Normal Electron Demand Research Articles

Synthesis of spiro[oxindole-2,3′-pyrrolidine] derivatives via exo-selective 1,3-dipolar cycloaddition reaction, characterization and DFT investigation

A series of spiro[oxindole-2,3′-pyrrolidine] derivatives (4a-q) were successfully synthesized via an exo-selective 1,3-dipolar cycloaddition reaction between a stabilized azomethine ylide and various (E)-3-arylidene-1-methylpyrrolidine-2,5-diones. The structures and stereochemistry of the cycloadducts were elucidated through 1D and 2D NMR spectroscopic techniques. The preferred reaction pathway was corroborated by DFT calculations using the B3LYP functional with the 6–31 G (d, p) basis set. The results revealed that the cycloaddition reaction follows a normal electron demand mechanism, where the azomethine ylide acts as the nucleophile and the dipolarophile as the electrophile. The Fukui function analysis favors the regio 2, contradicting the experimental observations while, transition state theory aligns perfectly with the experimental results.

Iso-Pentadienyl Carbonate as a Five Carbon Synthon in Manganese(I)-Catalyzed Selective Linear 1,3-Dienylation.

Selective linear 1,3-dienylations are essential transformations, and numerous synthetic efforts have been documented. However, a general method enabling access to electron-rich, -poor, and biologically relevant dienyl molecules is in high demand. Hence, we report a straightforward method of manganese(I)-catalyzed C-H dienylation of arenes by using iso-pentadienyl carbonate as a five carbon synthon. This is a highly unprecedented report for selective linear 1,3-dienylation using manganese C-H activation catalysis. Our method facilitates the synthesis of varieties of dienes, including those suitable for normal or inverse electron demand Diels-Alder reactions, dienyl glycoconjugates, and unnatural amino acids. Extensive mechanistic studies, including isolation of C-H activated organo-manganese complex and isotopic analyses, have supported the proposed mechanism of this dienylation. The synthetic applicability of this method eased to deliver a 6/6/5-fused tricyclic nagilactone scaffold.

Investigating the Diels-Alder reactivity of the natural pyrethrins

Pyrethrum-based insecticides have remained ideal for domestic and agricultural pest control due to the efficacy and environmentally favourable qualities of the active ingredients, the natural Pyrethrins. However, the propensity of the natural Pyrethrins to degrade with heat, light and oxygen affects their long-term storage and subsequent effectiveness as an insecticide. Whilst a number of processing and storage countermeasures have been implemented, efforts have recently been made to synthetically modify the pyrethrin scaffold with particular focus on functionality that is sensitive to these degradative processes. This work describes an investigation of the Diels-Alder reactivity of pyrethrin I and II and its potential to produce stabilised pyrethrin derivatives. Initial exploration into normal electron demand Diels-Alder cycloadditions of pyrethrin I and II found that the reactions did not proceed even under forcing conditions. However, a series of pyrethrin derivatives were obtained from the inverse electron demand Diels Alder reaction employing these natural products as dienophiles and electron-deficient 1,2,4,5-tetrazines as dienes.

Insights into the catalytic activity of boron-doped thiazoles in the Diels-Alder reaction.

The role of boron-doped thiazoles as a Lewis acid catalyst in [4+2] cycloaddition reaction between 1,3-butadiene and acrolein has been addressed. Three different organic heterocycles were designed to study their catalytic activity. It has been observed that these heterocycles efficiently work as catalysts than the well-known Lewis acid BF3. All the reactions follow the normal electron demand process and are exothermic. Different conceptual DFT-based reactivity descriptors and electronic structure principles such as maximum hardness and minimum electrophilicity lend additional support to the feasibility of the reaction mechanism. The reaction force (RF), reaction electronic flux (REF), and its different components exhibit a detailed electronic activity throughout the reaction.

How Bases Catalyze Diels-Alder Reactions.

We have quantum chemically studied the base-catalyzed Diels-Alder (DA) reaction between 3-hydroxy-2-pyrone and N-methylmaleimide using dispersion-corrected density functional theory. The uncatalyzed reaction is slow and is preceded by the extrusion of CO2 via a retro-DA reaction. Base catalysis, for example, by triethylamine, lowers the reaction barrier up to 10 kcal mol-1 , causing the reaction to proceed smoothly at low temperature, which quenches the expulsion of CO2 , yielding efficient access to polyoxygenated natural compounds. Our activation strain analyses reveal that the base accelerates the DA reaction via two distinct electronic mechanisms: i) by the HOMO-raising effect, which enhances the normal electron demand orbital interaction; and ii) by donating charge into 3-hydroxy-2-pyrone which accumulates in its reactive region and promotes strongly stabilizing secondary electrostatic interactions with N-methylmaleimide.

Synthesis, characterization and computational studies for (2′S*,3R*,3′S*,8a′R*)‐2′,3′‐bis(ethoxycarbonyl)‐2‐oxo‐2′,3′‐dihydro‐8a′H‐spiro[indoline‐3,1′‐indolizine]‐6′‐carboxylic acid and some derivatives

AbstractIn this article, we present advances related to 1,3‐dipolar cycloadditions of generated pyridinium ylides and apply these results to specific 1,3‐dipolar cycloaddition reactions with oxindole dipolarophiles. The ylide discussed in this article is generated from alkylation reactions between substituted pyridines and a primary electrophile. Cycloaddition reactions proceeding from pyridinium ylides and various oxindoles are reported with good stereo‐ and regioselectivity. Cycloaddition reactions take place by the overlap of the HOMO of the dipole and the LUMO of the dipolarophile when the two orbitals have similar energies, resulting in the formation of two new bonds. To get more insight into the reaction nature, a quantum chemical simulation was performed. A computational study is performed on the reactants (pyridinium ylides and oxindoles) and resulting cycloadducts. The present analysis reveals that the cycloaddition reactions under study can be classified in the normal electron demand category. Regioselectivity and mechanism of 1,3‐cycloaddition reactions are studied in the light of several theoretical approaches such as activation energy, Houk's rule based on the FMO theory, and the DFT reactivity indices.

Cyclopentadiene as a Multifunctional Reagent for Normal- and Inverse-Electron Demand Diels-Alder Bioconjugation.

Optimizing the Diels-Alder (DA) reaction for aqueous coupling has resulted in practical methods to link molecules such as drugs and diagnostic agents to proteins. Both normal electron demand (NED) and inverse electron demand (IED) DA coupling schemes have been employed, but neither mechanism entails a common multipurpose reactive group. This report focuses on expanding the bioconjugation toolbox for cyclopentadiene through the identification of reactive groups that couple through NED or IED mechanisms in aqueous solution. Dienophiles and tetrazine derivatives were screened for reactivity and selectivity toward antibodies bearing cyclopentadiene amino acids to yield bioconjugates. Twelve NED dienophiles and four tetrazine-based IED substrates were identified as capable of practical biocoupling. Furthermore, tetrazine ligation to cyclopentadiene occurred at a rate of 3.3 ± 0.5 M-1 s-1 and was capable of bioorthogonal transformations, as evidenced by the selective protein labeling in serum. Finally, an antibody-drug conjugate (ADC)-bearing monomethyl auristatin E was prepared via tetrazine conjugation to cyclopentadiene. The resulting ADC was stable and demonstrated potent activity in vitro. These findings expand the utility of cyclopentadiene as a tool to couple entities to proteins via dual DA addition mechanisms.

4 + 2] and [2 + 4] cycloaddition reactions on single- and double-stranded DNA: a dual-reactive nucleoside.

Here we report dual reactivity of diene-modified duplex DNA containing 5-(1,3-butadienyl)-2′-deoxyuridine “BDdU”. Normal-electron demand [4 + 2] cycloaddition proceeded upon addition of a maleimide, whereas inverse-electron demand [2 + 4] cycloaddition occurred upon addition of a tetrazine to give a novel, photoswitchable product.

Reactions of C60 with Pyridazine and Phthalazine.

Cage-opened bisfulleroids are one of suitable building blocks for making a large hole on fullerenes. This work focuses on the Diels-Alder reaction of C60 with azines, among synthetic methods developed thus far, to provide bisfulleroids. Surprisingly, the computational study predicted that the reaction proceeds with normal electron demand in contrast to hitherto considered inverse-electron-demand pathway. The benzoannulation to the pyridazine ring, i. e., phthalazine, resulted in the remarkably shortened reaction time due to the better interaction between the HOMO of phthalazine and the LUMO of C60 as well as stronger 2,3-diaza-1,3-butadiene character in the phthalazine as confirmed crystallographically. Contrary to expectations, the benzobisfulleroid was converted into corresponding orifice-enlarged derivative via the photooxygenation slightly faster than the fulleroid derived from pyridazine.

Catalytic Asymmetric Aza‐Diels‐Alder Reaction: Pivotal Milestones and Recent Applications to Synthesis of Nitrogen‐Containing Heterocycles

AbstractIn this review, the pivotal achievements and recent advances in catalytic asymmetric aza‐DAR reported up to 2020 are retrospectively considered and their potency for enantioselective synthesis of useful chiral piperidine, quinoline, pyridazine, oxazine and oxadiazine derivatives and fused compounds of higher molecular complexity bearing these pharmacology‐relevant heterocyclic scaffolds is demonstrated. The reported data are systematized according both to key electron transfer modes (normal or invers electron demand reactions) and to main types of attainable heterocyclic products. Of significant attention are an analysis of activation strategies (complexation, enamine or enolate formation, H‐bonding, etc.) applicable to reactions with particular types of dienes and dienophiles and identification of plausible reaction pathways (either concerted or stepwise) over stereoselective cyclization processes. The review contains 310 references and 122 synthetic schemes.magnified image

Isolation, characterization and semi-synthesis of natural products dimeric amide alkaloids

Isolation, characterization and semi-synthesis of natural products dimeric amide alkaloids

How Oriented External Electric Fields Modulate Reactivity.

A judiciously oriented external electric field (OEEF) can catalyze a wide range of reactions and can even induce endo/exo stereoselectivity of cycloaddition reactions. The Diels–Alder reaction between cyclopentadiene and maleic anhydride is studied by using quantitative activation strain and Kohn–Sham molecular orbital theory to pinpoint the origin of these catalytic and stereoselective effects. Our quantitative model reveals that an OEEF along the reaction axis induces an enhanced electrostatic and orbital interaction between the reactants, which in turn lowers the reaction barrier. The stronger electrostatic interaction originates from an increased electron density difference between the reactants at the reactive center, and the enhanced orbital interaction arises from the promoted normal electron demand donor–acceptor interaction driven by the OEEF. An OEEF perpendicular to the plane of the reaction axis solely stabilizes the exo pathway of this reaction, whereas the endo pathway remains unaltered and efficiently steers the endo/exo stereoselectivity. The influence of the OEEF on the inverse electron demand Diels–Alder reaction is also investigated; unexpectedly, it inhibits the reaction, as the electric field now suppresses the critical inverse electron demand donor–acceptor interaction.

(3 + 2) cycloaddition reaction of 7-isopropylidenebenzonorbornadiene and diazomethane derivatives: A theoretical study

The ability to synthesize targeted molecules hinges on detailed mechanistic insight of the reaction. The 1,3-dipolar cycloaddition reaction between diazomethane derivatives and 7-isopropylidenebenzonorbornadiene have been extensively studied using density functional theory (DFT) at the M06–2X/6-311G(d,p) level of theory in order to delineate the peri-, regio-, and stereo-selectivities of the reaction. The diazomethane is shown to periselectively add across the endocyclic olefinic bond of the 7-isopropylidenebenzonorbornadiene and stereoselectively in the exo fashion, yielding the exo-cycloadduct as the major product, with a rate constant of 3.83 × 104 s−1. The endo approach of this periselective path is the closest competing pathway with a rate constant of 8.78 × 101 s−1. Neither electron-donating groups (R = methyl, ethyl, amine, cyclopropyl) nor electron-withdrawing groups (R = cyano, nitro, carbonyl) on the diazomethane alters the peri- and stereo-selectivity of the reaction. However, the substituents do have an effect on whether the addition follow normal or inverse electron demand mechanisms. EDGs favor a normal electron demand mechanism while EWGs favor an inverse electron demand 1,3-dipolar cycloaddition reaction. While EDGs-substituted diazomethane derivatives behave as nucleophiles in reactions with 7-isopropylidenebenzonorbornadiene, EWGs-substituted diazomethane derivatives behave as electrophiles. The 1,3-dipole adds across the dipolarophile via a concerted asynchronous mechanism, but a stepwise diradical mechanism has been ruled out. The selectivities observed in the title reaction are kinetically controlled. Analysis of the nucleophilic Parr function (PK−) at the different reaction sites in the dipolarophile indicates that the diazomethane adds across the atomic centers with highest NBO and Mulliken atomic spin densities.

A conceptual DFT analysis of the plausible mechanism of some pericyclic reactions

Out of several pericyclic reactions, Diels-Alder (DA) reaction is one of the most widely used synthetic processes. In the present work, several models and methodologies have been used to determine and to analyze the plausible mechanism of some representative DA cycloaddition reactions. A comparison between the dual descriptor and the bond reactivity indices corresponding to the natural bond orbital of the reagents is included, which provides a complete description of the plausible reaction mechanism. In the next step, two very recent models are used to determine the local electronic density transfer and redistribution between the reactants involved. The description of the local electronic density transfer has been made in two stages; first, the variation in the net charge on the atoms is obtained, and then, the electronic density transfer between the natural bond orbitals is calculated. The values obtained using the two models are correlated with the experimental rate constants of the reactions. Finally, the natural bond orbitals are obtained at several steps along the reaction path and the variation in their partial occupation is compared with the corresponding electron density transfer among these orbitals. Furthermore, frontier molecular orbital (FMO) approach has been employed to understand the more feasible way of interaction between the DA pair. Relative electrophilicity descriptors like net electrophilicity (∆ω±), net reactivity index (NRI, Δ $$ {\omega}_R^{\pm } $$ ), and electrophilicity difference (∆ω) between DA pairs have also been employed to describe the studied reaction mechanisms especially whether they follow non-polar-concerted/polar-stepwise pathway along with their classification in terms of normal or inverse electron demand. Furthermore, adaptive natural density partitioning method (AdNDP) and energy decomposition analyses (EDA) in conjunction with natural orbital for chemical valence (NOCV) have been made use of in order to analyze the actual bonding situation in the transition state (TS).

Substituent Effect on the Himbert Intramolecular Arene/Allene Diels-Alder Reaction: NBO Analysis and State Specific Dual Descriptors.

Conceptual density functional theory has been applied to study the Himbert intramolecular arene/allene Diels-Alder reaction. The effect of substitutions at different positions on the kinetics of these reactions has been analyzed. Therefore, from the calculation of the activation energies of more than 27 reactions involving concerted mechanisms, the selectivity of these reactions can be predicted and rationalized with the aid of conceptual DFT descriptors. An application of the two concepts, natural population analysis (NBO) and the state-specific dual descriptor (SSDD) for evaluating substituent effects, allows the investigation of the different interactions that promote a reaction compared to another. The SSDDs computed for the transition state structures provide important information about charge transfer interactions during the chemical reaction. In our case, the SSDD results show that the substituents promoting Himbert reaction have the lowest excitation energies, a fact which facilitates the allene/arene interaction. The NBO results show that according to the nature of the substituent, the Himbert reaction stands as a normal-electron demand or reverse. Thus, the interactions favoring each reaction are mentioned. The geometric deformation observed in the case of OCH3 is at the origin to the emergence of other low interactions between diene and dienophile as well as a strong electronic delocalization stabilizing the arene moiety. The calculated synchronicity indexes show that the Himbert intramolecular Diels-Alder reactions are very synchronous.

Enzyme-Catalyzed Inverse-Electron Demand Diels–Alder Reaction in the Biosynthesis of Antifungal Ilicicolin H

The pericyclases are a growing superfamily of enzymes that catalyze pericyclic reactions. We report a pericyclase IccD catalyzing an inverse-electron demand Diels-Alder (IEDDA) reaction with a rate acceleration of 3 × 105-fold in the biosynthesis of fungal natural product ilicicolin H. We demonstrate IccD is highly periselective toward the IEDDA cycloaddition over a competing normal electron demand Diels-Alder (NEDDA) reaction from an ambimodal transition state. A predicted flavoenzyme IccE was identified to epimerize the IEDDA product 8- epi-ilicicolin H to ilicicolin H, a step that is critical for the observed antifungal activity of ilicicolin H. Our results reveal the ilicicolin H biosynthetic pathway and add to the collection of pericyclic reactions that are catalyzed by pericyclases.

Access to 1‐Phospha‐2‐azanorbornenes by Phospha‐aza‐Diels–Alder Reactions

The unprecedented phospha-aza-Diels-Alder reaction between an activated electron-poor imine and 2H-phospholes yields 1-phospha-2-azanorbornenes in a highly chemoselective and moderately diastereoselective reaction. The intermediate 2H-phospholes, which act as dienes, are formed in situ from the corresponding 1H-phospholes. Theoretical calculations confirm that the phospha-aza-Diels-Alder reaction is of normal electron demand. The reactive P-N bond in 1-phospha-2-azanorbornenes can be cleaved by nucleophiles leading to the formation of 2,3-dihydrophospholes.

A Theoretical Investigation on the Regioselectivity of the Diels–Alder Cycloaddition of 9-(Methoxymethyl) Anthracene And Citraconic Anhydride

The mechanism and regioselectivity of the Diels–Alder cycloaddition reaction between 9- (methoxymethyl)anthracene and citraconic anhydride are explored using the valuable density functional theory (DFT) methods. The solvent effects are considered using the polarizable continuum model in the toluene solution. Due to a small electrophilicity difference of the reactants, the reaction has a low polar character. The investigated Diels–Alder reaction has a normal electron demand character. Depending on the respective position of substituents in the cycloadducts (head-to-head (ortho) or head-to-tail (meta)) the reaction can be progressed via two different pathways: ortho and meta. Due to a very high activation energy, the meta pathway is rejected. The product of the ortho pathway is demonstrated to be the final product of the reaction in the toluene solution. The obtained DFT results are in good agreement with the experimental results.

A Typical NEDDA Cycloaddition Strategy between C-3- andN-Substituted Indoles and Butadienes Using Silica-supported Copper Triflate as an Efficient Catalytic System: A Correlative Experimental and Theoretical Study

The present paper elicits a [4+2] Diels–Alder cycloaddition strategy between C-3- and N-substituted indoles I-1 to I-6 with two dienes of different nucleophilicity using silica-supported Cu(OTf)2. Theoretical studies computed at the B3LYP/6-311G(d) level of theory reveal that all the indoles undertaken behave as electron-poor dienophiles and, therefore, prefer to participate through a normal electron demand Diels–Alder (NEDDA) pathway. The analysis of the local reactivity descriptors further ascertained the completely regioselective outcome of the reaction profile.

Sequential SNAr and Diels–Alder reactivity of superelectrophilic 10π heteroaromatic substrates

Using the DFT concept of global electrophilicity (ω), it is shown that 4,6-dinitro-7-chloro-benzo-furoxan and -benzofurazan are two 10π-heteroaromatics that rank to the top of the ω scale, comparing well with the related 4,6-dinitrobenzofuroxan reference. This superelectrophilic behaviour is demonstrated by the high propensity of these chloro-substituted superelectrophiles to undergo SNAr substitutions with an extremely weak carbon nucleophile such as 1,3,5-trimethoxybenzenze (pKaH2O=−5.72). The resulting TMB-substituted products are still ranking in the superelectrophilic region, making it possible to engage these compounds in Normal and Inverse electron demand [4+2] cycloadditions and [3+2] cycloaddition, which proceed with high regioselectivity and high stereoselectivity.