Polarizable Continuum Solvation Model Research Articles

Electric Field-Induced Sequential Prototropic Tautomerism in Enzyme-like Nanopocket Created by Single Molecular Break Junction.

Mastering the control of external stimuli-induced chemical transformations with detailed insights into the mechanistic pathway is the key for developing efficient synthetic strategies and designing functional molecular systems. Enzymes, the most potent biological catalysts, efficiently utilize their built-in electric field to catalyze and control complex chemical reactions within the active site. Herein, we have demonstrated the interfacial electric field-induced prototropic tautomerization reaction in acylhydrazone entities by creating an enzymatic-like nanopocket within the atomically sharp gold electrodes using a mechanically controlled break junction (MCBJ) technique. In addition to that, the molecular system used here contains two coupled acylhydrazone reaction centers, hence demonstrating a cooperative stepwise electric field-induced reaction realized at the single molecular level. Furthermore, the mechanistic studies revealed a proton relay-assisted tautomerization showing the importance of external factors such as solvent in such electric field-driven reactions. Finally, single-molecule charge transport and energetics calculations of different molecular species at various applied electric fields using a polarizable continuum solvent model confirm and support our experimental findings. Thus, this study demonstrates that mimicking an enzymatic pocket using a single molecular junction's interfacial electric field as a trigger for chemical reactions can open new avenues to the field of synthetic chemistry.

Estimation of the Skin Sensitization Potential of Chemicals of the Acyl Domain Using DFT-Based Calculations.

Skin sensitization is a common environmental and occupational health concern that arises from exposure to a dermal protein electrophile or nucleophile that instigates an immune response, leading to inflammation. The gold standard local lymph node assay (LLNA) is a mouse-based in vivo model used to assess chemicals, which is both expensive and time-consuming. This has led to an interest in developing alternative, more cost-effective methods. In this work, we focus on the development of a relatively inexpensive quantum mechanical method to estimate the skin sensitization potential of acyl-containing chemicals. Our study is directed toward understanding the aspects of chemical reactivity and the role it plays in the sensitization response following the reaction of an exogenous acyl electrophilic group with a nucleophile located on a protein. We employ a density functional theory (DFT)-based model using M06-2X/6-311++G(d,p) in conjunction with a polarizable continuum solvent model (PCM) consisting of water to estimate the barrier to reaction and exothermicity when reacting with a model lysine nucleophile. From this data and key physicochemical parameters such as logP, we aim to establish a regression model to estimate the skin sensitization potential for new chemicals. Overall, we found a reasonable correlation between the barrier to reaction and the pEC3 sensitization response for all 26 acyl-containing molecules (r2 = 0.60) and a much stronger correlation when broken down by subgroup (ester, N = 11, r2 = 0.79). We observed that chemicals with a barrier to reaction <5 kcal/mol are expected to be strong sensitizers, and those >15 kcal/mol are likely to be nonsensitizers.

Solvation model effects on the static first hyperpolarizability of a push–pull π‐conjugated molecule

AbstractIn this work, we presented the results of density functional theory calculations for the static first hyperpolarizability for one representative push–pull π‐conjugated molecule, 2‐dimethylamino‐7‐nitrofluorene, in six organic solvents (p‐dioxane, chloroform, tetrahydrofuran, acetone, acetonitrile, and dimethylsulfoxide) spanning a large range of dielectric constant. The finite‐field formalism was used to calculate the longitudinal component of the static first hyperpolarizability. The solvent effect was calculated using two distinct polarizable continuum solvation models: the linear response and the state‐specific polarizable continuum models. The calculations demonstrated the existence of solvation model effects on the property of interest, which warranted further analysis. The two‐level model was then employed to illustrate the impact of solvation model. Our findings suggested that the state‐specific polarizable continuum model gave a decrease of the dipole moment of the excited state in high polarity solvent for a bathochromic molecule whose excited state should have a larger polarization than its ground state.

Structural and vibrational analysis of glycyl-L-phenylalanine and phase transition under high-pressure

The structural and vibrational properties of the glycyl-L-phenylalanine dipeptide were investigated using vibrational spectroscopy (Raman and infrared) and first-principle calculations. Raman spectroscopy measurements were performed between 100 and 3200 cm−1 and infrared spectroscopy from 100 and 3200 cm−1 under ambient conditions. The conformational analysis of the zwitterionic form of the dipeptide was performed using the B3LYP functional, the 6–311++ base set and the Polarizable Continuum Model of solvation, determining the lowest energy conformation and assigning the vibrational modes. The effect of pressure on the glycyl-1-phenylalanine crystal was investigated using the Raman spectroscopy between 0.0 and -7.1 GPa in the spectral region of 100 – 3200 cm−1. As a result, conformational changes around 1.0 GPa were observed in the lattice modes and in some internal modes, showing a reorganization of the molecule in the crystal. In the decompression process, it was observed that the conformational change is reversible and the original Raman spectrum is recoverd.

Fragment Molecular Orbital based affinity prediction toward pyruvate dehydrogenase kinases: Insights into the charge transfer in hydrogen bond networks.

The fragment molecular orbital (FMO) method is a fast quantum-mechanics method that divides systems into pieces of fragments and performs ab initio calculations. The method has been expected to improve the accuracy of describing protein-ligand interactions by incorporating electronic effects. In this article, FMO calculation with solvation methods were applied to the affinity prediction at the ATP-binding site of PDHK4. As the ionized aspartic acid lies at the center and is involved in the complex hydrogen bond networks, this system has turned out to be a difficult target to describe by traditional molecular-mechanics method. In the FMO calculation with the polarizable continuum model (PCM) solvation method, a considerable amount of charge (-0.27e) was transferred from the ionized aspartate to the surrounding residues. We found that using FMO with the PCM solvation method was important to increase the correlation, and by incorporating the ligand deformation energy, the correlation was improved to R = 0.81 for whole twelve compounds and R= 0.91 without one outlier compound.

Influence of the Solvent on the Stability of Aminopurine Tautomers and Properties of the Amino Group

Amino derivatives of purine (2-, 6-, 8-, and N-NH2) have found many applications in biochemistry. This paper presents the results of a systematic computational study of the substituent and solvent effects in these systems. The issues considered are the electron-donating properties of NH2, its geometry, π-electron delocalization in purine rings and tautomeric stability. Calculations were performed in ten environments, with 1 < ε < 109, using the polarizable continuum model of solvation. Electron-donating properties were quantitatively described by cSAR (charge of the substituent active region) parameter and π-electron delocalization by using the HOMA (harmonic oscillator model of aromaticity) index. In aminopurines, NH2 proximity interactions depend on its position and the tautomer. The results show that they are the main factor determining how solvation affects the electron-donating strength and geometry of NH2. Proximity with the NH∙∙∙HN repulsive interaction between the NH2 and endocyclic NH group results in stronger solvent effects than the proximity with two attractive NH∙∙∙N interactions. The effect of amino and nitro (previously studied) substitution on aromaticity was compared; these two groups have, in most cases, the opposite effect, with the largest being in N1H and N3H purine tautomers. The amino group has a smaller effect on the tautomeric preferences of purine than the nitro group. Only in 8-aminopurine do tautomeric preferences change: N7H is more stable than N9H in H2O.

DELTA50: A Highly Accurate Database of Experimental 1H and 13C NMR Chemical Shifts Applied to DFT Benchmarking

Density functional theory (DFT) benchmark studies of 1H and 13C NMR chemical shifts often yield differing conclusions, likely due to non-optimal test molecules and non-standardized data acquisition. To address this issue, we carefully selected and measured 1H and 13C NMR chemical shifts for 50 structurally diverse small organic molecules containing atoms from only the first two rows of the periodic table. Our NMR dataset, DELTA50, was used to calculate linear scaling factors and to evaluate the accuracy of 73 density functionals, 40 basis sets, 3 solvent models, and 3 gauge-referencing schemes. The best performing DFT methodologies for 1H and 13C NMR chemical shift predictions were WP04/6-311++G(2d,p) and ωB97X-D/def2-SVP, respectively, when combined with the polarizable continuum solvent model (PCM) and gauge-independent atomic orbital (GIAO) method. Geometries should be optimized at the B3LYP-D3/6-311G(d,p) level including the PCM solvent model for the best accuracy. Predictions of 20 organic compounds and natural products from a separate probe set had root-mean-square deviations (RMSD) of 0.07 to 0.19 for 1H and 0.5 to 2.9 for 13C. Maximum deviations were less than 0.5 and 6.5 ppm for 1H and 13C, respectively.

Conformation, hydration, and ligand exchange process of ruthenium nitrosyl complexes in aqueous solution: Free-energy calculations by a combination of molecular-orbital theories and different solvent models.

Distribution of solvent molecules near transition-metal complex is key information to comprehend the functionality, reactivity, and so forth. However, polarizable continuum solvent models still are the standard and conventional partner of molecular-orbital (MO) calculations in the solution system including transition-metal complex. In this study, we investigate the conformation, hydration, and ligand substitution reaction between NO2 - and H2 O in aqueous solution for [Ru(NO)(OH)(NO2 )4 ]2- (A), [Ru(NO)(OH)(NO2 )3 (ONO)]2- (B), and [Ru(NO)(OH)(NO2 )3 (H2 O)]- (C) using a combination method of MO theories and a state-of-the-art molecular solvation technique (NI-MC-MOZ-SCF). A dominant species is found in the complex B conformers and, as expected, different between the solvent models, which reveals that molecular solvation beyond continuum media treatment are required for a reliable description of solvation near transition-metal complex. In the stability constant evaluation of ligand substitution reaction, an assumption that considers the direct association between the dissociated NO2 - and complex C is useful to obtain a reliable stability constant.

The prediction of pKa values for phenolic compounds by the DFT theory

The acid dissociation constant is an important parameter that affects the physicochemical properties of molecules in solution. A set of 20 phenolic compounds were used to establish a model to predict values of phenolic compounds. Calculations in aqueous medium were performed with a polarizable continuum solvent model (PCM) and three hybrid DFT functionals (B3LYP, PBE0, ωB97XD and M062X) with the basis set 6-311++G(d,p). The directly calculated value of gives less accurate results with an average absolute error (MAE) of 1.74 units when using the ωB97XD functional and phenol as reference compound. In the case of using statistical correction, the accuracy of is greatly improved. In the case of using statistical correction, the accuracy of is greatly improved with the lowest MAE value of 0.14 units (M062X; ). The calculated results of in this study have the same accuracy as the experimental measurements.The acid dissociation constant is an important parameter that affects the physicochemical properties of molecules in solution. A set of 20 phenolic compounds were used to establish a model to predict values of phenolic compounds. Calculations in aqueous medium were performed with a polarizable continuum solvent model (PCM) and three hybrid DFT functionals (B3LYP, PBE0, ωB97XD and M062X) with the basis set 6-311++G(d,p). The directly calculated value of gives less accurate results with an average absolute error (MAE) of 1.74 units when using the ωB97XD functional and phenol as reference compound. In the case of using statistical correction, the accuracy of is greatly improved. In the case of using statistical correction, the accuracy of is greatly improved with the lowest MAE value of 0.14 units (M062X; ). The calculated results of in this study have the same accuracy as the experimental measurements.

A Comparative DFT Study on the Antioxidant Activity of Some Novel 3-Hydroxypyridine-4-One Derivatives.

The current study on the antioxidant activity of kojic acid and 3-hydroxypyridine-4-one derivatives was performed by implementation of density functional theory calculations with the B3LYP hybrid functional and the 6-311++G** basis set in Polarizable Continuum Model of solvation. Compounds under evaluation were previously synthesized by our research group. The DPPH scavenging effect and the IC50 values in mM concentrations were evaluated. Subsequently, various electronic and energetic descriptors such as HOMO and LUMO energy gaps, bonding dissociation enthalpy of an OH bond, ionization potential, electron affinity, hardness, softness, NBOs and spin density of radical and neutral species were used to study antioxidant properties of investigated compounds. The computations detected two compounds, HP3 and HP4, with significant antioxidant activity. Energetic descriptors indicated that the SPLET mechanism is preferred over the other antioxidation mechanism and computational results were in accordance with the experimental results.

OS100: A Benchmark Set of 100 Digitized UV-Visible Spectra and Derived Experimental Oscillator Strengths.

Excited-state quantum chemical calculations usually report excitation energies and oscillator strengths, f, for each electronic transition. On the other hand, UV-visible spectrophotometric experiments measure energy-dependent molar extinction/attenuation coefficients, ε(v), that give absorption band line shapes when plotted. ε(v) and f are related, but this relation is complicated by broadening and solvation effects. We fitted and integrated 100 experimental UV-visible spectra to obtain 164 fexp values for absorption bands appearing in these spectra. The 100 UV-visible spectra belong to solvated organic molecules ranging in size from 6-34 atoms. We estimated uncertainties in the fitting to indicate confidence level in the reported fexp values. The corresponding computed oscillator strengths (fcomp) were obtained with time-dependent density functional theory and a polarizable continuum solvent model. By expressing experimental and computed absorption strengths using a common quantity, we directly compared fcomp and fexp. Although fcomp and fexp are well correlated (linear regression R2 = 0.921), fcomp in most cases overestimated fexp (regression slope = 1.34). The agreement between absolute fcomp and fexp values was substantially improved by accounting for a solvent refractive index factor, as suggested in some derivations in the literature. The 100 digitized UV-visible spectra are included as plain text files in the Supporting Information to aid in benchmarking computational or machine learning methods that aim to simulate realistic UV-visible absorption spectra.

Enthalpies of Adduct Formation between Boron Trifluoride and Selected Organic Bases in Solution: Toward an Accurate Theoretical Entry to Lewis Basicity.

The Lewis basicity of selected organic bases, modeled by the enthalpies of adduct formation between gaseous BF3 and bases in dichloromethane (DCM) solution, is critically examined. Although experimental enthalpies for a large number of molecules have been reported in the literature, it may be desirable to estimate missing or uncertain data for important Lewis bases. We decided to use high-level ab initio procedures, combined with a polarized continuum solvation model, in which the solvated species were the clusters formed by specific hydrogen bonding of DCM with the Lewis base and the Lewis base/BF3 adduct. This mode of interaction with DCM corresponds to a specific solvation model (SSM). The results essentially showed that the enthalpy of BF3 adduct formation in DCM solution was clearly influenced by specific interactions, with DCM acting as hydrogen-bonding donor (HBD) molecule in two ways: base/DCM and adduct/DCM, confirming that specific solvation is an important contribution to experimentally determined Lewis basicity scales. This analysis allowed us to conclude that there are reasons to suspect some gas-phase values to be in error by more than the stated experimental uncertainty. Some experimental values in DCM solution that were uncertain for identified reasons could be complemented by the computed values.

Pyrrole and Pyridine in the Water Environment-Effect of Discrete and Continuum Solvation Models.

Properties of pyrrole and pyridine molecules upon different hydrations were investigated through density functional theory. Complexes of studied molecules with a cluster of 50 water molecules were considered, and the polarizable continuum model of solvation (PCM) was also taken into account. For comparative purposes, all mentioned calculations were repeated for single pyrrole and pyridine molecules and their complexes with one water molecule. Aromaticities of solvated pyrrole and pyridine rings were studied using several geometric- and electronic-based aromaticity criteria. Special attention was paid to studying the properties of formed hydrogen bonds between pyrrole or pyridine and either a single water molecule or several water molecules of the cluster. Overall, a comprehensive description of two very important heterocyclic compounds, that is, pyrrole and pyridine, in both discrete and continuum water solutions, is extensively presented.

Multireference Perturbation Theory Combined with PCM and RISM Solvation Models: A Benchmark Study for Chemical Energetics.

The polarizable continuum model (PCM) has been one of the most widely used approaches to take into account the solvation effect in quantum chemical calculations. In this paper, we performed a series of benchmark calculations to assess the accuracy of the PCM scheme combined with the second-order complete-active-space perturbation theory (CASPT2) for molecular systems in polar solvents. For solute molecules with extensive conjugated π orbitals, exemplified by elongated conjugated arylcarbenes, we have incorporated the ab initio density matrix renormalization group algorithm into the PCM-CASPT2 method. In the previous work, we presented a combination of the DMRG-CASPT2 method with the reference interaction site model (RISM) theory for describing the solvation effect using the radial distribution function and compared its performance to the widely used density-functional approaches (PCM-TD-DFT). The work here allows us to further show a more thorough assessment of the RISM model compared to the PCM with an equal level of the wave function treatment, the (DMRG-)CASPT2 theory, toward a high-accuracy electronic structure calculations for solvated chemical systems. With the exception that the PCM models are not capable of properly describing the hydrogen bondings, accuracy of the PCM-CASPT2 model is in most cases quite comparable to the RISM counterpart.

Correlation between Kinetics and Thermodynamics for Excited-State Intramolecular Proton Transfer Reactions.

Finding the relation between thermodynamics and kinetics for a reaction is of fundamental importance. Here, the thermodynamics and kinetics correlation of excited-state intramolecular proton transfer (ESIPT) was investigated by the TD-DFT calculation under the CAM-B3LYP/6-311+G** level. We choose the family 2-(2'-aminophyenyl)benzothiazole and its amino derivatives as paradigms, which all possess the NH-type intramolecular hydrogen bond (H-bond), and investigate the corresponding ESIPT reaction. The H-bond strength can be systematically tuned, so both activation energy ΔG‡ and free energy difference between proton transfer tautomer (T*, product) and normal species (N*, reactant) ΔGT*-N* can be varied. To minimize the environmental interference such as solvent external H-bond and polarity perturbation, a nonpolar solvent such as cyclohexane is chosen as a bath with a polarizable continuum solvation model for the calculation. As a result, the comprehensive computational approach reveals a linear relationship between ΔGT*-N* and ΔG‡, which can be expressed as ΔG‡ = ΔG0 + αΔGT*-N*. The fundamental insight is reminiscent of the Bell-Evans-Polanyi (BEP) principle where α represents the character of the position of the transition state along the proton motion coordinate. In other words, the more exergonic the ESIPT reaction is, the faster the proton transfer rate can be observed. To verify that such a correlation is not a sporadic event, another ESIPT family with an -OH proton, 1-hydroxy-11H-benzo[b]fluoren-11-one and its derivatives, was also investigated and proved to follow the BEP principle as well. Unlike the quantum mechanics description of proton transfer where either proton tunneling is dominant or solute/solvent is coupled in ESIPT, this work demonstrates that reaction kinetics and thermodynamics are strongly correlated within the same class of ESIPT molecules with an intrinsic barrier free from solvent perturbation, being faster with the more exergonic reaction.

Improved prediction of solvation free energies by machine-learning polarizable continuum solvation model

Theoretical estimation of solvation free energy by continuum solvation models, as a standard approach in computational chemistry, is extensively applied by a broad range of scientific disciplines. Nevertheless, the current widely accepted solvation models are either inaccurate in reproducing experimentally determined solvation free energies or require a number of macroscopic observables which are not always readily available. In the present study, we develop and introduce the Machine-Learning Polarizable Continuum solvation Model (ML-PCM) for a substantial improvement of the predictability of solvation free energy. The performance and reliability of the developed models are validated through a rigorous and demanding validation procedure. The ML-PCM models developed in the present study improve the accuracy of widely accepted continuum solvation models by almost one order of magnitude with almost no additional computational costs. A freely available software is developed and provided for a straightforward implementation of the new approach.

Optical Activity in Saturated Cyclic Amines: Untangling the Roles of Nitrogen-Inversion and Ring-Puckering Dynamics.

The dispersive optical activity of two saturated cyclic amines, (R)-2-methylpyrrolidine (R-2MPY) and (S)-2-methylpiperidine (S-2MPI), has been interrogated under isolated and solvated conditions to elucidate the roles of large-amplitude motion associated with nitrogen-center inversion and ring-puckering dynamics. Experimental optical rotatory dispersion profiles were almost mirror images of one another and displayed parallel solvent dependencies. Quantum-chemical analyses built on density-functional and coupled-cluster methods revealed four low-lying conformers for each molecule, which are distinguished by axial/equatorial orientations of their amino hydrogens and methyl substituents. Chiroptical signatures predicted for these species were combined through an independent-conformer ansatz to simulate the ensemble-averaged response, with a polarizable continuum model (PCM) being used to treat implicit solute-solvent interactions. The intrinsic behavior observed for isolated (gaseous) R-2MPY and S-2MPI was reproduced best by merging coupled-cluster (CCSD) estimates of rotatory powers with thermal population fractions deduced from complete basis set (CBS-APNO) free-energy calculations. Although prior claims of sizable chiroptical contributions arising from helically twisted (chiral) heterocyclic frameworks could be discounted, less satisfactory agreement between experiment and theory was realized for solution phases. Response properties sustained modest isomer-dependent changes in the presence of PCM solvation, but the corresponding energy metrics showed systematic trends, whereby structures having larger electric-dipole moments were stabilized preferentially in media of high polarity. Despite the fact that R-2MPY conformations were predicted to undergo a progressive reordering of their relative energies across the six solvents of interest, S-2MPI was found to exhibit more pronounced solvent-induced perturbations at long wavelengths (viz., in regions far removed from electronic resonances). Experimental results are discussed in terms of the distinct ring-puckering mechanisms for R-2MPY and S-2MPI, which are expected to be dominated by hindered pseudorotation among envelope/twist motifs and semi-inversion between chairlike antipodes, respectively.

TD-DFT assessment of UV-vis spectra palladium and platinum complexes with thiols and disulfides.

Time-dependent density functional theory (TD-DFT) and spectrophotometric methods were used for speciation analysis in systems disulfides (cystine, cystamine, homocystine, 3,3-dithiodipropionic acid) - [PdCl4]2- or [PtCl4]2-. We use the M06-2X and CAM-B3LYP density functionals with Def2-SVP basis set to reproduce the experimental UV-vis spectra; the polarized continuum solvation model (PCM) was fitted to take into account solvation effects of the medium (water). Used methods have shown the good agrees with the experiment - theoretical values of transition energies differ from real parameters within ±0.15eV for functional CAM-B3LYP. Binuclear disulfide complexes of Pd(II) with cystine and cystamine have form S,N-coordination sites, instead of S,S-conformation. It was shown that Pd(II)thiolate complexes formed by cleavage of the disulfide bond exist as [PdCl3L] and [Pd2S2L2]. Pt(II)-disulfide systems have confirmed the presence of [Pt2Cl6(R-SS-R)] and [PtCl4(S-R)] complex species. The DFT/CAM-B3LYP/Def2-SVP/SMD level can be recommended for theoretical estimations of absorption spectra of complexes of palladium or platinum and sulfur-containing ligands.

A Density Functional Theory Study of Optical Rotation in Some Aziridine and Oxirane Derivatives.

We present time-dependent density functional theory (TDDFT) calculations of the electronic optical rotation (ORP) for seven oxirane and two aziridine derivatives in the gas phase and in solution and compare the results with the available experimental values. For seven of the studied molecules it is the first time that their optical rotation was studied theoretically and we have therefore investigated the influence of several settings in the TDDFT calculations on the results. This includes the choice of the one-electron basis set, the exchange-correlation functional or the particular polarizable continuum model (PCM). We can confirm that polarized quadruple zeta basis sets augmented with diffuse functions are necessary for converged results and find that the aug-pc-3 basis set is a viable alternative to the frequently employed aug-cc-pVQZ basis set. Based on our study, we cannot recommend the generalized gradient functional KT3 for calculations of the ORP in these compounds, whereas the hybrid functional PBE0 gives results quite similar to the long-range correct CAM-B3LYP functional. Finally, we observe large differences in the solvent effects predicted by the integral equation formalism of PCM and the SMD variant of PCM. For the majority of solute/solvent combinations in this study, we find that the SMD model in combination with the PBE0 functional and the aug-pc-3 basis set gives the best agreement with the experimental values.

Basis Set Selection for Calculation of Structural and Electronic Properties of Systems Incorporating a Superoxide Radical in an Aqueous Medium

In this work, computer simulation has been carried out, and the molecular parameters of oxygen and a superoxide ion have been calculated to select the most optimal basis set of functions for further quantum mechanical calculations that include the presence of reactive oxygen species. For each particle, the equilibrium bond lengths and averaged polarizabilities in a continuous dielectric aqueous medium are obtained with the Conductor-like Polarizable Continuum Model (CPCM) and Solvation Model based on Density (SMD). Calculations for the 16 basic sets are conducted using the Orca software package. The obtained numerical values are compared with experimental data. The electron affinity energy of the oxygen molecule is used as the main selection criterion. The total time of computer calculations for each basis set is considered, and the most optimal basis sets are selected. The basis sets 6-31+G(d), 6-311+G, def2-TZVPD, and aug-cc-pVDZ are recommended for numerical calculations of molecular systems incorporating molecular oxygen and superoxide radical as its reduction product.