Dissociation of HNO3 in water revisited: experiment and theory.

Nitric acid dissociation in water is studied as a function of concentration, employing experimental techniques (1H NMR spectroscopy and calorimetry), quantum chemical methods (B3LYP and PBE functionals for molecular clusters) and molecular dynamics simulations (the PBE-D3 functional for solutions under periodic boundary conditions). The extent of dissociation, via proton transfer to a neighboring water molecule, as a function of concentration is studied computationally for molecular nitric acid clusters HNO3(H2O)x (x = 1-8), as well as periodic liquids (HNO3 mole fractions of 0.19 and 0.5, simulated at T = 300 K and 450 K). Despite the simple nature of these structural models, their computed and simulated average 1H chemical shifts compare well with the experimental measurements in this study. Finally, the measured and calculated chemical shifts have shown reasonable relationships with the enthalpy change upon mixing of this binary complex.

DNA preference of indenoisoquinolines: a computational approach.

The human topoisomerase IB (hTopoIB) enzyme is a monomeric protein that relaxes the supercoils on double-stranded DNA by forming a covalent DNA/hTopoIB complex by introducing a nick on the DNA strand. Inhibition of hTopoIB results in cell death, which makes this protein a strong target for the treatment of various cancer types, including small-cell lung cancers and ovarian cancers. Camptothecin (CPT) and indenoisoquinoline (IQN) classes of compounds inhibit the hTopoIB activity by intercalating to nicked DNA pairs; however, these inhibitors show different preferences towards DNA bases when bound to the DNA/hTopoIB complex. Here, we investigated the affinities of CPT and one IQN derivative towards different DNA base pairs. The two inhibitors showed different stacking behaviors in the intercalation site and interaction pattern with binding pocket residues, indicating that they have different inhibition mechanisms in the binding pocket that affects the base-pair selectivity. The results obtained from this study are expected to guide researchers in designing gene-specific and more potent compounds to fight cancer through hTopoIB poisoning.

Quantum Mechanical Prediction of Dissociation Constants for Thiazol-2-imine Derivatives.

As weak acids or bases, in solution, drug molecules are in either their ionized or nonionized states. A high degree of ionization is essential for good water solubility of a drug molecule and is required for drug-receptor interactions, whereas the nonionized form improves a drug's lipophilicity, allowing the ligand to cross the cell membrane. The penetration of a drug ligand through cell membranes is mainly governed by the pKa of the drug molecule and the membrane environment. In this study, with the aim of predicting the acetonitrile pKa's (pKa(MeCN)) of eight drug-like thiazol-2-imine derivatives, we propose a very accurate and computationally affordable protocol by using several quantum mechanical approaches. Benchmark studies were conducted on a set of training molecules, which were selected from the literature with known pKa(water) and pKa(MeCN). Highly well-correlated pKa values were obtained when the calculations were performed with the isodesmic method at the M062X/6-31G** level of theory in conjunction with SMD solvation model for nitrogen-containing heterocycles. Finally, experimentally unknown pKa(MeCN) values of eight thiazol-2-imine structures, which were previously synthesized by some of us, are proposed.

Solvent dependent hindered rotation versus epimerization in axially chiral thiohydantoin derivatives: an experimental and a computational study.

5-Benzyl-3-(o-aryl)-2-thiohydantoin and 5-isobutyl-3-(o-aryl)-2-thiohydantoin derivatives (o-aryl = o-tolyl and o-bromophenyl) have been synthesized by reacting o-aryl isothiocyanates with S-phenylalanine methyl ester hydrochloride or with S-leucine methyl ester hydrochloride in the presence of triethylamine (TEA). The synthesized compounds have a chirality center at C5 of the heterocyclic ring and a chirality axis, the N3-C(aryl) bond. The axially chiral compounds were shown to exist in unequal amounts of SM, SP, RM and RP stereoisomeric forms with a high prevalence of the P isomers over the M isomers. The isomeric assignments were done by comparing the 1H NMR spectra with the HPLC chromatograms. The stereoisomers were resolved micropreparatively by HPLC on chiral stationary phases and the interconversion of the single isomers has been investigated. The conversion type has been determined as epimerization or rotation by the HPLC analyses. It has been found that although the stereoisomers converted to each other only by rotation in toluene, in ethanol epimerization (racemization at C5 of the heteroring) was accompanied with rotation depending on the duration, temperature of the thermal interconversion experiment and the nature of the ortho substituent. The occurrence of epimerization was also proved through H/D exchange reactions via1H NMR experiments done in CD3OD. The rotation and epimerization mechanisms of synthesized compounds were further elucidated by Density Functional Theory (DFT) calculations at M062X/6-311 + G** level of theory and the results were shown to be in harmony with experimental findings.

Investigation of iron release from the N- and C-lobes of human serum transferrin by quantum chemical calculations.

Human serum transferrin binds ferric ions with high affinity and delivers them into cells via receptor-mediated endocytosis upon a decrease in pH in the endosome. Protonation events and conformational changes are known to play an important role in iron-release though the release is not yet fully understood. Human serum transferrin consists of two similar lobes which release iron at different rates. In this study, we investigate the iron binding sites of N- and C-lobes using quantum mechanical tools, particularly, the quantum chemical cluster approach. This study supports the inevitable role of axial tyrosine for the release of iron in quantum chemical models and provides valuable information about the proton transfer pathways for the protonation of Tyr188 and Tyr517 in N- and C-lobes, respectively. The calculations show that the release process is similar in both lobes; however, the energetic differences of the release process in N- and C-lobes, demonstrated for the first time, indicated that the release of iron in the N-lobe is thermodynamically favorable, in contrast to the one in the C-lobe.

Influence of ionic liquids on the electronic environment of atomically dispersed Ir on (MgO)(100).

Recently, ionic liquids (ILs) have been used as ligands for single-site Ir(CO)2 complexes bound to metal-oxide supports because of their electron-donor/acceptor capacities. The combined effects of supports and ILs as ligands may pave the way to the tuning of the surrounding electronic properties to increase electron-donor/acceptor efficiency in metal-oxide supported Ir(CO)2 complexes. Herein, we have used Density Functional Theory to model Ir(CO)2 complexes bound to MgO supports with and without the presence of an IL to explain the role of ILs in modifying the electronic structure of the supported complex. Comparison of the ν(CO) band stretching frequencies with experimental results has led to the rationalization of the factors driving the interactions between the IL, the support, and the catalyst as well as the justification of the methodology for further studies.

Computational descriptor analysis on excited state behaviours of a series of TADF and non-TADF compounds.

The thermally activated delayed fluorescence (TADF) behaviours of seventeen organic TADF emitters and two non-TADF chromophores bearing various donor and acceptor moieties were investigated, focusing on their torsion angles, singlet-triplet gap (ΔEST), spin orbit couplings (SOC) and topological ΦS index. Electronic structure calculations were performed in the framework of the Tamm-Dancoff approximation (TDA) allowing the possible reverse intersystem crossing (RISC) pathways to be characterized. The electronic density reorganization of the excited states was checked also with respect to the different exchange-correlation functional and absorption spectra were obtained by considering vibrational and dynamical effects through Wigner sampling of the ground state equilibrium regions. Examining all the parameters obtained in our computational study, we rationalized the influence of electron-donating and electron-accepting groups and the effects of geometrical factors, especially torsion angles, on a wide class of diverse compounds ultimately providing an easy and computationally effective protocol to assess TADF efficiencies.

Photophysical Properties of Benzophenone-Based TADF Emitters in Relation to Their Molecular Structure.

Thermally activated delayed fluorescence (TADF) materials are commonly used in various apparatus, including organic light-emitting device-based displays, as they remarkably improve the internal quantum efficiencies. Although there is a wide range of donor-acceptor-based compounds possessing TADF properties, in this computational study, we investigated TADF and some non-TADF chromophores, containing benzophenone or its structural derivatives as the acceptor core, together with various donor moieties. Following the computational modeling of the emitters, several excited state properties, such as the absorption spectra, singlet-triplet energy gaps (ΔEST), natural transition orbitals, and the topological ΦS indices, have been computed. Along with the donor-acceptor torsion angles and spin-orbit coupling values, these descriptors have been utilized to investigate potential TADF efficiency. Our study has shown that on the one hand, our photophysical/structural descriptors and computational methodologies predict the experimental results quite well, and on the other hand, our extensive benchmark can be useful to pinpoint the most promising functionals and descriptors for the study of benzophenone-based TADF emitters.

Using Atomic Charges to Describe the pKa of Carboxylic Acids.

In this study, we present an accurate protocol for the fast prediction of pKa's of carboxylic acids based on the linear relationship between computed atomic charges of the anionic form of the carboxylate fragment and their experimental pKa values. Five charge descriptors, three charge models, three solvent models, gas-phase calculations, several DFT methods (a combination of eight DFT functionals and fifteen basis sets), and four different semiempirical approaches were tested. Among those, the best combination to reproduce experimental pKa's is to compute the natural population analysis atomic charge using the solvation model based on density model at the M06L/6-311G(d,p) level of theory and selecting the maximum atomic charge on the carboxylic oxygen atoms (R2 = 0.955). The applicability of the suggested protocol and its stability along geometrical changes are verified by molecular dynamics simulations performed for a set of aspartate, glutamate, and alanine peptides. By reporting the calculated atomic charge of the carboxylate form into the linear relationship derived in this work, it should be possible to accurately estimate the amino acid's pKa's in a protein environment.

SAMPL7 blind challenge: quantum-mechanical prediction of partition coefficients and acid dissociation constants for small drug-like molecules.

The physicochemical properties of a drug molecule determine the therapeutic effectiveness of the drug. Thus, the development of fast and accurate theoretical approaches for the prediction of such properties is inevitable. The participation to the SAMPL7 challenge is based on the estimation of logP coefficients and pKa values of small drug-like sulfonamide derivatives. Thereby, quantum mechanical calculations were carried out in order to calculate the free energy of solvation and the transfer energy of 22 drug-like compounds in different environments (water and n-octanol) by employing the SMD solvation model. For logP calculations, we studied eleven different methodologies to calculate the transfer free energies, the lowest RMSE value was obtained for the M06L/def2-TZVP//M06L/def2-SVP level of theory. On the other hand, we employed an isodesmic reaction scheme within the macro pKa framework; this was based on selecting reference molecules similar to the SAMPL7 challenge molecules. Consequently, highly well correlated pKa values were obtained with the M062X/6-311+G(2df,2p)//M052X/6-31+G(d,p) level of theory.

Origins of the photoinitiation capacity of aromatic thiols as photoinitiatiors: a computational study.

In this work, we report the photophysical properties of three thiol derivatives, commonly used as photoinitiators in thiol-ene free radical polymerization, the ultimate goal being to rationalize the main reason behind the photoinitiation efficiency. For this aim, time dependent density functional theory is used to simulate the absorption spectra of alkyl thiol (R-SH), thiophenol (PhSH) and p-(trifluoromethyl) thiophenol (p-CF3PhSH), describe their excited state topologies, and explore their potential energy surfaces along the S-H dissociation. Excited state calculations have shown that the S-H photolysis is achieved through the triplet excited states following intersystem crossing from the originally populated singlet manifolds. More specifically, while in aromatic thiol derivatives dissociation is mainly triplet-state mediated, the first excited singlet state and first triplet state of alkyl thiol are both dissociative and hence potentially capable of generating the photoinduced radical species. We have also justified the experimental findings concerning the photoinitiator efficiency considering both their potential energy surface topologies and the absorption intensity, in the lowest energy region.

Elucidation of the atroposelectivity in the synthesis of axially chiral thiohydantoin derivatives.

Recently, Sarigul and Dogan have synthesized a number of enantiomerically enriched axially chiral atropoisomeric 2-thiohydantoins by the reaction of l-amino acid ester salts and o-aryl isothiocyanates in the presence of triethyl amine (TEA) in dichloromethane. The non-axially chiral derivative 5-methyl-3-phenyl-2-thiohydantoin gave a racemic product whereas the axially chiral 5-methyl-3-o-bromophenyl-2-thiohydantoin was less prone to racemize at C5 of the heterocyclic ring. In this study, we present a computational study (M06-2X/6-311+G(d,p) for C, H, O, N and S; M06-2X/6-311++G(3df,3pd) for Br) in order to propose plausible mechanisms for the racemization and cyclization steps for 2-thiohydantoin derivatives. The study includes rationalization based on steric as well as the electrostatic effects to elucidate the epimerization differences at C5.

A blind SAMPL6 challenge: insight into the octanol-water partition coefficients of drug-like molecules via a DFT approach.

In this study quantum mechanical methods were used to predict the solvation energies of a series of drug-like molecules both in water and in octanol, in the context of the SAMPL6 n-octanol/water partition coefficient challenge. In pharmaceutical design, n-octanol/water partition coefficient, LogP, describes the drug's hydrophobicity and membrane permeability, thus, a well-established theoretical method that rapidly determines the hydrophobicity of a drug, enables the progress of the drug design. In this study, the solvation free energies were obtained via six different methodologies (B3LYP, M06-2X and ωB97XD functionals with 6-311+G** and 6-31G* basis sets) by taking into account the environment implicitly; the methodology chosen (B3LYP/6-311+G**) was used later to evaluate ΔGsolv by using explicit water as solvent. We optimized each conformer in different solvents separately, our calculations have shown that the stability of the conformers is highly dependent on the solvent environment. We have compared implicitly and explicitly solvated systems, the interaction of one explicit water with drug-molecules at the proper location leads to the prediction of more accurate LogP values.

Pyrolysis of Alkanes: A Computational Approach.

In this study, we investigate the kinetic and thermodynamic aspects of thermal cracking reactions of short paraffin chains by density functional theory (DFT) methods. The thermal cracking reactions have been modeled for a series of shorter unbranched alkanes at 673 K by following a free-radical mechanism. Benchmark calculations have been carried out with different functionals (B3LYP, M06-2X, PBE0, BMK, B3PW91) and basis sets (6-31G(d,p), 6-311+G(d,p)) to determine the most suitable DFT method, and the results were compared to the available experimental data. Computations were also performed at the CBS-QB3 level to evaluate the accuracy of the DFT method. The thermodynamic and kinetic properties of the initiation, hydrogen atom transfer (HAT), and decomposition (ß-scission) reactions are intensely discussed to better understand the trends in product distributions at high temperatures. Evans-Polanyi (EP) relations have been used to build a linear relationship between the enthalpy of reactions and their activation energies; this process may be useful for the determination of the kinetic parameters of longer paraffin chains as well. Finally, the preexponential factors of short-chain paraffin have been calculated and classified based on the identity of the radicalic products. The latter, together with the activation energies derived from the EP relations can be used safely for the prediction of the rate constants for long paraffin chains.

Computational Study of Photo-oxidative Degradation Mechanisms of Boron-Containing Oligothiophenes.

We have modeled possible photo-oxidative degradation pathways for a set of boron-containing oligothiophenes, which have potential use in organic electronic devices. Photogenerated reactive oxygen species such as hydroxyl radical, hydroperoxyl radical, and singlet and triplet molecular oxygen are taken into account in three main pathways, namely, sulfoxide formation, sequential addition, and stepwise singlet molecular oxygen addition. Density functional theory at the B3LYP level is used to assess the reaction kinetics and thermodynamics. Our findings show that the influence of the number of thiophene rings and the presence of boron is in most cases minor in terms of degradation. The formation of sulfoxide on the thiophene ring is among the easiest degradation pathways if hydroxyl radical is present in the system. The hydroxyl radical attack on the Cß of thiophene ring of BMBE-1T (2,5-bis(E-dimesitylborylethenyl)thiophene) forms the BMBE-1T(C)OH radical adduct which is kinetically and thermodynamically more favorable than the hydroperoxyl radical attack. The stepwise triplet molecular oxygen addition on the BMBE-1T(C)OH radical adduct has a free energy barrier around 19 kcal·mol-1, and it results in thermodynamically stable degradation product via ring cleavage. Stepwise reactions with singlet molecular oxygen have energy barriers of roughly 40 kcal·mol-1. Singlet molecular oxygen attack on the α-carbon of the thiophene ring is kinetically much more favored than the attack on the beta carbon. Our results elucidate the preferred degradation mechanism of the thiophene backbone of the selected photoactive oligomers. Moreover, the findings of this theoretical study clarify the photostability, and hence the potential drawbacks, of the large-scale use of this class of polythiophenes.

Solvent Effects on Thiol-Ene Kinetics and Reactivity of Carbon and Sulfur Radicals.

The thiol-ene reaction is one of the fundamental reactions in biochemistry and synthetic organic chemistry. In this study, the effect of polar media on the reaction kinetics is taken into account by using the transition state theory; the reactivities of the carbon and sulfur radicals have also been rationalized by using conceptual DFT. The results have shown that the solvents have more impact on hydrogen atom transfer reactions and the chain transfer rate constant, kCT, can be increased by using nonpolar solvents, while propagation reactions are less sensitive to media. Similarly, the kP/kCT ratio can be manipulated by changing the environment in order to obtain tailor-made polymers. Regarding the DFT descriptors, the local and global electrophilicity indices are well correlated with the propagation rate constant kP, whereas the global electrophilicity index is associated with the chain transfer rate constant kCT. Overall, electrophilicity indices can be used with confidence to predict the kinetics of thiol-ene reactions.

Local vibrational mode analysis of ion-solvent and solvent-solvent interactions for hydrated Ca2+ clusters.

Hydrated calcium ion clusters have received considerable attention due to their essential role in biological processes such as bone development, hormone regulation, blood coagulation, and neuronal signaling. To better understand the biological role of the cation, the interactions between the Ca2+ ions and water molecules have been frequently investigated. However, a quantitative measure for the intrinsic Ca-O (ion-solvent) and intermolecular hydrogen bond (solvent-solvent) interactions has been missing so far. Here, we report a topological electron density analysis and a natural population analysis to analyze the nature of these interactions for a set of 14 hydrated calcium clusters via local mode stretching force constants obtained at the ωB97X-D/6-311++G(d,p) level of theory. The results revealed that the strength of inner Ca-O interactions for Ca(H2O)n 2+ (n = 1-8) clusters correlates with the electron density. The application of a second hydration shell to Ca(H2O)n 2+ (n = 6-8) clusters resulted in stronger Ca-O interactions where a larger electron charge transfer between lp(O) of the first hydration shell and the lower valence of Ca prevailed. The strength of the intermolecular hydrogen bonds, formed between the first and second hydration shells, became stronger when the charge transfers between hydrogen bond (HB) donors and HB acceptors were enhanced. From the local mode stretching force constants of implicitly and explicitly solvated Ca2+, we found the six-coordinated cluster to possess the strongest stabilizations, and these results prove that the intrinsic bond strength measures for Ca-O and hydrogen bond interactions form new effective tools to predict the coordination number for the hydrated calcium ion clusters.

Activity of Topotecan toward the DNA/Topoisomerase I Complex: A Theoretical Rationalization.

Topotecan (TPT) is a nontoxic anticancer drug characterized by a pH-dependent lactone/carboxyl equilibrium. TPT acts on the covalently bonded DNA/topoisomerase I (DNA/TopoI) complex by intercalating between two DNA bases at the active site. This turns TopoI into a DNA-damaging agent and inhibits supercoil relaxation. Although only the lactone form of the drug is active and effectively inhibits TopoI, both forms have been co-crystallized at the same location within the DNA/TopoI complex. To gain further insights into the pH-dependent activity of TPT, the differences between two TPT:DNA/TopoI complexes presenting either the lactone (acidic pH) or the carboxyl (basic pH) form of TPT were studied by means of molecular dynamic simulations, quantum mechanical/molecular mechanical calculations, and topological analysis. We identified two specific amino acids that have a direct relationship with the activity of the drug, i.e., lysine 532 (K532) and asparagine 722 (N722). K532 forms a stable hydrogen bond bridge between TPT and DNA only when the drug is in its active lactone form. The presence of the active drug triggers the formation of an additional stable interaction between DNA and protein residues, where N722 acts as a bridge between the two fragments, thus increasing the binding affinity of DNA for TopoI and further slowing the release of DNA. Overall, our results provide a clear understanding of the activity of the TPT-like class of molecules and can help in the future design of new anticancer drugs targeting topoisomerase enzymes.

Design of donor-acceptor copolymers for organic photovoltaic materials: a computational study.

80 different push-pull type organic chromophores which possess Donor-Acceptor (D-A) and Donor-Thiophene-Acceptor-Thiophene (D-T-A-T) structures have been systematically investigated by means of density functional theory (DFT) and time-dependent DFT (TD-DFT) at the B3LYP/6-311G* level. The introduction of thiophene (T) in the chain has allowed us to monitor the effect of π-spacers. Benchmark studies on the methodology have been carried out to predict the HOMO and LUMO energies and optical band gaps of the D-A systems accurately. The HOMO and LUMO energies and transition dipoles are seen to converge for tetrameric oligomers, and the latter have been used as optimal chain length to evaluate various geometrical and optoelectronic properties such as bond length alternations, distortion energies, frontier molecular orbital energies, reorganization energies and excited-state vertical transition of the oligomers. Careful analysis of our findings has allowed us to propose potential donor-acceptor couples to be used in organic photovoltaic cells.

Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions.

Remarkable progress in the area of asymmetric organocatalysis has been achieved in the last decades. Cinchona alkaloids and their derivatives have emerged as powerful organocatalysts owing to their reactivities leading to high enantioselectivities. The widespread usage of cinchona alkaloids has been attributed to their nontoxicity, ease of use, stability, cost effectiveness, recyclability, and practical utilization in industry. The presence of tunable functional groups enables cinchona alkaloids to catalyze a broad range of reactions. Excellent experimental studies have extensively contributed to this field, and highly selective reactions were catalyzed by cinchona alkaloids and their derivatives. Computational modeling has helped elucidate the mechanistic aspects of cinchona alkaloid catalyzed reactions as well as the origins of the selectivity they induce. These studies have complemented experimental work for the design of more efficient catalysts. This Account presents recent computational studies on cinchona alkaloid catalyzed organic reactions and the theoretical rationalizations behind their effectiveness and ability to induce selectivity. Valuable efforts to investigate the mechanisms of reactions catalyzed by cinchona alkaloids and the key aspects of the catalytic activity of cinchona alkaloids in reactions ranging from pharmaceutical to industrial applications are summarized. Quantum mechanics, particularly density functional theory (DFT), and molecular mechanics, including ONIOM, were used to rationalize experimental findings by providing mechanistic insights into reaction mechanisms. B3LYP with modest basis sets has been used in most of the studies; nonetheless, the energetics have been corrected with higher basis sets as well as functionals parametrized to include dispersion M05-2X, M06-2X, and M06-L and functionals with dispersion corrections. Since cinchona alkaloids catalyze reactions by forming complexes with substrates via hydrogen bonds and long-range interactions, the use of split valence triple-ζ basis sets including diffuse and polarization functions on heavy atoms and polarization functions on hydrogens are recommended. Most of the studies have used the continuum-based models to mimic the condensed phase in which organocatalysts function; in some cases, explicit solvation was shown to yield better quantitative agreement with experimental findings. The conformational behavior of cinchona alkaloids is also highlighted as it is expected to shed light on the origin of selectivity and pave the way to a comprehensive understanding of the catalytic mechanism. The ultimate goal of this Account is to provide an up-to-date overlook on cinchona alkaloid catalyzed chemistry and provide insight for future studies in both experimental and theoretical fields.