is essential to consider several transition states corresponding to different reaction orders to enable agreement with experimental observations. Urethane cleavage seems to be catalyzed by an isourethane, leading to an observed 2nd-order dependence of the reaction rate on the urethane concentration. The results of our study support a deeper understanding of the reactions as well as a better description of reaction kinetics and will therefore help in catalyst development and process optimization.

The first microsolvation step for furans: New experiments and benchmarking strategies.

The site-specific first microsolvation step of furan and some of its derivatives with methanol is explored to benchmark the ability of quantum-chemical methods to describe the structure, energetics, and vibrational spectrum at low temperature. Infrared and microwave spectra in supersonic jet expansions are used to quantify the docking preference and some relevant quantum states of the model complexes. Microwave spectroscopy strictly rules out in-plane docking of methanol as opposed to the top coordination of the aromatic ring. Contrasting comparison strategies, which emphasize either the experimental or the theoretical input, are explored. Within the harmonic approximation, only a few composite computational approaches are able to achieve a satisfactory performance. Deuteration experiments suggest that the harmonic treatment itself is largely justified for the zero-point energy, likely and by design due to the systematic cancellation of important anharmonic contributions between the docking variants. Therefore, discrepancies between experiment and theory for the isomer abundance are tentatively assigned to electronic structure deficiencies, but uncertainties remain on the nuclear dynamics side. Attempts to include anharmonic contributions indicate that for systems of this size, a uniform treatment of anharmonicity with systematically improved performance is not yet in sight.

Prediction of Solvation Free Energies of Ionic Solutes in Neutral Solvents.

The prediction of solvation free energies is essential for a variety of applications. Solvation free energies of neutral systems can be predicted quite accurately. The accuracy of predictions for solvation free energies of ionic solutes dissolved in neutral solvents, however, has been reported to be worse by at least 1 order of magnitude. In this study, the performance of three approaches for solvation free energy prediction of several hundred ions dissolved in neutral solvents is evaluated. The applied methods are COSMO-RS, cluster continuum model (CCM) together with COSMO-RS, and COSMO-RS-ES. It is emphasized that the reference data for model evaluation are subject to large uncertainties stemming from the impossibility to measure the so-called elusive absolute free energies of solvation of a single ion. Consequently, such uncertainty must be considered during the evaluation of prediction methods. Therefore, a straightforward approach to account for the underlying uncertainty is applied here. Hereby, it is revealed that the true performance of the method is better than what is often reported. The average absolute deviation (AAD) of COSMO-RS is calculated to be 2.3 kcal mol-1, while applying the CCM and COSMO-RS-ES each results in AADs of 2.0 kcal mol-1. This accuracy allows for qualitative assessment of solvation free energy-dependent quantities, such as reaction rate constants.

Correcting Rate Constants from Anharmonic Molecular Dynamics for Quantum Effects.

Anharmonicity can greatly affect rate constants. One or even several orders of magnitude of deviation are found for obtaining rate constants using the standard rigid-rotor harmonic-oscillator model. In turn, reactive molecular dynamics (MD) simulations are a powerful way to explore chemical reaction networks and calculate rate constants from the fully anharmonic potential energy surface. However, the classical nature of the dynamics and the required numerical efficiency of the force field limit the accuracy of the resulting kinetics. We combine the best of both worlds by presenting an approximation that pairs anharmonic information intrinsic to classical MD with high-accuracy energies and frequencies from quantum-mechanical electronic structure calculations. The proposed scheme is applied to hydrogen abstractions in the methane system, which allows for the benchmarking of rate constants corrected by our approach against experimental rate constants. This comparison reveals a standard deviation of factor 2.6. Two archetypes of possible failure are identified in the course of a detailed investigation of the CH3 • + H• → CH2 2• + H2 reaction. From this follows the application range of the method, within which the method shows a standard deviation of factor 2.1. The computational efficiency and beneficial scaling of the method allow for application to larger systems, as shown for hydrogen abstraction from 2-butanone by HO2 •.

Automated Chemical Kinetic Modeling via Hybrid Reactive Molecular Dynamics and Quantum Chemistry Simulations.

An automated scheme for obtaining chemical kinetic models from scratch using reactive molecular dynamics and quantum chemistry simulations is presented. This methodology combines the phase space sampling of reactive molecular dynamics with the thermochemistry and kinetics prediction capabilities of quantum mechanics. This scheme provides the NASA polynomial and modified Arrhenius equation parameters for all species and reactions that are observed during the simulation and supplies them in the ChemKin format. The ab initio level of theory for predictions is easily exchangeable, and the presently used G3MP2 level of theory is found to reliably reproduce hydrogen and methane oxidation thermochemistry and kinetics data. Chemical kinetic models obtained with this approach are ready to use for, e.g., ignition delay time simulations, as shown for hydrogen combustion. The presented extension of the ChemTraYzer approach can be used as a basis for methodological advancement of chemical kinetic modeling schemes and as a black-box approach to generate chemical kinetic models.