Sites For Nucleophilic Attack Research Articles

5-(Pyridin-3-yl)-3,4-dihydro-2H-furan-1-ium (NNKFI): a computational study of its physico-chemical properties.

Recent work on the diazonium ion metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKDI) suggests that 5-(pyridin-3-yl)-3,4-dihydro-2H-furan-1-ium (NNKFI) may form from NNKDI via an intramolecular reaction. NNKDI is an important carcinogen whose role as an alkylating agent has received significant attention. While there is some experimental evidence supporting NNKFI's production in vitro, it has not yet been directly observed. Little is known about NNKFI's structure and reactivity. We report the first in silico examination of this ion. Our study utilized Kohn-Sham density functional theory (B3LYP/6-311G**) and coupled cluster theory (CCSD/6-31G*) to produce energy-optimized structures, vibrational normal modes and molecular orbitals for NNKFI. To gain insight into the chemical properties of this species, we calculated electrostatic potential surfaces, natural population analysis charges and local Fukui indices. We report data and results for NNKFI's cis and trans conformers. Our work confirms C5 as the preferred site for nucleophilic attack in NNKFI. Stretching motions and predicted bond lengths near O1 are consistent with a somewhat weakened carbonyl structure in this ion. Partial charges, electrostatic potential surfaces and local Fukui indices reveal delocalization of cationic charge on the furanium moiety and notable carbocation character at C5.

Degree-based topological indices, quantum computational, molecular docking and biological evaluations of o-nitroacetanilide

In this current work, the solute–solvent, electron behavior, wave function, and biological properties of o-nitroacetanilide were computed using a B3LYP/6–311++G(d,p) set. The spectroscopic characterization of ONA has been observed using UV–Vis correlated with the TD-SCF method in the IEFPCM model, which interpreted gas and polar, non-polar solvents. The energy gap values are explored through gas, DMSO and benzene, which describes less stability, more reactivity and best biological activity of the ONA. The stable optimized structure was estimated with topological (ELF, LOL, and RDG) properties determined using wave function to predict electron density and non-covalent interaction of the bio-molecular ONA chemical structure. The MEP surface plot was used to predict the reactivity sites of nucleophilic attack and electrophilic attack in gas and various solvents. The drug-likeness of the title compounds have been determines their potential for bioavailability through Lipinski Rule of five. The degree-based topological indices are used to describe physiochemical parameters to predict biocomponents. Finally, the biological uses of ONA were discovered through antimicrobial analysis. Molecular docking examines the protein–ligand interaction and stability of the title molecules targeted by the anti-cancer activity receptors 4CG9 and 4CGA, which exhibit −5.63 and −5.25 kcal/mol of ONA, respectively. The theoretical evaluation may enable chemists and pharmaceutical professionals to forecast the medication qualities without need for experimental testing and time-consuming towards future perspective.

Regiochemical Analysis of the ProTide Activation Mechanism.

ProTides are nucleotide analogues used for the treatment of specific viral infections. These compounds consist of a masked nucleotide that undergoes in vivo enzymatic and spontaneous chemical transformations to generate a free mononucleotide that is ultimately transformed to the pharmaceutically active triphosphorylated drug. The three FDA approved ProTides are composed of a phosphoramidate (P-N) core coupled with a nucleoside analogue, phenol, and an l-alanyl carboxylate ester. The previously proposed mechanism of activation postulates the existence of an unstable 5-membered mixed anhydride cyclic intermediate formed from the direct attack of the carboxylate group of the l-alanyl moiety with expulsion of phenol. The mixed anhydride cyclic intermediate is further postulated to undergo spontaneous hydrolysis to form a linear l-alanyl phosphoramidate product. In the proposed mechanism of activation, the 5-membered mixed anhydride intermediate has been detected previously using mass spectrometry, but the specific site of nucleophilic attack by water (P-O versus C-O) has not been determined. To further interrogate the mechanism for hydrolysis of the putative 5-membered cyclic intermediate formed during ProTide activation, the reaction was conducted in 18O-labeled water using a ProTide analogue that could be activated by carboxypeptidase Y. Mass spectrometry and 31P NMR spectroscopy were used to demonstrate that the hydrolysis of the mixed anhydride 5-membered intermediate occurs with exclusive attack at the phosphorus center.

Effect of hydroxyl position on antioxidant ability of hydroxycoumarin derivatives: A theoretical investigation

Effect of the OH group position on the antioxidant ability of hydroxycoumarin derivatives (HOC) was investigated by quantum chemical computation. Frontier molecular orbitals, molecular electrostatic potential, and thermodynamic parameters were analyzed in detail. The results indicate that 3-HOC, 6-HOC, and 7-HOC exhibit as the best reactants with free radicals through analysis of global reactivity descriptor values, meanwhile H (in OH groups) of 4-HOC, 5-HOC, 6-HOC, and 7-HOC molecules are the most preferable sites for nucleophilic attacks. Besides, thermodynamic and kinetic studies reveal hydrogen atomic transfer is the primary mechanism when hydroxycoumarin derivatives react with HOO• free radical in the gas phase and pentyl ethanoate. Hydrogen atomic transfer products account for over 97 % of the total products of hydrogen atomic transfer and radical adduct formation mechanisms. According to the study, 6-HOC is the most effective scavenger of free radicals when compared to other derivatives, with a rate constant of 1.38 × 104 M−1s−1 in the gas phase and 6.5 × 103 M−1s−1 in pentyl ethanoate. The interaction of O20∙∙∙H21 in the transition state of 6-HOC is crucial in stabilizing its structure. This finding suggests that 6-HOC can be a potential candidate for developing antioxidants for various applications in the medical and industrial fields. The results of this study provide valuable insights into the mechanisms by which antioxidants can scavenge free radicals and protect against oxidative stress.

Reactivity of 9-anilinoacridine Derivatives as Potent Anticancer Agents: A DFT Approach

Background: Anticancer activity of 9-anilinoacridine derivatives has been well reported. Although, the DNA-drug sequence-specific binding of these compounds may be affected by the substituent(s) on the aniline ring, it is still unclear which substituent (NH2 or CH2–OH) on the anilino ring of the compound is the critical element. A good understanding of chemical properties such as steric, lipophilic and electronic properties at the molecular level may provide important background for mutagenic and carcinogenic properties. Objectives: The present study is an attempt to understand the reactive nature of some selected 9-anilinoacridine derivatives in both gas and solvent phases and to predict their anticancer activity by QSAR analysis. Methods: Full geometry optimizations of all derivatives were carried out at gradient corrected DFT using DMol3 program. We used DNP basis set in combination with BLYP to study all the derivatives. The molecular mechanics parameters used for QSAR analysis were calculated using Hyperchem software. Results: We found Compound (31) (R=COOC6H5) as the most stable compound and compound (6) (R1= NO2) as the most reactive one in both gas and solvent phases. Fukui function (f+) values of all the atoms showed that N10 is the most reactive atom in each of the molecule which indicates that N10 is the preferred site for nucleophilic attack. The final QSAR model with four parameters (electrophilicity, hardness, surface area, and molar refractivity) is capable of predicting anticancer activity of the compounds against leukemic HL-60 cell lines with r2 = 0.91 and 0.88 in both gas and solvent phases, respectively. Conclusion: The global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity were calculated to understand the reactive nature and reactive sites of the compounds. The comparative QSAR study with the help of DFT and MM + techniques provides the importance of the selected descriptors in predicting the activity of the selected derivatives.

Computational Density Functional Theory Investigation of Stability and Electronic Structures on Boron Nitride Systems Doped with/without Group IV Elements

In this paper, the stability as well as electronic structures of pure and group IV-substituted boron nitride (BN) cluster systems were investigated using Density Functional Theory (DFT) method. The results obtained from the DFT calculations found that the germanium-substituted BN model possessed the highest stability among all the group IV-substituted BN clusters. Although the energy gap values calculated were slightly different for all group IV-substituted single-layered BN clusters, the surface plots of HOMO and LUMO obtained were still the same. For the plots of molecular electrostatic potentials (MEPs), the nitrogen atom located in the middle of the pure BN system  has the most negative electrostatic potentials. In the case of the group IV-substituted BN models, three atoms (i.e., carbon, silicon, and germanium) presented the most reactive sites for nucleophilic attack on the cluster systems. Mulliken atomic charges reported a similar trend as observed in MEPs. In the Mulliken scheme, the nitrogen atom located in the middle of the pure BN system possesses the highest negative charge. While three atoms (i.e., carbon, silicon, and germanium) showed the highest negative charges in the group IV-substituted BN model clusters.

Molecular Simulations to Understand the Moisture, Carbon Dioxide, and Oxygen Barrier Properties of Pectin Films.

Density functional theory and molecular dynamic simulations were used to understand the microscopic-level interactions of pectin-based thin films with moisture (H2O), carbon dioxide (CO2), and oxygen (O2). Galacturonic acid (GA), which forms ~65% of the smooth region of pectin polymer, was chosen for the current study. The electrostatic potential and Fukui function maps indicate that oxygen atoms of -OH groups of GA are the most reactive sites for electrophilic attack and hydrogen atoms on the carboxylic group (-COOH) are the reactive sites for nucleophilic attack. The GA molecule has shown strong interaction via hydrogen bonding with H2O (E= ~ 40 kJ/mol) followed by CO2 (E = ~ -13 kJ/mol). Nucleophilic O2 showed insignificant interaction with GA. Surface interaction, adsorption, and diffusion of sorbate molecules on the GA film followed the order of H2O >CO2 > O2. Molecular interaction studies provided atomistic insights into the weak moisture and high gas barrier properties of pectin films.

Theoretical Study of the Chemical Reactivity of a Series of 2, 3-Dihydro-1H-Perimidine

This reactivity study was performed on seven molecules of a 2,3-dihydro-1H-perimidine series using density functional theory at the B3LYP / 6-311 G (d, p) level. Calculation of the dipole moment showed that compound 4 is more soluble in aqueous medium. The study of frontier molecular orbitals, in particular the energy gap (ΔE), electronegativity (c), chemical hardness (η) and the electrophilic index (ω) has provided a better overview molecular properties. Thus, the compound 5 with the highest energy gap between the boundary orbitals is the most stable and the least reactive. Analysis of local descriptors and the electrostatic potential map identified nitrogen atoms N26 and N28 as the preferred sites of electrophilic attack and the carbon atom C26 as the preferred site of nucleophilic attack.

Synthesis and spectral analysis of (S)-7-(4-chlorophenyl)-6,7-dihydrothiazolo [4,5-d]pyrimidine-2,5(3H,4H)-dione and study of its quantum chemical properties

In this article, synthesis and quantum chemical properties of novel (S)-7-(4-chlorophenyl)-6,7-dihydrothiazolo[4,5-d]pyrimidine-2,5(3H,4H)-dione (CPTHZ) are described. The aim of this synthesis was to obtain biologically active thiazolidinone scaffolds and correlates its quantum chemical properties with its experimental results. The structure of the compound was characterized by using different spectral analysis. The chemical calculations were computed with the help of DFT level of theory using Becke3–Lee–Yang–Parr (B3LYP)) and Coulomb–Attenuated–Method–Becke3–Lee–Yang–Parr (CAM-B3LYP)/6-31G(d,p) basis set. Thermodynamic properties were calculated at diverse temperatures. Various structural and thermodynamic parameters such as electrophilicity, chemical potential, chemical hardness and maximum amount of electronic charge transfer were done for this compound. The local reactivity descriptors showed that most reactive site for nucleophilic attack was C(7). In addition to it, correlation graphs between experimental and calculated values of 1 HNMR and 13 CNMR were also presented

Nucleophilic Transformations of Lewis Acid-Activated Disubstituted Epoxides with Catalyst-Controlled Regioselectivity.

Due to their inherent ring strain and electrophilicity, epoxides are highly attractive building blocks for fundamental organic reactions. However, controlling the regioselectivity of disubstituted epoxide transformations is often particularly challenging. Most Lewis acid-mediated processes take advantage of intrinsic steric or electronic substrate bias to influence the site of nucleophilic attack. Therefore, the scope of many of these systems is frequently quite limited. Recent efforts to generate catalysts that can overcome substrate bias have expanded the synthetic utility of these well-known reactions. In this Perspective, we highlight various regioselective transformations of disubstituted epoxides, emphasizing those that have inspired the production of challenging, catalyst-controlled processes.

Molecular structure and quantum descriptors of cefradine by using vibrational spectroscopy (IR and Raman), NBO, AIM, chemical reactivity and molecular docking.

This study aims to investigate the structural and vibrational features of cefradine (the first-generation cephalosporin antibiotic) based on spectroscopic experiments and theoretical quantum chemical approach. The fundamental structural aspects of cefradine have been examined based on optimized geometry, spectroscopic behavior, intermolecular interaction, chemical reactivity, intramolecular hydrogen bonding, and molecular docking analysis. The most stable minimum energy conformer of the title molecule was identified by performing a one-dimensional potential energy surface scan along the rotational bonds at B3LYP/6-311++G (d,p) level of theory. The vibrational features of the molecule and information about the coupled modes were predicted. The chemical reactivity and stability of all the possible conformers of cefradine were estimated based on the HOMO-LUMO energy gap and NBO approach. The overall picture of accumulation of charges on individual atoms of the molecule was predicted by molecular electrostatic potential (MEP) surface map which in turn identifies the nucleophilic and electrophilic region or sites. The quantitative analysis of electrophilicity and nucleophilicity indices was done by Hirshfeld charge analysis and it was found that N8 atom is the most prominent site for nucleophilic attack while C14 atom is feasible for electrophilic attack. QTAIM study has also been performed to investigate the nature and strength of hydrogen bonding interactions. Besides, molecular docking studies were performed to examine the active binding residues of the target.

Synthesis, spectroscopic, DFT, HSA binding and docking studies of new 1,5-bis(4-chlorophenyl)-3-(2-(4-methylpiperazin-1-yl)quinolin-3-yl)pentane-1,5-dione

1,5-Bis(4-chlorophenyl)-3-(2-(4-methylpiperazin-1-yl)quinolin-3-yl)pentane-1,5-dione was synthesised and characterised using single-crystal X-ray Crystallography, FT-IR, 1H-NMR, 13C-NMR and UV-Visible spectroscopy. DFT calculations were performed at the B3LYP/6-311++G (d.p) level of theory in the gas phase. Frontier Molecular Orbitals (FMO) yielded HOMO-LUMO energy as: EHOMO = -6.015 eV, ELUMO = -2.525 eV and energy gap, ΔEgap = 3.490 eV. Fukui Function Analysis (FFA) indicated the reactive sites for electrophilic, and nucleophilic attack. The molecule's electrophilic addition site is 4-N in the piperazine group with a value of 0.020. The site for nucleophilic attack is both 13-C and 15-C in the quinoline group with values of 0.02 and 0.031 respectively. The biological activity was elucidated by molecular docking studies that gave a ΔG value for HSA binding of -26.44 kJ mol−1 which is approximately similar to the experimental value obtained from emission spectral data of -32.15 kJ mol−1.

Spectroscopic, structural, electronic and bioactive characteristics of 3,5-bis(2,5-dimethylphenyl)pyridine (1): An experimental and theoretical investigations

3,5-bis(2,5-dimethylphenyl)pyridine (1); a novel derivative of 3,5-dibromopyridine was synthesized via Pd(0) catalyzed cross coupling reaction. The compound under investigation was characterized by XRD and different spectroscopic techniques. Density functional theory (DFT) was applied to compound 1 and experimental XRD data and DFT data are found in good agreement with each other. Calculated FT-IR results are found to be in excellent agreement with experimental FT-IR findings. Chemical shift values for NMR were calculated for compound (1) in the gas phase which show deviation to experimental values might be because of medium affects. Natural bond orbital (NBO) study was also performed which indicates that the methyl groups influence van der Waals interactions among the adjacent bonds, especially, delocalization of energy during the interaction. Energy gap values of HOMO-LUMO calculated through frontier molecular orbital (FMO) analysis provided enough evidence that molecule is biologically active. Molecular electrostatic potential (MEP) mapping indicated that electron density is located on nitrogen whereas carbon and hydrogen atom are favorable sites for nucleophilic attack. Moreover, the bioactivities of compound (1) have been confirmed by the experimental activity in terms of zones of inhibition against bacteria and fungus.

Electronic structure, reactivity, and Hirshfeld surface analysis of carvone

The density functional theory (at the B3LYP level using 6-311++G(2d,2p) basis set) was used for the investigation of the geometry and electronic properties of the carvone. The electronic properties and chemical activity of the titled compound were investigated by means of several theoretical approaches, molecular electrostatic potential surface, natural bond orbital, and frontier molecular orbital analyses. It was established that the oxygen atom in the structure characterized the electrophilic reactivity; the positive regions are localized on the hydrogen atoms, which can be considered as possible sites for nucleophilic attack. A detailed analysis of the intermolecular interactions via Hirshfeld surface analysis and fingerprint plots revealed that the carvone structure is stabilized mainly by the formation of O. . .H/H. . .O hydrogen bonds. However, close contacts were established between C. . .H/H. . .C and H. . .H contacts.

Interactions of thiol and alkoxy radical with coinage metal nanoclusters

Interaction of small neutral coinage metal clusters (M19 = Ag19/Au19) with thiol/alkoxy radical (E = -SCH3, -OCH3, and -OCH2CH3) has been investigated to understand the bonding mechanism in the coinage metal−molecule junctions, which would allow to design biocompatible materials. In this study, structure, reactivity, and energy decomposition analysis (EDA) of M19−E complexes have been unravelled using density functional theory (DFT) based Perdew, Burke and Ernzerhof (PBE) method. In addition, the theory of “atoms in molecules” (AIM) has also been used characterize the nature of interaction. The calculated reactivity descriptors predict that the vertex atoms (Ag/Au) are the most reactive site for nucleophilic attack. The atoms lying at the center of each face are favourable for an electrophilic attack in both the cases. Geometrical parameters illustrate that the structure of the molecules change significantly before and after interactions. The signatures of ∇2ρ(r) and Hc for the anchoring bonds are respectively positive and negative, revealing that these bonds are partially electrostatic and covalent in nature. EDA calculation indicates that the largest contribution to the M−X (X = O/S) bond arise from ΔEorb and ΔEelstat contributions. Specifically, contribution from the orbital interaction is higher than the electrostatic contribution, which further confirms the covalent nature of the interaction.

Stereoselective Convergent Synthesis of Tetrahydro-5 H-benzo[ c]fluorene via Nine-Membered Ring-Closing Metathesis and Transannular Acid-Mediated Cyclization/Nucleophilic Addition.

The diene methyl ethers or acetates, constructed from the Li-Br exchange/addition reactions of 2-vinylbenzaldehydes and 2-(but-3-en-1-yl)bromoarenes followed by etherification or acetylation of the corresponding alcohols, smoothly underwent the ring-closing metathesis (RCM) by using Hoveyda-Grubbs II as a catalyst to provide the corresponding benzannulated ( Z)-cyclononenes as single products in good yields (up to 75%). The ensuing one-pot acid-mediated transannular cyclization/nucleophilic addition at C7 furnished the corresponding tetrahydro-5 H-benzo[ c]fluorenes as single stereoisomers with the exclusive cis stereochemistry at the ring junction (C5-C6) and trans at the site of nucleophilic attack (C6-C7) on the three contiguous stereogenic centers in good to excellent yield (up to 94%). The developed strategy was general; the reaction conditions were compatible with hydride, azide, and electron-rich aromatics as nucleophiles. In addition, various methoxylated benzannulated cyclononene acetates could be employed as substrates. Thus, tetrahydro-5 H-benzo[ c]fluorenes could be prepared in four steps from appropriately substituted bromoarenes and benzaldehydes in good yields (up to 56%) with excellent stereo- and regio-control.

Studies of the Chemical Reactivity of a Series of Rhodanine Derivatives by Approaches to Quantum Chemistry

This theoretical chemical reactivity study was conducted using the Density Functional Theory (DFT) method, at computational level B3LYP/6-31G (d). It involved a series of six (06) 5-arylidene rhodanines and allowed to predict the chemical reactivity of these compounds. DFT global chemical reactivity descriptors (HOMO and LUMO energies, chemical hardness, softness, electronegativity) were examined to predict the relative stability and reactivity of rhodanin derivatives. Thus, the compound 6 which has an energy gap between the orbitals of ΔEgap = 3.004 eV is the most polarizable, the most reactive, the least stable, the best electron donor and the softest molecule. Calculation of the local indices of reactivity as well as dual descriptors revealed that the sulfur heteroatom of the Rhodanine ring is the privileged site of electrophilic attack in a state of sp3 hybridization and privileged site of nucleophilic attack in a state of sp2 hybridization.

Structural basis for the second step of group II intron splicing

The group II intron and the spliceosome share a common active site architecture and are thought to be evolutionarily related. Here we report the 3.7 Å crystal structure of a eukaryotic group II intron in the lariat-3′ exon form, immediately preceding the second step of splicing, analogous to the spliceosomal P complex. This structure reveals the location of the intact 3′ splice site within the catalytic core of the group II intron. The 3′-OH of the 5′ exon is positioned in close proximity to the 3′ splice site for nucleophilic attack and exon ligation. The active site undergoes conformational rearrangements with the catalytic triplex having different configurations before and after the second step of splicing. We describe a complete model for the second step of group II intron splicing that incorporates a dynamic catalytic triplex being responsible for creating the binding pocket for 3′ splice site capture.

Asymmetric Induction via the Structural Indenyl Effect

Constrained geometry, planar chiral, dichloro[η5:κS-indenyl-sulfanyl]rhodium complex (pS)-1 reacts with (E)-2-pentene in the presence of silver hexafluoroantimonate to afford syn,syn-1,3-dimethyl-π-allyl complex (pS)-2 in 88% yield. Reaction of (pS)-2 with the sodium or tetrabutylammonium salts of dimethyl malonate anion provided dimethyl 2-[(1R,2E)-1-methyl-2-buten-1-yl]-1,3-propanedioate ((R)-3) in 68–70% yield and 66–68% enantiomeric excess. NMR analysis and density functional theory calculations establish that asymmetric induction is substantially determined by the electronic asymmetry of the indenyl ligand polarizing the preferred site of nucleophilic attack on the π-allyl ligand toward the terminal carbon that is syn to the indenyl benzo-ring.

Regioselective Nucleophilic Additions to Diiron Carbonyl Complexes Containing a Bridging Aminocarbyne Ligand: A Synthetic, Crystallographic and DFT Study

Diiron µ‐aminocarbyne compounds, 1a–e, are prepared in two steps from Fe2Cp2(CO)4, negating the need for difficult purification procedures of intermediate species; they are efficiently isolated by alumina chromatography. Minor amounts of µ‐aminocarbyne aryl isocyanide compounds, 2a–c, are obtained as side products. The structures of the cations in 1a,c,e are calculated using DFT; the carbyne carbon is generally predicted to be the thermodynamic site of hydride addition, in agreement with a previous experimental finding concerning 1a. Accordingly, the reaction of 1e with NaBH4 affords a bridging aminocarbene complex, 4, in 85 % yield. Otherwise, the reaction of 1c with NaBH4 yields the aminocarbyne–cyclopentadiene derivative 3 (70 %), presumably as a consequence of the steric protection exerted by the xylyl–methyl groups towards the carbyne moiety. The sequential treatment of 1a,c with Li2CuCNMe2 and MeSO3CF3 affords 5a,b, comprising both aminocarbyne and alkoxycarbene ligands. In accordance with DFT calculations, the alkoxycarbene moiety in 5a is the most favourable site for nucleophilic attack. Thus, the reactions of 5a with NH2R (R = Et, iPr) and NBu4CN, respectively, give the aminocarbyne/aminocarbene complexes, 6a,b, and the aminocarbyne‐α‐cyanoalkyl 7. All the products are fully characterized by spectroscopic and analytical methods; moreover, the structures of 1a, 1d, 6a and 7 are elucidated by single‐crystal X‐ray diffraction studies.