Analysis Of Substituent Effects Research Articles

Computational analysis of substituent effects on proton affinity and gas-phase basicity of TEMPO derivatives and their hydrogen bonding interactions with water molecules

The study investigates the molecular structure of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and its derivatives in the gas phase using B3LYP and M06-2X functional methods. Intermolecular interactions are analyzed using natural bond orbital (NBO) and atoms in molecules (AIM) techniques. NO2-substituted TEMPO displays high reactivity, less stability, and softer properties. The study reveals that the stability of TEMPO derivatives is mainly influenced by LP(e) → σ∗ electronic delocalization effects, with the highest stabilization observed on the oxygen atom of the nitroxide moiety. This work also considers electron density, atomic charges, and energetic and thermodynamic properties of the studied NO radicals, and their relative stability. The proton affinity and gas-phase basicity of the studied compounds were computed at T = 298 K for O-protonation and N-protonation, respectively. The studied DFT method calculations show that O-protonation is more stable than N-protonation, with an energy difference of 16.64–20.77 kcal/mol (22.80–25.68 kcal/mol) at the B3LYP (M06-2X) method. The AIM analysis reveals that the N–O…H interaction in H2O complexes has the most favorable hydrogen bond energy computed at bond critical points (3, − 1), and the planar configurations of TEMPO derivatives exhibit the highest EHB values. This indicates stronger hydrogen bonding interactions between the N–O group and water molecules.

A multi-descriptor analysis of substituent effects on the structure and aromaticity of benzene derivatives: π-Conjugation versus charge effects.

This work provides a detailed multi-component analysis of aromaticity in monosubstituted (X = CH3, C , C , NH2, NH-, NH+, OH, O-, and O+) and para-homodisubstituted (X = CH3, CH2, NH2, NH, OH, and O) benzene derivatives. We investigate the effects of substituents using single-reference (B3LYP/DFT) and multireference (CASSCF/MRCI) methods, focusing on structural (HOMA), vibrational (AI(vib)), topological (ELFπ), electronic (MCI), magnetic (NICS), and stability (S0-T1 splitting) properties. The findings reveal that appropriate π-electron-donating and π-electron-accepting substituents with suitable size and symmetry can interact with the π-system of the ring, significantly influencing π-electron delocalization. While the charge factor has a minimal impact on π-electron delocalization, the presence of a pz orbital capable of interacting with the π-electron delocalization is the primary factor leading to a deviation from the typical aromaticity characteristics observed in benzene.

Computational analysis of substituent effect on indole derivatives as potential antibacterial agents

In recent years, indole derivatives have gained attention as an important class of antimicrobial drugs. The modification of 1,3,4-oxadiazole and 1,2,4-triazole, which are known bioactive agents, was carried out with indole. The resulting compounds namely 3-(1H-indole-3yl)-5-((2-((5-phenyl-1,3,4-oxadiazole-2-yl)thio)ethyl)thio)-4H-1,2,4-triazole-4-amine (S) and 2-(5-(benzylthio)-4H-1,2,4-triazole-3yl)-1H-indole (B) were further investigated for their chemical reactivity with 14 different substituents at the phenyl ring using the density functional theory (DFT). The quantum chemical data used to investigate the most effective drug was based on the optimized geometries, molecular electrostatic potential maps, frontier molecular orbital distributions, Hirschfeld charges, Mulliken charges and UV absorption parameters obtained from DFT calculations. Reduced density gradient (RDG) scatter plots and non-covalent interaction isosurfaces were obtained to visualize the intramolecular interactions in the molecules. Based on the DFT calculations, S14 (-NO2 substituted S) and B14 (-NO2 substituted B) exhibited a better chemical activity. Further, the pertinency of S14 and B14 was tested as an antibacterial agent against E. coli using molecular docking studies. The binding affinity of S14 and B14 showed significant binding with the active sites of the E. Coli macromolecule (PDB id- 2Y66). The boiled egg model was also analyzed to study the permeability and lead likeness of the molecules under investigation. From the synthetic accessibility score, the synthetic feasibility of S14 and B14 was analyzed.

Fluorination of benzene with disubstituted N-fluoropyridinium salts in acetonitrile solution: a DFT study

In this work, fluorination activities of disubstituted N-fluoropyridinium salts on the substrate of benzene in acetonitrile solution have been investigated by density functional theory. At SMD-B3LYP/6-311G(d,p) level, geometry optimizations and frequency calculations of the reactants, transition states and products were carried out in 16 fluorination reaction channels. A high level of SMD-M06-2x/6-311++G(d,p) was used to correct the single-point energy of the stationary points based on the optimized structure. On the basis of 2-nitro-substituted N-fluoropyridinium salt, nitro, cyano, chloro, methoxy groups were substituted, respectively, at 3-,4-,5-,6-position on pyridine ring to further clarify the influence of substituents and substitution sites on fluorination activity. According to the obtained potential energy surface information and substituent effect analysis, the fluorination channel of 2,6-dinitro-substituted N-fluoropyridinium salt is the most effective because of the lowest reaction energy barrier; as a result among the 16 studied N-fluoropyridinium salts, 2,6-dinitro-substituted N-fluoropyridinium salt is the most promising fluorinating reagent.

Chalcogen Bonding "2S-2N Squares" versus Competing Interactions: Exploring the Recognition Properties of Sulfur.

Chalcogen bonding (CB) is the focus of increased attention for its applications in medicinal chemistry, materials science, and crystal engineering. However, the origin of sulfur's recognition properties remains controversial, and experimental evidence for supporting theories is still emerging. Here, a comprehensive evaluation of sulfur CB interactions is presented by investigating 2,1,3-benzothiadiazole X-ray crystallographic structures gathered from the Cambridge Structure Database (CSD), Protein Data Bank (PDB), and own laboratory findings. Through the systematic analysis of substituent effects on a subset library of over thirty benzothiadiazole derivatives, the competing interactions have been categorized into four main classes, namely 2S-2N CB square, halogen bonding (XB), S⋅⋅⋅S, and hydrogen-bonding (HB). A geometric model is employed to characterize the 2S-2N CB square motifs and discuss the role of electrostatic, dipole, and orbital contributions toward the interaction.

Theoretical study on the fluorination of benzene with N-Fluoropyridinium salts in acetonitrile solution

The prominent roles of organofluorine compounds in various fields have aroused considerable interest in the development of new methods for carbon-fluorine bond formation. Electrophilic fluorination receives much attention. Density functional theory (DFT) was used to theoretically explore the fluorination activity of 12 N-Fluoropyridinium salts on the substrate of benzene in acetonitrile solution. Geometry optimizations and frequency calculations of the reactants, transition states, and products were performed at B3LYP/6-311G(d,p) level for the 12 fluorination reaction channels. Based on the optimized structure, all the stationary points have been corrected by the single point energy at a high-level of M06-2x/6-311++G (d,p). Four substituents were considered in this paper, they are nitro-, cyano-, chloro-, methoxy-, respectively. Three substituted sites (ortho-, meso-, para-) were also concluded. Based on the obtained potential energy surfaces information and analysis of substituent effect, the fluorination reaction channel of oNO2NFpyr is most efficient due to the lowest reaction energy barrier; therefore, oNO2NFpyr is a promising optimum fluorinating reagent among the studied 12 N-Fluoropyridinium salts.

In-silico analysis of substituent effect on the static first order hyperpolarizability of electron donating mono substituted Chalcone derivatives.

Noncentrosymmetric π conjugated systems with suitable electron donor acceptor groups play a crucial role in material NLO activity. The influence of an electron donating mono substituent at the para position of the phenylene ring of chalcone was investigated as a resource for second harmonic generation. The geometrical optimization of 11 electron donating group substituted chalcones were performed using density functional theory at the B3LYP/6-311G(d,p) level and compared with experimental geometrical parameters of five reported chalcones. All the derivatives are transparent to visible radiation as shown by the electronic absorption spectra investigated by the TDDFT-CAM B3LYP/6-311G(d,p) method, and the maximum absorption wavelength was due to the πPhB → π* transition. The first order hyperpolarizability βtot, calculated using the CAM B3LYP/6-311G(d,p) method, increases with the electron donating ability of the substituent, and the largest βtot was observed for dimethylamino substituent. The Hammett substituent constant (σp) shows good linear correlation with β, λmax, and Egap in the ground state. The Brown constant (σp+) was better correlated indicating the polarization of carbonyl group in the excited state. Frontier molecular orbitals also reveal the valence electron excitation. Correlation of σp with various parameters was analyzed to assess the property interrelationship with electronic reorganization in the molecule. The electronic structures of molecular fragments were described in terms of natural bond orbital analysis, which shows intramolecular interactions.

Predicting reduction potentials of 1,3,6-triphenyl fulvenes using molecular electrostatic potential analysis of substituent effects.

The influence of mono- and multiple substituent effect on the reduction potential (E0 ) of 1,3,6-triphenyl fulvenes is investigated using B3LYP-SMD/6-311+G(d,p) level density functional theory. The molecular electrostatic potential (MESP) minimum at the fulvene π-system (Vmin ) and the change in MESP at any of the fulvene carbon atoms (ΔVC ) for both neutral and reduced forms are used as excellent measures of substituent effect from the para and meta positions of the 1,3 and 6-phenyl moieties. Substitution at 6-phenyl para position has led to significant change in E0 than any other positions. By applying the additivity rule of substituent effects, an equation in ΔVC is derived to predict E0 for multiply substituted fulvenes. Further, E0 is predicted for a set of 2000 hexa-substituted fulvene derivatives where the substituents and their positions in the system are chosen in a random way. The calculated E0 agreed very well with the experimental E0 reported by Godman et al. Predicting E0 solely by substituent effect offers a simple and powerful way to select suitable combinations of substituents on fulvene system for light harvesting applications. © 2018 Wiley Periodicals, Inc.

Assessment of the electron donor properties of substituted phenanthroline ligands in molybdenum carbonyl complexes using molecular electrostatic potentials

Molecular electrostatic potential analysis of substituent effects in phenanthroline ligands clearly suggests that the coordination strength of the ligand to a metal complex is highly predictable solely from the quantification of substituent effects.

Highly oxygenated and structurally diverse diterpenoids from Euphorbia helioscopia

A phytochemical investigation on the aerial part of Euphorbia helioscopia (Euphorbiaceae) led to the isolation of 22 highly oxygenated diterpenoids with structural types of ent-abietane, ent-kaurane, lathyrane, ent-atisane and ingenane. 17 of them, named euphelionolides A – N, 16-epi-18-hydroxy-abbeokutone, as well as eupheliotriols A and B, were identified to be previously undescribed compounds by extensive analysis of spectroscopic data. The stereostructures of euphelionolides A – K were determined by single crystal X-ray diffraction combined with analysis of substituent effects and comparison of optical characteristics. Eupheliotriol B is the first example of natural occurring lathyrol with 12Z-ene, while ent-atisanes are the first reported from the title plant. Furthermore, euphelionolides F and L exhibited significant cytotoxicity against MCF-7 and PANC-1 cell lines.

Mechanism and Scope of Phosphinidene Transfer from Dibenzo-7-phosphanorbornadiene Compounds.

Dibenzo-7-phosphanorbornadiene compounds, RPA (A = C14H10 or anthracene), are investigated as phosphinidene sources upon thermally induced (70-90 °C) anthracene elimination. Analysis of substituent effects reveals that π-donating dialkylamide groups are paramount to successful phosphinidene transfer; poorer π-donors give reduced or no transfer. Substituent steric bulk is also implicated in successful transfer. Molecular beam mass spectrometry (MBMS) studies of each derivative reveal dialkylamide derivatives to be promising precursors for further gas-phase spectroscopic studies of phosphinidenes; in particular, we present evidence of direct detection of the dimethylamide derivative, [Me2N═P]. Kinetic investigations of iPr2NPA thermolysis in 1,3-cyclohexadiene and/or benzene-d6 are consistent with a model of unimolecular fragmentation to yield free phosphinidene [iPr2N═P] as a transient reactive intermediate. This conclusion is probed by density functional theory (DFT) calculations, which favored a mechanistic model featuring free singlet aminophosphinidenes. The breadth of phosphinidene acceptors is expanded to unsaturated substrates beyond 1,3-dienes to include olefins and alkynes; this provides a new synthetic route to valuable amino-substituted phosphiranes and phosphirenes, respectively. Stereoselective phosphinidene transfer to olefins is consistent with singlet phosphinidene reactivity by analogy with the Skell hypothesis for singlet carbene addition to olefins.

Reactions of quinones with organometallic compounds: correlation analysis of substituent effects

The effects of substituents in lithium, magnesium, zinc, and cadmium organometallic compounds in their reactions with p-benzoquinone and 3,6-di-tert-butyl-o-benzoquinone on the ratio of addition and reduction products were considered. The reduction of quinones follows a homolytic mechanism of single electron transfer. The results of correlation analysis confirmed a suggestion that the addition to quinones followed a nucleophilic (heterolytic) mechanism.

Experimental and theoretical analysis of substituent effect on charge transfer complexes of iodine and some alkylbenzenes in n-hexane solution at 303 K

Abstract The charge transfer (CT) interactions in n-hexane solutions containing iodine (acceptor) and aromatic compounds, benzene (BEN), toluene (TOL), o -xylene (OXYL), m -xylene (MXYL) and mesitylene (MESI) were investigated by ultrasonic, UV-Visible spectroscopic methods and DFT analysis. The trend in acoustical and excess properties with molar concentration in these systems established the existence of strong solute–solute interaction and formation of CT complex between iodine and the five aromatic compounds. Computed interaction energy values in the present investigation confirmed the formation of CT complex in these systems. Both the experimental methods and theoretical investigation of these systems indicated that tendency for formation of CT complex increases with increase in the number of methyl substituent in the aromatic ring. Our computed results are in good agreement with the experimental observations.

On the properties of Se⋯N interaction: the analysis of substituent effects by energy decomposition and orbital interaction.

The nature and strength of intermolecular Se⋯N interaction between selenium-containing compounds HSeX (X = CH3, NH2, CF3, OCH3, CN, OH, NO2, Cl, F), and NH3 have been investigated at the MP2/aug-cc-pVDZ level. The Se⋯N interaction is found to be dependent on the substituent groups, which greatly affect the positive electrostatic potential of Se atoms and the accepting electron ability of X-Se σ(∗) antibonding orbital. Energy decomposition of the Se ⋯N interaction reveals that electrostatic and induction forces are comparable in the weak-bonded complexes and induction becomes more significant in the complexes with strong electron-withdrawing substituents. Natural bond orbital (NBO) analysis indicates that the primary source of the induction is the electron transfer from the N lone pair to the X-Se σ(∗) antibonding orbital. The geometry of the complex and the interaction directionality of NH3 to X-Se bond can be regarded as a consequence of the exchange-repulsion. The topological analysis on the electron density reveals the nature of closed-shell interaction in these X-Se⋯N contacts. The Se⋯N interaction in the complexes with the strong electron-withdrawing substituent has a partly covalent character.

QSAR analysis of substituent effects on tambjamine anion transporters.

The transmembrane anion transport activity of 43 synthetic molecules based on the structure of marine alkaloid tambjamine were assessed in model phospholipid (POPC) liposomes. The anionophoric activity of these molecules showed a parabolic dependence with lipophilicity, with an optimum range for transport efficiency. Using a quantitative structure-transport activity (QSAR) approach it was possible to rationalize these results and to quantify the contribution of lipophilicity to the transport activity of these derivatives. While the optimal value of log P and the curvature of the parabolic dependence is a property of the membrane (and so similar for the different series of substituents) we found that for relatively simple substituents in certain locations on the tambjamine core, hydrophobic interactions clearly dominate, but for others, more specific interactions are present that change the position of the membrane hydrophobicity parabolic envelope.

Computational and Experimental Studies of Phthaloyl Peroxide-Mediated Hydroxylation of Arenes Yield a More Reactive Derivative, 4,5-Dichlorophthaloyl Peroxide.

The oxidation of arenes by the reagent phthaloyl peroxide provides a new method for the synthesis of phenols. A new, more reactive arene oxidizing reagent, 4,5-dichlorophthaloyl peroxide, computationally predicted and experimentally determined to possess enhanced reactivity, has expanded the scope of the reaction while maintaining a high level of tolerance for diverse functional groups. The reaction proceeds through a novel "reverse-rebound" mechanism with diradical intermediates. Mechanistic insight was achieved through isolation and characterization of minor byproducts, determination of linear free energy correlations, and computational analysis of substituent effects of arenes, each of which provided additional support for the reaction proceeding through the diradical pathway.

Singlet carbene stability: linear free energy analysis of substituent effects

The energies of a series of substituted methylene and methylcarbene singlet states were computed by quantum mechanical calculations at the CCSD(T)/cc-pVDZ//M06-2X/cc-pVDZ level. Stabilization energies relative to singlet methylene were correlated with polarizability, polar and resonance Hammett sigma constants using multiple regression analysis. The results revealed that most of the carbenes gave rise to inverse polar effects. It is concluded that separation of polar and resonance effects via linear free energy methods (LFE) fails for singlet carbenes with substituents directly attached to carbene carbons.

DFT analysis of substituent effects on electron-donating efficacy of pyridine

Studies on pyridine, C5H5N, and pyridine derivatives (simulations) of the type C5(X) n H5−n N (X = −C≡CH; –C≡CF; –C≡N; –CH(=O)) are carried out using the DFT method employing B3LYP/LanL2DZ level of theory. The effects of substituent modification (type and position) on electron density enrichment of pyridyl nitrogen atoms and thus its effectiveness as a donor atom for incoming metal ions have been investigated. Computational results showed that first, substituents exert interesting effects on both the accumulated charge density on nitrogen and the geometrical parameters (C2=N bond length and C2···N···C6 bond angle) of the examined pyridine simulations. Second, depending on the type of the substituent, substituents showed variable trends in effect. For example, –C≡CH and –C≡CF show a similar trend, which is overall noticed to be different from that observed for –C≡N –CH(=O). Third, the influence of substituent modification on electronic localization/delocalization is further viewed by calculating the charge density distribution surfaces and the occupancy of the frontier HOMO molecular orbitals. Gathered images of charge density surfaces and HOMO orbitals for all simulates clearly showed how charge density is distributed over the pyridine system and truly found to be very helpful in providing deep insight into how charge density is accumulated over nitrogen specifically. In result, –C≡CF among all, was found to enrich the charge density on pyridyl nitrogen the most. This was attributed to the existence of fluorine atoms in the structure of the attached substituent. Fluorine atom, was able of extending the electron density delocalization—pathway more than the other substituents do. Actually, this investigation is a pursuing to our research work which basically aims to put under control various variables that would promote the inorganic complex to be a good chromophore in low energy regions and to be further employed in chemosensation. In this report, we attempt to move one extra step ahead and expand our knowledge to wisely engineer and design a feasible chemosensor that is capable of responding in the visible region.

NMR Analysis of Substituent Effect of Arymethylene‐malononitriles and Malonates

AbstractA series of arylmethylene‐malononitriles and malonates were prepared from the condensation of arylaldehydes and malononitriles and malonates, respectively. The function of substituents on the carbon‐13 chemical shifts of the Cα and Cβ was studied. The correlation between Hammett's constants and the substituent chemical shifts demonstrates a negative slope for Cα and positive for Cβ (1, Cα:ρ = ‐3.877, r2 = 0.979; Cβ:ρ = 6.899, r2 = 0.984; 2, Cα:ρ = ‐2.817, r2 = 0.926; Cβ:ρ = 5.355, r2 = 0.950). The large slopes for Cβ for both series compounds resemble our previous studies on the arylcyclopropanes.The relaxation time of both proton and carbon are slightly affected by the size of substituents. In the viscosity study, an inverse‐law relationship between relaxation time and viscosity was observed.

Experimental and theoretical study on the oxidation mechanism of dopamine in n-octyl pyridinium based ionic liquids–carbon paste modified electrodes

This work describes the influence of n-octyl pyridinium cations based ionic liquids–carbon paste modified electrodes on the oxidation mechanism of dopamine. Ionic liquids formed by hexafluorophosphate anion and n-octyl pyridinium [R-OPy]+; R=CH3, H, CF3, where ionic liquids containing CH3 and CF3 are new products, were synthesized and characterized. Modified carbon paste electrodes with these salts were characterized by electrochemical impedance spectroscopy and cyclic voltammetry. Electrochemical oxidation of dopamine was studied in PBS buffer solution at pH=7.4. The influence of the ionic liquids in the oxidation of dopamine was studied by cyclic voltammetry and rotating disk electrode. The results show that typical carbon paste electrode presents an electrochemical/chemical mechanism; whereas [OPy]PF6 and [CF3-OPy]PF6 modified electrodes present an electrochemical/chemical/electrochemical mechanism. The experimental study is complemented with a theoretical analysis of substituent effects in terms of the molecular electrostatic potential, Mulliken population analysis and second order perturbation theory probed at the cation moiety of the IL. These indices consistently show an electron density accumulation at the ipso position of the pyridinium moiety of the IL that is in agreement with the electrochemical characterization.