σ-Hole Site-Based Interactions within Hypervalent Pnicogen, Halogen, and Aerogen-Bearing Molecules with Lewis Bases: A Comparative Study.

σ-Hole site-based interactions in the trigonal bipyramidal geometrical structure of hypervalent pnicogen, halogen, and aerogen-bearing molecules with pyridine and NCH Lewis bases (LBs) were comparatively examined. In this respect, the ZF5···, XF3O2···, and AeF2O3···LB complexes (where Z = As, Sb; X = Br, I; Ae = Kr, Xe; and LB = pyridine and NCH) were investigated. The electrostatic potential (EP) analysis affirmations outlined the occurrence of σ-holes on the systems under consideration with disparate magnitudes that increased according to the following order: AeF2O3 < XF3O2 < ZF5. In line with EP outcomes, the proficiency of σ-hole site-based interactions increased as the atomic size of the central atom increased with a higher favorability for the pyridine-based complexes over NCH-based ones. The interaction energy showed the most favorable negative values of -35.97, -44.53, and -56.06 kcal/mol for the XeF2O3···, IF3O2···, and SbF5···pyridine complexes, respectively. The preferentiality pattern of the studied interactions could be explained as a consequence of (i) the dramatic rearrangement of ZF5 molecules from the trigonal bipyramid geometry to the square pyramidal one, (ii) the significant and tiny deformation energy in the case of the interaction of XF3O2 molecules with pyridine and NCH, respectively, and (iii) the absence of geometrical deformation within the AeF2O3···pyridine and ···NCH complexes other than the XeF2O3···pyridine one. Quantum theory of atoms in molecules and noncovalent interaction index findings reveal the partially covalent nature of most of the investigated interactions. Symmetry-adapted perturbation theory affirmations declared that the electrostatic component was the driving force beyond the occurrence of the considered interactions. The obtained findings will help in improving our understanding of the effect of geometrical deformation on intermolecular interactions.

Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study.

The oxazaphosphorine cyclophosphamide (CP) is a DNA-alkylating agent commonly used in cancer chemotherapy. This anticancer agent is administered as a prodrug activated by a liver cytochrome P450-catalyzed 4-hydroxylation reaction that yields the active, cytotoxic metabolite. The primary metabolite, 4-hydroxycyclophosphamide, equilibrates with the ring-open aldophosphamide that undergoes ß-elimination to yield the therapeutically active DNA cross-linking phosphoramide mustard and the byproduct acrolein. The present paper presents a DFT investigation of the different metabolic phases and an insight into the mechanism by which CP exerts its cytotoxic action. A detailed computational analysis of the energy profiles describing all the involved transformations and the mechanism of DNA alkylation is given with the aim to contribute to an increase of knowledge that, after more than 60 years of unsuccessful attempts, can lead to the design and development of a new generation of oxazaphosphorines.

Hole interactions of aerogen oxides with Lewis bases: an insight into σ-hole and lone-pair-hole interactions.

σ-Hole and lone-pair (lp)-hole interactions of aerogen oxides with Lewis bases (LB) were comparatively inspected in terms of quantum mechanics calculations. The ZOn ⋯ LB complexes (where Z = Kr and Xe, n = 1, 2, 3 and 4, and LB = NH3 and NCH) showed favourable negative interaction energies. The complexation features were explained in light of σ-hole and lp-hole interactions within optimum distances lower than the sum of the respective van der Waals radii. The emerging findings outlined that σ-hole interaction energies generally enhanced according to the following order: KrO4 ⋯ < KrO⋯ < KrO3⋯ < KrO2⋯LB and XeO4⋯ < XeO⋯ < XeO2⋯ < XeO3⋯LB complexes with values ranging from -2.23 to -12.84 kcal mol-1. Lp-hole interactions with values up to -5.91 kcal mol-1 were shown. Symmetry-adapted perturbation theory findings revealed the significant contributions of electrostatic forces accounting for 50-65% of the total attractive forces within most of the ZOn⋯LB complexes. The obtained observations would be useful for the understanding of hole interactions, particularly for the aerogen oxides, with application in supramolecular chemistry and crystal engineering.

Sigma-Hole and Lone-Pair-Hole Site-Based Interactions of Seesaw Tetravalent Chalcogen-Bearing Molecules with Lewis Bases.

For the first time, sigma (σ)- and lone-pair (lp)-hole site-based interactions of SF4 and SeF4 molecules in seesaw geometry with NH3 and FH Lewis bases were herein comparatively investigated. The obtained findings from the electrostatic potential analysis outlined the emergence of sundry holes on the molecular entity of the SF4 and SeF4 molecules, dubbed the σ- and lp-holes. The energetic viewpoint announced splendid negative binding energy values for σ-hole site-based interactions succeeded by lp-hole analogues, which were found to be -9.21 and -0.50 kcal/mol, respectively, for SeF4···NH3 complex as a case study. Conspicuously, a proper concurrence between the strength of chalcogen σ-hole site-based interactions and the chalcogen's atomic size was obtained, whereas a reverse pattern was proclaimed for the lp-hole counterparts. Further, a higher preference for the YF4···NH3 complexes with elevated negative binding energy was promulgated over the YF4···FH ones, indicating the eminent role of Lewis basicity. The indications of the quantum theory of atoms in molecules generally asserted the closed-shell nature of all the considered interactions. The observation of symmetry-adapted perturbation theory revealed the substantial contributing role of the electrostatic forces beyond the occurrence of σ-hole site-based interactions. In comparison, the dispersion forces were specified to govern the lp-hole counterparts. Such emerging findings would be a gate for the fruitful forthcoming applications of chalcogen bonding interactions in crystal engineering and biological systems.

Preferability of Molnupiravir, an Anti-COVID-19 Drug, toward Purine Nucleosides: A Quantum Mechanical Study.

Structural aspects of molnupiravir complexed with the RNA of the SARS-CoV-2 virus have been recently resolved inside the RNA-dependent RNA polymerase (RdRp), demonstrating the interactions of molnupiravir with purine nucleosides. However, the preference of molnupiravir to interact with one purine nucleoside over another has not been clearly investigated. Herein, the complexation of molnupiravir in its active form with guanosine and adenosine was compared, using sundry density functional theory calculations. The plausible tautomeric structures of the molnupiravir drug in complex with guanosine/adenosine were minutely scrutinized. The relative energy findings outlined the favorability of amino-molnupiravir···keto-amino-guanosine and imino-molnupiravir···amino-adenosine optimized complexes. According to the interaction (Eint) and binding (Ebind) energy values, higher preferential base-pairing of molnupiravir with guanosine over the adenosine one was recognized with Eint/Ebind values of -31.16/-21.81 and -13.93/-12.83 kcal/mol, respectively. This could be interpreted by the presence of three and two hydrogen bonds within the former and latter complexes, respectively. Observable changes in the electronic properties and global indices of reactivity of the studied complexes also confirmed the preferential binding within the studied complexes. The findings from the quantum theory of atoms in molecules and the noncovalent interaction index also support the partially covalent nature of the investigated interactions. For both complexes, changes in thermodynamic parameters outlined the spontaneous, exothermic, and nonrandom states of the inspected interactions. Inspecting the solvent effect on the studied interactions outlined more observable amelioration within the water medium compared with the gas one. These results would be a durable ground for the forthcoming studies concerned with the interactions of the molnupiravir drug with purine nucleosides.

Effects of Lewis Basicity and Acidity on σ-Hole Interactions in Carbon-Bearing Complexes: A Comparative Ab Initio Study.

The effects of Lewis basicity and acidity on σ-hole interactions were investigated using two sets of carbon-containing complexes. In Set I, the effect of Lewis basicity was studied by substituting the X3/X atom(s) of the NC-C6H2-X3 and NCX Lewis bases (LB) with F, Cl, Br, or I. In Set II, the W-C-F3 and F-C-X3 (where X and W = F, Cl, Br, and I) molecules were utilized as Lewis acid (LA) centers. Concerning the Lewis basicity effect, higher negative interaction energies (Eint) were observed for the F-C-F3∙∙∙NC-C6H2-X3 complexes compared with the F-C-F3∙∙∙NCX analogs. Moreover, significant Eint was recorded for Set I complexes, along with decreasing the electron-withdrawing power of the X3/X atom(s). Among Set I complexes, the highest negative Eint was ascribed to the F-C-F3∙∙∙NC-C6H2-I3 complex with a value of -1.23 kcal/mol. For Set II complexes, Eint values of F-C-X3 bearing complexes were noted within the -1.05 to -2.08 kcal/mol scope, while they ranged from -0.82 to -1.20 kcal/mol for the W-C-F3 analogs. However, Vs,max quantities exhibited higher values in the case of W-C-F3 molecules compared with F-C-X3; preferable negative Eint were ascribed to the F-C-X3 bearing complexes. These findings were delineated as a consequence of the promoted contributions of the X3 substituents. Dispersion forces (Edisp) were identified as the dominant forces for these interactions. The obtained results provide a foundation for fields such as crystal engineering and supramolecular chemistry studies that focus on understanding the characteristics of carbon-bearing complexes.

External Electric Field Effect on the Strength of σ-Hole Interactions: A Theoretical Perspective in Like⋯Like Carbon-Containing Complexes.

For the first time, σ-hole interactions within like⋯like carbon-containing complexes were investigated, in both the absence and presence of the external electric field (EEF). The effects of the directionality and strength of the utilized EEF were thoroughly unveiled in the (F-C-F3)2, (F-C-H3)2, and (H-C-F3)2 complexes. In the absence of the EEF, favorable interaction energies, with negative values, are denoted for the (F-C-F3)2 and (H-C-F3)2 complexes, whereas the (F-C-H3)2 complex exhibits unfavorable interactions. Remarkably, the strength of the applied EEF exhibits a prominent role in turning the repulsive forces within the latter complex into attractive ones. The symmetrical nature of the considered like⋯like carbon-containing complexes eradicated the effect of directionality of the EEF. The quantum theory of atoms in molecules (QTAIM), and the noncovalent interaction (NCI) index, ensured the occurrence of the attractive forces, and also outlined the substantial contributions of the three coplanar atoms to the total strength of the studied complexes. Symmetry-adapted perturbation theory (SAPT) results show the dispersion-driven nature of the interactions.

Type I-IV Halogen⋯Halogen Interactions: A Comparative Theoretical Study in Halobenzene⋯Halobenzene Homodimers.

In the current study, unexplored type IV halogen⋯halogen interaction was thoroughly elucidated, for the first time, and compared to the well-established types I−III interactions by means of the second-order Møller−Plesset (MP2) method. For this aim, the halobenzene⋯halobenzene homodimers (where halogen = Cl, Br, and I) were designed into four different types, parodying the considered interactions. From the energetic perspective, the preference of scouted homodimers was ascribed to type II interactions (i.e., highest binding energy), whereas the lowest binding energies were discerned in type III interactions. Generally, binding energies of the studied interactions were observed to decline with the decrease in the σ-hole size in the order, C6H5I⋯IC6H5 > C6H5Br⋯BrC6H5 > C6H5Cl⋯ClC6H5 homodimers and the reverse was noticed in the case of type IV interactions. Such peculiar observations were relevant to the ample contributions of negative-belt⋯negative-belt interactions within the C6H5Cl⋯ClC6H5 homodimer. Further, type IV torsional trans → cis interconversion of C6H5X⋯XC6H5 homodimers was investigated to quantify the π⋯π contributions into the total binding energies. Evidently, the energetic features illustrated the amelioration of the considered homodimers (i.e., more negative binding energy) along the prolonged scope of torsional trans → cis interconversion. In turn, these findings outlined the efficiency of the cis configuration over the trans analog. Generally, symmetry-adapted perturbation theory-based energy decomposition analysis (SAPT-EDA) demonstrated the predominance of all the scouted homodimers by the dispersion forces. The obtained results would be beneficial for the omnipresent studies relevant to the applications of halogen bonds in the fields of materials science and crystal engineering.

Unusual chalcogen⋯chalcogen interactions in like⋯like and unlike YCY⋯YCY complexes (Y = O, S, and Se).

Chalcogen⋯chalcogen interactions were investigated within four types of like⋯like and unlike YCY⋯YCY complexes (where Y = O, S, or Se). A plethora of quantum mechanical calculations, including molecular electrostatic potential (MEP), surface electrostatic potential extrema, point-of-charge (PoC), quantum theory of atoms in molecules (QTAIM), noncovalent interaction (NCI), and symmetry-adapted perturbation theory-based energy decomposition analysis (SAPT-EDA) calculations, were executed. The energetic findings revealed a preferential tendency of the studied chalcogen-bearing molecules to engage in type I, II, III, or IV chalcogen⋯chalcogen interactions. Notably, the selenium-bearing molecules exhibited the most potent ability to favorably participate in all the explored chalcogen⋯chalcogen interactions. Among like⋯like complexes, type IV interactions showed the most favorable negative binding energies, whereas type III interactions exhibited the weakest binding energies. Unexpectedly, oxygen-containing complexes within type IV interactions showed an alien pattern of binding energies that decreased along with an increase in the chalcogen atomic size level. QTAIM analysis provided a solo BCP, via chalcogen⋯chalcogen interactions, with no clues as to any secondary ones. SAPT-EDA outlined the domination of the explored interactions by the dispersion forces and indicated the pivotal shares of the electrostatic forces, except type III σ-hole⋯σ-hole and di-σ-hole interactions. These observations demonstrate in better detail all the types of chalcogen⋯chalcogen interactions, providing persuasive reasons for their more intensive use in versatile fields related to materials science and drug design.

R•-hole interactions of group IV-VII radical-containing molecules: A comparative study.

For the first time, the potentiality of the sp2-hybridized group IV-VII radical (R•)-containing molecules to participate in R•-hole interactions was comparatively assessed using •SiF3,•POF2, •SO2F, and •ClO3 models in the trigonal pyramidal geometry. In that spirit, a plethora of quantum mechanical calculations was performed at the MP2/aug-cc-pVTZ level of theory. According to the results, all the investigated R•-containing molecules exhibited potent versatility to engage in R•-hole … Lewis base interactions with significant negative binding energies for the NCH-based complexes. The strength of R•-hole interactions was perceived to obey the •ClO3 … > â€¢SO2F … > â€¢POF2 … > â€¢SiF3 … Lewis base order, outlining an inverse correlation between the binding energy and the atomic size of the R•-hole donor. Benchmarking of the binding energy at the CCSD/CBS(T) computational level was executed for all the explored interactions and addressed an obvious similarity between the MP2 and CCSD energetic findings. QTAIM analysis critically unveiled the closed-shell nature of the explored R•-hole interactions. SAPT-EDA proclaimed the reciprocal contributions of electrostatic and dispersion forces to the total binding energy. These observations demonstrate in better detail the nature of R•-hole interactions, leading to a convincing amelioration for versatile fields relevant to materials science and drug design.