Hyperconjugative Effects Research Articles

Computational study of an oxetane 4H-pyrazole as a Diels–Alder diene

We combine the effects of spirocyclization and hyperconjugation to increase the Diels–Alder reactivity of the 4H-pyrazole scaffold. A density functional theory (DFT) investigation predicts that 4H-pyrazoles containing an oxetane functionality at the saturated center are extremely reactive despite having a relatively high-lying lowest unoccupied molecular orbital (LUMO) energy.

Enamine N-oxides: Design, Synthesis, and Function in Bioorthogonal Reactions.

Enamine N-oxides act as a chemical linchpin bridging two bioorthogonal associative and dissociative reactions. This article describes the design of enamine N-oxides; their synthesis through the retro-Cope elimination reaction; the use of solvent, hyperconjugation, strain, and rehybridization effects to achieve bioorthogonal reactivity; and their rapid reductive cleavage with diboron reagents. The coordinated assembly and disassembly of the enamine N-oxide motif constitutes a powerful chemical operation that enables the attachment and detachment of small molecules from biomacromolecules in a biological setting.

Functionalized boron doped graphene (BGP) as smart nanocarrier for delivery of hydroxyurea (HU) drug

The concerning toxicity associated with hydroxyurea (HU), an anticancer drug used in cancer treatment, has spurred significant attention within the research community over the years. To address this adverse effect, there is a critical need for a smart and targeted drug delivery system (Nano carrier) that can effectively deliver the drug to the tumor site while minimizing side effects for the patient. In this study, we employed density functional theory computations at (DFT)/ωB97XD/6–311++G (d, p) level of theory to evaluate the adsorption properties of functionalized boron-doped graphene (BGP) surfaces, namely COOH@BGP, NH2@BGP, and OH@BGP, for the delivery of the HU anticancer drug. The electronic properties analysis revealed that COOH@BGP/HXU (M2) exhibited the most favorable reactivity with an energy gap value of 5.3756 eV, making it the most reactive surface compared to other complexes investigated. Moreover, a comprehensive natural bond orbital analysis was conducted to investigate hyper-conjugative effects, hybridization, charge transfer, and H-bonding interactions within the systems studied. The results confirmed the following trend: HXU-COOH@BGP (M2) > HXU-OH@BGP (K2) > HXU-NH2@BGP (Q2). Additionally, topological analysis (QTAIM) and Non-covalent interaction (NCI) analysis were performed to ascertain the interaction forces at play. The results strongly support the significant electrostatic force of interaction in the M2 complex, suggesting the presence of hydrogen bond interactions that facilitate the doped surface's ability to bind with HXU and enhance the smooth delivery of the investigated drug. Furthermore, the adsorption studies revealed negative adsorption energy values, indicating favorable adsorption. Among all the analyzed complexes, M2 nanocarrier demonstrated the most suitable characteristics for the delivery of the HXU anticancer drug. These findings hold promise for the development of an efficient and targeted drug delivery system that could potentially mitigate the toxicity associated with HU and enhance cancer treatment outcomes."

Synthesis and Structural Analysis of N3‐Methyluridine and 2’‐Alkoxy/Fluoro‐N3‐Methyluridine Nucleosides by Using NMR Spectroscopy, X‐Ray Crystallography, and Computational Methods

AbstractDual modifications (base and sugar) in siRNA have the potential to overcome off‐target effects and impart nuclease resistance. Here we present the synthesis and detailed structural analysis of N3‐methyluridine and 2’‐alkoxy/fluoro‐N3‐methyluridine modifications, the rationally designed modifications for oligonucleotide therapeutics. Using X‐ray crystallography and 1H NMR spectral data, it is clear that the C2’‐endo conformation of N3‐methyluridine switches to the C3’‐endo pucker state preferentially due to the introduction of electron‐withdrawing 2’‐alkoxy or fluoro substituents. DFT study confirms that the modifications preferentially acquire the C3’‐endo conformation. NBO analysis indicates that in the presence of the 2’‐alkoxy/fluoro substituents, the C3’‐endo conformation is stabilized due to nO4’→σ*C1’‐N1 anomeric as well as σC3’‐H→σ*C2’‐R and σC1’‐C2’→σ*C3’‐OH hyperconjugation effects. The W−C hydrogen bond energies of the modified nucleosides were calculated using the DFT and SAPT methods at the modified base pair regions, and it was observed that one of the hydrogen bonds gets disrupted due to the presence of the N3‐methyl group, causing significant decline in hydrogen bond energy. These detailed structural studies will help to expand the scope of these destabilizing modifications in the rational design of RNAi‐based therapeutics.

Near-Infrared-I to III Absorption and Emission via Core Engineering of Open-shelled Organic Mixed-Valence Systems.

A novel class of agents was developed based on the core engineering of open-shelled organic mixed-valence (MV) systems, which enabled tunable absorption and emission across the NIR-I to III biowindow (700-1850nm) by adjusting the number of central nitrogen oxidation sites and the length of the conjugated bridge. Organic mixed-valence (MV) systems were synthesized through a one-step partial chemical oxidation of starburst oligoarylamines, with varying nitrogen oxidation sites and conjugated bridge lengths, including T4EPAn+ , TPDAn+ , and TMPBn+ . The absorption wavelength of the MV systems red-shifted clearly as the number of central nitrogen oxidation sites increased or the conjugated bridge length was prolonged. T4EPAn+ with one central nitrogen oxidation site exhibited fluorescence emission in the range of 900-1400nm, while TPDAn+ with two central nitrogen oxidation sites demonstrated strong heat generation capabilities. Additionally, the absorption peak of TMPBn+ with a biphenyl conjugated bridge reached up to 1610nm. Especially, these MV systems are highly stable for biological applications due to their high steric hindrance and hyperconjugation effect. These characteristics make MV systems promising candidates for constructing NIR-I/II/III emitters and photothermal agents, representing a significant advance towards developing the next generation of NIR-I to III agents. This article is protected by copyright. All rights reserved.

Density functional analysis of molecular crystal: bis-l-Phenyl alanine mandelate

A novel organic nonlinear four component molecular crystal bis-l-phenylalanine mandelate (BLPAMA) has been synthesized and single crystal has been grown by slow evaporation method in an aqueous solution at ambient temperature. The characterization studies support the formation of the neutral novel organic molecular crystal containing 68 atoms in a molecule. The experimental and theoretical density functional analysis (DFT) have been compared for the vibrational changes, dipolar interactions, 1H and 13C NMR values, UV-Vis absorption pattern, HOMO-LUMO interactions, hyperconjugation effects, Natural Bond Orbital (NBO) and Natural Hybridisation Orbital (NHO) analysis. The molecular structure obtained from the solid state experimental data using ORTEP diagram has been compared with the gaseous state optimized stucture obtained from DFT data using Gaussian 98 software with MO6-31++(d,p) basis set. The DFT study of the title compound has confirmed the crystal formation through charge transfer mechanism, hydrogen bonding interactions and van der Waals forces of attraction. The stress and strain in the title compound leads to the low energy gap nonlinear molecular sheet formation. The title compound shows electrochemical activity due to the highly reactive and relatively unstable structure.

Boundaries of the Hyperconjugation from π-Extended Six-Membered Phosphorus Heterocycles.

In the context of materials science, six-membered phosphorus heterocycles are intriguing building blocks due to their tunable properties through phosphorus post-functionalization and their unique hyperconjugative effects arising from the phosphorus substituents that contribute to further tuning the optoelectronic properties of the system. Seeking for the discovery of improved materials, the latter features have triggered an astonishing evolution of molecular architectures based on phosphorus heterocycles. Theoretical calculations showed that the hyperconjugation causes a reduction in the S0-S1 gap, which strongly depends on the nature of both the P-substituent and the π-conjugated core, but where are the limits? Outlining the hyperconjugative effects of six-membered phosphorus heterocycles would allow scientists to know how to design next-generation organophosphorus systems with enhanced properties. Herein, we discovered that, in cationic six-membered phosphorus heterocycles, an increase in the hyperconjugation does not affect the S0-S1 gap anymore; i.e., quaternizing the phosphorus atoms leads to properties that go beyond those provoked by hyperconjugative effects. DFT calculations revealed that the latter is particularly marked in phosphaspiro derivatives. Our detailed investigations spotlight the potential of π-extended systems based on six-membered phosphorus spiroheterocycles for accessing properties beyond those achieved to date through hyperconjugative effects, thus laying the groundwork for new research possibilities toward improved organophosphorus systems.

Validation of valence bond and molecular orbital models in analyzing the anionic hyperconjugation effect on the stability of alkyl and fluorinated carbanions in gaseous phase

AbstractIn this paper, the anionic hyperconjugation occurring in alkyl and fluorinated carbanions in the gaseous phase is examined at density functional theory (DFT) at the level of theory B3LYP/6‐31++G (d,p) with empirical dispersion‐GD3 theory. First, a contribution of this study is to confirm that the C‐H bond in (CH3)3C‐H (isobutane) is more acidic than the C‐H bonds in CH3CH2‐H (ethane) and (CH3)2CH‐H (propane) based on a comparison of conjugate base stability. Also, the natural population analysis (NPA) and CHELPG methods are well‐performed for calculating charge distribution on carbon atoms, and in contrast, the Mulliken population is better for hydrogen atoms to describe the anionic hyperconjugation in the valence bond (VB) model. The molecular orbital model accounts for the stability order of alkyl and perfluorinated carbanions through the number, strength, and overlap geometry between the lone electron pair on carbon atom and the vicinal σ*C‐H/σ*C‐F orbitals. On the other hand, the utility of VB theory becomes invalid because of the strong inductive effect of the fluorine element and the steric repulsion among CF3 groups in perfluorinated carbanions. Also, the hybridization of the carbon atom holding the lone electron pair can become more s‐character or p‐character dependent on the size of surrounding groups.

Effect of conjugation length on fluorescence characteristics of carbon dots.

The influence of sp2- and sp3-hybridized carbon coexisting in carbon cores on fluorescence characteristics of carbon dots (CDs) was revealed by density functional theory calculations. Based on the constructed coronene-like structures, the fluorescence emission spectra, transition molecular orbital pairs and several physical quantities describing the distribution of electrons and holes were investigated. The results indicate that due to the interaction between sp2 and sp3 carbon atoms, two main factors including the hyperconjugative effect and the separation of sp2 domain by sp3 carbon atoms can regulate the fluorescence wavelength. By analyzing the transition molecular orbital pairs, it was found that the fluorescence wavelength has a close correlation with the conjugation length, suggesting that the conjugation length can predict the shift of the emission spectra of CDs. The theoretical results provide a comprehensive understanding of fluorescence mechanism and help to synthesize CDs with expected fluorescence wavelength.

Ab Initio Group Additive Values for Thermodynamic Carbenium Ion Property Prediction

Carbenium ions are important intermediates in both zeolite and plasma chemistry. The construction of kinetic models for zeolite and plasma chemistry requires the incorporation of thermodynamic properties of these carbenium ions. In this way, thermodynamic equilibrium is incorporated resulting in more accurate and general kinetic models, which facilitate rational zeolite design and plasma process development. In this work, a consistent set of 46 group additive values (GAVs) and non-nearest neighbor interactions (NNIs) is determined for the standard enthalpy of formation, standard molar entropy, and heat capacity. The GAVs are regressed based on 165 quantum chemistry calculations with the CBS-QB3 composite method for carbenium ions as CBS-QB3 was proven a valid method for carbenium property prediction. The presented group additive approach gives the first GAVs and NNIs for entropy and heat capacity and 33 novel values for enthalpy prediction. The determined non-nearest neighbor interactions account for the effect of longer range hyperconjugation, resonance stabilization, and inductive stabilization, which are shown to be crucial for the carbenium stability. The presented group additivity scheme ensures an accurate prediction of all properties with a mean absolute error of 4.82 kJ/mol, 4.92 J/(mol·K), and 1.95 J/(mol·K) for the standard enthalpy of formation, standard molar entropy, and heat capacity, respectively. The reported GAVs and NNIs ensure the thermodynamic property prediction of paraffinic, olefinic, alkynic, aromatic, and five- and six-ring naphthenic cations.

Singlet Oxygen's Potential Role as a Nonoxidative Facilitator of Disulfide S-S Bond Rotation†.

The role of singlet oxygen potentially mediating increased conformational flexibility of a disulfide was investigated. Density functional theory (DFT) calculations indicate that the singlet oxygenation of 1,2-dimethyldisulfane produces a peroxy intermediate. This intermediate adopts a structure with a longer S-S bond distance and a more planar torsional angle θ (C-S-S-C) compared with the nonoxygenated 1,2-dimethyldisulfane. The lengthened S-S bond enables a facile rotation about the torsional angle in the semicircle region 0° < θ < 210°, that is ~5 kcal mol-1 lower in energy than the disulfane. The peroxy intermediate bears nO → σS-S and nO → σ*S-S interactions that stabilize the S-O bond but destabilize the S-S bond, which contrasts with stabilizing nS → σ*S-S hyperconjugative effects in the disulfane S-S bond. Subsequent departure of O2 from the disulfane peroxy intermediate is reminiscent of peroxy intermediates which also expel O2 , yet facilitate cis-trans isomerizations of stilbenes, hexadienes, cyanines, and carotenes. "Non-oxidative" 1 O2 interactions with a variety of bond types are currently underappreciated. We hope to raise awareness of how these interactions can help elucidate the origins of molecular twisting.

Halogen Atom Participation in Guiding the Stereochemical Outcomes of Acetal Substitution Reactions.

Acetal substitution reactions of α-halogenated five- and six-membered rings can be highly stereoselective. Erosion of stereoselectivity occurs as nucleophilicity increases, which is consistent with additions to a halogen-stabilized oxocarbenium ion, not a three-membered-ring halonium ion. Computational investigations confirmed that the open-form oxocarbenium ions are the reactive intermediates involved. Kinetic studies suggest that hyperconjugative effects and through-space electrostatic interactions can both contribute to the stabilization of halogen-substituted oxocarbenium ions.

Halogen Atom Participation in Guiding the Stereochemical Outcomes of Acetal Substitution Reactions

AbstractAcetal substitution reactions of α‐halogenated five‐ and six‐membered rings can be highly stereoselective. Erosion of stereoselectivity occurs as nucleophilicity increases, which is consistent with additions to a halogen‐stabilized oxocarbenium ion, not a three‐membered‐ring halonium ion. Computational investigations confirmed that the open‐form oxocarbenium ions are the reactive intermediates involved. Kinetic studies suggest that hyperconjugative effects and through‐space electrostatic interactions can both contribute to the stabilization of halogen‐substituted oxocarbenium ions.

Experimental and Theoretical Investigation of Reactions of Formyl (HCO) Radicals in the Gas Phase: (I) Kinetics of HCO Radicals with Ethyl Formate and Ethyl Acetate in Tropospherically Relevant Conditions.

Formyl (HCO) radicals were generated in situ in the gas phase via the photolysis of glyoxal in N2 at 248 nm using the pulsed laser photolysis-cavity ring-down spectrometry technique, and the absorption cross-section of the radical was measured to be σHCO = (5.3 ± 0.9) × 10-19 cm2 molecule-1 at 298 K and 615.75 nm, which was the probing wavelength. The kinetics of the reactions of HCO radicals with ethyl formate (EF) and ethyl acetate (EA) were investigated experimentally in the temperature range of 260-360 (±2) K at a pressure of 60 Torr/N2. The absolute rate coefficient for the reaction between HCO and EF was measured to be (298 K) = (1.39 ± 0.30) × 10-14 cm3 molecule-1 s-1 at ambient temperature, whereas that for the reaction of HCO with EA was measured tobe (298 K) = (2.05 ± 0.43) × 10-14 cm3 molecule-1 s-1. The reaction of HCO with EA was faster than that with EF, which might be due to the greater stability of the formed radical intermediate due to hyperconjugative and inductive effects. The dependency of the measured kinetics on experimental pressures and laser fluences was examined within a certain range. To complement the experiments, kinetics of the title reactions in the temperature range of 200-400 K were deciphered theoretically via the canonical variational transition-state theory with small-curvature tunneling and interpolated single-point energy (CVT/SCT/ISPE) method using a dual-level approach at the CCSD(T)/cc-pVTZ//MP2/6-311++G(d,p) level of theory/basis set. A good degree of agreement was detected between the rate coefficients measured experimentally and those calculated theoretically both at room temperature and throughout the range of temperatures studied. The kinetic branching ratios and thermochemistry of the reactions were investigated to understand the thermodynamic feasibility and kinetic lability of each pathway throughout the studied temperatures. Atmospheric implications of these reactions of HCO radicals are also discussed.

Annellated 1,3,4,2-Triazaphospholenes-Simple Modular Synthesis and a First Exploration of Ligand Properties.

The successful use of 1,3,4,2-triazaphospholenes (TAPs) as organo-catalysts stresses the need for efficient synthetic routes to these molecules. In this study, we establish the [1 + 4]-cycloaddition of PBr3 to azo-pyridines as a new approach to preparing pyrido-annellated TAPs in a single step from easily available precursors. The modular assembly of the azo-component via condensation of primary amines and nitroso compounds along with the feasibility of post-functionalization at the P–Br bond under conservation of the heterocyclic structure allows, in principle, to address a wide range of target molecules, which is illustrated by prototypical examples. The successful synthesis of a transition metal complex confirms for the first time the ability of a TAP to act as a P-donor ligand. Crystallographic studies suggest that hyperconjugation effects and intermolecular interactions induce a qualitatively similar ionic polarization of the P–Br bonds in TAPs as in better known isoelectronic diazaphospholenes.

Impact of surface-active site heterogeneity and surface hydroxylation in Ni doped ceria catalysts on oxidative dehydrogenation of propane

Using periodic Density Functional Theory calculations, propane oxidative dehydrogenation (ODH) and overoxidation over bare and hydroxylated Ni-doped CeO2 nanorods with predominantly exposed (110) facets were studied. Ab-initio thermodynamics-based surface phase analysis and computational Raman spectroscopic analysis predicted an 8.3 % surface oxygen vacancy concentration (Ce0.83Ni0.17O1.83) at typical ODH conditions. Only one-third of the surface oxygens, adjacent to the dopant, were selective for propene formation. Moreover, activated oxygen (O22–*) favored the formation of overoxidation products over propene. A monolayer hydroxyl coverage from water dissociation was stable at typical ODH conditions. This reduced the activation energy barrier for propene formation by 0.38 eV, increased the barrier for undesired acetone formation by 0.54 eV, and increased the barrier for propene activation by 0.6 eV. These promotional effects were due to the destabilization and induced hyperconjugation effects in the C3 adsorbates due to surface hydroxylation. Hence, surface hydroxylation (Lewis Base addition) is a potential strategy to improve propene selectivity.

Using Physical Organic Chemistry Knowledge to Predict Unusual Metabolites of Synthetic Phenolic Antioxidants by Cytochrome P450.

Biotransformation, especially by human CYP450 enzymes, plays a crucial role in regulating the toxicity of organic compounds in organisms, but is poorly understood for most emerging pollutants, as their numerous "unusual" biotransformation reactions cannot retrieve examples from the textbooks. Therefore, in order to predict the unknown metabolites with altering toxicological profiles, there is a realistic need to develop efficient methods to reveal the "unusual" metabolic mechanism of emerging pollutants. Combining experimental work with computational predictions has been widely accepted as an effective approach in studying complex metabolic reactions; however, the full quantum chemical computations may not be easily accessible for most environmentalists. Alternatively, this work practiced using the concepts from physical organic chemistry for studying the interrelationships between structure and reactivity of organic molecules, to reveal the "unusual" metabolic mechanism of synthetic phenolic antioxidants catalyzed by CYP450, for which the simple pencil-and-paper and property-computation methods based on physical organic chemistry were performed. The phenol-coupling product of butylated hydroxyanisole (BHA) (based on spin aromatic delocalization) and ipso-addition quinol metabolite of butylated hydroxytoluene (BHT) (based on hyperconjugative effect) were predicted as two "unusual" metabolites, which were further confirmed by our in vitro analysis. We hope this easily handled approach will promote environmentalists to attach importance to physical organic chemistry, with an eye to being able to use the knowledge gained to efficiently predict the fates of substantial unknown synthesized organic compounds in the future.

Probing into the Outcome of Charge Transfer Interactions and Hyperconjugative Effect on the Antibacterial Molecule 4-dimethylaminopyridine using Spectroscopic Elucidations and DFT Calculations

The prospective compound 4-dimethylaminopyridine was probed using FT-IR, FT-Raman, UV-Visible spectra and quantum chemical computations. Vibrational assignments pertaining to different modes of vibration with potential energy distribution have been augmented by normal coordinate analysis. Electronic stability of the compound arising from hyper conjugative interactions and charge delocalization is scrutinized using natural bond orbital analysis. The frontier molecular orbital energy gap probably indicates a compound's strong chemical reactivity and enables eventual charge transfer inside the molecule. The molecular electrostatic potential map and Fukui functions reveal that electronegative nitrogen and electropositive hydrogen atoms can be attacked by electrophiles and nucleophiles. The molecule's electron-hole distribution showed a charge transfer within the molecule, and the chemical implications of the molecule were described using electron localization function and localized orbital locator. Antibacterial activity of the compound with different bacterial strains was validated by agar well diffusion method. Ligand–protein interaction was explored by using molecular docking studies, while the pharmacokinetic aspects of the compound were probed using drug likeness and Absorption, Distribution, Metabolism, Excretion, and Toxicity properties.

Spectroscopic characterization and Electronic structure of Linagliptin by DFT analysis method

Linagliptin (LGP) is the one of the most important drug in type 2 diabetes. In this compound to study on the spectroscopic and electronic behavior by the quantum mechanical method. The optimized molecular structure, electronic properties, dipole moment, rotational constants and important thermodynamic parameters of LGP molecule are computed and compared using HF (Hartree-Fock) and DFT( Density Functional Theory ) methods with 6-311++G (d,p) basis sets. Spectroscopic characterization of experimental FT-IR and Raman frequencies are compared with the calculated scaled vibrational frequencies and also compared theoretical and experimental obtained wavelengths of maximum absorption (λmax) of LGP in different solvents of water, ethanol, and methanol are calculated by the TD-DFT method. The various types of intra-molecular interactions such as conjugative, hyper conjugative and other structural effects are analyzed in Natural bonds orbital of LGP. The relationship between linear polarizability (α) and refractive index (n) was used to describe the polarization behavior of LGP in a different solvent. The electronic charge density at different positions and reactivity descriptors of LGP are used in identifying the site of drug interaction. The various intra-molecular interactions were explained in terms of HOMO and LUMO energies. Mulliken charges and thermodynamic properties of LGP are discussed.

Isomers of the Allyl Carbocation C3H5 + in Solid Salts: Infrared Spectra and Structures.

Three isomers of the allyl cation C3H5+ were obtained in salts with the carborane anion CHB11Cl11–. Two of them, angular CH3–CH=CH+ (I) and linear CH3–C+=CH2 (II), were characterized by X-ray crystallography, and the third one, (CH2CHCH2)+ (III), is formed in an amorphous salt. The stretch vibration of the charged double bond C=C+ of I and II is decreased by 162 cm–1 (I) or 76 cm–1 (II) as compared to that of neutral propene. This result contradicts the prediction of DFT and MP2 calculations with the 6-311G++(d,p) basis set that the appearance of the positive charge on the C=C bond should increase its stretch vibration by 200 cm–1 (I) or 210 cm–1 (II). According to infrared spectra, the CC bonds in isomer III have one-and-a-half bond status. Isomers I and II in the crystal lattice are stabilized due to uniform ionic interactions with neighboring anions with partial transfer of a positive charge to them. Additional stabilization of II is provided by a weak hyperconjugation effect. Isomer III is stabilized in the amorphous phase due to ion paring with a counterion and a strong intramolecular hyperconjugation effect.