Molecular Electron Density Theory Study Research Articles

A molecular electron density theory study on the [3 + 2] cycloaddition reaction of a 2,4-dienone and a nitrone: regioselectivity, diastereoselectivity, energetic aspects, and molecular mechanism

A molecular electron density theory study on the [3 + 2] cycloaddition reaction of a 2,4-dienone and a nitrone: regioselectivity, diastereoselectivity, energetic aspects, and molecular mechanism

Revealing the Critical Role of Global Electron Density Transfer in the Reaction Rate of Polar Organic Reactions within Molecular Electron Density Theory.

The critical role of global electron density transfer (GEDT) in increasing the reaction rate of polar organic reactions has been studied within the framework of Molecular Electron Density Theory (MEDT). To this end, the series of the polar Diels-Alder (P-DA) reactions of cyclopentadiene with cyanoethylene derivatives, for which experimental kinetic data are available, have been chosen. A complete linear correlation between the computed activation Gibbs free energies and the GEDT taking place at the polar transition state structures (TSs) is found; the higher the GEDT at the TS, the lower the activation Gibbs free energy. An interacting quantum atoms energy partitioning analysis allows for establishing a complete linear correlation between the electronic stabilization of the electrophilic ethylene frameworks and the GEDT taking place at the polar TSs. This finding supports Parr's proposal for the definition of the electrophilicity ω index. The present MEDT study establishes the critical role of the GEDT in the acceleration of polar reactions, since the electronic stabilization of the electrophilic framework with the electron density gain is greater than the destabilization of the nucleophilic one, making a net favorable electronic contribution to the decrease in the activation energy.

A molecular electron density theory study of hydrogen bond catalysed polar Diels–Alder reactions of α,β-unsaturated carbonyl compounds

The hydrogen bond (HB) catalysed Diels-Alder (DA) reactions of acrolein with cyclopentadiene have been investigated within the Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) computational level. The formation of HBs increases the electrophilicity of these species, suggesting an acceleration of these polar Diels-Alder (P-DA) reactions with forward electron density flux. Formation of one or two HBs with acrolein decreases the activation energies of the HB-catalysed P-DA reactions by 1.7 (methanol) and 4.0 (squaramide) kcal·mol−1, with the corresponding DA reactions exhibiting low endo stereoselectivity. These HB-catalysed DA reactions proceed through non-concerted one-step mechanisms via asynchronous transition state structures (TSs). An Interacting Quantum Atoms (IQA) energy partitioning analysis of the TSs indicates that the intra-atomic stabilization of the acrolein framework, coupled with the increase of the global electron density transfer, plays a crucial role in reducing the activation energies of these HB-catalysed DA reactions.

A molecular electron density theory study to understand intramolecular [3 + 2] cycloaddition reactions of azides and diazoalkanes

A molecular electron density theory study to understand intramolecular [3 + 2] cycloaddition reactions of azides and diazoalkanes

MEDT Study, hemisynthesis via regioselective ring opening of α-Himachalene-Epoxides, ADME survey and docking studies designed to target coronavirus and HIV-1

The ring-opening reaction of the two diepoxides, α-himachalenes 6 and 7, with aluminum lithium hydride (LiAlH4) in ether produced the title compounds C15H24O2 sesquiterpene alcohol. Both experimentally and conceptually, the regio- and stereospecificity of this ring opening reaction were investigated using the Molecular Electron Density Theory (MEDT). The Parr functions and the energy study correctly predicted the best interaction to be between the C13 carbon and the hydride, as evidenced by the attained regio- and stereo-specificity revealed through the experimental research. Moreover, the alcohol 8 is obtained from a kinetic and thermodynamic control while the alcohol 9 is obtained only by a kinetic control, in the maximum conformity with the findings of the experiments. In addition, the performed docking calculations to examine the coronavirus and HIV-1 activities of the products 1–9 revealed that alcohol 9 has a higher affinity against coronavirus while β-himachalene 1 against the HIV-1.

A molecular electron density theory study of asymmetric Diels-Alder [4 + 2] reaction's mechanism of furan with three substituted alkynes (5-R substituted-3-(3-(phenylsulfonyl)-propioloyl)-oxazolidin-2-one).

The [4 +2 ] cycloaddition reactions between furan and three substituted alkynes (5-R-substituted-3-(3-(phenylsulfonyl)-propioloyl)-oxazolidin-2-one) have been investigated using the MEDT approach. Reactivity indices, reaction pathways, and activation energies are calculated. In an investigation of conceptual DFT indices, furan acts as a nucleophile, while the three substituted alkynes (5-R-substituted-3-(3-(phenylsulfonyl)-propioloyl)-oxazolidin-2-one) function as electrophiles in this reaction. The cycloaddition is regioiselective, as demonstrated by the activation and reaction energies, in clear agreement with the experiment's results. Hetero Diels-Alder [4 + 2] cycloadditions occur following a non-concerted two stages one-step molecular mechanism. For the purpose of this study, all calculations were performed using the Gaussian 09 software. Optimization was achieved through Berny's computational gradient optimization method, employing the B3LYP functional and the 6-31G(d) basis set. Analysis of both local and global reactivity indices provided insights into the reactivity tendencies of the reactants, distinguishing between electrophilic and nucleophilic characteristics via Parr functions. Frequency calculations were employed to identify and characterize stationary points, with transition states indicated by a single imaginary frequency and positive values of all frequencies for reactants and product. The electron localization function (ELF) was investigated using the Multiwfn software within the context of topological analyses.

A Molecular Electron Density Theory Study of the Domino Reaction of N-Phenyl Iminoboranes with Benzaldehyde Yielding Fused Bicyclic Compounds.

The reaction of N-phenyl iminoborane with benzaldehyde yielding a fused aromatic compound, recently reported by Liu et al., has been studied within the Molecular Electron Density Theory (MEDT). Formation of the fused aromatic compound is a domino process that comprises three consecutive reactions: (i) formation of a weak molecular complex between the reagents; (ii) an intramolecular electrophilic attack of the activated carbonyl carbon of benzaldehyde on the ortho position of the N-phenyl substituent of iminoborane; and (iii) a formal 1,3-hydrogen shift yielding the final fused aromatic compound. The two last steps correspond to a Friedel-Crafts acylation reaction, the product of the second reaction being the tetrahedral intermediate of an electrophilic aromatic substitution reaction. However, the presence of the imino group adjacent to the aromatic ring strongly stabilizes the corresponding intermediate, being the reaction product when the ortho positions are occupied by t-butyl substituents. This domino reaction shows a great similitude with the Brønsted acid catalyzed Povarov reaction. Although N-phenyl iminoborane can experience a formal [2+2] cycloaddition reaction with benzaldehyde, its higher activation Gibbs free energy compared to the intramolecular electrophilic attack of the activated carbonyl carbon of benzaldehyde on the ortho position of the N-phenyl substituent, 6.6 kcal·mol-1, prevents the formation of the formal [2+2] cycloadduct. The present MEDT study provides a different vision of the molecular mechanism of these reactions based on the electron density.

Investigation of the molecular mechanism and diastereoselectivity in the [3 + 2] cycloaddition reaction between acetonitrile oxide and Cis-3,4-Dichlorocyclobutene: Insights from MEDT and docking study

[3 + 2] cycloaddition (32CA) reactions involving acetonitrile oxide 1 and cis-3,4-dichlorocyclobutene 2 has been investigated via Molecular Electron Density Theory (MEDT) at B3LYP and M06-2X associated with the basis 6–311++G(d,p). The calculated energy profile demonstrates clearly that this reaction is considerably high diastereoselectivity, which is perfectly in accordance with the results of the experiments. The cycloaddition reaction's molecular mechanism has been examined in bonding evolution theory (BET) terms that displays several changes in electron densities along the reaction pathway and demonstrates a one-step process with highly asynchronous transition states. The acetonitrile oxide under study was classified as zwitter-ionic species from the topological analysis of the electron localization function (ELF). In addition, the optimum solvent for performing this cycloaddition is cyclohexane, which is followed by ether and then chloroform. In a further step, a docking survey was carried out for cycloadducts 3, 3-F, 4 and 4-F docked to the main protease of SARS-CoV2 (6LU7) in comparison with ribavirin, revealing that these cycloadducts have lower binding energies than ribavirin.

Synthesis of tetrazoles through a domino reaction: A molecular electron density theory study of energetics, selectivities, and molecular mechanistic aspects

This study corresponds to a molecular electron density theory (MEDT) investigation to shed light on the energetics, selectivities, and molecular mechanistic aspects of an experimental domino reaction. Theoretical evidences at the M06–2X/6-31G(d) level indicates that this domino reaction includes three different successive steps and is initialized by a stepwise HCl elimination from precursor chlorohydrazone NPCH to yield nitrile imine NI-2. A subsequent stepwise and highly regioselective [3 + 2] cycloaddition (32CA) reaction of NI-2 toward tetramethylguanidine TMG-3 affords corresponding formal [3 + 2] cycloadduct CA-1 as the sole product. Finally, a stepwise HNMe2 elimination experienced by CA-1 leads to amino triazole ATA as an aromatic five-membered target product. Computed rate constants reveal that the HCl elimination step should be considered as the bottleneck of this domino reaction. However, a topological analysis of electron localization function (ELF) of NI-2 demonstrates a zwitterionic type (zw-type) 32 C A reaction is expected between NI-2 and TMG-3. This 32CA reaction also displays an almost noticeable polar character arising from moderate electrophilicity and strong nucleophilicity of NI-2 and TMG-3, respectively. The regioselectivity of 32CA reaction can be explained via analysis of Parr functions values calculated at the reactive sites of reagents. The molecular mechanism of the 32CA reaction was explored through portraying bond forming/breaking patterns involved in this polar, stepwise, and zw-type reaction by means of the ELF analysis. Indeed, formation of both C–N single bonds along the first and second steps takes place through coupling of the corresponding pseudoradical centers.

Unveiling substituent effects in [3+2] cycloaddition reactions of benzonitrile N-oxide and benzylideneanilines from the molecular electron density theory perspective

The zw- type [3+2] cycloaddition (32CA) reactions of benzonitrile N-oxide with a series of substituted benzylideneanilines have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-31G(d) computational level. The presence of dimethylamino and methoxy substituents in the aromatic rings of benzylideneaniline makes the reaction more facile relative to the unsubstituted one, while the electron withdrawing nitro substituents relatively induce minimal changes in the energy profile complying with the experimentally observed reaction rates. The presence of non-bonding electron density at the nitrogen atom and the formation of pseudoradical centre at the carbon atom of benzonitrile N-oxide characterise the difference in electronic structure of the TSs relative to the reagents, while the topological analysis of the electron localization function (ELF) and the atoms-in-molecules (AIM) reveal no covalent bond formation at the early TSs. The present MEDT study analyses the experimentally observed substituent effects and complete regioselectivity in the studied 32CA reactions.

Exploring the factors controlling the mechanism and the high stereoselectivity of the polar [3+2] cycloaddition reaction of the N,N'-cyclic azomethine imine with 3-nitro-2-phenyl-2H-chromene. A molecular electron density theory study

Exploring the factors controlling the mechanism and the high stereoselectivity of the polar [3+2] cycloaddition reaction of the N,N'-cyclic azomethine imine with 3-nitro-2-phenyl-2H-chromene. A molecular electron density theory study

A molecular electron density theory study of mechanism and selectivity of the intramolecular [3+2] cycloaddition reaction of a nitrone–vinylphosphonate adduct

A molecular electron density theory study of mechanism and selectivity of the intramolecular [3+2] cycloaddition reaction of a nitrone–vinylphosphonate adduct

A Molecular Electron Density Theory Study of the Polar Diels-Alder Reaction of Naphtoquinone:Cr(CO)3 Complex with Cyclic Dienes

The role of the Cr(CO)3 coordination to the aromatic ring of naphtoquinone (NQ) in the polar Diels-Alder (P-DA) reactions with cyclic dienes, cyclopentadiene (Cp), cyclohexadiene (Ch), and 1-methoxy-cyclohexadiene (ChOMe), has been studied within Molecular Electron Density Theory (MEDT). Electron Localization Function (ELF) of the NQ:Cr(CO)3 complex indicates that Cr(CO)3 does not cause any remarkable change in the electronic structure of NQ. While the NQ:Cr(CO)3 complex is categorized as a strong electrophile, the cyclic dienes are categorized as strong nucleophiles, suggesting P-DA reactions. Formation of the NQ:Cr(CO)3 complex reduces the activation energy by only 0.7 kcal·mol−1. While Ch shows a lower reactivity than Cp, ChOMe presents the highest reactivity of this series of cyclic dienes. Analysis of the activation Gibbs free energies of the P-DA reaction with Cp indicates that the reaction is completely endo and anti stereoselective. The present MEDT study shows that the Cr(CO)3 complex has no effective catalytic activity in the P-DA reactions of NQ with cyclic dienes, but only permits the reaction to take place experimentally with a total endo and anti facial stereoselectivity, yielding a single cycloadduct.

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of an Azomethine Ylide with an Electrophilic Ethylene Linked to Triazole and Ferrocene Units.

The [3+2] cycloaddition (32CA) reaction of an azomethine ylide (AY) with an electrophilic ethylene linked to triazole and ferrocene units has been studied within the Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) level. The topology of the electron localization function (ELF) of this AY allows classifying it as a pseudo(mono)radical species characterized by the presence of two monosynaptic basins, integrating a total of 0.76 e, at the C1 carbon. While the ferrocene ethylene has a strong electrophilic character, the AY is a supernucleophile, suggesting that the corresponding 32CA reaction has a high polar character and a low activation energy. The most favorable ortho/endo reaction path presents an activation enthalpy of 8.7 kcal·mol−1, with the 32CA reaction being exergonic by −42.1 kcal·mol−1. This reaction presents a total endo stereoselectivity and a total ortho regioselectivity. Analysis of the global electron density transfer (GEDT) at the most favorable TS-on (0.23 e) accounts for the high polar character of this 32CA reaction, classified as forward electron density flux (FEDF). The formation of two intermolecular hydrogen bonds between the two interacting frameworks at the most favorable TS-on accounts for the unexpected ortho regioselectivity experimentally observed.

Mechanistic aspects of the Diels-Alder reaction between (E)-N-benzylidene-2,2-difluoro-1-phenylethenamine and 2-vinyl pyridine: A molecular electron density theory study

A MEDT study is carried out on dehydrofluorination of benzyltrifluoromethylketimine (BFK) to (E)-N-benzylidene-2,2-difluoro-1-phenylethenamine (BFPA), and the Diels-Alder (DA) reaction of BFPA with 2-vinylpyridine (2VP), which has been performed experimentally by Fu and co-workers. PES analysis indicated that in the dehydrofluorination reaction, the deprotonation of BFK is the RDS in the presence of 2,2,6,6-tetramethylpiperidine (TMP), and the presence of 2,2,6,6-tetramethylpiperidinium ion generated in the deprotonation step, is essential for defluorination. In consistent with the experimental work, it was found that the formation of cis ortho disubstituted cycloadduct from the DA reaction is more favorable kinetically. The high activation barriers rationalize the performing of reactions in harsh conditions. The ELF analysis suggested that the DA reaction takes place through a two-stage one-step mechanism via the coupling of pseudoradical centers. IGM analysis confirmed the endo stereoselectivity predominance of the reaction. Finally, it was found that the BF3 Lewis acid makes the reaction unfavorable.

Unveiling thecb‐typeIntramolecular [3+2] Cycloaddition Reactions of Fluorinated Azomethine Ylides to Ester Carbonyls with a Molecular Electron Density Theory Perspective

AbstractThe carbenoid‐type (cb‐type) intramolecular [3+2] cycloaddition (IM32CA) reactions of four fluorinated azomethine ylides (AYs) bearing an ester carbonyl substituent have been studied from the molecular electron density theory (MEDT) perspective. The presence of two fluorine atoms in these species changes thepseudodiradicalstructure of the simplest AY to that of a carbenoid one, according to thecb‐typemolecular reactivity of these IM32CA reactions. These IM32CA reactions present low activation energies, lesser than 3.0 kcal ⋅ mol−1, and a strongly exothermic character, more than −34.0 kcal ⋅ mol−1, showing a complete chemo‐ and regioselectivity. The presence of the electron‐withdrawing −CN group at the aryl ester framework increases the global electron density transfer (GEDT) at the transition state structure (TS), which fluxes from the nucleophilic AY moiety to the electrophilic carbonyl ester, diminishing the activation energy by 2 kcal ⋅ mol−1relative to that of the phenyl substituent. Electron Localization Function and Atom‐in‐Molecules topological analyses of the most favorable TSs show the early character of thesecb‐typeIM32CA reactions. The present MEDT study makes it possible to establish that the carbenoid structure of these fluorinated AYs together with their supernucleophilic character are responsible for the high reactivity and selectivities shown by these three‐atom‐components participating incb‐type32CA reactions towards carbonyl compounds.

Does Cr(CO)3 Really behave as Catalyst in the Diels‐Alder Reaction of Styrene with Cyclopentadiene? A Molecular Electron Density Theory Study

AbstractThe role of the coordination of the Cr(CO)3 complex to the aromatic ring of styrene in the Diels‐Alder (DA) reaction towards cyclopentadiene (Cp) has been studied within the Molecular Electron Density Theory (MEDT) at the ωB97X−D/6‐311G(d,p) level. While Electron Localization Function (ELF) topological analysis of the reagents indicates that coordination of Cr(CO)3 to the aromatic ring of styrene does not cause any remarkable change in its electronic structure, it increases its global electrophilicity but does not efficiently activate the C−C double bond. Thus, the DA reaction of styrene with Cp, which has a high activation energy, 15.9 kcal ⋅ mol−1, is decreased by only 2.1 kcal ⋅ mol−1 with the formation of the corresponding Cr(CO)3 complex. This DA reaction is endo and anti stereoselective. Analysis of the geometrical parameters and the electron density distribution at the endo TSs confirms that coordination of the Cr(CO)3 complex to the aromatic ring of styrene does not produce any appreciable change at the corresponding TSs. These DA reactions, which have low polar character, take place through a one‐step mechanism via an asynchronous endo TS, in which the formation of the C4−C5 simple bond is more advanced than the C1−C6 one. The present MEDT study shows that the Cr(CO)3 complex has no effective catalytic activity in the non‐polar DA reactions of styrene with Cp.

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Pseudo(mono)radical Azomethine Ylides with Phenyl Vinyl Sulphone

The [3+2] cycloaddition (32CA) reaction of an azomethine ylide (AY), derived from isatin and L-proline, with phenyl vinyl sulphone has been studied within Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) level. ELF topological analysis of AY classifies it as a pseudo(mono)radical species with two monosynaptic basins at the C1 carbon, integrating a total of 0.76 e. While vinyl sulphone has a strong electrophilic character, AY is a supernucleophile, suggesting a high polar character and low activation energy for the reaction. The nucleophilic Parr functions indicate that the pseudoradical C1 carbon is the most nucleophilic center. The 32CA reaction presents an activation Gibbs free energy of 13.1 kcal·mol−1 and is exergonic by −26.8 kcal·mol−1. This reaction presents high endo stereoselectivity and high meta regioselectivity. Analysis of the global electron density transfer (GEDT) at the most favorable meta/endo TS, 0.31 e, accounts for the high polar character of this 32CA reaction, classified by forward electron density flux (FEDF). A Bonding Evolution Theory (BET) study along the most favorable meta/endo reaction path characterizes this 32CA reaction, taking place through a non-concerted two-stage one-step mechanism, as a pseudo(mono)radical-type 32CA reaction, in agreement with the ELF analysis of the AY.

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Pseudo(mono)radical Azomethine Ylides with Phenyl Vinyl Sulphone

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Pseudo(mono)radical Azomethine Ylides with Phenyl Vinyl Sulphone

A molecular electron density theory study on the Chichibabin reaction: The origin of regioselectivity

A Molecular Electron Density Theory (MEDT) study was performed on the nucleophilic amination of pyridine and benzene to elucidate the observed regioselectivity in the Chichibabin reaction. For this purpose, three possible reaction paths were considered between NaNH2 and the 2-, 3- and 4-positions of pyridine. The reaction of NaNH2 and benzene was also investigated. The results indicated that in each reaction, the first step involves the nucleophilic attack of the NH2‾ ion toward the aromatic system to produce an anionic intermediate. The second step, proceeds via hydride elimination of the anionic intermediate to produce the corresponding aromatic amine. This step is more favourable both kinetically and thermodynamically for the reaction at the 2-position of pyridine relative to the 4-position. In contrast to the Parr functions analysis which indicates that the 4-position is activated more electrophilically in pyridine, the PES analysis reveals that the 2-position attack with the NH2‾ ion is more favourable both thermodynamically and kinetically. The results for the reaction of sodium amide and benzene indicated that this reaction is not feasible due to the high activation barriers. In consistent with the experimental results, the ELF analysis indicated that in the first step of the reaction between pyridine and sodium amide, the formation of the C2–N bond takes place via a pseudoradical coupling between the C2 carbon atom of pyridine and the N atom of NaNH2. These variations occur in the second-half of the first step of the reaction. NCI analysis on the reaction revealed that the more attractive forces between the fragments, make the transition states for the 2-position attack more stable relative to the others. Thus, the NCI analysis can satisfactorily describe the observed regioselectivity in the Chichibabin reaction.