Investigating the Solvent Effects on Binding Affinity of PAHs–ExBox⁴⁺ Complexes: An Alchemical Approach

Polycyclic aromatic hydrocarbons (PAHs) are polluting agents, produced naturally or artificially, widely dispersed in the environment and potentially carcinogenic and immunotoxic to humans and animals, mainly for marine life. Recently, a tetracationic box-shaped cyclophane (ExBox4+) was synthesized, fully characterized, and revealed to form host–guest complexes with PAHs in acetonitrile, demonstrating the potential ability for it to act as a PAHs scavenger. This work investigates, through Molecular Dynamics (MD) simulations, the binding affinity between different PAHs and ExBox4+ in different solvents: chloroform (nonpolar), acetonitrile (polar protic), and water (polar protic). An alchemical method of simultaneous decoupling-recoupling (SDR) was used and implemented in a newly developed Python program called GHOAT, which fully automates the calculation of binding free energies and invokes the AMBER 2020 simulation package. The results showed that the affinity between ExBox4+ and PAHs in water is much larger than in organic media, with free energies between −5 and −20 kcal/mol, being able to act as a PHAs scavenger with great potential for applications in environmental chemistry such as soil washing. The results also reveal a significant correlation with the experimental available ΔG values. The methodology employed presents itself as an important tool for the in silico determination of binding affinities, not only available for charged cyclophanes but also extensible to several other HG supramolecular systems in condensed media, aiding in the rational design of host–guest systems in a significant way

Investigating the Solvent Effects on Binding Affinity of PAHs–ExBox⁴⁺ Complexes: An Alchemical Approach

Polycyclic aromatic hydrocarbons (PAHs) are polluting agents, produced naturally or artificially, widely dispersed in the environment and potentially carcinogenic and immunotoxic to humans and animals, mainly for marine life. Recently, a tetracationic box-shaped cyclophane (ExBox4+) was synthesized, fully characterized, and revealed to form host–guest complexes with PAHs in acetonitrile, demonstrating the potential ability for it to act as a PAHs scavenger. This work investigates, through Molecular Dynamics (MD) simulations, the binding affinity between different PAHs and ExBox4+ in different solvents: chloroform (nonpolar), acetonitrile (polar protic), and water (polar protic). An alchemical method of simultaneous decoupling-recoupling (SDR) was used and implemented in a newly developed Python program called GHOAT, which fully automates the calculation of binding free energies and invokes the AMBER 2020 simulation package. The results showed that the affinity between ExBox4+ and PAHs in water is much larger than in organic media, with free energies between −5 and −20 kcal/mol, being able to act as a PHAs scavenger with great potential for applications in environmental chemistry such as soil washing. The results also reveal a significant correlation with the experimental available ΔG values. The methodology employed presents itself as an important tool for the in silico determination of binding affinities, not only available for charged cyclophanes but also extensible to several other HG supramolecular systems in condensed media, aiding in the rational design of host–guest systems in a significant way

Ruthenophanes: Evaluating Cation−π Interactions in [Ru(η⁶‑C₁₆H₁₂R₄)(NH₃)₃]^2+/3+ Complexes. A Computational Insight

The nature of cation−π interactions in a set of [Ru­(η⁶-C₁₆H₁₂R₄)­(NH₃)₃]²⁺³⁺ (R = F, CN, CH₃, and others), complexes was investigated with Su–Li energy decomposition analysis and the natural orbitals for chemical valence and the extended transition state method EDA-NOCV. The long-distance effects of electron-donating and electron-withdrawing substituents as well as protonation of the <i>ipso</i> carbon on the nature of cation−π interactions were investigated. Both energy decomposition analyses, Su–Li EDA and EDA-NOCV, are in total agreement, showing that the presence of electron-donating substituents such as CH₃, NH₂, and H₃CO tends to stabilize the ruthenium–arene interaction while electron-withdrawing substituents such as F, CN, and NO₂ tend to weaken such interactions. The electrostatic component of the ruthenium–arene interaction is the most affected by the substitution, despite the fact that the covalent character is much more significant than the electrostatic character. EDA-NOCV reveals that the most important orbital stabilization comes from donation and back-donation between the interacting fragments, while the σ density deformations present a moderate contribution to total orbital stabilization energy in ruthenium–arene interactions of complexes <b>1</b>–<b>8</b>

Metal–Ligand Bonding Situation in Ruthenophanes Containing Multibridged Cyclophanes

Cation−π interactions in a set of ruthenophanes [Ru­(η⁶-C_<i>n</i>H_<i>n</i>)­(NH₃)₃]²⁺ (<i>n</i> = 16, 18, 20, 22, and 24) (<b>1</b>–<b>9</b>), containing multibridged cyclophanes as ligands, including [2.2]­paracyclophane and its multibridged analogs, [2_<i>n</i>]­cyclophanes, are analyzed in terms of SAPT0/TZP and Su–Li EDA analyses. The calculations reveal that the coordination with cation [Ru­(NH₃)₃]²⁺ affects the structures of [2_<i>n</i>]­ciclophane ligands, mainly the planarity of the coordinating ring. The EDA results show that the gradual addition of ethano bridges in [2_<i>n</i>]­cyclophanes tends to strengthen the cation−π interaction between [Ru­(NH₃)₃]²⁺ and [2_<i>n</i>]­cyclophane. Both Su–Li EDA and SAPT0 are in line, suggesting that the cation−π interactions present a predominant covalent character in complexes <b>1</b>–<b>9</b>

Metal–Ligand Bonding Situation in Ruthenophanes Containing Multibridged Cyclophanes

Cation−π interactions in a set of ruthenophanes [Ru­(η⁶-C_<i>n</i>H_<i>n</i>)­(NH₃)₃]²⁺ (<i>n</i> = 16, 18, 20, 22, and 24) (<b>1</b>–<b>9</b>), containing multibridged cyclophanes as ligands, including [2.2]­paracyclophane and its multibridged analogs, [2_<i>n</i>]­cyclophanes, are analyzed in terms of SAPT0/TZP and Su–Li EDA analyses. The calculations reveal that the coordination with cation [Ru­(NH₃)₃]²⁺ affects the structures of [2_<i>n</i>]­ciclophane ligands, mainly the planarity of the coordinating ring. The EDA results show that the gradual addition of ethano bridges in [2_<i>n</i>]­cyclophanes tends to strengthen the cation−π interaction between [Ru­(NH₃)₃]²⁺ and [2_<i>n</i>]­cyclophane. Both Su–Li EDA and SAPT0 are in line, suggesting that the cation−π interactions present a predominant covalent character in complexes <b>1</b>–<b>9</b>

Quest for Insight into Ultrashort C–H···π Proximities in Molecular “Iron Maidens”

Molecular iron maidens are a strained type of cyclophane in which a methine hydrogen, by the action of the bridges, is placed closer to the center of an aromatic ring. Such constrained molecular frameworks are in fact a noteworthy synthetic challenge. The present study provides a comprehensible theoretical analysis that elucidates unique structural and energetic aspects of this class of molecules, evaluating, in the light of quantum chemistry, both the influence of the aromatic moiety, from π-basic to π-acid, and the nature of the heteroatoms located at the bridges. Our results not only propose the shortest intramolecular centered C–H···π distance to date, which is supported by calculated ¹H chemical shifts, but also shed light on the main factors that rationalize and justify such proximity. QTAIM, NBO, and NCI analyses allow us prematurely to conclude that the ultrashort C–H···π distance is sustained by an interplay between a large stabilizing electrostatic component with a non-negligible covalent character. However, the energetics involving such strained molecular scaffolds, addressed by means of isodesmic reactions, revealed that the C–H···π proximity is modulated mainly by the capacity of the bridges to support the strain imposed by the whole structure, hence compressing the C–H bond against the π-system

Anion Recognition by Organometallic Calixarenes: Analysis from Relativistic DFT Calculations

The physical nature of the noncovalent interactions involved in anion recognition was investigated in the context of metalated calix[4]­arene hosts, employing Kohn–Sham molecular orbital (KS-MO) theory, in conjunction with a canonical energy decomposition analysis, at the dispersion-corrected DFT level of theory. Computed data evidence that the most stable host–guest bonding occurs in ruthenium complexed hosts, followed by technetium and molybdenum metalated macrocyclic receptors. Furthermore, the guest’s steric fit in the host scaffold is a selective and crucial criterion to the anion recognition. Our analyses reveal that coordinated charged metals provide a larger electrostatic stabilization to anion recognition, shifting the calixarenes cavity toward an electron deficient acidic character. This study contributes to the design and development of new organometallic macrocyclic hosts with increased anion recognition specificity

Tuning Heterocalixarenes to Improve Their Anion Recognition: A Computational Approach

We have explored and analyzed the physical factors through which noncovalent interactions in anion sensing based on calixarene-type hosts can be tuned, using dispersion-corrected DFT and Kohn–Sham molecular orbital (KS-MO) theory in conjunction with a canonical energy decomposition analysis (EDA). We find that the host–guest interaction can be enhanced through the introduction of strongly electron-withdrawing groups at particular positions of the arene and triazine units in the host molecule as well as by coordination of a metal complex to the arene and triazine rings. Our analyses reveal that the enhanced anion affinity is caused by increasing the electrostatic potential in the heterocalixarene cavities. This insight can be employed to further tune and improve their selectivity for chloride ions

Spectroscopy and theoretical studies of natural melanin (<i>eumelanin</i>) and its complexation by iron(III)

<p><i>Eumelanin</i> is an oligomeric pigment that has a high affinity for metal ions, which induces the formation of reactive oxygen species, causing melanoma cell apoptosis due to the acceleration of intracellular or extracellular oxidative stress. Melanin in the skin and in dark hair, known as <i>eumelanin</i>, has three main groups that serve as donors: carboxylic acid, catechol, and quinone-imine. In this study, <i>eumelanin</i> was extracted and purified from dark hair using a modified Prota method and characterized by elemental analysis. The sample shows the absence of sulfur-containing groups, and the infrared spectrum shows characteristic <i>ν</i>O–H, <i>ν</i>C–H, <i>ν</i>C=C, <i>ν</i>C=O, and <i>ν</i>C–O stretches, which are confirmed by electronic structure calculations. The major interactions with Fe(III) in solution are at acidic pH values: [Fe(Ac)]²⁺ and [Fe(Qi)]²⁺, and at neutral and alkaline pH values: [Fe(OH)(Cat)] and [Fe(OH)₂(Cat)₂]³⁻, evaluated by electronic structure calculations. Electron paramagnetic resonance measurements in the solid state showed that the species isolated at acidic pH provided <i>g</i> = 4.3, characteristic for high-spin Fe(III) and the presence of a discrete semi-quinone with <i>g</i> = 2.003; at alkaline pH, it was observed that <i>g</i> = 4.3, and there was also a large increase in the radical species, suggesting interaction of the metal ion with the catechol.</p

Shedding Light on the Nature of Host–Guest Interactions in PAHs-ExBox⁴⁺ Complexes

Host–guest (HG) systems formed by polycyclic aromatic hydrocarbons and ExBox⁴⁺ are suitable models to gain a deeper understanding of π–π interactions, which are fundamental in supramolecular chemistry. The physical nature of HG interactions between ExBox⁴⁺ (<b>1</b>) and polycyclic aromatic hydrocarbons (PAHs) (<b>2</b>-<b>12</b>) is investigated at the light of the energy decomposition (EDA-NOCV), noncovalent interactions (NCI), and magnetic response analyses. The EDA-NOCV results show that the dispersion forces play a crucial role in the HG interactions in PAHs⊂ExBox⁴⁺ complexes. The HG interaction energies are dependent on both the size of the PAH employed and the number of π-electrons in the guest molecules. The parallel face-to-face arrangement between HG aromatic moieties is also fundamental to maximize the dispersion interaction and consequently for the attractive energy which leads to the inclusion complex formation