Nucleophilicity Index Research Articles

A new approach to compute atomic electrophilicity index in terms of Gordy’s electronegativity

Electrophilicity index is a well-known Conceptual Density Functional Theory–based reactivity descriptor to explain a wide range of physicochemical behaviours. In the present work, an attempt is made to evaluate a new electrophilicity index scale in terms of nucleophilicity index relying on Gordy’s electronegativity scale. The computation is performed for 103 elements of the periodic table invoking regression analysis. The new set of electrophilicity index satisfies the sine qua non of a standard scale. Electrophilicity Equalization Principle is also validated by our computed data. It is put forward that the new scale will be useful in understanding various physicochemical properties and related phenomenon.

Negative solvatochromic behavior and theoretical investigation on 2-amino-4-(4-(dimethyl amino)phenyl)buta-1,3-diene-1,1,3-tricarbonitrile

In the present work, 2-amino-4-(4-(dimethylamino)phenyl)buta-1,3-diene-1,1,3-tricarbonitrile (AMAPB), a polyfunctional compound, which can serve as a solvatochromic probe, was obtained via condensation of malononitrile dimers with N,N-dimethylamino benzaldehyde. The influence of solvent polarity on the absorption spectra of the synthesized compound was investigated. The spectral characteristics in different solvents at room temperature were analyzed. We discuss how variables, including the empirical solvent polarity ET (30), (π*, α, β) and (SA, SB, SPP) contribute to solute-solvent interactions. A multi-parameter regression models for quantitative assessment of the solute/solvent interaction and the absorption has been used to explain the solvent effect. DFT and TD-DFT calculations coupled with the polarizable continuum model (PCM) were performed to investigate the solvent-dependent spectral and geometrical properties of AMAPB. The calculations exhibited good agreements with the experimental results using the B3LYP/6–31+ G ** functional. The delocalization and intramolecular charge transfer are calculated and discussed in terms of natural bond orbital analysis (NBO) and second-order perturbation interactions between donor and acceptor MOs. The calculated E HOMO and E LUMO energies were used to calculate the global properties such as electronic chemical potential (μ), chemical hardness (η), global electrophilicity index (ω), nucleophilicity index (N), and global softness (S). Experimental and theoretical results promoted that the chemical properties of AMAPB are dependent on the polarity of the chosen solvent and its hydrogen bonding capability.

Computation of absolute radii of 103 elements of the periodic table in terms of nucleophilicity index

The size of an atom is a very significant parameter in associating and understanding a wide range of atomic or molecular physico-chemical properties. Considering importance of the size descriptor, an ansatz to compute absolute radius (r) in terms of nucleophilicity index (N) is proposed in the present work for atoms of 103 elements of periodic table. We have followed a very simple empirical approach to compute the absolute radii of the elements invoking regression analysis the new set of radii satisfy all the sine qua non of periodic properties. Relativistic effects are pronounced in the computed radii. A close agreement is noted on comparing the computed data with the existing scales. A strong quantitative correlation is observed with ionization potential and electronegativity for the computed data. Moreover, the absolute radius calculated in the present effort is employed in calculating internuclear bond distance, a real field descriptor, for several heteronuclear diatomic molecules. A significant agreement between the theoretically computed and experimentally determined internuclear bond distances is observed, thus corroborating the consistency of our proposed model.

A scale of atomic electronegativity in terms of atomic nucleophilicity index

Electronegativity (χ) is an important physico-chemical concept to study the chemical structure and reactivity. Although, the conundrum related to measurement of electronegativity still persists. In view of this fact, a simple yet rigorous scale of electronegativity (χ), invoking an inverse relationship with atomic nucleophilicity index (N), has been proposed for 103 elements of the periodic table. The computed data follows periodicity distinctly satisfying all the sine qua non of a standard scale of electronegativity. Further, electronegativity values display a sound similarity with the standard electronegativity scales validating the suitability of the proposed model. Molecular electronegativities of some polyatomic molecules have also been calculated using the proposed scale of electronegativity.

N-t-Butyl-α-aryl Nitrones as Potent Spin Traps: DFT Analysis of Electron Localization Function Topology, Local Selectivity, Reactivity and Solvent Effects

Density functional theory studies were performed to analyze the reactivity and selectivity of radical capture by N-t-butyl-α-aryl nitrones. Biologically relevant three important radicals viz. hydroxyl, methyl and hydroperoxyl were selected for the study. Topological analysis of the electron localization function (ELF) allows to classify these nitrones as zwitter-ionic type three atom components (TAC). Effects of electron withdrawing and electron donating C-aryl substituents on the electronic chemical potentials, global hardness, electrophilic and nucleophilic indices of nitrones were observed. Radical attack at the carbon atom was predicted by Merz-Kollman algorithm, which is in agreement with the experiments unlike the natural population analysis. Hydroxyl adducts were predicted to be more stable than methyl and hydroperoxyl adducts. cis-Adducts were more stable than the trans-, with the highest differences in stability noted for the methyl adducts. Relative energies of adducts was lowered in non-polar solvents and thus increase in stability was observed along the series from water to heptane.

Investigating the behaviors of corticosterone hormone in different solvents by using DFT calculations and experimental data

In this work, structural, electronic, topological and vibrational properties of corticosterone hormone have been investigated in aqueous, ethanol and methanol solutions by using DFT calculations and experimental available infrared, attenuated total reflectance (ATR), Raman and Ultraviolet spectra. The properties predicted in the different solvents at the B3LYP/6-31G* level of theory were compared with those obtained in gas phase and, with others reported for steroids species at the same level of theory. The universal solvation model has evidenced higher solvation energy for corticosterone in aqueous solution and a higher value in methanol, as compared with the corresponding values to equilenin, equilin and estrone steroids in the same medium. Higher Mulliken charges on O atoms of C=O group of side chain are observed in the three solvents than the corresponding to C=O group of ring A while the MK charges on O atoms of OH group of ring C present higher values than the corresponding to O atoms of OH group of side chain. The natural bond orbital (NBO) studies have revealed a low stability of corticosterone in aqueous solution, as compared with the values in ethanol and methanol solutions, in total agreement with the higher solvation energy and dipole moment in this medium. On the other hand, the atoms in molecules (AIM) analyses support the lower stabilities of corticosterone in the three solutions because only five H bonds interactions different from of gas phase where six interactions are observed. The gap values suggests that corticosterone is most reactive in aqueous solution than the other solutions, as supported by the low stability and higher solvation energy and dipole moment values in this medium. This study shows clearly that the steroid species most reactive, equilenin and corticosterone, are characterized by a high global electrophilicity index value and low nucleophilicity index. Reasonable correlations in the predicted IR, Raman and UV spectra were observed, as compared with the corresponding experimental ones. Additionally, the complete vibrational assignments of all 159-vibration modes of corticosterone together with the harmonic force fields and force constants in the different media are for the first time presented.

Spectroscopic studies on the potassium 1-fluorobenzoyltrifluoroborate salt by using the FT-IR, Raman and UV–Visible spectra and DFT calculations

Potassium 1-fluorobenzoyltrifluoroborate (FBTFB) salt was characterized using Fourier Transformed Infrared (FT-IR) and Raman solid-state spectroscopies as well as ultraviolet–visible spectroscopy in aqueous solution. The functional hybrid B3LYP with the 6-311++G** basis set have optimized the structures of salt in gas phase and in aqueous solution with CS symmetries. In solution, the influence of solvent was studied at the same level of theory with the integral equation formalism variant polarised continuum method (IEFPCM) and the universal solvation model. FBTFB has evidenced the lower solvation energy (−81.54 kJ/mol), as compared with other trifluoroborate salts probably due to the presence of F in the 1st position of phenyl ring that decreases the solubility of this salt. NBO studies clearly support the ionic characteristics of K+F− and K+O− bonds and the high energy values of LPF17→ LP*B14 transitions (ΔΕn→n*) while AIM analyses suggest a high stability of salt in both media due to three ionic and one C–H⋅⋅⋅F interactions. Analyses of frontier orbitals have suggested that the FBTFB salt is more reactive in solution than in gas phase and, than 2-phenylacetyl-trifluoroborate (PTFB) in the two media possibly because FBTFB presents higher global electrophilicity (ω) and nucleophilicity indexes (E) in both media than PTFB. Here, the calculated harmonic force fields, scaled force constants and complete assignments of all vibration normal modes expected for FBTFB in both media are reported. Predicted IR, Raman and UV–Visible spectra have shown good concordance when they are compared with the corresponding experimental ones.

2D/1D graphitic carbon nitride/titanate nanotubes heterostructure for efficient photocatalysis of sulfamethazine under solar light: Catalytic “hot spots” at the rutile–anatase–titanate interfaces

2D/1D graphitic carbon nitride hybridized with titanate nanotubes (g-C3N4/TNTs) was prepared through a hydrothermal reaction–calcination method. The photocatalyst exhibited high degradation efficiency for sulfamethazine (SMT) through photocatalysis under simulated solar light. The optimized material was composed of anatase, rutile, titanate and g-C3N4 crystalline phases. In situ transformation of titanate to anatase and rutile with specific content proportion (∼80:20, P25-type composition) leaded to formation of nanoscale “hot spots” at rutile–anatase–titanate interfaces, and then subsequent charge transfer occurred. Large specific surface area of TNTs as skeleton resulted in high-efficient interface reaction, while heterojunction with g-C3N4 further extended the adsorption to visible light region and retarded electron-hole pairs recombination. Density functional theory (DFT) calculation indicated the SMT sites with high Fukui nucleophilic (f-) index prefered to be attacked by radacils. Reduced toxicity of SMT degradation intermediates, good reusability and stability of g-C3N4/TNTs all suggested the great application potential in practical water treatment area.

Anticancer Indole-Based Chalcones: A Structural and Theoretical Analysis.

The crystal structures of five new chalcones derived from N-ethyl-3-acetylindole with different substituents were investigated: (E)-3-(4-bromophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one (3a); (E)-3-(3-bromophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one (3b); (E)-1-(1-ethyl-1H-indol-3-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (3c); (E)-1-(1-ethyl-1H-indol-3-yl)-3-mesitylprop-2-en-1-one (3d); and (E)-1-(1-ethyl-1H-indol-3-yl)-3-(furan-2-yl)prop-2-en-1-one (3e). The molecular packing of the studied compounds is controlled mainly by C–H⋅⋅⋅O hydrogen bonds, C–H⋅⋅⋅π interactions, and π···π stacking interactions, which were quantitatively analyzed using Hirshfeld topology analysis. Using density functional theory (DFT) calculations, the order of polarity (3b ˂ 3d ˂ 3e ˂ 3a ˂ 3c) was determined. Several chemical reactivity indices such as the ionization potential (I), electron affinity (A), chemical potential (μ), hardness (η), electrophilicity (ω) and nucleophilicity (N) indices were calculated, and these properties are discussed and compared. In addition, the antiproliferative activity of the five new chalcones was studied.

Characterization of potassium (2-phenylacetyl) trifluoroborate salt by using the UV–Visible, FT-IR and FT-Raman spectra

The potassium 2-phenylacetyl-trifluoroborate (PTFB) salt has been experimentally characterized by using FT-IR, FT-Raman and ultraviolet–visible spectroscopies while its structures were theoretically determined in gas phase and in aqueous solution by using B3LYP/6–311++G** method. The studies in solution were performed at the same level of theory with the integral equation formalism variant polarised continuum method (IEFPCM) and the universal solvation model. The comparisons among the predicted IR, Raman and UV–Visible spectra have evidenced good concordance with the corresponding experimental ones. PTFB presents a solvation energy of −87.64 kJ/mol, a value lower than the observed for 5-hydroxypentanoyl-trifluoroborate (HTFB) (−103.73 kJ/mol) and 2-isonicotinoyl-trifluoroborate (ITFB) (−95.05 kJ/mol) and higher than 3-furoyl-trifluoroborate (FTFB) (−84.72 kJ/mol). Evidently, the phenyl ring in PTFB decreases the solubility of this salt, as compared with hydroxypentanoyl chain in HTFB, furoyl ring in FTFB and pyridine ring in IFTB. The bond orders studies support the ionic characteristics of K⋯B bonds while the NBO studies reveal a lower stability of PTFB in aqueous solution, as compared with the value in gas phase probably due to the low solvation energy of PTFB in this medium. The four interactions observed for PTFB in gas phase by the AIM analyses support the high stability of PTFB in gas phase. The gap values show that PTFB is most reactive in gas phase than in aqueous solution while the comparisons with other salts containing pyridine ring instead phenyl one reveal that reactivity increase when in the 5 position of pyridine ring is incorporates a Br atom in the structure of salt. Hence, the following reactivity order it is observed in gas phase: Br-ITFB > ITFB > PTFB changing in solution to: ITFB > Br-ITFB > PTFB. In solution, probably the salt is most reactive due to the most negative nucleophilicity index and higher electrophilicity index. The harmonic force fields, force constants and complete assignments of all vibration normal modes for PTFB in both media for first time are reported.

Density Functional Theory and Electrochemical Noise Analysis of Corrosion Inhibition Behavior of N,N '-bis(1-(3,5-dihydroxyphenyl)ethylidene)propane-1,3-diamine on Steel in HCl Solution

The inhibition effect of N,N ′-bis(1-(3,5-dihydroxyphenyl)ethylidene)propane-1,3-diamine was studied on steel corrosion in 1 M hydrochloric acid solutions. The density functional theory was applied to calculate quantum chemical parameters such as the highest occupied molecular orbital energy, the lowest unoccupied molecular orbital energy, electron affinity, global electrophilicity index, the fraction of electron transferred, global nucleophilicity index, and Mulliken charges. According to quantum calculation, the diamine compound showed high interaction and effective adsorption on steel surface and high inhibition efficiencies and therefore nitrogen atoms of inhibitor indicated more tendencies for the electrophilic effect in the adsorption. Electrochemical impedance and potentiodynamic polarization indicated that this material has excellent inhibiting features in very low concentrations. The influence of DC trend on the explanation of electrochemical noise data was evaluated by polynomial fitting and the optimum polynomial order m = 4 was obtained. Noise resistance and the inhibition efficiency was calculated and compared in different methods. The theory of shot noise in frequency domain was used to obtain the electrochemical event charge. The corroded surface of steel in the absence and existence of thiazole compound was studied by Atomic force microscopy.

S(-) and R(+) species derived from antihistaminic promethazine agent: structural and vibrational studies

Structural and vibrational properties of free base, cationic and hydrochloride species derived from both S(-) and R(+) enantiomers of antihistaminic promethazine (PTZ) agent have been theoretically evaluated in gas phase and in aqueous solution by using the hybrid B3LYP/6-31G* calculations. The initial structures of S(-) and R(+) enantiomers of hydrochloride PTZ were those polymorphic forms 1 and 2 experimentally determined by X-ray diffraction. Here, all structures in aqueous solution were optimized at the same level of theory by using the polarized continuum (PCM) and the universal solvation model. As was experimentally reported, variations in the unit cell lead to slight energy, density, and melting point differences between the two forms but, this behavior is not carried through in isotropic condition, like in solution with non-chiral solvents. Hence, the N–C distances, Mulliken, atomic natural population (NPA) and Merz-Kollman (MK) charges, bond orders, stabilization and solvation energies, frontier orbitals, some descriptors and their topological properties were compared with the antihistaminic cyclizine agent. The frontier orbitals studies show that the free base species of both forms in solution are more reactive than cyclizine. Higher electrophilicity indexes are observed in the cationic and hydrochloride species of PTZ than cyclizine while the cationic species of cyclizine have higher nucleophilicity index than both species of PTZ. The presences of bands attributed to cationic species of both enantiomers are clearly supported by the infrared and Raman spectra in the solid phase. The expected 114, 117 and 120 vibration normal modes for the free base, cationic and hydrochloride species of both forms were completely assigned and the force constants reported. Reasonable concordances among the predicted infrared, Raman, UV-Vis and Electronic Circular Dichroism (ECD) with the corresponding experimental ones were found.

Structural and SQMFF study of potent insecticide 4′,4′-DDT combining the FT-IR and FT-Raman spectra with DFT calculations

The experimental FT-IR and FT-Raman spectra in the solid state have been employed to vibrationally characterize the potent insecticide dichlorodiphenyltrichloroethane (4′,4′-DDT). The complete vibrational assignments of 4′,4′-DDT in gas phase and in acetone and diethyl-ether were performed combining hybrid B3LYP/6-31G* and B3LYP/6–311++G** calculations with the internal coordinates, the scaled quantum mechanical force field (SQMFF) methodology and the experimental spectra. Here, the molecular structures of 4′,4′-DDT were theoretically determined in gas phase and in acetone and diethyl-ether solutions by using those two methods. The self-consistent reaction field (SCRF) method and the integral equation formalism variant polarised continuum model (IEFPCM) model were employed to study the properties in solution while the solvation energies were predicted by using the solvation model. The B3LYP/6–311++G** calculations show higher solvation energy in the solvent with lower permittivity, diethyl-ether. A clear and direct correlation was found with both basis sets between solvation energy and dipole moment for those two solvents. NBO studies clearly show that dichlorodiphenyl groups confer to 4,4′-DDT higher stability than the trichloroethyl group due to the fact that the lone pairs of Cl21 and Cl22 atoms present the n→π* transitions while the AIM study shows the participation of trichloroethyl group in halogen bonds clearly justifying the stability of 4′,4′-DDT in the three media and with both basis sets. The MK and NPA charges evidence different behaviors in both media and with both basis sets. The frontier orbitals show that the reactivity of 4,4′-DDT strongly depends on the basis set while it is more reactive than dieldrin, hexachlorobenzene and saxitoxin but 3,3′,4,4′-tetrachloroazobenzene, 3,3′,4,4′ tetrachloroazoxybenzene, CN− and CO species present higher reactivity than 4,4′-DDT. The number of Cl atoms could justify the differences observed in the nucleophilicity indexes of 4,4′-DDT, dieldrin, hexachlorobenzene, 3,3′,4,4′-tetrachloroazobenzene and 3,3′,4,4′ tetrachloroazoxybenzene.

Placenta–heart axis: abnormal cardiovascular development and VEGF expression after perigestational alcohol intake at mid-gestation in mouse.

Potassium 1-fluorobenzoyltrifluoroborate (FBTFB) salt was characterized using Fourier Transformed Infrared (FT-IR) and Raman solid-state spectroscopies as well as ultraviolet–visible spectroscopy in aqueous solution. The functional hybrid B3LYP with the 6-311++G** basis set have optimized the structures of salt in gas phase and in aqueous solution with CS symmetries. In solution, the influence of solvent was studied at the same level of theory with the integral equation formalism variant polarised continuum method (IEFPCM) and the universal solvation model. FBTFB has evidenced the lower solvation energy (−81.54 kJ/mol), as compared with other trifluoroborate salts probably due to the presence of F in the 1st position of phenyl ring that decreases the solubility of this salt. NBO studies clearly support the ionic characteristics of K+F− and K+O− bonds and the high energy values of LPF17→ LP*B14 transitions (ΔΕn→n*) while AIM analyses suggest a high stability of salt in both media due to three ionic and one C–H⋅⋅⋅F interactions. Analyses of frontier orbitals have suggested that the FBTFB salt is more reactive in solution than in gas phase and, than 2-phenylacetyl-trifluoroborate (PTFB) in the two media possibly because FBTFB presents higher global electrophilicity (ω) and nucleophilicity indexes (E) in both media than PTFB. Here, the calculated harmonic force fields, scaled force constants and complete assignments of all vibration normal modes expected for FBTFB in both media are reported. Predicted IR, Raman and UV–Visible spectra have shown good concordance when they are compared with the corresponding experimental ones.

A New Model of Atomic Nucleophilicity Index and Its Application in the Field of QSAR

A new ansatz is suggested for computing the atomic nucleophilicity index (N) for atoms of 103 elements of the periodic table resting upon the mutual action of two periodic properties, atomic polarizability (α) and effective nuclear charge (Zeff). The effectiveness of the model is illustrated by the explicit periodic behaviour. In addition, molecular nucleophilicity (NAM) is being proposed as an arithmetic mean of the atomic nucleophilicities of the constituent atoms of the given molecule. Due to the nonexistence of a benchmark for atomic nucleophilicity, molecular nucleophilicity index is evaluated and a comparative analysis is made with the existing data as a validity test. Furthermore, computed density functional theory (DFT) based reactivity descriptor, viz. atomic nucleophilicity index, have been employed to construct a quantitative structure–activity relationship (QSAR) model, using regression analysis, to study the biological activities of testosterone derivatives.

FT-IR, FT-Raman and UV-visible spectra of motrilin acetogenin isolated from Annona cherimolia

Annonaceous acetogenin (ACG), motrilin was experimentally isolated and characterized by using the FT-IR and FT-Raman spectra in the solid state and by UV-visible spectrum in methanol solution. The main bands observed in the vibrational spectra were assigned combining their predicted spectra with hybrid functional B3LYP/6-31G* calculations. The structural, electronic and topological properties were predicted for motrilin in gas phase and in methanol solution. The corrected solvation energy by ZPVE and by total non-electrostatic terms reveals for motrilin in methanol solution a value of −147.54 kJ/mol. The NPA charges have evidenced higher changes on the atoms of motrilin in methanol solution than the values in gas phase while the studies of electrostatic potentials have revealed strongest nucleophilic regions on the two O atoms of lactone ring while electrophilic sites on the H atoms of OH groups. Both NBO and AIM studies support the high stabilities of motrilin, especially in methanol solution probably due to the solute-solvent association phenomenom, as suggested by the expansion of volume in solution and by the H bond formation in this medium predicted by the AIM program. A higher reactivity of motrilin in methanol solution was evidenced by using the frontier orbitals while both electrophilicity and nucleophilicity indexes show values for motrilin similar to those observed in the antimicrobial thione agent. The predicted IR, Raman and UV-visible spectra has evidenced reasonable concordance with the corresponding experimental ones.

Why are rhodanines less efficient reagents in Diels\u2013Alder reactions than isorhodanines? A quantum chemical study

The reactivity of the 5-arylidenerhodanine and 5-arylideneisorhodanine derivatives in reactions with dimethyl maleate was computationally studied at the DFT(M06-2X)/6–311+G(d,p) theory level. Eight stereoisomers of the reaction products were considered. The effect of the solvent was taken into account by means of the continuous and discrete models for acetic acid (PCM and three CH3COOH molecules). Aromatic stabilization of the transition states was documented by the values of HOMA, NICS(0), and NICS(1) indices. The higher reactivity of the isorhodanine derivative was associated with a relatively low activation energy, ∆Ea (15.2–22.3 kcal mol–1), which is needed to cross the TS. For the rhodanine derivative, higher values of ∆Ea (34.1–36.1 kcal mol–1) were obtained. The reactivity was also studied from the perspective of the frontier molecular orbitals, the energy gaps between the HOMO and LUMO, the flux of electron density, the Fukui functions, f+(r), f−(r), and f0(r), and the global indexes defined in the conceptual DFT, i.e., the electronic chemical potential, chemical hardness, global electrophilicity, and empirical nucleophilicity index.

Insights into N-Heterocyclic Carbene (NHC)-Catalyzed Asymmetric Addition of 2H-Azirine with Aldehyde.

The possible mechanisms and origin of the enantioselectivity of the reaction between 2H-azirine and an aldehyde catalyzed by an N-heterocyclic carbene (NHC) were theoretically studied and predicted at the M06-2X/6-31G(d,p)/IEF-PCMMTBE //M06-2X-GD3/6-311++G(2df, 2pd)/IEF-PCMMTBE level. The most favorable reaction pathway consists of four steps, i.e., complexation of the NHC and the aldehyde, stepwise [1,2]-proton transfer, C-C bond formation coupled with another proton transfer, and recycling of the NHC. The computational results indicate that the stereoselectivity-determining step is also the rate-determining step, which is the third step (i.e., intermolecular addition). The calculated 99 % ee is very close to the experimentally observed value of 96 % ee, demonstrating that the calculations are reliable. Two important roles of the NHC were identified by global reaction index (GRI) analysis and natural population analysis (NPA), that is, realizing the umpolung reactivity of the aldehyde and facilitating the deprotonation of aldehyde. Moreover, the efficiency of different NHC catalysts can be mainly predicted by computing the nucleophilic index of the corresponding Breslow intermediates. Furthermore, distortion/interaction and noncovalent interaction (NCI) analyses revealed that the π⋅⋅⋅π interactions between the NHC and substrates were the key factor in the reaction enantioselectivity.

Microwave-assisted synthesis of novel 5-aminouracil-based compound with DFT calculations

In this investigation, microwave assisted synthesis of novel pyrazole ring formation via three reaction steps. In the beginning, nucleophilic acyl substitution reaction of the 5-aminouracil with ethyl cyanoacetate to afford 2-cyano-N-(2,4-dioxo-1,2,3,4-tetrahydropyridine-5-yl)acetamide (3). Knoevenagel Condensation of acetamide 3 with benzaldehyde afforded the corresponding acrylamide derivative 6 under microwave irradiation. Finally, Michael addition reaction of acrylamide with hydrazine hydrate to afford the novel 5-aminouracil-based compound 9. Computational studies for the three reactions have been carried out utilizing DFT/B3LYP/6-31 + G(d) theory level. The regioselectivity elucidated in terms of frontier molecular orbital (FMO), local electrophilicity, global electrophilicity and nucleophilicity indexes. The analysis of FMO showed the selectivity of these reactions was controlled through HOMO–LUMO interaction. Also, the molecular electrostatic potential (ESP) associated the hydrogen bonding interactions between electrophiles and nucleophiles. The IR of the optimized structures were examined by DFT/B3LYP/6 + 31G(d) and compared with experimental FT-IR. Furthermore, comparative study between experimental UV–Vis and calculated utilizing TD-DFT.

Insights into N-Heterocyclic Carbene-Catalyzed Oxidative α-C(sp3)-H Activation of Aliphatic Aldehydes and Cascade [2 + 2] Cycloaddition with Ketimines.

Predicting the chemoselectivity of [2 + 2] cyclizations is an important challenge in organic chemistry. Herein, we provided a valuable case for this issue. Density functional theory calculations were performed to systematically study the possible mechanisms and origin of selectivities for the N-heterocyclic carbene (NHC)-catalyzed oxidative α-C(sp3)-H activation of aliphatic aldehydes and the cascade [2 + 2] cycloaddition with ketimines. The [2 + 2] cycloaddition of azolium enolate intermediates to the C═N bond, rather than the C═O bond of ketimine, is revealed to be determined by chemo- and stereoselectivity. By comparing the energy gap between the frontier molecular orbitals (FMOs) of the two reacting parts involved in the [2 + 2] cycloaddition transition states, we propose a new strategy to determine the origin of the reaction chemoselectivity. Moreover, the local nucleophilic index can efficiently predict the active site of ketimines. Further analyses illustrate that NHC can increase the nucleophilicity of aldehydes and the acidity of the α-C(sp3)-H bond, and 3,3',5,5'-tetra- tert-butyl diphenoquinone (DQ) acts as an oxidant and promotes α-C(sp3)-H bond deprotonation. This work is useful not only for understanding the NHC-catalyzed oxidative [2 + 2] annulation but also for developing new applications of the FMO theory in organocatalytic cyclizations.