Search Results (21)

Molecules sourced from marine environments hold immense promise for the development of novel therapeutic drugs, owing to their distinctive chemical compositions and valuable medicinal attributes. Notably, Talarolide A and Talaropeptides A–D have gained recent attention as potential candidates for pharmaceutical applications. This study aims to explore the chemical reactivity of Talarolide A and Talaropeptides A–D through the application of molecular modeling and computational chemistry techniques, specifically employing Conceptual Density Functional Theory (CDFT). By investigating their chemical behaviors, the study seeks to contribute to the understanding of the potential pharmacological uses of these marine-derived compounds. The molecular geometry optimizations and frequency calculations were conducted using the Density Functional Tight Binding (DFTBA) method. This was followed by a subsequent round of geometry optimization, frequency analysis, and computation of electronic properties and chemical reactivity descriptors. We employed the MN12SX/Def2TZVP/H2O model chemistry, utilizing the Gaussian 16 program and the SMD solvation model. The analysis of the global reactivity descriptors arising from CDFT was achieved as well as the graphical comparison of the dual descriptor DD revealing the areas of the molecules with more propensity to suffer a nucleophilic or electrophilic attack. Additionally, Molinspiration and SwissTargetPrediction were considered for the calculation of molecular characteristics and predicted biological targets. These include enzymes, nuclear receptors, kinase inhibitors, GPCR ligands, and ion channel modulators. The graphical results show that Talarolide A and the Talaropeptides A–D are likely to behave as protease inhibitors. Full article

Organophosphorus chemicals are versatile and important in industry. Trivinylphosphine oxide (TVPO), for example, exhibited a promising precursor as a flame-retardant additive for industrial applications. Density functional theory (DFT) simulations were used to explore the kinetic and thermodynamic chemical processes underlying the nucleophilic addition reactions of TVPO in order to better understand their polymerization mechanisms. An experimental X-ray single-crystal study of TVPO supported this work’s theory based on its computed findings. TVPO was prepared using POCl₃ and VMB in a temperature-dependent reaction. TVPO, the thermodynamically favourable product, is preferentially produced at low temperatures. The endothermic anionic addition polymerization reaction between TVPO and VMB begins when the reaction temperature rises. An implicit solvation model simulated TVPO and piperazine reactions in water, whereas a hybrid model modelled VMB interactions in tetrahydrofuran. The simulations showed a pseudo-Michael addition reaction mechanism with a four-membered ring transition state. The Michael addition reaction is analogous to this process. Full article

Methyl trifluoromethanesulfonate was found to catalyze the reaction of the nucleophilic substitution of the hydroxyl group of alcohols by N-heterocycles followed by X- to N- alkyl group migration (X = O, S) to obtain N-functionalized benzoxazolone, benzothiazolethione, indoline, benzoimidazolethione and pyridinone derivatives. A high degree of solvent dependency on the yield of the products was observed during optimization of the reaction parameters. The yield of the product was found to be 0%, 48% and 70% in acetonitrile, 1,2-dichloroethane and chloroform, respectively. The mechanism of the reaction was established through experiments as well as DFT calculations. The functional B3LYP and 6-311++G(d) basis function sets were used to optimize the molecular geometries. D3 Grimme empiric dispersion with Becke–Johnson dumping was employed, and harmonic vibrational frequencies were calculated to characterize the stationary points on the potential energy surface. To ensure that all the stationary points were smoothly connected to each other, intrinsic reaction coordinate (IRC) analyses were performed. The influence of solvents was considered using the solvation model based on density (SMD). The free energy profiles of the mechanisms were obtained with vibrational unscaled zero-point vibrational energy (ZPE), thermal, enthalpy, entropic and solvent corrections. Full article

The adeninate anion (Ade⁻) is a useful nucleophile used in the synthesis of many prodrugs (including those for HIV AIDS treatment). It exists as a contact ion-pair (CIP) with Na⁺ and K⁺ (M⁺) but the site of coordination is not obvious from spectroscopic data. Herein, a molecular-wide and electron density-based (MOWED) computational approach implemented in the implicit solvation model showed a strong preference for bidentate ion coordination at the N3 and N9 atoms. The N3N9-CIP has (i) the strongest inter-ionic interaction, by −30 kcal mol⁻¹, with a significant (10–15%) covalent contribution, (ii) the most stabilized bonding framework for Ade⁻, and (iii) displays the largest ion-induced polarization of Ade⁻, rendering the N3 and N9 the most negative and, hence, most nucleophilic atoms. Alkylation of the adeninate anion at these two positions can therefore be readily explained when the metal coordinated complex is considered as the nucleophile. The addition of explicit DMSO solvent molecules did not change the trend in most nucleophilic N-atoms of Ade⁻ for the in-plane M-Ade complexes in M-Ade-(DMSO)₄ molecular systems. MOWED-based studies of the strength and nature of interactions between DMSO solvent molecules and counter ions and Ade⁻ revealed an interesting and unexpected chemistry of intermolecular chemical bonding. Full article

Nucleophilic ionic sources of fluoride are essential reagents in the synthetic toolbox to access high added-value fluorinated building blocks unattainable by other means. In this review, we provide a concise description and rationale of the outstanding features of one of these reagents, tetramethylammonium fluoride (TMAF), as well as disclosing the different methods for its preparation, and how its physicochemical properties and solvation effects in different solvents are intimately associated with its reactivity. Furthermore, herein we also comprehensively describe its historic and recent utilization, up to December 2021, in C-F bond-forming reactions with special emphasis on nucleophilic aromatic substitution fluorinations with a potential sustainable application in industrial settings, as well as its use as a base capable of rendering unprecedented transformations. Full article

Aryldiazonium, ${\mathrm{ArN}}_2^{+}$, ions decompose spontaneously through the formation of highly reactive aryl cations that undergo preferential solvation by water, showing a low selectivity towards the nucleophiles present in their solvation shell. In this work, we investigate the effects of electrolytes (NaCl, LiCl, and LiClO₄) on the dediazoniation of 2-, 3-, and 4-methylbenzenediazonium ions in acidic MeOH/H₂O mixtures. In the absence of electrolytes, the rates of dediazoniation, k_obs, increase modestly upon increasing the MeOH content of the reaction mixture. At any solvent composition, the rate of ${\mathrm{ArN}}_2^{+}$ loss is the same as that for product formation. The main dediazoniation products are cresols (ArOH) and methyl phenyl ethers (ArOMe). Only small amounts (less than 5%) of the reduction product toluene (ArH), which are detected at high percentages of MeOH. Quantitative yields of are obtained at any solvent composition. The addition of LiCl or NaCl ([MCl] = 0–1.5 M) to the reaction mixtures has a negligible effect on k_obs but leads to the formation, in low yields (<10%), of the ArCl derivative. The addition of LiClO₄ (0–1.5 M) to 20% MeOH/H₂O mixtures has a negligible effect on both k_obs and on the product distribution. However, at 99.5% MeOH, the addition of the same amounts of LiClO₄ leads to a modest decrease in k_obs but to a significant decrease in the yields of ArOMe. Results are interpreted in terms of the preferential solvation of perchlorate ions by the aryl cations, removing MeOH molecules from the solvation shell. Full article

Intra- and intermolecular interactions have been explored in selected N-oxide derivatives: 2-(N,N-dimethylamino-N-oxymethyl)-4,6-dimethylphenyl (1) and 5,5’-dibromo-3-diethylaminomethyl-2,2’-biphenol N-oxide (2). Both compounds possess intramolecular hydrogen bonding, which is classified as moderate in 1 and strong in 2, and resonance-assisted in both cases. Density Functional Theory (DFT) in its classical formulation as well as Time-Dependent extension (TD-DFT) were employed to study proton transfer phenomena. The simulations were performed in the gas phase and with implicit and explicit solvation models. The obtained structures of the studied N-oxides were compared with experimental data available. The proton reaction path was investigated using scan with an optimization method, and water molecule reorientation in the monohydrate of 1 was found upon the proton scan progress. It was found that spontaneous proton transfer phenomenon cannot occur in the electronic ground state of the compound 1. An opposite situation was noticed for the compound 2. The changes of nucleophilicity and electrophilicity upon the bridged proton migration were analyzed on the basis of Fukui functions in the case of 1. The interaction energy decomposition of dimers and microsolvation models was investigated using Symmetry-Adapted Perturbation Theory (SAPT). The simulations were performed in both phases to introduce polar environment influence on the interaction energies. The SAPT study showed rather minor role of induction in the formation of homodimers. However, it is worth noticing that the same induction term is responsible for the preference of water molecules’ interaction with N-oxide hydrogen bond acceptor atoms in the microsolvation study. The Natural Bond Orbital (NBO) analysis was performed for the complexes with water to investigate the charge flow upon the polar environment introduction. Finally, the TD-DFT was applied for isolated molecules as well as for microsolvation models showing that the presence of solvent affects excited states, especially when the N-oxide acceptor atom is microsolvated. Full article

A study was carried out on the solvolysis of 1-adamantyl chlorothioformate (1-AdSCOCl, 1) in hydroxylic solvents. The rate constants of the solvolysis of 1 were well correlated using the Grunwald–Winstein equation in all of the 20 solvents (R = 0.985). The solvolyses of 1 were analyzed as the following two competing reactions: the solvolysis ionization pathway through the intermediate (1-AdSCO)⁺ (carboxylium ion) stabilized by the loss of chloride ions due to nucleophilic solvation and the solvolysis–decomposition pathway through the intermediate 1-Ad⁺Cl⁻ ion pairs (carbocation) with the loss of carbonyl sulfide. In addition, the rate constants (k_exp) for the solvolysis of 1 were separated into k_1-Ad⁺Cl⁻ and k_{1-AdSCO⁺Cl⁻} through a product study and applied to the Grunwald–Winstein equation to obtain the sensitivity (m-value) to change in solvent ionizing power. For binary hydroxylic solvents, the selectivities (S) for the formation of solvolysis products were very similar to those of the 1-adamantyl derivatives discussed previously. The kinetic solvent isotope effects (KSIEs), salt effects and activation parameters for the solvolyses of 1 were also determined. These observations are compared with those previously reported for the solvolyses of 1-adamantyl chloroformate (1-AdOCOCl, 2). The reasons for change in reaction channels are discussed in terms of the gas-phase stabilities of acylium ions calculated using Gaussian 03. Full article

Nickel(II) complexes of mono-functionalized pyridine-tetraazamacrocycles (PyMACs) are a new class of catalysts that possess promising activity similar to biological peroxidases. Experimental studies with ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), substrate) and H₂O₂ (oxidant) proposed that hydrogen-bonding and proton-transfer reactions facilitated by their pendant arm were responsible for their catalytic activity. In this work, density functional theory calculations were performed to unravel the influence of pendant arm functionalization on the catalytic performance of Ni(II)–PyMACs. Generated frontier orbitals suggested that Ni(II)–PyMACs activate H₂O₂ by satisfying two requirements: (1) the deprotonation of H₂O₂ to form the highly nucleophilic HOO⁻, and (2) the generation of low-spin, singlet state Ni(II)–PyMACs to allow the binding of HOO⁻. COSMO solvation-based energies revealed that the O–O Ni(II)–hydroperoxo bond, regardless of pendant arm type, ruptures favorably via heterolysis to produce high-spin (S = 1) [(L)Ni³⁺–O·]²⁺ and HO⁻. Aqueous solvation was found crucial in the stabilization of charged species, thereby favoring the heterolytic process over homolytic. The redox reaction of [(L)Ni³⁺–O·]²⁺ with ABTS obeyed a 1:2 stoichiometric ratio, followed by proton transfer to produce the final intermediate. The regeneration of Ni(II)–PyMACs at the final step involved the liberation of HO⁻, which was highly favorable when protons were readily available or when the pK_a of the pendant arm was low. Full article

Bimolecular nucleophilic substitution (S_N2) reaction is one of the most frequently processes chosen as model mechanism to introduce undergraduate chemistry students to computational chemistry methodology. In this work, we performed a computational analysis for the ionic S_N2 reaction, where the nucleophile charged (X⁻; X=F, Cl, Br, I) attacks the carbon atom of the substrate (CH₃Cl) through a backside pathway, and simultaneously, the leaving group is displaced (Cl⁻). The calculations were performed applying DFT methods with the Gaussian09 program, the B3LYP functional, the 6-31+G* basis set for all atoms except iodine (6-311G*), and the solvents effects (acetonitrile and cyclohexane) were evaluated with the PCM model. We evaluated the potential energy surface (PES) for the mentioned reaction considering the reactants, the formation of an initial complex between the nucleophile and the substrate, the transition state, a final complex where the leaving group is still bound to the substrate and the products. We analyzed the atomic charge (ESP) and the bond distance throughout the process. Gas phase and solvent studies were performed in order to analyze the solvation effects on the reactivity of the different nucleophiles. We observed that increasing solvent polarity, decreases reaction rates. On the other hand, we thought it would be enriching, to carry out a reactivity analysis from the point of view of molecular orbitals. Therefore, we analyzed the MOs HOMO and the MOs LUMO of the different stationary states on PES, both in a vacuum (gas phase) and in acetonitrile as the solvent. Full article

Carba analogues of biologically relevant natural carbohydrates are promising structures for the development of future drugs endowed with enhanced hydrolytic stability. An open synthetic challenge in this field is the optimization of new methodologies for the stereo- and regioselective opening of α-gluco carbasugar 1,2-epoxides that allow for the preparation of pseudo mono- and disaccharides of great interest. Therefore, we investigated the effect of Lewis acids and solvate ionic liquids (SILs) on the epoxide ring opening of a model substrate. Of particular interest was the complete stereo- and regioselectivity, albeit limited to simple nucleophiles, toward the desired C(1) isomer that was observed using LiClO₄. The results obtained with SILs were also remarkable. In particular, Li[NTf₂]/tetraglyme ([Li(G4)]TFSI) was able to function as a Lewis acid and to direct the attack of the nucleophile preferentially at the pseudo anomeric position, even with a more complex and synthetically interesting nucleophile. The regioselectivity observed for LiClO₄ and [Li(G4)]TFSI was tentatively ascribed to the formation of a bidentate chelating system, which changed the conformational equilibrium and ultimately permitted a trans-diaxial attack on C(1). To the best of our knowledge, we report here the first case in which SILs were successfully employed in a ring-opening process of epoxides. Full article

deMon2k is a readily available program specialized in Density Functional Theory (DFT) simulations within the framework of Auxiliary DFT. This article is intended as a tutorial-review of the capabilities of the program for molecular simulations involving ground and excited electronic states. The program implements an additive QM/MM (quantum mechanics/molecular mechanics) module relying either on non-polarizable or polarizable force fields. QM/MM methodologies available in deMon2k include ground-state geometry optimizations, ground-state Born–Oppenheimer molecular dynamics simulations, Ehrenfest non-adiabatic molecular dynamics simulations, and attosecond electron dynamics. In addition several electric and magnetic properties can be computed with QM/MM. We review the framework implemented in the program, including the most recently implemented options (link atoms, implicit continuum for remote environments, metadynamics, etc.), together with six applicative examples. The applications involve (i) a reactivity study of a cyclic organic molecule in water; (ii) the establishment of free-energy profiles for nucleophilic-substitution reactions by the umbrella sampling method; (iii) the construction of two-dimensional free energy maps by metadynamics simulations; (iv) the simulation of UV-visible absorption spectra of a solvated chromophore molecule; (v) the simulation of a free energy profile for an electron transfer reaction within Marcus theory; and (vi) the simulation of fragmentation of a peptide after collision with a high-energy proton. Full article

Non-planar amides are usually transitional structures, that are involved in amide bond rotation and inversion of the nitrogen atom, but some ground-minimum non-planar amides have been reported. Non-planar amides are generally sensitive to water or other nucleophiles, so that the amide bond is readily cleaved. In this article, we examine the reactivity profile of the base-catalyzed hydrolysis of 7-azabicyclo[2.2.1]heptane amides, which show pyramidalization of the amide nitrogen atom, and we compare the kinetics of the base-catalyzed hydrolysis of the benzamides of 7-azabicyclo[2.2.1]heptane and related monocyclic compounds. Unexpectedly, non-planar amides based on the 7-azabicyclo[2.2.1]heptane scaffold were found to be resistant to base-catalyzed hydrolysis. The calculated Gibbs free energies were consistent with this experimental finding. The contribution of thermal corrections (entropy term, –TΔS^‡) was large; the entropy term (ΔS^‡) took a large negative value, indicating significant order in the transition structure, which includes solvating water molecules. Full article

The MN12SX density functional, in connection with the Def2TZVP basis set, was assessed, together with the SMD solvation model (Solvation Model based on the Density), for calculation of the molecular properties and structure of a group of peptides of marine origin named Mirabamides A–H. All the chemical reactivity descriptors for the systems were calculated via Conceptual Density Functional Theory (CDFT). The active sites suitable for nucleophilic, electrophilic, and radical attacks were chosen by linking them with the Fukui function indices, nucleophilic and electrophilic Parr functions, and condensed Dual Descriptor $\mathsf{\Delta }f\left(\mathbf{r}\right)$ , respectively. Additionally, the p $K_{\mathrm{a}}$ values for the different peptides are predicted with great accuracy as well as the ability of the studied molecule in acting as an efficient inhibitor of the formation of Advanced Glycation Endproducts (AGEs), which constitutes a useful knowledge for the development of drugs for fighting Diabetes, Alzheimer and Parkinson diseases. Finally, the bioactivity scores for the Mirabamides A–H are predicted through different methodologies. Full article

Novel collector lead(II)-benzohydroxamic acid (Pb(II)–BHA) complexes in aqueous solution were characterized by using experimental approaches, including Ultraviolet-visible (UV-Vis) spectroscopy and electrospray ionization-mass spectrometry (ESI-MS), as well as first-principle density functional theory (DFT) calculations with consideration for solvation effects. The Job plot delineated that a single coordinated Pb(BHA)⁺ should be formed first, and that the higher coordination number complexes can be formed subsequently. Moreover, the Pb(II)–BHA species can aggregate with each other to form complicated structures, such as Pb(BHA)₂ or highly complicated complexes. ESI-MS results validated the existence of Pb-(BHA)_n=1,2 under different solution pH values. Further, the first-principles calculations suggested that Pb(BHA)⁺ should be the most stable structure, and the Pb atom in Pb(BHA)⁺ will act as an active site to attack nucleophiles. These findings are meaningful to further illustrate the adsorption mechanism of Pb(II)–BHA complexes, and are helpful for developing new reagents in mineral processing. Full article