Computational Organic Chemistry Research Articles

A transferable active-learning strategy for reactive molecular force fields.

Predictive molecular simulations require fast, accurate and reactive interatomic potentials. Machine learning offers a promising approach to construct such potentials by fitting energies and forces to high-level quantum-mechanical data, but doing so typically requires considerable human intervention and data volume. Here we show that, by leveraging hierarchical and active learning, accurate Gaussian Approximation Potential (GAP) models can be developed for diverse chemical systems in an autonomous manner, requiring only hundreds to a few thousand energy and gradient evaluations on a reference potential-energy surface. The approach uses separate intra- and inter-molecular fits and employs a prospective error metric to assess the accuracy of the potentials. We demonstrate applications to a range of molecular systems with relevance to computational organic chemistry: ranging from bulk solvents, a solvated metal ion and a metallocage onwards to chemical reactivity, including a bifurcating Diels–Alder reaction in the gas phase and non-equilibrium dynamics (a model SN2 reaction) in explicit solvent. The method provides a route to routinely generating machine-learned force fields for reactive molecular systems.

Hamiltonian-Reservoir Replica Exchange and Machine Learning Potentials for Computational Organic Chemistry.

This work combines a machine learning potential energy function with a modular enhanced sampling scheme to obtain statistically converged thermodynamical properties of flexible medium-size organic molecules at high ab initio level. We offer a modular environment in the python package MORESIM that allows custom design of replica exchange simulations with any level of theory including ML-based potentials. Our specific combination of Hamiltonian and reservoir replica exchange is shown to be a powerful technique to accelerate enhanced sampling simulations and explore free energy landscapes with a quantum chemical accuracy unattainable otherwise (e.g., DLPNO-CCSD(T)/CBS quality). This engine is used to demonstrate the relevance of accessing the ab initio free energy landscapes of molecules whose stability is determined by a subtle interplay between variations in the underlying potential energy and conformational entropy (i.e., a bridged asymmetrically polarized dithiacyclophane and a widely used organocatalyst) both in the gas phase and in solution (implicit solvent).

Toward Exploring Novel Organic Materials: MP4-DFT Properties of 4-Amino-3-Iminoindene.

Tautomerism links with many applications and remains an attracting feature in exploring novel systems. In this regard, properties of indene-based HNCCCN segments have not received any considerable attention. In this computational organic chemistry study, first, to calculate the proton transfer energy barrier at a reasonable cost, the study identified an accurate forth order Møller–Plesset perturbation theory-density functional theory (MP4-DFT) protocol equivalent to the outstanding pioneering benchmark calculations. The calculations illustrate that the two tautomers of the 4-amino-3-iminoindene nucleus are separated by a considerable energy barrier while featuring different molecular orbital characteristics; frontier orbital distribution, λmax, and energies, which are known basic requirements in molecular switching and logic circuit applications. The N-H/BH2 substitution was found to have significant influence on the electronic structure of the skeleton. Similarities in the two tautomers and the boron derivative to properties of known molecular materials have been found.

Diagnostics in computational organic chemistry

Focusing on computational studies of pericyclic reactions from the late twentieth century into the twenty-first century, this paper argues that computational diagnostics is a key methodological development that characterize the management and coordination of plural approximation methods in computational organic chemistry. Predictive divergence between semi-empirical and ab initio approximation methods in the study of pericyclic reactions has issued in epistemic dissent. This has resulted in the use of diagnostics to unpack computational greyboxes in order to critically assess the effect of specific misrepresentations on predictive accuracy given that approximations and idealizations must be made to render computational models tractable. Furthermore, benchmarking is used to determine the applicability of approximation methods depending on how accurate the results need to be in a given research context. The epistemology of benchmarking consists of the co-generation of data sets in a hybrid computational–experimental form used to standardize computational methods but does not determine a unique quantitative method to be used across computational organic chemistry.

ChemInform Abstract: Challenges in Computational Organic Chemistry

AbstractReview: 35 refs.

Beyond static structures: Putting forth REMD as a tool to solve problems in computational organic chemistry.

Computational studies of organic systems are frequently limited to static pictures that closely align with textbook style presentations of reaction mechanisms and isomerization processes. Of course, in reality chemical systems are dynamic entities where a multitude of molecular conformations exists on incredibly complex potential energy surfaces (PES). Here, we borrow a computational technique originally conceived to be used in the context of biological simulations, together with empirical force fields, and apply it to organic chemical problems. Replica‐exchange molecular dynamics (REMD) permits thorough exploration of the PES. We combined REMD with density functional tight binding (DFTB), thereby establishing the level of accuracy necessary to analyze small molecular systems. Through the study of four prototypical problems: isomer identification, reaction mechanisms, temperature‐dependent rotational processes, and catalysis, we reveal new insights and chemistry that likely would be missed using static electronic structure computations. The REMD‐DFTB methodology at the heart of this study is powered by i‐PI, which efficiently handles the interface between the DFTB and REMD codes. © 2015 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

ChemInform Abstract: Computational Organic Chemistry: Bridging Theory and Experiment in Establishing the Mechanisms of Chemical Reactions

AbstractReview: [186 refs.

Computational organic chemistry: bridging theory and experiment in establishing the mechanisms of chemical reactions.

Understanding the mechanisms of chemical reactions, especially catalysis, has been an important and active area of computational organic chemistry, and close collaborations between experimentalists and theorists represent a growing trend. This Perspective provides examples of such productive collaborations. The understanding of various reaction mechanisms and the insight gained from these studies are emphasized. The applications of various experimental techniques in elucidation of reaction details as well as the development of various computational techniques to meet the demand of emerging synthetic methods, e.g., C-H activation, organocatalysis, and single electron transfer, are presented along with some conventional developments of mechanistic aspects. Examples of applications are selected to demonstrate the advantages and limitations of these techniques. Some challenges in the mechanistic studies and predictions of reactions are also analyzed.

Challenges in computational organic chemistry

Despite tremendous progress over the past four decades, challenges remain in the field of computational organic chemistry. Challenges that are likely to be addressed in the near term include tackling the complexity of large configuration spaces, reactions where dynamic effects dictate product outcomes, design of enzymes to catalyze specific reactions, and the quest for a standard computational method. WIREs Comput Mol Sci 2014, 4:482–487.This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis

MODULATING THE ELECTRONIC STRUCTURE OF AMINO ACIDS: INTERACTION OF MODEL LEWIS ACIDS WITH ANTHRANILIC ACID

On the basis of theoretical B3LYP calculations, Yanez and co-workers (J. Chem. Theory Comput. 2012, 8, 2293) illustrated that beryllium ions are capable of significantly modulating (changing) the electronic structures of imidazole. In this computational organic chemistry study, the interaction of this β-amino acid and five model Lewis acids (BeF1+, Be2+, AlF21+, AlF2+, and Al3+) were investigated. Several aspects were addressed: natural bond orbitals, including second order perturbation analysis of intra-molecular charge delocalization and the natural population analysis atomic charges; molecular geometries; selected infrared stretching frequencies (C-N, C-O, and N-H), and selected 1H-NMR chemical shifts. The data illustrate that this interaction can weaken the H-O bond and goes beyond strengthening the intra-molecular hydrogen bond (N...H-O) to cause a spontaneous transfer of the proton to the nitrogen atom in five cases generating zwitterion structures. Many new features are observed. Most importantly, the zwitterion structures include a stabilizing hydrogen bond (N-H...O) that varies in relative strength according to the Lewis acid. These findings explain the experimental observations of α-amino acids (for example: J. Am. Chem. Soc. 2001, 123, 3577) and are the first reported fundamental electronic structure characterization of β-amino acids in zwitterion form.

ChemInform Abstract: Chemistry Computationally and Experimentally: How Will Computational Organic Chemistry Impact Organic Theories, Mechanisms, and Synthesis in the Twenty‐first Century?

AbstractReview: 121 refs.

On the carbonaceous carriers of infrared plateau and continuum emission

This study explores the molecular origins of plateaus and continua underlying the infrared and far-infrared (far-IR) bands emitted by compact nebulae, especially protoplanetary nebulae. Computational organic chemistry codes are used to deliver the vibrational integrated band intensities of various large, typical carbonaceous structures. These spectra are composed of a rather continuous distribution of weak modes from which emerge the fingerprints. The 6–18 μm region is interspersed with a great many weak lines, to which the plateaus are assigned. Similarly, the far-IR spectrum is ascribed to the phonon (skeletal) spectrum which is readily identified beyond 18 μm. The absorptivities and absorption cross-sections per interstellar H atom deduced from these spectra are comparable with those of laboratory dust analogues and astronomical measurements, respectively. Moreover, the 5–35 μm spectra of two typical protoplanetary nebulae were reasonably well simulated with combinations of molecules containing functional groups which carry the 21- and 30-μm bands, and molecules devoid of these but carrying strong phonon spectra. These results may help understand the emergence of plateaus, the origin of continua underlying far-IR bands, as well as the composition of circumstellar dust.

On the Factors Affecting H-Bonding : A CCSD(T) // B3LYP Study on Malonaldehyde Cation-Radical

Among the factors that may affect H-bond strength, the effect of the molecular ionization has not received any considerable attention. Here, malonaldehyde and its cation-radical as models were studied using DFT (B3LYP) and ab-initio theories (HF, MP2, and CCSD(T)). Based on establishing a comparison with the CCSD(T)/CBS energy barrier (from literature), we have found that the CCSD(T)/D95(d,p)//B3LYP/6-31G(d,p) computational protocol can be used as a reference for evaluating performance of the B3LYP and the MP2 methods on this model. In this computational organic chemistry study several aspects were investigated, they are: structures, energies, natural population analysis (NPA) charges, intramolecular charge transfer (delocalization) energies, and atoms in molecule (AIM) electron densities with regard to the Hbonding. The results indicate that loss of an electron can cause considerable effects on the various electronic structure aspects and the details are presented and discussed. All the aspects confirm that ionizing the molecule disturbs the electron density distribution in the HOMO orbital and makes the two oxygen atoms, relatively, electron deficient centers which consequently weakens both the H1-O1 bond and the O2/H1-O1 H-bond. The details of this investigation are new addition to the hydrogen bond theory. Other types of molecular models and computational protocols are of interest for future investigations. Keyword: Malonaldehyde cation-radical; DFT; MP2; CCSD(T); NBO; AIM; H-bond.

Effect of the metal ion and the medium on the electronic structure of anthranilic acid: a modelling study on the Li and the BeH derivatives

This computational organic chemistry study illustrates that the size of the metal ion is a critical point in determining the bonding mode of the anthranilate (2-aminobenzoate). The beryllium model structure is the first example in the chemical literature on the ability of this amino acid to bond as N–O chelate. The medium has variable effect on the energies and the dipole moments of the studied models, which was found originating essentially from the differences in the atomic charges of the metals. Analysis of the molecular charge distribution allowed stating a new theory on the effect of the medium on the two pairs of isomers.

Computational organic chemistry

The 2010 literature pertaining to computational organic chemistry is summarized and reviewed. Highlights include the novel structure of the propellane radical cation, the putative claim for the preparation and characterization of 1,3-dimethylcyclobutadiene, new annulenes with Möbius topology, tunneling within phenylhydroxycarbene, a new method for using computed NMR spectra to identify structure, and a new model to rationalize the protobranching effect.

The Effect of Substituents on Characteristics of Functional Material: Consequences of Fusing Schiff Bases and Some of Its Proton Substitutes on Isobenzofuran

Research on functional materials is one of the hot technology-related topics. Isobenzofurans and Schiff bases are important building blocks for functional materials. In this study, fundamental aspects of hybrid structures were studied based on B3LYP calculations. The results confirm that fused ortho-amino Schiff bases can have significant impact on the electronic structure of isobenzofuran. The derivatives are unique structures, the magnetic (NICS(0)) / geometric (HOMA) data illustrate that they exhibit the highest π -system localization known for aromatic compounds. The data also provide evidence that the elements in groups 1A, 2A, and 3A can induce a ring current, which is described by “percent aromatic character” with respect to the reference structure. The moderate induction of aromaticity in the fused chelates is associated with significant localization of the atomic charges (APT scheme). However, this computational organic chemistry study identifies for the first time in the chemical literature structures that can be described as aromatic metalla-hetero[14]annulenes (metal-based polycyclic aromatic structures). The band gap calculations of the frontier orbitals revealed that these derivatives are better conductors and chromophores at the molecular level than isobenzofuran. This approach suggests that similar chelates may be used to fine-tune the physical properties of building blocks of functional materials. From a fundamental organic chemistry point of view, the molecular changes are unique and novel as it appears from the chemical literature.

On the factors affecting tautomerism: consequences of N-substituents (Me/NR2) in structures derived from salicylaldimines

This computational organic chemistry study was performed using the B3LYP and the Hartree–Fock methods. Other methods were compared using two model compounds, and these methods are: second-order Møller–Plesset, fourth-order Møller–Plesset, quadratic configuration interaction with single and double excitation and coupled cluster single and double excitations. The study included discussions of the following aspects: the molecular structures, the harmonic oscillator measure of aromaticity, the energy differences between the tautomers, selected infrared stretching frequencies, the atomic charges (Mulliken and natural population analysis), selected NMR chemical shifts, the molecular orbital diagrams and the R groups. The calculations revealed that the electronic structure of salicylaldimines is sensitive to this substitution and may change the physical organic aspects including tautomerism significantly. The results illustrate that the proton–electron delocalisation as a sub-molecular event might be a controllable process when a powerful H-bond exists. This is a new discovery in the area of tautomerism-based functional materials that will help in fine-tuning their properties.

What can the geometry tell about the charge distribution in the mesoionic heterocycles? A DFT study on the SCN4R2 system

AbstractThis computational organic chemistry study was performed using the hybrid functional B3LYP. Many basis sets were evaluated and the basis set 6‐31G(d) was found to be the most practical in terms of time and accuracy. The study presents the first method in the chemical literature that allows estimation of submolecular charges in mesoionic compounds. The theory was built on a reference model structure for which the absolute value of charge of the aromatic p‐orbitals is known. This is the cornerstone, and by employing the harmonic oscillator model of aromaticity (HOMA) many parameters can be quantified. The electronic structure of the title compound was the subject of this approach. The study addressed the following points: geometries, infrared frequencies, NMR chemical shifts, calculated charges, a chemical reactivity, and the frontier orbitals. The calculations illustrate that the π‐system of the CN4 segment includes considerable aromatic character and carries a positive charge while the overall charge is negative. This allows classifying it as a σ‐acceptor/π‐donor while the exocyclic counter anion, the sulfur atom, is a σ‐donor/π‐acceptor. The substituents (R groups) in this case are only σ‐donors. The approach may be applied to other mesoionic and mesoaromatic systems. Copyright © 2009 John Wiley & Sons, Ltd.

Perspectives on computational organic chemistry.

The author reviews how his early love for theoretical organic chemistry led to experimental research and the extended search for quantitative correlations between experiment and quantum calculations. The experimental work led to ion pair acidities of alkali-organic compounds and most recently to equilibria and reactions of lithium and cesium enolates in THF. This chemistry is now being modeled by ab initio calculations. An important consideration is the treatment of solvation in which coordination of the alkali cation with the ether solvent plays a major role.

A DFT study on the mono lithium and sodium salts of N-(2-hydroxyphenyl)salicylaldimine

This computational organic chemistry study presents results based on density functional theory at the B3LYP/6-31G(d) and B3LYP/cc-PVTZ//B3LYP/6-31G(d) levels of theory. Other computational procedures (HF and MP2) are presented for model structures. Three main points were investigated: some of the electronic structure aspects, the relative stability of isomers, and aromaticity. The results suggest that the title salts are the first Schiff base systems in the literature to exist only in the N–H form, which is characterized as the zwitterion form. Also, the estimated delocalization of the π-electron density in the middle ring indicates that these compounds are the first examples of metalla-hetero[10]annulenes. Analysis of the electron density delocalization indicates that the title compounds are better conductors at the molecular level than the parent Schiff base, and therefore, can be considered as new building blocks for organic materials.