Formation Of Cycloadducts Research Articles

Energetic Aspects and Molecular Mechanism of 3-Nitro-substituted 2-Isoxazolines Formation via Nitrile N-Oxide [3+2] Cycloaddition: An MEDT Computational Study.

Regioselectivity and the molecular mechanism of the [3+2] cycloaddition reaction between nitro-substituted formonitrile N-oxide 1 and electron-rich alkenes were explored on the basis of the wb97xd/6-311+G(d) (PCM) quantum chemical calculations. It was established that the thermodynamic factors allow for the formation of stable cycloadducts along all considered models. The analysis of the kinetic parameters of the main processes show that all [3+2] cycloadditions should be realized with full regioselectivity. In all cases, the formation of 5-substituted 3-nitro-2-isoxazolidines is clearly preferred. It is interesting that regiodirection is not determined by the local electrophile/nucleophile interactions but by steric effects. From a mechanistic point of view, all considered reactions should be treated as polar, one-step reactions. All attempts to locate the hypothetical zwitterionic intermediates along the cycloaddition paths were, however, not successful.

1,3-dipolar cycloaddition of stable azomethine ylide based on ninhydrin and l-proline to phosphorylated acetylenes

The reaction of 1,3-dipolar cycloaddition of a stable azomethine ylide formed from ninhydrin and L-proline to activated acetylenic phosphonates was studied. It was found that the reactions proceed under mild conditions with high regioselectivity with the formation of cycloadducts with a spiro[inden-2,3’-pyrrolysine]-1,3-dione backbone.

Unveiling the Stereoselectivity and Regioselectivity of the [3+2] Cycloaddition Reaction between N-methyl-C-4-methylphenyl-nitrone and 2-Propynamide from a MEDT Perspective.

[3+2] cycloaddition reactions play a crucial role in synthesizing complex organic molecules and have significant applications in drug discovery and materials science. In this study, the [3+2] cycloaddition (32CA) reactions of N-methyl-C-4-methyl phenyl-nitrone 1 and 2-propynamide 2, which have not been extensively studied before, were investigated using molecular electron density theory (MEDT) at the B3LYP/6-311++G(d,p) level of theory. According to an electron localization function (ELF) study, N-methyl-C-4-methyl phenyl-nitrone 1 is a zwitterionic species with no pseudoradical or carbenoid centers. Conceptual density functional theory (CDFT) indices were used to predict the global electronic flux from the strong nucleophilic N-methyl-C-4-methyl phenylnitrone 1 to the electrophilic 2-propynamide 2 functions. The 32CA reactions proceeded through two pairs of stereo- and regioisomeric reaction pathways to generate four different products: 3, 4, 5, and 6. The reaction pathways were irreversible owing to their exothermic characters: -136.48, -130.08, -130.99, and -140.81 kJ mol-1, respectively. The enthalpy of the 32CA reaction leading to the formation of cycloadduct 6 was lower compared with the other path owing to a slight increase in its polar character, observed through the global electron density transfer (GEDT) during the transition states and along the reaction path. A bonding evolution theory (BET) analysis showed that these 32CA reactions proceed through the coupling of pseudoradical centers, and the formation of new C-C and C-O covalent bonds did not begin in the transition states.

Understanding the origin of reactivity, mechanism and regioselectivity of the [3+2] cycloaddition reaction between nitrile imine and pyrrolopyrazine

AbstractIn this work, we have performed a computational study on the [3+2] cycloaddition (32CA) reaction between nitrile imine and pyrrolopyrazine within molecular electron density theory (MEDT) using B3LYP and M06‐2X DFT functionnals together with 6‐31G(d,p) basis set. This study shows that the popular B3LYP is the appropriate functional for performing this study. The analysis of energy profiles indicates that this 32CA reaction favours kinetically the formation of a single product as observed experimentally. The favour cycloadduct (P1) is formed through a moderate polar stepwise mechanism, in which the first step is the determining one that is characterised by a moderate polarity and the second step by a highly polar character, while the unfavoured one is formed via a nonpolar one‐step asynchronous mechanism. Solvent effects do not change the regioselectivity, but it increases the activation energies. Thermodynamic parameters analysis indicates that this 32CA reaction is characterised by an exothermic and endergonic characters favouring the formation of cycloadduct (P1), as observed experimentally. Conceptual DFT (CDFT) reactivity indices analysis shows that pyrrolopyrazine 2 reacts as a nucleophile, while nitrile imine 3 as an electrophile. Local reactivity descriptors, such as Parr functions and dual descriptors, show that this 32CA reaction is regioselective leading to the formation of P1. Analysis of ELF electron density demonstrated that the interaction between the high electron density reactive centre with that of low electron density leads to the formation of P1 cycloadduct. The obtained results using MEDT method are in great agreement with what observed in the experimental data.

Molecular Docking and Antibacterial Assessment of Monocyclic β‐Lactams against Broad‐Spectrum and Nosocomial Multidrug‐Resistant Pathogens

Abstractβ‐Lactam antibiotics are critical antibacterial agents and have rapidly become active ingredients in modern medicine. On the other hand, in the face of increasing rate of antibacterial resistance, there are many concerns requiring the design and synthesis of new antibacterial agents. Herein, we synthesized some monocyclic β‐lactams with various substituents through the Staudinger cycloaddition reaction. The formation of cycloadducts was confirmed by elemental analysis and different spectral data, including NMR, FTIR, and Mass spectroscopy. The investigation of in vitro antibacterial activity of synthesized β‐lactams was performed against some broad‐spectrum strains, including Escherichia coli (E. coli), streptococcus aureus (S. aureus), Salmonella Typhi (S. Typhi), Enterococcus faecalis (E. faecalis), and Candida albicans (C. albicans) and also some nosocomial multidrug‐resistant pathogens such as methicillin‐resistant Staphylococcus aureus (MRSA), and vancomycin‐resistant enterococci (VRE). Penicillin Binding Proteins (PBPs) are responsible for the cell wall synthesis process as an enzymatic target for β‐lactam antibiotics. The molecular docking study exhibited a good correlation between the calculated binding affinity to PBP and the experimental data. Based on the obtained results, compound 4 d was successfully fitted in the BPB active site, and could potentially serve as a promising lead compound for the treatment of infectious diseases.

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.

Do Antarafacial Cycloadditions Occur? Cycloaddition of Heptafulvalene with Tetracyanoethylene.

The cycloaddition of heptafulvalene (1) with tetracyanoethylene (TCNE) was previously described as an example of an antarafacial cycloaddition, a [π14 a +π2 s ] process that afforded only the trans cycloadduct by virtue of the edge-to-face approach of TCNE, facilitated by the S shape of 1. The reaction has been investigated in depth and found not to be a concerted antarafacial process. At low temperature, the reaction is observed to give a mixture of cis and trans cycloadducts as well as a [4+2] cycloadduct. The mixture of products is converted to the trans cycloadduct by equilibration upon warming to room temperature. Studies with diethyl 2,3-dicyanofumarate and -maleate confirmed the formation of cis cycloadducts. DFT studies at the M06-2X/6-311+G(2d,p) SCRF=acetone level of theory show that the originally proposed edge-to-face approach of TCNE to 1 is highly disfavored, whereas a stepwise mechanism involving the addition of TCNE at C2 to form a zwitterion followed by collapse at either C2' or C7' is energetically accessible. The Diels-Alder adduct is also formed in a stepwise reaction by competitive addition of TCNE at C4 of 1. These studies suggest that edge-to-face interactions are prohibitive in even the most favorable cases.

Effect of hydrogen bonds and CF3 group on the regioselectivity and mechanism of [3 + 2] cycloaddition reactions between nitrile oxide and 2,4-disubstitutedcyclopentenes. A MEDT study.

The mechanism and the regioselectivity of the non-polar [3 + 2] cycloaddition reactions between nitrile oxide and two cyclopentenes were theoretically investigated within the molecular electron density theory (MEDT) using DFT methods, namely the B3LYP, MPWB1K and ωB97XD functionals together with the standard 6-31G(d) basis set. The activation energies of these 32CA reactions are relatively high, due to the low nucleophilic power of both cycloalkenes and the relatively moderate electrophilic nature of the nitrile oxide. The B3LYP and MPWB1K functionals reproduced high relative energies values, while the ωB97XD one yields better values in the kinetic and thermodynamic energies. The completely 4-regioselectivity that observed experimentally has been explained by the analysis of the relative energies, in which the formation of 4-regioismeric cycloadducts is always the more kinetically favored one. The electron localization function (ELF) topological analysis showed that the studied 32CA reactions proceed through two-stage one-step nonconcerted mechanism. The effects of the hydrogen bonds on the regioselectivity determination have been investigated by mean both noncovalent interactions (NCI) and quantum theory of atoms in molecule (QTAIM) analyses, which confirm the presence of high strength N - H···O hydrogen bond and a supplementary weak stabilized H…F hydrogen bonds.

Study and optimization of Diels-Alder reaction of piperine in aqueous ionic solutions using Gn.HCl as a catalyst

Study and optimization of Diels-Alder reaction of piperine in aqueous ionic solutions using Gn.HCl as a catalyst

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

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

Understanding the Reactivity of C-Cyclopropyl-N-Methylnitrone Participating in [3+2] Cycloaddition Reactions Towards Styrene with a Molecular Electron Density Theory Perspective

Abstract. The [3+2] cycloaddition (32CA) reactions of C-cyclopropyl-N-methylnitrone 1 with styrene 2 have been studied within molecular electron density theory (MEDT) at the B3LYP/6-311++G(d,p) level of theory. These zwitterionic type 32CA reactions occur through a one-step mechanism. The 32CA reactions undergo four stereo- and regioisomeric reaction paths to form four different products, 3, 4, 5 and 6. Analysis of the conceptual density functional theory (CDFT) indices predict the global electronic flux from the strong nucleophilic nitrone 1 to the styrene 2. These 32CA reactions are endergonic with reactions Gibbs free energies between 2.83 and 7.39 kcal.mol-1 in the gas phase. The 32CA reaction leading to the formation of cycloadduct 3 presents the lowest activation enthalpy than the other paths due to a slightly increase in polar character evident from the global electron density transfer (GEDT) at the transition states and along the reaction path. The bonding evolution theory (BET) study suggests that these 32CA reactions occur through the coupling of pseudoradical centers and the formation of new C-C and C-O covalent bonds has not been started in the transition states.
 
 Resumen.

Mechanistic study of the formation of quercetine cycloadducts under microwave conditions: a theoretical approach

A theoretical mechanistic investigation of the cycloaddition reaction of quercetine with 3,5-di-tert-butyl-o-quinone has been carry out employing density functional calculations at M06-2X/6-31G(d,p) level of theory. This computational study was performed in order to gain insight in the energetic and structural parameters that rule the observed experimental selectivity in the synthetised cyclodimers obtained under classical heating and microwave irradiation conditions and the influence of the solvent on their chemical reactivity. The effect of the solvent in the selectivity was studied implicitly using the polarisable continuum model in absence and presence of one explicit solvent’s molecule. The theoretical results explain the main issues of the classical heating and the MWI reaction and suggest that thermal effects are directly responsible for the reaction selectivity observed. The comparison of the mechanistic pathway and the non-covalent interactions, shows that a dioxane assisted mechanism can explain the observed experimental selectivity of the two synthetised compounds, thus the dioxane molecule play a catalytic role on this hetero Diels–Alder reaction.

Simple protocol for preparation of Diels-Alder adducts of perfluorinated thioketones

A simple procedure for the preparation of new Diels-Alder adducts of perfluorinated thioketones is reported. The corresponding adducts were prepared in 30–78% yield by reaction of alicyclic perfluorinated olefin, sulfur, diene and CsF catalyst. While the synthesis of quadricyclane, cyclohexadiene-1,3, cycloheptatriene-1,3,5 and 2,3-dimethylbutadiene-1,3 adducts was straightforward, a modified protocol was used in the case of the reaction of cyclopentadiene-1,3,F-pentene-2 and sulfur in order to avoid the formation of cycloadduct of cyclopentediene and F-pentene-2. In this case the olefin first was reacted with sulfur and cyclopentadiene was added later. In separate experiments it was demonstarted that the reaction of F-pentene-2, sulfur and CsF catallyst leds to the formation of two isomeric perfluorinated 1,3-dithiolanes along with equimolar amount of branched polysulfides (Rf)2Sx. Due to broadening of signals in 19F NMR spectra of the most cycloadducts, additiononal variable temperature NMR experiments were carried out, and rotational barriers several adducts were found to be in the range 9.5–11 Kcal/mol.

DFT study on the regio- and stereoselectivity of the organocatalytic aza-Diels-Alder reaction of crotonaldehyde and cyclic 1-aza-1,3-butadiene

The mechanism of 1,4-, 1,2-, and 3,4-cyclization reactions of cyclic 1-azadiene 1 with an organocatalyst 4 has been studied theoretically using DFT method. The reactions proceed in a stepwise fashion, with zwitterionic intermediates. The most favorable cyclization reaction takes place along the C–C pathway of the 1,4-cyclization reaction, under a combination of kinetic and thermodynamic control. The reaction is characterized by the nucleophilic attack of 4 (C5) to the electrophilic center of 1 (C1), leading to the formation of cycloadduct 6, which correctly explains the source of the regioselectivity.

Synthesis of Pyrrole-Fused C,N-Cyclic Azomethine Imines and Pyrazolopyrrolopyrazines: Analysis of Their Aromaticity Using Nucleus-Independent Chemical Shifts Values

The AgOTf-catalyzed reaction of C-2 substituted pyrrole hydrazones having an N-propargyl group was studied. The selective 6-endo-dig mode of cyclization was observed, giving rise to the formation of pyrrole-fused C,N-cyclic azomethine imine derivatives. The reaction of one azomethine imine derivative with various dipolarophiles resulted in the formation of cycloadducts having a pyrazolopyrrolopyrazine skeleton. The aromaticity of C,N-cyclic azomethine imines as well as that of pyrazolopyrrolopyrazines was determined by calculating of nucleus-independent chemical shifts values.

Complete 2,5‐Diastereocontrol in the Organocatalytic Enantioselective [3+2] Cycloaddition of Enals with Azomethine Ylides Derived from α‐Iminocyanoacetates: Asymmetric Synthesis of Pyrrolidines with Four Stereocentres

AbstractRacemic α‐iminocyanoacetates have been used as azomethine ylide precursors in the catalytic enantioselective [3+2] cycloaddition with α,β‐unsaturated aldehydes catalyzed by (S)‐α,α‐diphenylprolinol leading to the fully stereocontrolled formation of pyrrolidine cycloadducts with four stereocentres, one of them being a quaternary one. The reaction proceeded with excellent yields, endo‐selectivities and enantioselectivities. Remarkably, complete 2,5‐diastereoselection has also been achieved under the optimized reaction conditions, which has been explained in terms of the participation of intramolecular H‐bonding interaction which contributes to stabilize one determined geometry for the in situ generated azomethine ylide.

Photoinducible Bioorthogonal Chemistry: A Spatiotemporally Controllable Tool to Visualize and Perturb Proteins in Live Cells

Visualization in biology has been greatly facilitated by the use of fluorescent proteins as in-cell probes. The genes coding for these wavelength-tunable proteins can be readily fused with the DNA coding for a protein of interest, which enables direct monitoring of natural proteins in real time inside living cells. Despite their success, however, fluorescent proteins have limitations that have only begun to be addressed in the past decade through the development of bioorthogonal chemistry. In this approach, a very small bioorthogonal tag is embedded within the basic building blocks of the cell, and then a variety of external molecules can be selectively conjugated to these pretagged biomolecules. The result is a veritable palette of biophysical probes for the researcher to choose from. In this Account, we review our progress in developing a photoinducible, bioorthogonal tetrazole-alkene cycloaddition reaction ("photoclick chemistry") and applying it to probe protein dynamics and function in live cells. The work described here summarizes the synthesis, structure, and reactivity studies of tetrazoles, including their optimization for applications in biology. Building on key insights from earlier reports, our initial studies of the reaction have revealed full water compatibility, high photoactivation quantum yield, tunable photoactivation wavelength, and broad substrate scope; an added benefit is the formation of fluorescent cycloadducts. Subsequent studies have shown fast reaction kinetics (up to 11.0 M(-1) s(-1)), with the rate depending on the HOMO energy of the nitrile imine dipole as well as the LUMO energy of the alkene dipolarophile. Moreover, through the use of photocrystallography, we have observed that the photogenerated nitrile imine adopts a bent geometry in the solid state. This observation has led to the synthesis of reactive, macrocyclic tetrazoles that contain a short "bridge" between two flanking phenyl rings. This photoclick chemistry has been used to label proteins rapidly (within ∼1 min) both in vitro and in E. coli . To create an effective interface with biology, we have identified both a metabolically incorporable alkene amino acid, homoallylglycine, and a genetically encodable tetrazole amino acid, p-(2-tetrazole)phenylalanine. We demonstrate the utility of these two moieties, respectively, in spatiotemporally controlled imaging of newly synthesized proteins and in site-specific labeling of proteins. Additionally, we demonstrate the use of the photoclick chemistry to perturb the localization of a fluorescent protein in mammalian cells.

ChemInform Abstract: Nickel‐Catalyzed [3 + 2 + 2] Cycloadditions Between Alkynylidenecyclopropanes and Activated Alkenes.

AbstractContrary to previous palladium‐ or rhodium‐catalyzed cycloadditions of alkynylidenecyclopropanes, which result in the formation of cycloadducts arising from the distal opening of the cyclopropane, the current method gives complementary 6,7‐fused bicyclic systems resulting from cleavage of the proximal bond of the ring.

ChemInform Abstract: Selective Formation of α-Cleavage Cycloadduct of Oxirane with Heterocumulene Promoted by High-Coordinated Trialkyltin Complexes.

In the reaction of monosubstituted oxiranes and heterocumulenes, trialkyltin iodides coordinated by phosphine oxides effectively catalyzed the formation of heterocycles via cleavage at the substituted site in the oxirane ring, while other types of organotin complexes or noncomplexed organotin iodides promoted selective cleavage at the opposite site. A mechanistic investigation demonstrated that the coordination of phosphine oxide promotes the reverse reaction of the oxirane-ring cleavage leading to the predominant formation of α-cleavage cycloadducts.

ChemInform Abstract: Intramolecular (4 + 4) Photocycloaddition of 2-Pyridones Tethered by a Three-Carbon Chain: Studies on the Formation of Cycloadducts and Control of Stereogenesis. Part 3.

ChemInform Abstract: Intramolecular (4 + 4) Photocycloaddition of 2-Pyridones Tethered by a Three-Carbon Chain: Studies on the Formation of Cycloadducts and Control of Stereogenesis. Part 3.