Direct Estimation of Aromatization Energy from 1H NMR and UV-Vis Absorption Data of Homodesmotic Molecules.

This study delves into the ring-opening reaction of two distinct diaryl-ring-pyran systems, referred to as drnp1 and drnp2, where the term 'ring' encompasses aromatic, nonaromatic, or antiaromatic motifs. These systems transform into the corresponding cis-ortho quinonoid systems, denoted as c-drnq1 and c-drnq2. Homodesmotic pairs (drnp1, drnp2) and (c-drnq1, c-drnq2) are categorized as (aromatic, nonaromatic), (aromatic, partially aromatic), (antiaromatic, nonaromatic), and (nonaromatic, nonaromatic), with their energy difference representing aromatization energy (Earoma). Using reliable density functional theory, Earoma is assessed for various aromatic and antiaromatic ring motifs, including borderline cases and nonaromatic structures. For example, benzene exhibits an Earoma of 23.4 kcal/mol, indicating 3.9 kcal/mol aromatic stabilization per CC bond, while cyclobutadiene shows -29.9 kcal/mol, indicating a 7.5 kcal/mol destabilization of the CC bond. This approach extends to evaluating global and local aromatic stabilization effects in polycyclic hydrocarbons, nonbenzenoid systems, and heterocyclic compounds. Additionally, variation in 1H NMR chemical shift (δavg) correlates with Earoma, suggesting that a -1.0 ppm shift corresponds to 24.2 kcal/mol aromatization energy. UV-vis absorption maxima difference (Δλavg) correlates linearly with Earoma, enabling direct assessment of aromatization energy from UV-vis spectra using suitable homodesmotic pairs. This comprehensive approach enhances our understanding of structural, energetic, and spectroscopic aspects of aromatic and antiaromatic systems.

Unraveling pnicogen bonding cooperativity: Insights from molecular electrostatic potential analysis.

A theoretical investigation on the cooperativity of a series of binary, ternary, and quaternary complexes interconnected by pnicogen bonds has been conducted using calculations at the M06-2X/aug-cc-pVTZ level of density functional theory. By measuring changes in the molecular electrostatic potential (MESP) at the nucleus of interacting atoms in all of the complexes, it is possible to quantify the substantial reorganization of the electron density triggered by the formation of pnicogen bonds. The positive change in MESP, indicating a loss of electron density from the donor molecule in a dimer, facilitates the acceptance of electron density from a third molecule, resulting in the formation of a ternary complex with a stronger pnicogen bond compared to the one present in the binary complex. Similarly, the acceptor molecule in a dimer with a negative change in MESP showed an enhanced tendency to donate electron density to an electron-deficient third molecule. The MESP analysis provided valuable insights into the donor/acceptor characteristics of pnicogen bonds within the quaternary complexes. The proposed MESP hypotheses are consistent with the positive cooperativity observed in the pnicogen-bonded clusters. To quantify the changes in MESP, both at the donor atom (ΔVdonor ) and the acceptor atom (ΔVacceptor ), for all pnicogen bonds in the cluster, the total change in MESP (ΔΔVn ) was measured as ΔΔVn = ∑(ΔVdonor )-∑(ΔVacceptor ). Remarkably, ΔΔVn exhibited a strong linear relationship with the sum of the bond energies of the pnicogen bonds in the cluster. This establishes the MESP analysis as a robust approach for understanding the strength and cooperative behavior of pnicogen-bonded clusters. Additionally, the MESP features provided clear evidence of pnicogen bond formation, further supporting the reliability of this approach.

Utilization of the through-space effect to design donor-acceptor systems of pyrrole, indole, isoindole, azulene and aniline.

Molecular electrostatic potential (MESP) topology analysis reveals the underlying phenomenon of the through-space effect (TSE), which imparts electron donor-acceptor properties to a wide range of chemical systems, including derivatives of pyrrole, indole, isoindole, azulene, and aniline. The TSE is inherent in pyrrole owing to the strong polarization of electron density (PoED) from the formally positively charged N-center to the C3C4 bonding region. The N → C3C4 directional nature of the TSE has been effectively employed to design molecules with high electronic polarization, such as bipyrroles, polypyrroles, phenyl pyrroles, multi-pyrrolyl systems and N-doped nanographenes. In core-expanded structures, the direction of electron flow from pyrrole units towards the core leads to highly electron-rich systems, while the opposite arrangement results in highly electron-deficient systems. Similarly, the MESP analysis reveals the presence of the TSE in azulene, indole, isoindole, and aniline. Oligomeric chains of these systems are designed in such a way that the direction of electron flow is consistent across each monomer, leading to substantial electronic polarization between the first and last monomer units. Notably, these designed systems exhibit strong donor-acceptor characteristics despite the absence of explicit donor and acceptor moieties, which is supported by FMO analysis, APT charge analysis, NMR data and λmax data. Among the systems studied, the TSEs of many experimentally known systems (bipyrroles, phenyl pyrroles, hexapyrrolylbenzene, octapyrrolylnaphthalene, decapyrrolylcorannulene, polyindoles, polyazulenes, etc.) are unraveled for the first time, while numerous new systems (polypyrroles, polyisoindoles, and amino-substituted benzene polymers) are predicted to be promising materials for the creation of donor-acceptor systems. These findings demonstrate the potential of the TSE in molecular design and provide new avenues for creating functional materials.

Topology of electrostatic potential and electron density reveals a covalent to non-covalent carbon-carbon bond continuum.

The covalent and non-covalent nature of carbon-carbon (CC) interactions in a wide range of molecular systems can be characterized using various methods, including the analysis of molecular electrostatic potential (MESP), represented as V(r), and the molecular electron density (MED), represented as ρ(r). These techniques provide valuable insights into the bonding between carbon atoms in different molecular environments. By uncovering a fundamental exponential relationship between the distance of the CC bond and the highest eigenvalue (λv1) of V(r) at the bond critical point (BCP), this study establishes the continuum model for all types of CC interactions, including transition states. The continuum model is further delineated into three distinct regions, namely covalent, borderline cases, and non-covalent, based on the gradient, , with the bond distance of the CC interaction. For covalent interactions, this parameter exhibits a more negative value than -5.0 a.u. Å-1, while for non-covalent interactions, it is less negative than -1.0 a.u. Å-1. Borderline cases, which encompass transition state structures, fall within the range of -1.0 to -5.0 a.u. Å-1. Furthermore, this study expands upon Popelier's analysis of the Laplacian of the MED, denoted as ∇2ρ, to encompass the entire spectrum of covalent, non-covalent, and borderline cases of CC interactions. Therefore, the present study presents compelling evidence supporting the concept of a continuum model for CC bonds in chemistry. Additionally, this continuum model is further explored within the context of C-N, C-O, C-S, N-N, O-O, and S-S interactions, albeit with a limited dataset.

Molecular Electrostatic Potential Topology Analysis of Noncovalent Interactions.

ConspectusThe topology of molecular electrostatic potential (MESP), V(r), derived from a reliable quantum chemical method has been used as a powerful tool for the study of intermolecular noncovalent interactions. The MESP topology mapping is achieved by computing both ∇V(r) data and the elements of the Hessian matrix at ∇V(r) = 0, the critical point. MESP minimum (Vmin) as well as MESP at a reaction center, specific to an atom (Vn), have been employed as electronic parameters to interpret the variations in the reactivity (activation/deactivation) of chemical systems with respect to the influence of substituents, ligands, π-conjugation, aromaticity, trans influence, hybridization effects, steric effects, cooperativity, noncovalent interactions, etc. In this Account, several studies involving MESP topology analysis, which yielded interpretations of various noncovalent interactions and also provided new insights in the area of chemical bonding, are highlighted. The existence of lone pairs in molecules is distinctly reflected by the topology features of the MESP minima (Vmin). The Vmin is able to probe lone pairs in molecules, and it has been used as a reliable electronic parameter to assess their σ-donating power. Furthermore, MESP topology analysis can be used to forecast the structure and energetics of lone pair π-complexes. The MESP approach to rationalize lone pair interactions in molecular systems has led to the design of cyclic imines for CO2 capture. The MESP topology analysis of intermolecular complexes revealed a hitherto unknown phenomenon in chemical bonding theory─formation of a covalent bond due to the influence of a noncovalent bond. The MESP-guided approach to intermolecular interactions provided a successful design strategy for the development of CO2 capture systems. The MESP parameters Vmin and MESP at the nucleus, Vn, derived for the molecular systems have been used as powerful measures for the extent of electron donor-acceptor (eDA) interactions in noncovalent complexes. Noncovalent bond formation leads to more negative MESP at the acceptor nucleus (VnA) and less negative MESP at the donor nucleus (VnD). The strong linear relationship observed between ΔΔVn = ΔVnD - ΔVnA and bond energy suggested that MESP data provide a clear evidence of bond formation. Furthermore, MESP topology studies established a cooperativity rule for understanding the donor-acceptor interactive behavior of a dimer D...A with a third molecule. According to this, the electron reorganization in the dimer due to the eDA interaction enhances electron richness at "A", the acceptor, and enhances electron deficiency at "D", the donor. Resultantly, D in D...A is more accepting toward trimer formation, while A in D...A is more donating. MESP topology offers promising design strategies to tune the electron-donating strength in various noncovalent interactions in hydrogen-, dihydrogen-, halogen-, tetrel-, pnicogen-, chalcogen-, and aerogen-bonded complexes and thereby to predict the interactive behavior of molecules. To sum up, MESP topology analysis has become one of the most effective modern techniques for understanding, interpreting, and predicting the intermolecular interactive behavior of molecules.

Polycyclic Aromatic Hydrocarbons as Anode Materials in Lithium-Ion Batteries: A DFT Study.

The structure and energetics of the interactive behavior of Li+ and Li with polycyclic aromatic hydrocarbons (PAHs) have been studied at the wB97XD/6-311G(d,p) level of DFT. The electron distribution in the PAHs, analyzed using the topology of the molecular electrostatic potential (MESP), led to the categorization of their aromatic rings into five types, viz Rs, Rn, Rd, Rb, and Re. Among the different rings, sextet-type Rs and naphthalene-type Rn rings showed the highest interaction with Li+. The change in MESP at the nucleus of Li+ (ΔVLi+) due to the formation of the complex Li+...PAH is found to be proportional to the adsorption energy (E1). In Li...PAH, the spin density on Li is close to zero, suggesting the formation of Li+...PAH•- due to the electron transfer from Li to PAH. The adsorption energy (E2) for Li...PAH does not correlate with the change in MESP at the nucleus of Li, whereas the dissociation energy (E3) of Li+...PAH•- to yield Li+ and PAH•- correlates well with the MESP data, ΔVLi. The study confirms that the change in MESP at the nucleus of Li+ due to complex formation gives a quantitative measure of the electronic effect of the cation-π binding. The cell potential (Vcell) is predicted for the lithium ion battery (LIB) using the Li+...PAH and Li...PAH adsorption energies. On the basis of the Vcell data, "carbon nanoflake"-type systems, viz coronene, circumbiphenyl, C42H16, and C50H18 are suggested as good anode materials for LIBs.

Electrostatic Potential for Exploring Electron Delocalization in Infinitenes, Circulenes, and Nanobelts.

The π-conjugation, aromaticity, and stability of the newly synthesized 12-infinitene and of other infinitenes comprising 8-, 10-, 14-, and 16-arene rings are investigated using density functional theory. The π-electron delocalization and aromatic character rooted in infinitenes are quantified in terms of molecular electrostatic potential (MESP) topology. Structurally, the infinitene bears a close resemblance of its helically twisted structure to the infinity symbol. The MESP topology shows that infinitene possesses an infinity-shaped delocalization of the electron density that streams over the fused benzenoid rings. The parameter ∑i=13Δλi, derived from the eigenvalues (λi) corresponding to the MESP minima, is used for quantifying the aromatic character of arene rings of infinitene. The structure, stability, and MESP topology features of 8-, 10-, 12-, 14-, and 16-infinitenes are also compared with the corresponding isomeric circulenes and carbon nanobelts. Further, the strain in all such systems is evaluated by considering the respective isomeric planar benzenoid hydrocarbons as reference systems. The 12-infinitene turns out to be the most aromatic and the least strained among all the systems examined.

Hydrogen bonds of OCNH motif in rings in drugs: A molecular electrostatic potential analysis.

The OCNH unit is one of the most frequently encountered structural motifs in rings in drugs which serves dual role as the proton donor through NH bond and proton acceptor through the CO bond. Here, we predicted the HB strength (Eint ) of OCNH motif with H2 O for commonly observed 37 rings in drugs with DFT method M06L/6-311++G(d,p). The HB strength is rationalized in terms of molecular electrostatic potential (MESP) topology parameters ΔVn(NH) and ΔVn(CO) which describe the relative electron deficient/rich nature of NH and CO, respectively, with respect to the reference formamide. The Eint of formamide is -10.0 kcal/mol whereas the Eint of ring systems is in the range -8.6 to -12.7 kcal/mol-a minor increase/decrease compared to the formamide. The variations in Eint are addressed using the MESP parameters ΔVn(NH) and ΔVn(CO) and proposed the hypothesis that a positive ΔVn(NH) enhances NH…Ow interaction while a negative ΔVn(CO) enhances the CO…Hw interaction. The hypothesis is proved by expressing Eint jointly as ΔVn(NH) and ΔVn(CO) and also verified for twenty FDA approved drugs. The predicted Eint for the drugs using ΔVn(NH) and ΔVn(CO) agreed well with the calculated Eint . The study confirms that even delicate variations in the electronic feature of a molecule can be quantified in terms of MESP parameters and they provide a priori prediction of the HB strength. The MESP topology analysis is recommended to understand the tunability of HB strength in drug motifs.

Rh(I) and Organo-Rh(III) Complexes of meso-Triarylbiphenylcorrole.

Rhodium complexes of biphenylcorrole are reported, and the molecular structures of the complexes are unambiguously confirmed by single-crystal X-ray analysis. The adj-CCNN core of the dicarbacorrole efficiently stabilizes a rhodium metal ion in its two different oxidation states. It is pertinent to point out that the Rh(I) metal complex attains square-planar geometry while organo-Rh(III) forms an octahedral complex. Furthermore, density functional theory studies corroborate the experimental findings.

Fulleride-metal η5 sandwich and multi-decker sandwich complexes: A DFT prediction.

The (C60 CN)- formed by the reaction of CN- with fullerene shows high electron rich character, very similar to C60 ˙- , and it behaves as a large anion. Similar to Cp- , the bulky anion, (C60 CN)- , acts as a strong η5 ligand towards transition metal centers. Previous studies on η5 coordination of fullerene cage are reported for pseudo fullerenes whereas the present study deals with sandwich complexes of (C60 CN)- with Fe(II), Ru(II), Cr(II), Mo(II), and Ni(II) and multi-decker sandwich complexes of CN-fullerides with Fe(II). The structural parameters of these complexes and the corresponding Cp- complexes showed very close resemblance. Analysis of the metal-to-carbon bonding molecular orbitals showed that sandwich complex [Fe(η5 -(C60 CN)- )2 ] exhibit bonding features very similar to that of ferrocene. Also, a 6-fold decrease in the band gap energy is observed for [Fe(η5 -(C60 CN)- )2 ] compared to ferrocene. The energy of dissociation (ΔE) of the ligand (C60 CN)- from [Fe(η5 -(C60 CN)- )2 ] is slightly lower than the ΔE of a Cp* ligand from a ferrocene derivative wherein each cyclopentadienyl unit is substituted with four tertiary butyl groups. The (C60 CN)- ligand behaved as one of the bulkiest ligands in the chemistry of sandwich complexes. Further, the coordinating ability of the dianion, (C60 (CN)2 )2- is evaluated which showed strong coordination ability simultaneously with two metal centers leading to the formation of multi-decker sandwich and pearl-necklace type polymeric structures.

Quantum chemical studies on the binding domain of SARS-CoV-2 S-protein: human ACE2 interface complex.

A two-layer ONIOM(B3LYP/6-31G*:PM7) method is used to model the binding of several drug/drug-like molecules (L) at the SARS-CoV-2 S-protein: human ACE2 protein interface cavity. The selected molecules include a set of thirty-five ligands from the study of Smith and Smith which showed a high docking score in the range of -7.0 to -7.7 kcal/mol and another set of seven repurposing drugs, viz. favipiravir, remdesivir, EIDD, galidesivir, triazavirin, ruxolitinib, and baricitinib. The ONIOM model of the cavity (M) showed a highly polarized electron distribution along its top-to-bottom direction while Ls with lengths in the range 1.0 - 1.5 nm fitted well inside the cavity in a head-to-tail fashion to yield ML complexes. The ligands showed a large variation in the ONIOM-level binding energy (Eb), in the range -2.7 to -85.4 kcal/mol. The Eb of ML complexes better than -40.0 kcal/mol is observed for myricetin, fidarestat, protirelin, m-digallic acid, glucogallin, benserazide hydrochlorideseradie, remdesivir, tazobactum, sapropterin, nitrofurantoin, quinonoid, pyruvic acid calcium isoniazid, and aspartame, and among them the highest Eb -85.4 kcal/mol is observed for myricetin. A hydroxy substitution is suggested for the phenyl ring of aspartame to improve its binding behavior at the cavity, and the resulting ligand 43 showed the best Eb -84.5 kcal/mol. The ONIOM-level study is found to be effective for the interpretation of the noncovalent interactions resulting from residues such as arginine, histidine, tyrosine, lysine, carboxylate, and amide moieties in the active site and suggests rational design strategies for COVID-19 drug development.Communicated by Ramaswamy H. Sarma.

Polyanionic cyano-fullerides for CO2 capture: a DFT prediction.

The reaction of C60 fullerene with 'n' molecules (n = 1 to 6) of 1,3-dimethyl-2,3-dihydro-2-cyano-imidazole (IMCN) results in the exothermic formation of imidazolium cation-polyanionic fulleride complexes, (IM+)n⋯((C60(CN)n)n-). The binding energy of IM+ with (C60(CN)n)n- in the imidazolium-fulleride ionic complexes increased from -69.6 kcal mol-1 for n = 1 to -202.9 kcal mol-1 for n = 6. The energetics of the complex formation and cation-anion interaction energy data suggest the formation of imidazolium-fulleride ionic liquid (IL) systems. Furthermore, the dimer formation of such ionic complexes showed more exergonic nature due to multiple cooperative electrostatic interactions between oppositely charged species and suggested improved energetics for higher order clusters. The molecular electrostatic potential (MESP) analysis has revealed that the extra 'n' electrons in the ionic complex as well as that in the bare (C60(CN)n)n- are delocalized mainly on the unsaturated carbon centers of the fullerene unit, while the CN groups remain as a neutral unit. The MESP minimum (Vmin) values of (C60(CN)n)n- on the carbon cage have shown that the addition of each CN- unit on the cage enhances the negative character of Vmin by ∼54.7 kcal mol-1. This enhancement in MESP is comparable to the enhancement observed when one electron is added to C60 to produce (-62.5 kcal mol-1) and suggests that adding 'n' CN- groups to the fullerene cage is equivalent to supplying 'n' electrons to the carbon cage. Also the high capacity of the fullerene cage to hold several electrons can be attributed to the spherical delocalization of them onto the electron deficient carbon cage. The interactive behavior of CO2 molecules with (IM+)n⋯(C60(CN)n)n- systems showed that the interaction becomes stronger from -2.3 kcal mol-1 for n = 1 to -18.6 kcal mol-1 for n = 6. From the trianionic fulleride onwards, the C⋯CO2 noncovalent (nc) interaction changes to C-CO2 covalent (c) interaction with the development of carboxylate character on the adsorbed CO2. These results prove that cyano-fullerides are promising candidates for CO2 capture.

A novel aureothin diepoxide derivative from Streptomyces sp. NIIST-D31 strain.

A novel vicinal diepoxide of alloaureothin was isolated from Streptomyces sp. NIIST-D31 strain along with three carboxamides, p-aminobenzoic acid and 1,6-dimethoxyphenazine. Exhaustive 2D NMR analysis and analysis of experimental, theoretical CD spectra aided in establishing the structure of compound 1. Compound 1 inhibits adipogenesis and accumulation of lipid droplets during the differentiation of 3T3-L1 cells.

Amplified Spontaneous Emission from Zwitterionic Excited-State Intramolecular Proton Transfer.

The unique four-level photocycle characteristics of excited-state intramolecular proton transfer (ESIPT) materials enable population inversion and large spectral separation between absorption and emission through their respective enol and keto forms. This leads to minimal or no self-absorption losses, a favorable feature in acting as an optical gain medium. While conventional ESIPT materials with an enol-keto tautomerism process are widely known, zwitterionic ESIPT materials, particularly those with high photoluminescence, are scarce. Facilitated by the synthesis and characterization of a new family of 2-hydroxyphenyl benzothiazole (HBT) with fluorene substituents, HBT-Fl1 and HBT-Fl2, we herein report the first efficient zwitterionic ESIPT lasing material (HBT-Fl2). The zwitterionic ESIPT HBT-Fl2 not only shows a remarkably low solid-state amplified spontaneous emission (ASE) threshold of 5.3 µJ/cm2 with an ASE peak at 609 nm but also exhibits high ASE photostability. Coupled with its substantially large Stokes shift (≈236 nm ≈10,390 cm-1) and an extremely small overlap of excited-state absorption with ASE emission, comprehensive density functional theory (DFT) and time-dependent DFT studies reveal the zwitterionic characteristics of HBT-Fl2. In opposition to conventional ESIPT with π-delocalized tautomerism as observed in analogue HBT-Fl1 and parent HBT, HBT-Fl2 instead shows charge redistribution in the proton transfer through the fluorene conjugation. This structural motif provides a design tactic in the innovation of new zwitterionic ESIPT materials for efficient light amplification in red and longer-wavelength emission.

Demarcating Noncovalent and Covalent Bond Territories: Imine-CO2 Complexes and Cooperative CO2 Capture.

Chemical bond territory is rich with covalently bonded molecules wherein a strong bond is formed by equal or unequal sharing of a quantum of electrons. The noncovalent version of the bonding scenarios expands the chemical bonding territory to a weak domain wherein the interplay of electrostatic and π-effects, dipole-dipole, dipole-induced dipole, and induced dipole-induced dipole interactions, and hydrophobic effects occur. Here we study both the covalent and noncovalent interactive behavior of cyclic and acyclic imine-based functional molecules (XN) with CO2. All parent XN systems preferred the formation of noncovalent (nc) complex XN···CO2, while more saturated such systems (XN') produced both nc and covalent (c) complexes XN'+-(CO2)-. In all such cases, crossover from an nc to c complex is clearly demarcated with the identification of a transition state (ts). The complexes XN'···CO2 and XN'+-(CO2)- are bond stretch isomers, and they define the weak and strong bonding territories, respectively, while the ts appears as the demarcation point of the two territories. Cluster formation of XN with CO2 reinforces the interaction between them, and all become covalent clusters of general formula (XN+-(CO2)-)n. The positive cooperativity associated with the NH···OC hydrogen bond formation between any two XN'+-(CO2)- units strengthened the N-C coordinate covalent bond and led to massive stabilization of the cluster. For instance, the stabilizing interaction between the XN unit with CO2 is increased from 2-7 kcal/mol range in a monomer complex to 14-31 kcal/mol range for the octamer cluster (XN'+-(CO2)-)8. The cooperativity effect compensates for the large reduction in the entropy of cluster formation. Several imine systems showed the exergonic formation of the cluster and are predicted as potential candidates for CO2 capture and conversion.

NADH-depletion triggered energy shutting with cyclometalated iridium (III) complex enabled bimodal Luminescence-SERS sensing and photodynamic therapy.

The nicotinamide adenine dinucleotide-reduced (NADH) function as a hydride (H) carrier to maintain cellular homeostasis. Herein, we report a quinoline appended iridium complex (QAIC) as a molecular probe in fluorescence and surface-enhanced Raman spectroscopy (SERS) modalities to evaluate the endogenous NADH status. NADH-triggered activation of QAIC enabled luminescence (turn-ON) and SERS (turn-OFF) switching phenomenon with a detection limit of 25.6 nM and 15 pM for NADH in luminescence and SERS respectively. Transition state modelling using density functional theory calculations proved that a facile migration of H from NADH to QAIC transformed the activated QAIC (N-QAIC) with an energy span of 19.7 kcal/mol. Furthermore, N-QAIC is probed as a photosensitizer to source singlet oxygen by blocking the photo induced electron transfer (PeT) and generate NAD radicals. Therefore, an efficient light triggered cyclometalated iridium-based molecular probe has been divulged to promote bimodal NADH sensing and multiphase photodynamic therapy.

Hydration patterns of rings in drugs and relationship to lipophilicity: A DFT study.

Rings are one of the major scaffold components of drugs in medicinal chemistry, due to their unique electronic distribution, scaffold rigidity, and three-dimensionality while lipophilicity is considered as a vital parameter of rings that can influence the reactivity, metabolic stability, and toxicity. We have analyzed the electronic features, hydration patterns, solvation effect and lipophilicity data for 51 most widely used ring systems in drugs. Molecular electrostatic potential (MESP) topology analysis has been used to assess the electronic distribution in rings which provided an easy interpretation of the most suitable hydration patterns of the ring with H2 O molecule. Further, the global minimum of ring…H2 O complex has been utilized to predict lipophilicity (logP) with the incorporation of implicit solvation effect. Classification of ring systems based on their molecular weight into four categories, viz. small ring 'sr', medium ring 'mr', large ring 'lr' and extra large ring 'xlr' systems has led to the finding of strong correlations between logP and hydration energy with R = 0.942, 0.933, 0.968 and 0.933, respectively. The micro solvation model is found to be useful for locating the hydrophobic-hydrophilic border for each category of rings in terms of hydration energy whereas the implicit solvation model used for two solvents, n-octanol and water on the most stable hydrated structure led to a global correlation between logP and solvation energy ratio. This correlation predicts a limiting logP value -7.03 for the most hydrophilic ring system and also suggests a clear partitioning of the ring molecules into hydrophobic and hydrophilic classes. The MESP topology-guided approach to understand the electronic features and hydration patterns of rings in drugs lead to powerful predictions on their lipophilicity behavior.

Dynamic self-assembly of mannosylated-calix[4]arene into micelles for the delivery of hydrophobic drugs.

Carbohydrate-lectin interactions and glycol-molecule-driven self-assembly are powerful yet challenging strategies to create supramolecular nanostructures for biomedical applications. Herein, we develop a modular approach of micellization with a small molecular mannosylated-calix[4]arene synthetic core, CA4-Man3, to generate nano-micelles, CA4-Man3-NPs, which can target cancer cell surface receptors and facilitate the delivery of hydrophobic cargo. The oligomeric nature of the calix[4]arene enables the dynamic self-assembly of calix[4]arene (CA4), where an amphiphile, functionalized with mannose units (CA-glycoconjugates) in the upper rim and alkylated lower rim, afforded the CA4-Man3-NPs in a controllable manner. The presence of thiourea units between calixarene and tri-mannose moiety facilitated the formation of a stable core with bidentate hydrogen bonds, which in turn promoted mannose receptor targeted uptake and helped in the intracellular pH-responsive release of antineoplastic doxorubicin (Dox). Physiochemical features including the stability of the nanomicelle could circumvent the undesirable leakage of the cargoes, ensuring maximum therapeutic output with minimum off-targeted toxicity. Most importantly, surface-enhanced Raman scattering (SERS) was utilized for the first time to evaluate the critical micelle concentration during the formation, cellular uptake and intracellular drug release. The present study not only provides an architectural design of a new class of organic small molecular nanomicelles but also unveils a robust self-assembly approach that paves the way for the delivery of a wide range of hydrophobic chemotherapeutic drugs.

Imidazolium-fulleride ionic liquids - a DFT prediction.

Ionic liquids (ILs) exhibit tunable physicochemical properties due to the flexibility of being able to select their cation-anion combination from a large pool of ions. The size of the ions controls the properties of the ILs in the range from ionic to molecular, and thus large ions play an important role in regulating the melting temperature and viscosity. Here, we show that the exohedral addition of anionic X- moieties to C60 (X = H, F, OH, CN, NH2, and NO2) is a thermodynamically viable process for creating large X-fulleride anions (C60X)-. The addition of X- to C60 is modelled by locating the transition state for the reaction between C60 and 1,3-dimethyl-2X-imidazole (IMX) at the M06L/6-311++G(d,p)//M06L/6-31G(d,p) level. The reaction yields the ion-pair complex IM+⋯(C60X)- for X = H, F, OH, CN, NH2, and NO2 and the ordered pair of (activation free energy, reaction free energy) is found to be (14.5, 1.1), (6.1, 3.1), (16.7, 2.3), (14.7, -7.9), (27.9, 0.5) and (11.9, 12.4), respectively. The low barrier of the reactions suggests their feasibility. The reaction is slightly endergonic for X = H, F, OH, and NH2, while X = CN shows a significant exergonic character. The X-fulleride formation is not observed when X = Cl and Br. The ion-pair interactions (Eion-pair) observed for IM+⋯(C60X)- range from -64.0 to -73.0 kcal mol-1, which is substantially lower (∼10%) than the typically reported values for imidazolium-based ionic liquids such as [EMIm]+[trz]-, [EMIm]+[dc]-, [EMIm]+[dtrz]-, and [EMIm]+[NH2tz]-. The quantum theory of atoms in molecules (QTAIM) analysis showed that the C-X bonding in (C60X)- is covalent, while that in (IM+⋯X-)⋯C60 (for X = Cl and Br) is non-covalent. Furthermore, molecular electrostatic potential (MESP) analysis showed that the X-fulleride could behave as a large spherical anion due to the delocalization of the excess electron in the system over the entire carbon framework. The large anionic character of the X-fulleride is also revealed by the identification of several close lying local energy minima for the IM+⋯(C60X)- ion-pair. The low Eion-pair value, the significant contribution of dispersion to the Eion-pair and the spherical nature of the anion predict low-melting point and highly viscous IL formation from X-fullerides and the imidazolium cation.

Antiaromaticity-Aromaticity Interplay in Fused Benzenoid Systems Using Molecular Electrostatic Potential Topology.

The phenomenon of antiaromaticity-aromaticity interplay in aromatic-antiaromatic (A-aA)-fused systems is studied using molecular electrostatic potential (MESP) analysis, which clearly brings out the electron-rich π-regions of molecular systems. Benzene, naphthalene, phenanthrene, and pyrene are the aromatic units and cyclobutadiene and pentalene are the antiaromatic units considered to construct the A-aA-fused systems. The fused system is seen to reduce the antiaromaticity by adopting a configuration containing the least number of localized bonds over antiaromatic moieties. This is clearly observed in 25 isomers of a fused system composed of three naphthalene and two cyclobutadiene units. Denoting the number of π-bonds in the cyclobutadiene rings by the notation (n, n'), the systems belonging to the class (0, 0) and (2, 2) turn out to be the most and least stable configurations, respectively. The stability of the fused system depends on the empty π-character of the antiaromatic ring, hence naphthalene and benzene prefer to fuse with cyclobutadiene in a linear and angular fashion, respectively. Generally, a configuration with the maximum number of 'empty' rings (0, 0, 0, ...) is considered to be the most stable for the given A-aA system. The stability and aromatic/antiaromatic character of A-aA-fused systems with pentalene is also interpreted in a similar way. MESP topology, clearly bringing out the distribution of double bonds in the fused systems, leads to a simple interpretation of the aromatic/antiaromatic character of them. Also, it leads to powerful predictions on stable macrocyclic A-aA systems.